OA19120A - Imidazopyridazine compounds - Google Patents

Abstract

The present invention is directed to compounds of Formula I : or a pharmaceutically acceptable salt thereof, wherein the substituents R1 , R3 , R6 , R7 , and b are as defined herein. The invention is also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, and methods of preparing the compounds.

Description

IMIDAZOPYRIDAZINE COMPOUNDS

Field of the Invention

The présent invention relates to imidazopyridazine 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 central nervous system (CNS), metabolic, autoimmune and inflammatory diseases or disorders.

Background of the Invention io Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave the phosphodiester bond in second messenger molécules adenosine 3',5'-cyclic monophosphate (cGMP) and guanosine 3’,5'-cyclic monophosphate (cGMP). The cyclic nucléotides cAMP and cGMP serve as secondary messengers in various cellular pathways.

cAMP functions as a second messenger regulating many intracellular processes within the body. One example is in the neurons of the central nervous system, where the activation of cAMP-dependent kinases and the subséquent phosphorylation of proteins are involved in acute régulation of synaptic transmission as well as neuronal différentiation and survival. The complexity of cyclic nucléotide signaling is indicated by 20 the molecular diversity of the enzymes involved in the synthesis and dégradation of cAMP. There are at least ten familles of adenylyl cyclases, and eleven families 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 fonction for different isozymes within a given neuron.

A principal mechanism for regulating cyclic nucléotide signaling is via phosphodiesterase-catalyzed cyclic nucléotide catabolism. The eleven 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 30 distinguished functionally based on cyclic nucléotide substrate specificity, mechanism(s) of régulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, 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 particular therapeutic effects, fewer side effects, or both (Deninno, M., Future Directions in

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.

io The PDE4 isozymes carry out sélective, high-affinity hydrolytic dégradation of the second messenger adenosine S'.S'-cyclic monophosphate (cAMP). Bénéficiai pharmacological effects resulting from that inhibition hâve been shown in a variety of disease models. A number of 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 prevent exacerbations of COPD symptoms. Apremilast (Otezla®) has been approved by the U.S. Food and Drug Administration for the treatment of adults with active psoriatic arthritis.

While bénéficiai pharmacological activity of PDE4 inhibitors has been shown, a 20 common side effect of these treatments has been the induction of gastrointestinal symptoms such as nausea, emesis, and diarrhea, which are currently believed to be associated with inhibition of the PDE4D isoform. Attempts hâve been made to develop compounds with an affinity for the PDE4B isoform over the PDE4D isoform (See: Donnell, A. F. et al., Identification of pyridazino[4,5-bjindolizines as sélective PDE4B 25 inhibitors. Bioorganic & Médicinal Chemistry Letters 2010, 20, 2163-7; and Naganuma,

K. et al., Discovery of sélective PDE4B inhibitors. Bioorganic and Médicinal Chemistry Letters 2009, 19, 3174-6). However, there remains a need to develop sélective PDE4 inhibitors, especially those having an affinity for the PDE4B isoform. In particular, compounds with enhanced binding affinity for the PDE4B isoform over the PDE4D 30 isoform are anticipated to be useful in 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.

Treatment with the PDE4B inhibitors of the present 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 o2-Adrenoreceptor-Mediated Anesthésia, A

Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, 110, 1045-1052).

Summary of the Invention

The present invention is directed to compounds of Formula I:

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of -(CH2)m-(C3-C8)cycloalkyl, -(Chhjm(4- to 10-membered)heterocycloalkyl, -(CH2)m-(C6-Cio)aryl and -(CH2)m-(5- to 14membered)- heteroaryl, and, where chemically permissible, the (Cs-Csjcycloalkyl, (4- to 10-membered)heterocycloalkyl, (Ce-Cio)aryl and (5- to 14-membered)heteroaryl 15 moieties are optionally substituted with one to five R²;

when present, each R² is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-Cejalkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), 20 -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and optionally substituted (C3-Ca)cycloalkyl;

when present, each R³ is independently selected from the group consisting of halogen, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-Cejalkyl, optionally substituted (C2-Ce)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted 25 (Ci-C6)alkylthio, optionally substituted (Ci-Cejalkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and optionally substituted (Ci-C6)alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, optionally substituted (Ci-C6)alkyl, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-(4- to 5 10-membered) heterocycloalkyl, -(CH2)n-(C6-Cio)aryl, and -(CH2)n-(5- to 10membered)heteroaryl, and where chemically permissible, the (Ca-Cejcycloalkyl, (4- to 10-membered)heterocycloalkyl, (Ce-Cio)aryl, and (5- to 10-membered)heteroaryl are optionally substituted with one to five R⁸; or

R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (410 to 10-membered)heterocycloalkyl, and where chemically permissible, the (4- to 10membered)- heterocycloalkyl is optionally substituted with one to five R⁹;

when present, each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-Cejalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted 15 (Ci-Cejalkylthio, optionally substituted (Ci-Ce)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

when present, each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-Csjalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (Ca-Cejalkynyl, optionally substituted 20 (Ci-C6)alkylthio, optionally substituted (Ci-C6)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

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

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

Compounds of the invention include Examples 1 — 104 or a pharmaceutically acceptable sait thereof as described herein.

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

The compounds of Formula I are useful for treating or preventing diseases and/or disorders of the central nervous system (CNS), pain, trauma, cardiologie, 30 thrombotic, metabolic, autoimmune and inflammatory diseases or disorders, and disorders associated with enhanced endothélial activity/impaired endothélial barrier function.

The present invention is also directed to the use of the compounds described herein, or a pharmaceutically acceptable sait thereof, in the préparation of a médicament for the treatment or prévention of a condition amenable to modulation of the PDE4B gene family (i.e., PDE4B enzymes).

The présent invention is also directed to pharmaceutically acceptable formulations containing an admixture of a compound(s) of the présent invention and at 5 least one excipient formulated into a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, suppositories, gels, creams, ointments, lotions, solutions/suspensions for injection (e.g., depot), aérosols for inhalation and solutions/suspensions for oral ingestion.

Detailed Description of the Invention

The headings within this document are being utilized only to expedite its 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 defined below, unless specifically indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number:

As used herein, the term “n-membered” where n is an integer typically describes 20 the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiazole is an example of a 5-membered heteroaryl group.

At various places in the présent spécification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the 25 invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “(Ci-Cejalkyl” is specifically intended to include Ci alkyl (methyl), C2 alkyl (ethyl), C₃ alkyl, C4 alkyl, Cs alkyl, and Ce alkyl. For another example, the term “a (5- to 10-membered)heterocycloalkyl group” is specifically intended to include any 5-, 6-, 7-, 8-, 9-, and 10-membered heterocycloalkyl group.

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

The term “optionally substituted (Ci-Cejalkyl”, as used herein, refers to a (CiCe)alkyl as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=0)-05 N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Ca-Cejcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-C6)alkyl. For example, a (Ci-C6)alkyl moiety can be substituted with one or more halogen atoms to form a “halo(Ci-C6)alkyl”. Représentative examples of a halo(Ci-C6)alkyl include, but are not limited to, fluoromethyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 10 and 2-chloro-3-fluoropentyl.

The term (C2-C6)alkenyl refers to an aliphatic hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond, including straight chain or branched chain groups having at least one carbon-carbon double bond. Représentative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl 15 (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. When the compounds of the invention contain a (C2-Ce)alkenyl group, the compound may exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

The term optionally substituted (C2-C6)alkenyl refers to a (C2-C6)alkenyl as defined above, in which one or more hydrogen atoms are replaced by a substituent 20 selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Cs-Cajcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-Cejalkyl.

The term (C2-C6)alkynyl refers to an aliphatic hydrocarbon having two to six 25 carbon atoms and at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond. Représentative examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term optionally substituted (C2-C6)alkynyl refers to a (C2-Ce)alkynyl as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Cs-Cejcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-Cejalkyl.

The term “(Ci-C6)alkoxy” as used herein, refers to a (Ci-C6)alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom.

Représentative examples of a (Ci-C6)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “optionally substituted (Ci-C6)alkoxy” as used herein, refers to a (Ci-C6)alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consîsting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Cs-Csjcycloalkyl, in which R⁴ and R⁵ 10 are each independently hydrogen or optionally substituted (Ci-Cejalkyl. For example, a (Ci-Ce)alkoxy can be substituted with one or more halogen atoms to form a “halo(CiCejalkoxy”. Représentative examples of a halo(Ci-C6)alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term “(Ci-C6)alkythio”, as used herein, refers to a (Ci-Cejalkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom. Représentative examples of a (Ci-Csjalkylthio include, but are not limited to, methylthio, ethylthio, propylthio, and the like.

The term “optionally substituted (Ci-Cejalkythio”, as used herein, refers to a (Ci-C6)alkylthio group, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consîsting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (C3-Cs)cycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-CejalkyL

As used herein, the term “(C3-C8)cycloalkyl” refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molécule wherein the cyclic framework has 3 to 8 carbons. A “(Cs-Cejcycloalkyl” refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molécule having from 3 to 6 carbon atoms. A “cycloalkyl’ may be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Also included in the définition of cycloalkyl are unsaturated non-aromatic cycloalkyls such as, but not limited to, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. Alternatively, a cycloalkyl may contain more than one ring such as a “(C4-C8)bicycloalkyl”. The term “(C4-C8)bicycloalkyl” refers to a bicyclic ring system containing from 4 to 8 carbon atoms. The bicycloalkyl may be fused, such as bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, and bicyclo[3.3.0]- octanyl. The term “bicycloalkyl” also includes bridged bicycloalkyl Systems such as, but not limited to, bicyclo[2.2.1]heptanyl and bicyclo[1.1.1]pentanyl.

The term “optionally substituted “(C3-Cs)cycloalkyl” refers to a (Ca-Csjcycloalkyl, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), 10 -C(=O)-R⁴, -C(=O)-OR⁴, and (Ca-Csjcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-Cejalkyl.

A “heterocycloalkyl,” as used herein, refers to a cycloalkyl as defined above, wherein at least one of the ring carbon atoms is replaced with a heteroatom selected from nitrogen, oxygen or sulfur. The term “(4- to 6-membered)heterocycloalkyl” means 15 the heterocycloalkyl substituent contains a total of 4 to 6 ring atoms, at least one of which is a heteroatom. The term “(4- to 8-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 4 to 8 ring atoms, at least one of which is a heteroatom. A “(4- to 10-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 4 to 10 ring atoms. A “(6-membered)heterocycloalkyl” 20 means the heterocycloalkyl substituent contains a total of 6 ring atoms, at least one of which is a heteroatom. A “(5-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 5 ring atoms at least one of which is a heteroatom. 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 25 least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). The heterocycloalkyl substituent may be attached to the imidazopyridazine core of the compounds of the présent invention via a nitrogen atom having the appropriate valence, or via any ring carbon atom. The heterocycloalkyl substituent may also be attached to the nitrogen of the amide moiety on the imidazopyridazine core. The 30 heterocycloalkyl moiety may be optionally substituted with one or more substituents at a nitrogen atom having the appropriate valence, or at any available carbon atom.

Also included in the définition of “heterocycloalkyl” are heterocycloalkyls that are fused to a phenyl or naphthyl ring or to a heteroaryl ring such as, but not limited to, a pyridinyl ring or a pyrimidinyl ring.

Examples of heterocycloalkyl rings include, but are not limited to, azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, 5 pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidïnyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydro-oxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl, dihydro10 1 H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl, 3-azabicyclo[3.1.0]hexanyl, 3azabicyclo[4.1.0]heptanyl and the like. Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1 -yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1 -yl, piperidin-2yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,415 oxazepan-1-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), and the like.

The term “optionally substituted heterocycloalkyl” [e.g., optionally substituted (420 to 10-membered)heterocycloalkyl] refers to a heterocycloalkyl, as defined above, in which one or more hydrogen atoms, where chemically permissible, are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-ON(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (C3-Ce)cycloalkyl, in which R⁴ and R⁵ are each 25 independently hydrogen or optionally substituted (Ci-Cejalkyl.

A “(C6-Cio)aryl” refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system containing from 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term “optionally substituted (C6-Cio)aryl” refers to a (C6-Cio)aryl, as defined 30 above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Cs-Csjcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci-Ce)alkyl.

As used herein, the term “heteroaryl” refers to monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independently selected from oxygen (O), sulfur (S) and nitrogen (N) in at least one ring. A “(5- to 14-membered)heteroaryl” ring refers to a 5 heteroaryl ring having from 5 to 14 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 consisting of carbon, oxygen, nitrogen, and sulfur. A “(5- to 10-membered)heteroaryl” ring refers to a heteroaryl ring having from 5 to 10 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, 10 nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A “(5- to 10membered)nitrogen-containing heteroaryl” ring refers to a heteroaryl ring having from 5 to 10 ring atoms in which at least one of the ring atoms is nitrogen, with the remaining ring atoms being independently selected from the group consisting of carbon and 15 nitrogen. A “(5- to 6-membered)heteroaryl” refers to a heteroaryl ring having from 5 to 6 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 consisting of carbon, oxygen, nitrogen, and sulfur. A “(5- to 6membered)nitrogen-containing heteroaryl” refers to a heteroaryl ring having from 5 to 6 20 ring atoms in which ail of the heteroatoms in the ring are nitrogen. A “(6membered)nitrogen-containing heteroaryl refers to a heteroaryl ring having 6 ring atoms in which ail of the heteroatoms in the ring are nitrogen. A “(5membered)nitrogen-containing heteroaryl” refers to a heteroaryl ring having 5 ring atoms in which ail of the heteroatoms in the ring are nitrogen. A heteroaryl may be a 25 single ring or 2 or 3 fused rings. Examples of heteroaryls include, but are not limited to, 6-membered ring substituents such as pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl;

5-membered heteroaryls such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl,

1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, and pyrazolyl; 6/5-membered fused ring substituents such as indolyl, indazolyl, 30 benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl (e.g., 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl.

It is to be understood that the heteroaryl may be optionally fused to a cycloalkyl group, or to a heterocycloalkyl group, as defined herein.

The heteroaryl substituent may be attached to the imidazopyridazine core of the compounds of the present invention via a nitrogen atom having the appropriate valence, or via any ring carbon atom or to the nitrogen of the amide moiety on the imidazopyridazine core. The heteroaryl moiety may be optioanally substituted with one or more substituents at a nitrogen atom having the appropriate valence, or at any 10 available carbon atom.

The terms “optionally substituted (5- to 14-membered)heteroaryr, “optionally substituted (5- to 6-membered)heteroaryl” and “optionally substituted (5- to 6membered)nitrogen-containing heteroaryl” refer to a (5- to 14-membered)heteroaryl, a (5- to 6-membered)heteroaryl, and a (5- to 6-membered)nitrogen-containing heteroaryl, 15 as defined above, in which one or more hydrogen atoms are replaced, where chemically permissible, by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, -N(R⁴)(R⁵), -N(R⁴)(C(=O)R⁵), -N(R⁴)C(=O)-OR⁵, -C(=O)-N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, -C(=O)-OR⁴, and (Cs-Csjcycloalkyl, in which R⁴ and R⁵ are each independently hydrogen or optionally substituted (Ci20 Cejalkyl. The substituent can be attached to the heteroaryl moiety at any available carbon atom or to a heteroatom when the heteroatom is nitrogen having the appropriate valence.

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

“hydroxy” or “hydroxyl”, as used herein, means an -OH group.

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

C=N “nitro”, as used herein, means an -NO2 group.

“oxo”, as used herein, means a =O moiety. When an oxo is substituted on a carbon atom, they together form a carbonyl moiety [-C(=O)-]. When an oxo is substituted on a sulfur atom, they together form a sulfoxide moiety [-S(=O)-]; when two oxo groups are substituted on a sulfur atom, they together form a sulfonyl moiety [S(=O)₂-].

Optionally substituted”, as used herein, means that substitution is optional and therefore inciudes 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 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., -CHa) 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 Formula I above, R³ may be bonded to any ring-forming atom of the pyridazine ring that is substitutable.

“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, as used herein, unless otherwise indicated, refers to the act of treating as treating is defined immediately above. The term “treating” also inciudes adjuvant and neo-adjuvant treatment of a subject.

“Pharmaceutically acceptable” indicates that the substance or composition must be compatible, chemically and/or toxicologically, with the other ingrédients comprising a 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 substîtuents are described as being “independently selected” from a group, each instance of a substituent is selected independent of any other. Each substituent therefore may be identical to or different from the other substituent(s).

As used herein the term “Formula I” 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 the invention including hydrates, solvatés, isomers, crystalline and noncrystalline forms, isomorphs, polymorphs, and métabolites thereof. For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or water is tightly 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 present in stoichiometric or nonstoichiometric amounts. Also included are complexes of the compounds of the invention containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August 1975).

Some of the compounds of the invention hâve asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line (------), a solid wedge ( ^JUJB ), or a dotted wedge ( ^ll111 ). 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 indicate that the stereoisomer shown is present. When present 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 (+/-). Unless stated otherwise, it is intended that the compounds of the invention can exist as stereoisomers, which include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, géométrie isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof (such as racemates 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 DLarginine.

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 humidities, or a désirable 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 of the present invention with an acid whose anion, or a base whose cation, is generally considered suitable for mammalian consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as, 5 but not limited to, hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, meta- phosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids 10 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, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, 15 aspartate, glutamate, benzoate, anthranilate, stéarate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylamino- ethansulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, 20 cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycérophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalene- sulfonate, 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., 25 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 aiuminum, 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, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (AZ-methylglucamine), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (Ci-Ce) 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, hemisulfate 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 present invention includes ail the individual stereoisomers and géométrie isomers of the compounds of the invention and 10 mixtures thereof. Individual enantiomers can be obtained by chiral séparation or using the relevant enantiomer in the synthesis.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered équivalent to the 15 unsolvated forms for the purposes of the present invention. The compounds may also exist in one or more crystalline states, i.e., polymorphe, or they may exist as amorphous solids. AH such forms are encompassed by the claims.

Also within the scope of the present invention are so-called “prodrugs” of the compound of the invention. Thus, certain dérivatives of the compound of the invention 20 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) 25 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 present in the compounds of the present invention with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H. 30 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 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, WileyInterscience (1999).

The présent invention also includes ail pharmaceutically acceptable isotopically labeled compounds, which are identical to those recited herein, 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 10 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 ¹⁸F; iodine, such as ¹²³l and ¹²⁵l; nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O, and ¹⁸O; phosphorus, such as ³²P; and sulfur, such as ³⁵S. Certain isotopically-labeled compounds of the présent invention, for example, those incorporating a radioactive 15 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, 20 increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Substitution with positron-emitting isotopes, such as ¹¹C, ¹⁵F, ¹⁸F, ¹⁵O 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 conventional techniques known to those 25 skilled in the art or by processes analogous to those described in the accompanying

Schemes and/or in the 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, 30 acetone-de, or DMSO-de. Compounds of the invention, which include compounds exemplified in Examples 1-104 described below, include isotopically labeled versions of these compounds, such as, but not limited to, the deuterated and tritiated isotopes and ali other isotopes discussed above.

Compounds

The compounds of Formula I, as described above, contain an imidazo[1,2b]pyridazine core wherein the core is substituted at the 3-position by an R¹ moiety that is optionally substituted with one to three R²; optionally substituted at the 5-, 6- and/or

7-positions by an R³ moiety; and the nitrogen of the amide moiety attached to the 2position of the imidazo[1,2-b]pyridazine core is substituted with R⁶ and R⁷.

In one embodiment, in Formula I as described above, m is 0 and R¹ is a (4- to 10-membered)heterocycloalkyl optionally substituted with one to three R².

In certain embodiments, when R¹ is an optionally substituted (4- to 1010 membered)heterocycloalkyl, the heterocycloalkyl is selected from the group consisting of azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octaohydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isothiazolidinyl, 15 thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, dihydrooxazinyl, oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromanyl, dihydro-1 /7-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl, 20 3-azabicyclo[3.1,0]hexanyl, and 3-azabicyclo[4.1.0]heptanyl.

In certain other embodiments, when R¹ is an optionally substituted (4- to 10membered)heterocycloalkyl, the heterocycloalkyl is selected from dihydrobenzofuranyl, benzodioxolyl, or dihydrobenzodioxinyl.

In another embodiment, in Formula I as described above, R¹ is a (Ce-Cio)aryl 25 optionally substituted with one to three R².

In certain embodiments, when R¹ is an optionally substituted (Ce-Cio)aryl the aryl is selected from phenyl or naphthyl.

In certain other embodiments, when R¹ is an optionally substituted (Ce-Cio)aryl the aryl is phenyl.

|n another embodiment, in Formula I as described above, R¹ is a (5- to 14membered)heteroaryl optionally substituted with one to three R².

In certain embodiments, R¹ is an optionally substituted (5- to 10membered)heteroaryl.

In certain other embodiments, when R¹ is an optionally substituted (5- to 10membered)heteroaryl, the heteroaryl is selected from the group consisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and 1,4-benzoxazinyl.

In certain other embodiments, R¹ is an optionally substituted (5- to 10membered)nitrogen-containing heteroaryl. For example, when R¹ is an optionally substituted (5- to 10-membered)nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, triazolopyrimidinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, cinnolinyl, quinazolinyl, isoquinolinyl, or quinoxalinyl.

In certain other embodiments, when R¹ is an optionally substituted (5- to 10membered)nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, or quinoxalinyl.

In certain other embodiments, R¹ is an optionally substituted (6membered)nitrogen-containing heteroaryl. For example, when R¹ is an optionally substituted (6- membered)nitrogen-containing heteroaryl, the heteroaryl is selected from pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In certain embodiments, when R¹ is an optionally substituted (6membered)nitrogen-containing heteroaryl, the heteroaryl is selected from pyrimidinyl or pyridinyl.

In certain other embodiments, R¹ is an optionally substituted (5membered)nitrogen-containing heteroaryl. For example, when R¹ is an optionally substituted (5- membered)nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, or pyrazolyl.

In any of the preceding embodiments, where chemically permissible, when R¹ is substituted with one to three R², each R² is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-Cejalkyl, and optionally substituted (Ci-Ce)alkoxy.

In certain embodiments, when R² is a halogen, the halogen is selected from fluoro and chloro.

In certain other embodiments, when R² is an optionally substituted (Ci-C6)alkyl, the alkyl is selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like.

In yet another embodiment, when R² is an optionally substituted (Ci-Cejalkoxy, the alkoxy is selected from methoxy, ethoxy or propoxy and the methoxy, ethoxy and propoxy are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkoxy includes, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

It is to be understood that any of the above-mentioned subgenuses of R¹ can be combined together with any of the embodiments for R³, R⁶ and R⁷ as described above and hereinafter. For example, in one embodiment, when R¹ is an optionally substituted (C6-Cio)aryl and the aryl is phenyl, b can be 0 (R³ is absent); and one of R⁶ and R⁷ can be hydrogen and the other an optionally substituted (Cs-Csjcycloalkyl, such as cyclopropyl.

In another embodiment, in Formula I as described above, n is an integer selected from 0, 1, or 2; and R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, optionally substituted (Ci-Csjalkyl, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-(C6-Cio)aryl, and -(CH2)n-(5- to 6-membered)heteroaryl, and where chemically permissible, the (Ca-Cejcycloalkyl, (Ce-Cio)aryl, and (5- to 6-membered)heteroaryl are optionally substituted with one to three R⁸; or

R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4to 6-membered)heterocycloalkyl, and where chemically permissible, the (4- to 6membered)-heterocycloalkyl is optionally substituted with one to three R⁹;

when présent, each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-C6)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵),

-C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴; and when présent, each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally 5 substituted (Ca-Cejalkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (C-i-Cejalkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴,and -C(=O)-OR⁴.

In certain embodiments, in Formula I as described above, one of R⁶ and R⁷ is hydrogen and the other is an optionally substituted (C-i-Cejalkyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (CiCsjalkyl, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl are optionally substituted with one or more fluorine atoms.

In certain other embodiments, when one of R⁶ and R⁷ is an optionally substituted (Ci-Cejalkyl, the alkyl is selected from methyl, ethyl or propyl and the methyl, ethyl and propyl are optionally substituted with one to three fluorine atoms. For example, the optionally substituted (Ci-Ce)alkyl is selected from fluoromethyl, difluoromethyl, trifluoromethyi, fluoroethyl, difluoroethyl, or trifluoroethyl.

In another embodiment, in Formula I as described above; n is an integer selected from 0, 1, or 2; and one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(C3Cejcycloalkyl, wherein the cycloalkyl is optionally substituted with one to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (C3Cejcycloalkyl, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, 25 cyclohexyl, cyclooctyl or bicyclo[1.1.1 ]pentyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (C3Csjcycloalkyl, the cycloalkyl is selected from cyclopropyl or bicyclo[1.1.1]pentyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (C3Csjcycloalkyl, the cycloalkyl is cyclopropyl.

|n another embodiment, in Formula I as described above; n is selected from 0, 1, or 2; and one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(C6-Cio)aryl, wherein the aryl is optionally substituted with one to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (CeCw)aryl the (C6-Cw)aryl is selected from phenyl or naphthyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (CeCw)aryl the (C6-Cw)aryl is phenyl.

In another embodiment, in Formula I as described above; one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(5- to 6-membered)heteroaryl, wherein the heteroaryl is optionally substituted with one to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (5- to

6-membered)heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (5- to 6-membered)heteroaryl, the heteroaryl is oxazolyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (5- to 6-membered)heteroaryl, the heteroaryl is a (5- to 6-membered)nitrogen-containing heteroaryl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (5- to 6-membered)nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionally substituted (5- to 6-membered)nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, pyrazolyl, or pyrimidinyl.

In any of the preceding embodiments, when one of R⁶ and R⁷ is a (C3Cejcycloalkyl, (Ce-Cio)aryl, or (5- to 6-membered)heteroaryl substituted with one to three R⁸, each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-Cejalkyl, and optionally substituted (C1Cejalkoxy.

In certain embodiments, when R⁸ is a halogen, the halogen is selected from fluoro and chloro.

In certain other embodiments, when R⁸ is an optionally substituted (Ci-Ce)alkyl, the alkyl is selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like.

In yet another embodiment, when R⁸ is an optionally substituted (C-i-Cejalkoxy, the alkoxy is selected from methoxy, ethoxy or propoxy and the methoxy, ethoxy and propoxy are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkoxy inciudes, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

ln another embodiment, in Formula I as described above, R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 6membered)heterocycloalkyl optionally substituted with one to three R⁹.

ln certain embodiments, when R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl, the heterocycloalkyl is selected from azetidinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, or pyrrolidinyl.

In certain embodiments, when R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl, the heterocycloalkyl is azetidinyl.

ln any of the preceding embodiments, when R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl substituted with one to three R⁹, each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-Cejalkyl, and optionally substituted (Ci-Cejalkoxy.

In certain embodiments, when R⁹ is a halogen, the halogen is selected from fluoro and chloro.

ln certain other embodiments, when R⁹ is an optionally substituted (Ci-C6)alkyl, the alkyl is selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkyl inciudes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like.

In yet another embodiment, when R⁹ is an optionally substituted (Ci-Ce)alkoxy, the alkoxy is selected from methoxy, ethoxy or propoxy and the methoxy, ethoxy and propoxy are optionally substituted with one to three fluorine atoms. For example, an optionally substituted alkoxy inciudes, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

It is to be understood that any of the above-mentioned subgenuses of R⁶ and R⁷ can be combîned together with any of the embodiments for R¹ and R³ as described above and hereinafter. For example, in one embodiment, when one of R⁶ and R⁷ is hydrogen and the other is an optionally substituted (Ca-Csjcycloalkyl, such as cyclopropyl, R¹ can be an optionally substituted (C6-Cio)aryl wherein the aryl is phenyl, and b can be 0 (R³ is absent).

In another embodiment, in Formula I as described above, when present, each R³ is independently selected from the group consisting of halogen, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, and optionally substituted (Ci-Cejalkoxy.

In certain embodiments, when R³ is halogen, the halogen is selected from fluoro orchloro.

In certain other embodiments, when R³ is an optionally substituted (Ci-C6)alkyl and/or an optionally substituted (Ci-Cejalkoxy, the (Ci-Cejalkyl and (Ci-Ce)alkoxy are as described above in any of the preceding embodiments.

It is to be understood that any of the above-mentioned subgenuses of R³ can be combined together with any of the embodiments for R¹, R⁶ and R⁷ as described above.

In another embodiment, in Formula I as described above in any of the preceding embodiments, b is 0.

In another embodiment, selected compounds of the present 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 certain other embodiments, selected compounds of the present invention may exhibit a binding affinity for the PDE4B isoform.

In certain embodiments, the compounds of the present 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 325-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display about a 5-fold to about a 50-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display about a 51-fold to about a 100-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display about a 101-fold to about a 200-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display about a 201-fold to about a 250-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display about a 251-fold to about a 300-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other 5 embodiments, the compounds of the present invention display about a 301 -fold to about a 325-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain embodiments, the compounds of the present 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 present invention display at least about a 10-fold 10 binding affinity for the PDE4B isoform over the PDE4D isoform. In certain embodiments, the compounds of the present 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 present invention display at least about a 40-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other 15 embodiments, the compounds of the present invention display at least about a 50-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display at least about a 75-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display at least about a 10O-fold 20 binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display at least about a 200-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the present invention display at least about a 300-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other 25 embodiments, the compounds of the present invention display up to about a 325-fold binding affinity for the PDE4B isoform over the PDE4D isoform. The binding affinities of the compounds of the present invention for the PDE4B and PDE4D isoforms are shown in Table 3 of the Experimental Section below.

In another embodiment, the present invention provides a pharmaceutical 30 composition comprising a compound of the present 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 present 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 present invention provides a method of treating central nervous system (CNS), neuroinflammatory, 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 present invention, or a pharmaceutically acceptable sait thereof.

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

Pharmacoloqy

Phosphodiesterases (PDEs) of the PDE4 family are characterized by sélective, high-affinity hydrolytic dégradation of the second messenger cyclic nucléotide, adenosine 3',5'-cyclic monophosphate (cAMP). The PDE4A, PDE4B and PDE4D subtypes are known to be widely expressed throughout the brain, with régional and 20 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 25 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

Αβ-induced memory déficits via the atténuation of neuronal inflammation and apoptosis-mediated cAMP/CREB signaling; thus PDE4 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 may also possess antidepressant effects by normalizing the cAMP cascade (See: Fujita, M. et al., Downregulation of Brain Phosphodiesterase Type IV Measured with ¹¹C-(B)-Rolipram Positron Emission Tomography in Major Dépressive Disorder, Biological Psychiatry, 72, 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 promotes 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 embodiments, 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 which include neurologie, neurodegenerative and/or psychiatrie disorders. Neurologie, neurodegenerative and/or psychiatrie disorders include but are not limited to, (1) mood [affective] disorders; (2) neurotic, stress-related and somatoform disorders including anxiety disorders; (3) disorders comprising the symptom of cognitive deficiency in a mammal, including a human; (4) disorders comprising attention déficits, executive function déficits (working memory déficits), dysfunction of impulse control, extrapyramidal symptoms, disorders that are based on a malfunction of basal ganglia; (5) behavioral and emotional disorders with onset usually occurring in childhood and adolescence; (6) disorders of psychological development; (7) systemic atrophies primarily affecting the central nervous system; (8) extrapyramidal and movement disorders; (9) behavioral syndromes associated with physiological disturbances and physical factors; (10) disorders of adult personality and behavior; (11) schizophrenia and other psychotic disorders; (12) mental and behavioral disorders due to psychoactive substance use; (13) sexual dysfunction comprising excessive sexual drive; (14) mental retardation; (15) factitious disorders, e.g., acute hallucinatory mania; (16) episodic and paroxysmal disorders, epilepsy; (17) narcolepsy; and (18) dementia.

Examples of mood [affective] disorders that can be treated according to the présent invention include, but are not limited to, bipolar disorder I, hypomania (manie and mixed form), bipolar disorder II; dépressive disorders such as single dépressive épisode or récurrent major dépressive disorder, chronic dépréssion, psychotic dépréssion, minor dépressive disorder, dépressive disorder with postpartum onset, dépressive disorders with psychotic symptoms; persistent mood [affective] disorders such as cyclothymia, dysthymia, euthymia; premenstrual syndrome (PMS) and premenstrual dysphorie disorder.

Examples of neurotic, stress-related and somatoform disorders that can be treated according to the present invention include, but are not limited to, anxiety disorders, social anxiety disorder, general anxiety disorder, panic disorder with or without agoraphobia, spécifie phobia, social phobia, chronic anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders, such as post-traumatic stress disorder (PTSD), acute stress disorder; other neurotic 10 disorders such as depersonalization-derealization syndrome.

The phrase cognitive deficiency as used here in disorders comprising the symptom of cognitive deficiency refers to a subnormal functioning or a suboptimal functioning in one or more cognitive aspects such as memory, intellect, learning and logic ability, or attention and executive function (working memory) in a particular 15 individual comparative to other individuals within the same general age population.

Examples of “disorders comprising the symptom of cognitive deficiency” that can be treated according to the present invention include, but are not limited to, cognitive déficits primarily but not exclusively related to amnesia, psychosis (schizophrenia), Parkinson's disease, Alzheimer's disease, multi infarct dementia, senile dementia, 20 Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington's disease, HIV disease (HIV-associated dementia), cérébral trauma and drug abuse; mild cognitive disorder ADHD, Asperger's syndrome, and age-associated memory impairment; cognitive décliné or delerium post operative or in association with intensive care therapy.

Examples of disorders usually first diagnosed in infancy, childhood and adolescence that can be treated according to the present invention include, but are not limited to, hyperkinetic disorders including disturbance of activity and attention, attention deficit/hyperactivity disorder (ADHD), hyperkinetic conduct disorder; attention déficit disorder (ADD); conduct disorders, including but not limited to dépressive conduct 30 disorder; tic disorders including transient tic disorder, chronic motor or vocal tic disorder, combined vocal and multiple motor tic disorder (Gilles de la Tourette's syndrome), substance induced tic disorders; autistic disorders; Batten disease, excessive masturbation, naii-biting, nose-picking and thumb-sucking.

Examples of disorders of psychological development that can be treated according to the present invention include, but are not limited to pervasive developmental disorders, including but not limited to Asperger's syndrome and Rett syndrome, autistic disorders, childhood autism and overactive disorder associated with 5 mental retardation and stereotyped movements, spécifie developmental disorder of motor fùnction, spécifie developmental disorders of scholastic skills.

Examples of systemic atrophies primarily affecting the central nervous system that can be treated according to the present invention include, but are not limited to, multiple sclerosis systemic atrophies primarily affecting the basal ganglia including 10 Huntington's disease, , and amyotrophie latéral sclerosis.

Examples of extrapyramidal and movement disorders with malfunction and/or degeneration of basal ganglia that can be treated according to the present invention include, but are not limited to, Parkinson's disease; second Parkinsonism such as postencephalitic Parkinsonism; Parkinsonism comprised in other disorders; Niemann15 Pick disease, Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal and movement disorders including tremor, essential tremor and druginduced tremor, myoclonus, chorea and drug-induced chorea, drug-induced tics and tics of organic origin, drug-induced acute dystonia, drug-induced tardive dyskinesia, muscular spasms and disorders associated with muscular spasticity or weakness 20 including tremors; mental deficiency (including spasticity, Down syndrome and fragile X syndrome), L-dopa-induced dyskinesia; restless leg syndrome and Stïff-man syndrome.

Further examples of movement disorders with malfunction and/or degeneration of basal ganglia that can be treated according to the present invention include, but are not limited to, dystonia including but not limited to focal dystonia, multiple-focal or 25 segmentai dystonia, torsion dystonia, hemispheric, generalized and tardive dystonia (induced by psychopharmacological drugs). Focal dystonia include cervical dystonia (torticolli), blepharospasm (cramp of the eyelid), appendicular dystonia (cramp in the extremities, like the writer's cramp), or mandibular dystonia and spasmodic dysphonia (cramp of the vocal cord); neuroleptic-induced movement disorders including but not 30 limited to neuroleptic malignant syndrome (NMS), neuroleptic-induced Parkinsonism, neuroleptic-induced early onset or acute dyskinesia, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, neuroleptic-induced tremor.

Examples of behavioral syndromes associated with physiological disturbances and physical factors according to the présent invention include, but are not limited to, nonorganic sleep disorders, including but not limited to nonorganic hypersomnia, nonorganic disorder of the sleep-wake schedule (circadian rhythm sleep disorder), 5 insomnia, parasomnia and sleep deprivation; mental and behavioral disorders associated with the puerpérium including postnatal and postpartum dépréssion; eating disorders, including but not limited to anorexia nervosa, bulimia nen/osa, binge eating disorder, hyperphagia, obesity, compulsive eating disorders and pagophagia.

Examples of disorders of adult personality and behavior that can be treated io according to the présent invention include, but are not limited to, personality disorders, including but not limited to emotionally unstable, borderline, obsessive-compulsive, anankastic, dépendent and passive-aggressive personality disorder; habit and impulse disorders (impulse-control disorder) including intermittent explosive disorder, pathological gambling, pathological fire-setting (pyromania), pathological stealing 15 (kleptomania), trichotillomania; Munchausen syndrome.

Examples of schizophrenia and other psychotic disorders that can be treated according to the présent invention include, but are not limited to, continuous or episodic schizophrenia of different types (for instance paranoid, hébéphrénie, catatonie, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such 20 as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different type (for instance manie dépressive or mixed type); puerpéral psychosis and other and unspecified nonorganic psychosis.

Examples of mental and behavioral disorders due to psychoactive substance use that can be treated according to the présent invention include, but are not limited to, mental and behavioral disorders due to use of alcohol, opioids, cannabinoids, sédatives or hypnotics, cocaïne; mental and behavioral disorders due to the use of other stimulants including caffeine, mental and behavioral disorders due to drug dependence 30 and abuse (e.g., narcotic dependence, alcoholism, amphétamine and methamphetamine dependence, opioid dependence, cocaïne addiction, nicotine dependence, and drug withdrawal syndrome, and relapse prévention), use of hallucinogens, tobacco (nicotine), volatile solvents and mental and behavioral disorders due to multiple drug use and use of other psychoactive substances including the

following subtype symptoms: harmful use, dependence syndrome, withdrawal state, and withdrawal state with delirium.

Examples of dementia that can be treated according to the present invention include, but are not limited to, vascular dementia, dementia due to Creutzfeld-Jacob 5 disease, HIV, head trauma, Parkinson's, Huntington's, Pick's disease, dementia of the

Alzheimer's type.

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

In addition to the central nervous system disorders mentioned above, there is 15 extensive literature in the art describing the effects of PDE inhibitors on various autoimmune and inflammatory cell responses, which in addition to cAMP increase, include inhibition of superoxide production, degranulation, chemotaxis and tumor necrosis factor (TNF) release in eosinophils, neutrophils and monocytes. Therefore, the compounds of the present invention may be useful for treating autoimmune and 20 Inflammatory diseases. (See: Schett, G. et al., Apremilast: A novsl PDE4 Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases, Ther. Adv. Musculoskeletal Dis. 2010; 2(5):271-278). For example, the compounds of the present invention may be useful for treatment of oral ulcers associated with Behçet’s disease. The compounds of the present invention may also be useful for the treatment of pain associated with 25 arthritis (See: Hess, A. et al., Blockade of TNF-α rapidly inhibits pain responses in the central nervous system, PNAS, vol. 108, no. 9, 3731 -3736 (2011 ) or for the treatment of psoriasis or psoriatic arthritis (See: Schafer, P., Apremilast mechanism of action and application to psoriasis and psoriatic arthritis, Biochem. Pharmacol. (2012), 15;83(12):1583-90). Accordingly, compounds of the present invention may also be 30 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 present invention include, but are not limited to, acute and chronic airway diseases such as, but not limited to, asthma, chronic or acute bronchoconstriction, chronic bronchitis, bronchiectasis, small airways obstruction, emphysema, obstructive or inflammatory airways diseases, acute respiratory distress syndrome (ARDS), COPD, pneumoconiosis, seasonal allergie rhinitis or perennial allergie rhinitis or sinusitis, and acute lung injury (ALI).

In yet another embodiment, the compounds of the present invention may be useful for treating rheumatoid arthritis, goût, and fever, edema and pain associated with inflammation, eosinophil-related disorders, dermatitis or eczema, urticaria, conjunctivitis, uveitis, psoriasis, inflammatory bowel disease, sepsis, septic shock, iiver injury, pulmonary hypertension, pulmonary edema, bone loss disease, and infection.

io In yet another embodiment, the compounds of the present invention may be useful for treating cancer. For example, the compounds of the present 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 present 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 Leukemia, Blood Journal of The American Society of Hematology, October 1, 1998, vol. 92, no. 7 24842494). In other embodiments, the compounds may be useful for treating brain or ophthamological tumors.

In certain other embodiments, the compounds of the present invention may be useful for treating diabètes or diseases associated with diabètes (See: Vollert, S. et al., The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice, Diabetologia (2012) 55:2779-2788. Wouters, E. F. M. et al., Effect ofthe 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). Other examples include, but are not limited to, diabetic macular degeneration, diabetic neuropathy, obesity, type 2 diabètes (non-insulin dépendent diabètes), metabolic syndrome, glucose intolérance, urinary incontinence (e.g., bladder overactivity), diabetic macular edema, nephropathy

and related health risks, symptoms or disorders. As such, the compounds can also be used to reduce body fat or body weight of an overweight or obese individual.

In certain other embodiments, the compounds of the present invention may be useful in the prévention and treatment of disorders associated with enhanced 5 endothélial activity, impaired endothélial barrier function and/or enhanced neoangiogenesis, such as septic shock; angioedema, peripheral edema, communicating or non-communicating hydrocephalus, vascular edema, cérébral edema; reduced natriuria pathology; inflammatory diseases, including asthma, rhinitis, arthritis and rheumatoid diseases and autoimmune diseases; acute rénal or liver failure, 10 liver dysfunction; psoriasis, Irritable Bowel Disease (IBD), Crohns disease, and benign/malignant neoplasia.

In certain other embodiments, the compounds of the present invention may be useful for treating diseases of the spinal cord and/or peripheral nervous system, including spinal cord injury, spinal cord edema, spinal cord tumors, vascular 15 malformations or anomalies of the spinal cord, syringomyelia, and hydromyelia.

In certain other embodiments, the compounds described herein are further useful in the prévention and treatment of disorders associated with thrombosis, embolism, or ischémie disorders including, but not limited to, thrombosis-induced tissue infarction in coronary artery disease, in cerebrovascular disease (including cérébral arteriosclerosis, 20 cérébral amyloid angiopathy, hereditary cérébral hemorrhage, and brain hypoxiaischemia) and/or in peripheral vascular disease; stable and unstable angina, transient ischémie attacks, stroke, atherosclerosis, myocardial infarct, cérébral infarct, reperfusion injury (brain/cardiac), traumatic brain injury, subdural, épidural or subarachnoid hemorrhage, migraine, cluster and tension headaches, placental 25 insufficiency, thrombosis after surgical procedures, such as bypass, angioplasty, stent placement, and heart valve replacement.

In certain other embodiments, the compounds described herein are further useful for treating pain conditions and disorders. Examples of such pain conditions and disorders include, but are not limited to, inflammatory pain, hyperalgesia, inflammatory 30 hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, noninflammatory pain, neuropathie pain, sub-categories of neuropathie pain including peripheral neuropathie pain syndromes, chemotherapy-induced neuropathy, complex régional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia,

......................................-......19120 »

postmastectomy pain, trigeminal neuralgia, central neuropathie pain syndromes, central post-stroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain.

In certain other embodiments, the compounds described herein are further useful for treating wounds (or promoting wound healing), burns, scarring, and related conditions.

In certain other embodiments, the compounds described herein are further useful for treating neuronal damage disorders (including ocular damage, retinopathy including diabetic macular edema or macular degeneration of the eye, tinnitus, hearing 10 impairment and loss, and brain edema).

In certain other embodiments, the compounds described herein are further useful for treating transplant rejection, allograft rejection, rénal and liver failure, and restless leg syndrome.

Formulations

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters 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. Suitabie means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subeutaneous. Suitabie devices for parentéral administration include 25 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 the invention can also be formulated such that administration intranasally or by 30 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 compounds is based on a variety of factors, including the type, age, weight, sex and . . - -..........................19120

B 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 usefui in the treatment of the above5 indicated conditions. In one 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 ίο embodiment, dosing is from 0.01 to 10 mg/kg/day. 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 pluraiity 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, 15 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 20 0.01 mg to about 500 mg of the active ingrédient, or in another embodiment, from about 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, 25 canine, feline, 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 conditions recited herein.

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

In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the 5 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 10 also be present.

The compounds of the present invention may be administered by any suitable route, preferabiy 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, for example, may be administered orally, rectally, parenterally, or 15 topically (e.g., intranasal or ophthalmic).

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 present invention. In another embodiment, the oral administration may be in a powder or granule form. In 20 another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the present 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 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 present invention comprises a parentéral dose form. Parentéral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and 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, and include depot formulations.

ln another embodiment, the présent invention comprises a topical dose form. Topical administration inciudes, for example, transdermal administration, such as via 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 10 administered by a transdermal device, administration will be accomplished using a patch either of the reservoir 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 15 carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be încorporated see, for example, Finnin and Morgan, J. Pharm. Soi., 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 20 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 nonbiodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular 25 Systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be încorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be 30 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 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 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, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional 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 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 Publishing 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 Pharmaceutical Association, Washington, 1999.

The compounds of the present 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 present 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 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 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 additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a 10 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, 20 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, 25 huperzine A (HUP-A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

(ii) amyloid-B (or fragments thereof), such as ABi-isconjugated to pan HLA DRbinding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24, AN-1792, Affitope AD-01, CAD106, and V-950;

₃₀ (üi) antibodies to amyloid-β (or fragments thereof), such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan), ACI01-Ab7, 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 European 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, colostrinin, 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 fî-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (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(4-nitrophenoxy)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 ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ12304146, 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 agonists, 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, modafinil (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 (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (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), trimipramine (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 (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), aripiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP104), 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), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), lifarizine, diltiazem φ 42 (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 (RITALIN), dexmethylphenidate (FOCALIN), 10 amphétamine (alone or in combination with other CNS stimulants, e.g., ADDERALL (amphétamine aspartate, amphétamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine (VYVANSE), and benzphetamine (DIDREX);

₁₅ (xiü) corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PRED FORTE), prednisolone sodium 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 (TR1VASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKIine), cariprazine, pardoprunox and sarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine, fluphenazine, haloperidol, loxapine, rispéridone, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopride,

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-583, and amineptine;

V (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, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP404, SAR-110894, frans-A/-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxamide (PF-3654746 and those disclosed in US Patent Publication Nos US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175, and US2008-0176925; International Patent Publication Nos 10 W02006/136924, 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 copolymer1; 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), 20 mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURINETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-177,1 '/7-2,2'-bipyrrole (also known 25 as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta-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), 30 benserazide (MADOPAR), α-methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

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

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM), selegiline hydrochloride (l-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID, IPROZID, IPRONID), CHF3381 (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 (particularly 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, riluzole, /V-hydroxy-1,2,4,9-tetrahydro3H-carbazol-3-imine, desmoteplase, anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both Allon Therapeutics), neurostrol, perampenel, ispronicline, bis(4-p-D-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 (ONO2506, 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-38-7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220 (17-B-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5‘-phosphate (also known as MC-1), microplasmin, S-18986, piclozotan, NP031112, tacrolimus, L19120 seryl-L-methionyl-L-alany l-L-lysy l-L-glutamyl-glycyl-L- valine, AC-184897 (Acadia

Pharmaceuticals), ADNF-14 (National Institues of Health), stilbazulenyl nitrone, SUNN8075 (Daiichi Suntory Biomédical Research), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropion, 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, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (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 US Patent No 6,235,742, (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3nonyl)adenine (EHNA), BAY 60-7550, and those described in US Patent No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, 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), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, mirodenafil, DA-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) PDES 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 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as 2-({4-[1 -methyl-4-(pyridin-4-yl)-1 H-pyrazol-3-yl]phenoxy}methyl)quinolin-3(4H)-one and SCH-1518291; and Q) PDE11 inhibitors;

........... . .................................19120 •

(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 LY2434074), KMI-574, SCH-745966, Ac-rER (N²-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), and CA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163 (Avagacest), 10 W020060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G,

ELAN-Z, 4-chloro-/\/-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HTia) 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 15 vabicaserin and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, such as PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HTe) receptor antagonists, such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), 20 methiothepin (also known as metitepine), ritanserin, ALX-1161, ALX-1175, MS-245, LY483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 630563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB357134, SB-699929, SB-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), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, 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, brain19120

derived neurotrophic 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 inhibitors such as paliflutine, ORG-25935, JNJ17305600, and ORG-26041;

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

(xli) Janus kinase inhibitors (JAK) such as, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, and TG101348.

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 dosage form comprising one or more of the compounds of the présent 15 invention and a container for the dosage, in quantities 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 20 be prepared by a variety of methods that are analogously known in the art. The reaction Scheme 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 a method 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, 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; and T. W. Greene and P. G. M. Wuts,

Protective Groups in Organic Chemistry, John Wiley & Sons, 2006, which are hereby incorporated by reference.

Compounds of the présent invention, or the 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 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 Scheme 1 will be generated as a mixture of diastereomers and/or enantiomers; these may be separated at various stages of the synthetic Scheme using conventional techniques or a combination of such techniques, such as, but not limited to, crystallization, normal-phase 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 Scheme, methods and examples are used for convenience of représentation and/or to reflect the order in which they are introduced in the Scheme, and 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 refers to the general synthetic préparation of compounds represented by Formula I. The préparation of compounds represented by Formula A, where R = lower alkyl, hâve been described previously. A few examples: Journal of Heterocyclic Chemistry 1968, 5(1), 35-39; Il Farmaco - Ed. Sci. 1977, 36(6), 430-437; Journal of Heterocyclic Chemistry 2002, 39, 737-742. The direct installation of the R¹ substituent to give the compound of Formula B can be accomplished by C-H insertion/direct arylation reactions. These transformations can be carried out by treatment with an appropriate aryl halide, a métal source (palladium(ll) acetate, tetrakis(trlphenylphosphine)palladium(0), trîs(dibenzylideneacetone)dipalladium(0), copper iodide), a ligand (triphenylphosphine, bis(adamant-1-yl)(butyl)phosphine, 1,10phenanthroline) and a base (potassium carbonate, césium carbonate, potassium tertbutoxide) in an appropriate solvent usually heated to températures above 50 C (FISC

Advances 2012, 2(14), 5972-5975; Organic Letters 2012, 14(7), 1688-1691; PCT Int.

Appl. 2011075643). During this step the (R³)b and R¹ moieties should be represented by the same moiety as is desired in the final product. For instance, in the compound of

Example 1, b is 0, and R¹ is a 4-chlorophenyl moiety. The intermediate of Formula B can then be converted to compounds of Formula I through treatment of the ester with the appropriate amine using heat and a Lewis acid, such as magnésium methoxide or calcium chloride, in an appropriate solvent (see Tetrahedron Letters 2010, 51, 38793882). During this step, the R⁶ and R⁷ moieties should be represented by the same moiety as is desired in the final product. For instance, in Example 4, R⁶ is cyclopropyl 10 and R⁷ is hydrogen. Altematively, the conversion of ester of Formula B to the amide of

Formula I can be effected through a two-step process in which the ester is first hydrolyzed to the acid, via acidic or basic treatment in water and a co-solvent; the acid is subsequently converted to the amide by treatment with the appropriate amine in the presence of an amide coupling/dehydrating reagent such as 2,4,6-tripropyl-1,3,5,2,4,615 trioxatriphosphinane 2,4,6-trioxide (T3P), O-(7-azabenzotriazol-1-yl)-/\/,A/,A/,/\/tetramethyluronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc., at températures ranging from -20 °C to 100 °C to afford compounds of Formula I. During either of these steps the R¹ moiety should be represented by the same moiety as is desired in the final product. For instance, in Example 1, R¹ should be represented 20 by a 4-chlorophenyl moiety.

Alternately, halogénation of the compound of Formula A by treatment with an electrophilic halogen reagent such as /V-iodosuccinimide (NIS), /V-bromosuccinimide (NBS), iodine monochloride (ICI), iodine (la), bromine (Bfë), etc., in an inert solvent, optionally acid-catalyzed, from room température to 100 °C, results in the compound of 25 Formula C wherein X is represented by bromine or iodine. The compound of Formula C can be converted into a compound of Formula I in two ways. The first method employs a substitution of the halogenated imidazopyridazine of Formula C via a Suzuki-Miyaura reaction (Chemical Society Reviews 2014, 43, 412-443; Accounts of Chemical Research 2013, 46, 2626-2634): treatment with an appropriate alkyl, aryl, or heteroaryl 30 boronate in the presence of base, a transition métal catalyst [potentially palladium(ll) acetate or tris(dibenzylideneacetone)dipalladium(0)], and a metal-chelating ligand (generally phosphine-based), in an appropriate solvent installe the appropriate R moiety and affords Formula B. The compound of Formula B is then converted to the compound of Formula I as described previously. In a second approach, the intermediate of Formula C may be converted to amide D by treatment of the ester with the appropriate amine in the presence of heat and a Lewis acid, such as magnésium methoxide or calcium chloride. Alternatively, transformation of the intermediate of Formula C to the compound of Formula D may be carried out in a two-step process in 5 which the ester is hydrolyzed to an acid by treatment with basic or acidic water in a suitabie co-solvent. The resulting acid is then converted to the compound of Formula D by treatment with the appropriate amine in the presence of an amide coupling/dehydrating reagent such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P), O-(7-azabenzotriazol-1-yl)-/V,A/,N’,/V’-tetramethyluronium 10 hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc., at températures ranging from -20 °C to 100 °C. The intermediate of Formula D can then be transformed into the compound of Formula I through a Suzuki-Miyaura reaction (Chemical Society Reviews 2014, 43, 412-443; Accounts of Chemical Research 2013, 46, 2626-2634): treatment with an appropriate alkyl, aryl, or heteroaryl boronate in the 15 presence of base, a transition métal catalyst [potentially palladium(ll) acetate or tris(dibenzylideneacetone)dipalladium(0)], and a metal-chelating ligand (generally phosphine-based), in an appropriate solvent, installs the requisite R¹ moiety.

Scheme 1

x

D

Experimental Procedures

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 5 techniques generally known in the art.

Expérimente were generally carried out under inert atmosphère (nitrogen or argon), particuiarly 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, 10 generally AcroSeal® products from Acros Organics or DriSolv® products from EMD Chemicals. In other cases, commercial solvents were passed through columns packed with 4Â molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, Λ/,/V-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol, éthanol, 1,4-dioxane and diisopropylamine. For very 15 sensitive reactions, solvents were further treated with metallic sodium, calcium hydride or molecular sieves, and distilled just prior to use. 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 Iiquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas 20 chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic résonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed. In some examples, chiral séparations were carried out to separate enantiomers of certain compounds of the invention (in some examples, the separated enantiomers are 25 designated as ENT-1 and ENT-2, according to their order of elution). In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its spécifie rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer.

Reactions proceeding through détectable intermediates were generally followed by LCMS, and allowed to proceed to full conversion prior to addition of subséquent reagents. For synthèses referencing procedures in other Examples or Methods, reaction conditions (reaction time 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 Rts or rétention times.

Example 1

Azetidin-1 -yl[3-(4-chlorophenyl)imidazo[ 1,2-b]pyridazin-2-yl]methanone ( 1)

Step 1. Synthesis of ethyl imidazo[1,2-b]pyridazine-2-carboxylate (C1).

A mixture of pyridazin-3-amine (20 g, 210 mmol) and ethyl 3-bromo-2-oxopropanoate (82 g, 420 mmol) in éthanol (300 mL) was heated at reflux for 16 hours. After removal of solvent via distillation, the residue was taken up in 2 M hydrochloric acid (100 mL) and washed with ethyl acetate. The aqueous layer was basified to a pH of 15 approximately 8 via addition of aqueous sodium bicarbonate solution and then extracted with chloroform; this organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) afforded the product as a brown solid. Yield: 8.0 g, 42 mmol, 20%. LCMS m/z 192.0 [M+H]⁺. ¹H NMR (400 MHz, CDCb) δ 8.53 (s, 1H), 8.39 (dd, J=4.4, 1.6 20 Hz, 1H), 8.01-8.04 (m, 1H), 7.12 (dd, J=9.3, 4.4 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t,

J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl 3-iodoimidazo[1,2-b]pyridazine-2-carboxylate (C2).

ALIodosuccinimide (24.6 g, 109 mmol) was added to a solution of C1 (19 g, 99 mmol) in acetonitrile (250 mL), and the reaction mixture was stirred at room température for 24 hours. Additional /V-iodosuccinimide (1 équivalent after every 24 hours) was introduced and stirring continued for a further 48 hours (72 hours overall), until complété consumption of starting material was indicated via thin layer chromatographie analysis. After removal of solvent in vacuo, the residue was taken up in dichloromethane and washed with 1 M hydrochloric acid and with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure; silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) provided the product as an off-white solid. Yield: 14.5 g, 45.7 mmol, 46%. LCMS m/z 318.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-de) δ 8.74 (dd, J=4.3, 1.3 Hz, 1H), 8.18 (dd, J=9.2, 1.4 Hz, 1H), 7.41 (dd, J=9.3, 4.4 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of ethyl 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (C3).

Aqueous sodium carbonate solution (3 M, 8.4 mL, 25 mmol) was added to a mixture of C2 (2.00 g, 6.31 mmol), (4-chlorophenyl)boronic acid (1.48 g, 9.46 mmol), and [1,1’bis(dicyclohexylphosphino)ferrocene]dichloropalladium(ll) (382 mg, 0.505 mmol) in 1,4dioxane (32 mL). The reaction mixture was heated at 90 °C overnight, whereupon it was partitioned between ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 150 mL), and the combined organic layers were dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product. Yield: 1.25 g, 4.14 mmol, 66%. LCMS m/z 302.0, 304.0 [M+H]⁺. ¹H NMR (400 MHz, CDCh) δ 8.39 (dd, J=4.3, 1.5 Hz, 1H), 8.09 (dd, J=9.3, 1.5 Hz, 1H), 7.65 (br d, J=8.5 Hz, 2H), 7.50 (br d, J=8.5 Hz, 2H), 7.17 (dd, J=9.3, 4.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).

Step 4. Synthesis of 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid, sodium sait (C4).

A solution of C3 (1.75 g, 5.80 mmol) in methanol (25 mL) and tetrahydrofuran (25 mL) was added to an aqueous solution of sodium hydroxide (2 M, 25 mL), and the reaction mixture was stirred at room température for 4 hours. The resulting solid was collected via filtration and washed with cold water (2 x 25 mL) to provide the product as a solid.

Yield: 1.50 g, 5.07 mmol, 87%. LCMS m/z 274.0, 276.0 [M+H]⁺.

Step 5. Synthesis of azetidin-1 -yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2yljmethanone (1).

Compound C4 (1.40 g, 4.74 mmol) was combined with (>(benzotriazol-1-yl)-A/,/V,A/',/Vtetramethyluronium hexafluorophosphate (HBTU, 2.92 g, 7.70 mmol) and N,Ndiisopropylethylamine (3.56 mL, 20.4 mmol) in N,M-dimethylformamide (75 mL). After 2 minutes, azetidine hydrochloride (957 mg, 10.2 mmol) was added, and the reaction 15 mixture was stirred at 50 °C overnight. After removal of solvent in vacuo, the residue was subjected to chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) followed by trituration with ethyl acetate (30 mL) at 50 °C; this mixture was cooled to 0 °C and fïltered. The collected solid was washed with diethyl ether (50 mL) and with cold ethyl acetate (15 mL). Subséquent recrystallization from ethyl acetate 20 provided the product as an off-white solid. Yield: 980 mg, 3.13 mmol, 66%. LCMS m/z 313.2, 315.2 [M+H]⁺. ¹H NMR (400 MHz, CDCh) 6 8.41 (dd, J=4.4,1.6 Hz, 1H), 8.10 (br d, J=9.2 Hz, 1H), 7.75 (br d, J=8.6 Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.19 (dd, J=9.2, 4.3 Hz, 1H), 4.46-4.57 (m, 2H), 4.17-4.28 (m, 2H), 2.28-2.39 (m, 2H).

Example 2

3-(4-Chlorophenyl)-l·i-cycloρropylimidazo[1,2-b]pyridazine-2-carboxamide (2)

corresponding acid of C4

O-Benzotriazol-l-yl-Λ/,Λ/,Ν'W’-tetramethyluronium hexafluorophosphate (97%, 3.21 g, 8.21 mmol) was added to a mixture of the carboxylic acid of C4 (prepared in the same manner as C4, but in this case acidified with hydrochloric acid, to afford the carboxylic acid rather than the sodium sait) (1.50 g, 5.48 mmol) and Λ/,/V-diisopropylethylamine (2.86 mL, 16.4 mmol) in tetrahydrofuran (100 mL), and the reaction mixture was stirred at room température for 2 minutes. Cyclopropylamine (0.77 mL, 11 mmol) was introduced, and stirring was continued at room température overnight. The reaction mixture was concentrated in vacuo and the residue was subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane). The resulting solid was triturated with a 10:1 mixture of diethyl ether and dichloromethane, and subsequently purified once more via chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) to afford the product as a solid. Yield: 1.39 g, 4.44 mmol, 81%. LCMS m/z 313.3, 315.2 [M+H]⁺. ¹H NMR (400 MHz, CD3OD) δ 8.46 (dd, J=4.3, 1.6 Hz, 1H), 8.06 (dd, J=9.3, 1.7 Hz, 1H), 7.71 (br d, J=8.7 Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.31 (dd, J=Q.3, 4.4 Hz, 1H), 2.79-2.86 (m, 1 H), 0.78-0.84 (m, 2H), 0.620.68 (m, 2H).

Example 3

Azetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone

(3)

Step 1. Synthesis of ethyi 3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazine-2carboxylate (C5).

A mixture of C1 (500 mg, 2.6 mmol), 5-bromo-1,3-difluoro-2-methoxybenzene (864 mg, 3.87 mmol), and potassium carbonate (866 mg, 6.27 mmol) in A/,A/-dimethylformamide (10 mL) was degassed with nitrogen several times. Palladium(ll) acetate (50 mg, 0.22 mmol) and tetrakîs(triphenylphosphine)palladium(0) (30 mg, 26 pmol) were added, and the reaction mixture was stirred at 110 °C ovemight. After addition of water (50 mL), the mixture was extracted with ethyi acetate (3 x 30 mL); the combined organic layers were concentrated in vacuo and purified by chromatography on silica gel to provide the product as a yellow solid. Yield: 500 mg, 1.5 mmol, 58%. LCMS m/z 334.0 [M+H]*.

Step 2. Synthesis of 3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazine-2carboxylic acid (C6).

To a solution of C5 (500 mg, 1.5 mmol) in éthanol (30 mL) was added a solution of lithium hydroxide (2 équivalents) in water (10 mL), and the reaction mixture was stirred at room température for 4 hours, whereupon it was concentrated in vacuo. The residue was diluted with water and acidified to a pH of 4 with hydrochloric acid. After extraction of the mixture with dichloromethane (3 x 30 mL), the combined organic layers were concentrated under reduced pressure to afford the product as a yellow solid, which was used in the next step without additional purification. Yield: 500 mg, quantitative. LCMS m/z305.9 [M+H]*.

Step 3. Synthesis of azetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2b]pyridazin-2-yl]methanone (3).

A mixture of C6 (100 mg, 0.328 mmol), azetidine hydrochloride (45 mg, 0.48 mmol), O(7-azabenzotriazol-1 -yl)-/V,/V,/V',A/'-tetramethyluronium hexafluorophosphate (HATU, 186 mg, 0.489 mmol), A/,A/-diisopropylethylamine (126 mg, 0.975 mmol) and N,Ndimethylformamide (10 mL) was stirred at room température ovemight. The reaction mixture was then diluted with water and extracted with ethyi acetate (3x10 mL). The combined organic layers were concentrated in vacuo and purified by reversed phase HPLC (Column: Phenomenex Synergi C18, 4 pm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: acetonitrile; Gradient: 33% to 53% B) to provide the product as a yeilow solid. Yield: 35.7 mg, 0.104 mmol, 32%. LCMS m/z 344.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-cte) δ 8.63 (dd, J=4.4, 1.6 Hz, 1H), 8.24 (dd, J=Q.3, 1.6 Hz, 1H), 7.56 (brd, J=9.9 Hz, 2H), 7.39 (dd, J=9.4, 4.4 Hz, 1H), 4.46-4.53 (m, 2H), 4.01-4.07 (m, 2H),

4.01 (br s, 3H), 2.22-2.32 (m, 2H).

Example 4

N -Cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (4)

Step 1. Synthesis of ethyl 3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2carboxylate (C7).

A mixture of C2 (1.8 g, 5.7 mmol), (2-methoxypyrimidin-5-yl)boronic acid (1.3 g, 8.4 mmol), sodium carbonate (1.8 g, 17 mmol) and 1,4-dioxane (30 mL) was degassed several times with nitrogen. (1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (30 mg, 40 pmol) was added, and the reaction mixture was stirred at 110 °C overnight. It was then diluted with water and extracted with ethyl acetate (4 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via chromatography on silica gel provided the product as a yeilow solid. Yield: 800 mg, 2.7 mmol, 47%. LCMS m/z 299.7 [M+H]⁺.

Step 2. Synthesis of ^-cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2b]pyridazine-2-carboxamide (4).

Cyclopropylamine (5 mL, 70 mmol) was added to a mixture of C7 (800 mg, 2.7 mmol) and calcium chloride (200 mg, 1.8 mmol) in methanol (200 mL). The reaction mixture was stirred at 50 °C for 5 hours, whereupon it was diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, 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: acetonitrile;

Gradient: 29% to 49% B) afforded the product as a white solid. Yield: 430.3 mg, 1.39 mmol, 51%. LCMS m/z 311.0 [M+H]⁺· ¹H NMR (400 MHz, CDCh) δ 9.01 (s, 2H), 8.40 (dd, J=4.4, 1.6 Hz, 1H), 7.97 (dd, J=9.2, 1.7 Hz, 1H), 7.60 (br s, 1H), 7.20 (dd, J=9.3, 4.3 Hz, 1H), 4.10 (s, 3H), 2.88-2.95 (m, 1H), 0.84-0.91 (m, 2H), 0.66-0.72 (m, 2H).

Example 5

3-(6-Cyanopyridin-3-yl)-N -cyclopropylimidazo[ 1,2-b]pyridazine-2-carboxamide (5)

Step 1. Synthesis of ethyl 3-bromoimidazo[1,2-b]pyridazine-2-carboxylate (C8).

A/-Bromosuccinimide (25.6 g, 144 mmol) was added to a 0 °C solution of C1 (25.0 g, 15 131 mmol) in dichloromethane (250 mL). The reaction mixture was allowed to gradually warm to room température and stir ovemight, whereupon the reaction was quenched with 10% aqueous sodium bisulfite solution. The resulting mixture was diluted with additional dichloromethane and washed with saturated aqueous sodium bicarbonate solution and with water. The organic layer was dried over magnésium sulfate, filtered, 20 and concentrated in vacuo. Trituration with tert-butyl methyl ether afforded the product as a pinkish-mauve solid (25.4 g). Concentration of the filtrate under reduced pressure was followed by trituration with tert-butyl methyl ether and hexanes to give a second batch of product (6.46 g). Combined yield: 31.9 g, 118 mmol, 90%. LCMS m/z 270.0, 272.0 [M+H]⁺. ¹H NMR (400 MHz, CDCh) δ 8.55 (dd, J=4.4, 1.6 Hz, 1H), 8.05 (dd,

7=9.3, 1.6 Hz, 1H), 7.22 (dd, 7=9.3, 4.4 Hz, 1H), 4.53 (q, 7=7.1 Hz, 2H), 1.49 (t, 7=7.1

Hz, 3H).

Step 2. Synthesis of 3-bromo-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 5 (C9).

A mixture of C8 (27.0 g, 100 mmol), cyclopropylamine (25.0 mL, 349 mmol), and calcium chloride (12.2 g, 110 mmol) in methanol (250 mL) was heated at 50 °C for 3 days, whereupon it was cooled to room température and concentrated in vacuo. The 10 residue was partitioned between dichloromethane and water, and the organic layer was concentrated under reduced pressure. Trituration of the residue with diethyl ether and water afforded the product as a pink solid. Yield: 24.4 g, 86.8 mmol, 87%. LCMS m/z 281.0, 283.0 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) Ô 8.52 (dd, 7=4.4, 1.6 Hz, 1H), 7.90 (dd, 7=9.3, 1.6 Hz, 1 H), 7.46 (br s, 1 H), 7.20 (dd, 7=9.2, 4.4 Hz, 1 H), 2.91-2.98 (m, 1 H), 15 0.86-0.92 (m, 2H), 0.67-0.72 (m, 2H).

Step 3. Synthesis of 3-(6-cyanopyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2carboxamide (5).

To a degassed solution of C9 (300 mg, 1.07 mmol) in 2-methyltetrahydrofuran (7 mL) and water (2 mL) was added potassium phosphate (80%, 849 mg, 3.20 mmol). The mixture was heated to 80 °C, and then treated with [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex (97%, 53.9 mg, 64.0 pmol). After 2 minutes, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-225 y|)pyridine-2-carbonitrile (319 mg, 1.39 mmol) was added, and the reaction mixture was maintained at 80 °C overnight. It was then allowed to cool to room température and was filtered through diatomaceous earth; the filter pad was rinsed with ethyl acetate, and the combined filtrâtes were washed with water. After the organic layer had been concentrated in vacuo, the residue was purified via silica gel chromatography (Gradient.

50% to 100% ethyl acetate in heptane) to afford a white solid (196 mg).

Recrystallization from methanol afforded the product as colorless needles. Yield: 135 mg, 0.444 mmol, 41%. LCMS m/z 305.1 [M+H[⁺. ¹H NMR (400 MHz, CDCh) δ 9.18 (d, 7=1.5 Hz, 1H), 8.41-8.46 (m, 2H), 8.01 (dd, 7=9.2, 1.4 Hz, 1H), 7.82 (d, 7=8.0 Hz, 1H),

7.66 (br s, 1H), 7.26 (dd, J=9.2, 4.4 Hz, 1H), 2.86-2.94 (m, 1H), 0.85-0.92 (m, 2H),

0.66-0.72 (m, 2H).

Example 6

N-Cyclopropyl-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2carboxamide (6)

C9 6

Compound C9 (1.90 g, 6.76 mmol) was combined with 6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)[1,2,4]triazolo[1,5-a]pyridine (1.82 g, 7.43 mmol), [1,1'10 bis(dicyclohexylphosphino)ferrocene]dichloropalladium(ll) (51.4 mg, 68.0 pmol), and

1,4-dioxane (34 mL). Aqueous sodium carbonate solution (3 M, 9.0 mL, 21 mmol) was added, and the reaction mixture was purged with nitrogen for 15 minutes, then heated at 100 °C for 20 hours. The reaction mixture was cooled to room température and the supematant was immediately filtered through a pad of diatomaceous earth, rinsing with 15 10% methanol in ethyl acetate. Remaining solids were partitioned between half- saturated aqueous sodium chloride solution (25 mL) and 10% methanol in ethyl acetate by stirring for 5 minutes; this mixture was also filtered through diatomaceous earth. The combined filtrâtes were diluted with saturated aqueous sodium chloride solution (25 mL) and additional 10% methanol in ethyl acetate. The aqueous layer was extracted three 20 times with 10% methanol in ethyl acetate, and the combined organic iayers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed onto diatomaceous earth (4-fold the weight of the crude product) using dichloromethane and methanol, and subjected to chromatography on silica gel (Gradient: 0% to 20% methanol in ethyl 25 acetate). The resulting material (1.83 g) was mixed with methanol (20 mL) and heated to 72 °C for 20 minutes; after cooling, the mixture was filtered and washed with methanol to afford the product as an off-white solid. This material was found to be crystalline via powder X-ray diffraction. Yield: 1.66 g, 5.20 mmol, 77%. LCMS m/z 320.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (dd, J=1.4, 1.3 Hz, 1H), 8.64 (dd, J=4.4,

1.6 Hz, 1H), 8.61 (br d, J=5 Hz, 1H), 8.60 (s, 1H), 8.24 (dd, J=9.3, 1.6 Hz, 1H), 7.937.99 (m, 2H), 7.44 (dd, J=9.3, 4.4 Hz, 1H), 2.82-2.90 (m, 1H), 0.64-0.70 (m, 4H).

Example 7

3-(4-Chloro-3-fluorophenyl)-l·! -(1 -methyl-1H -pyrazol-4-yl)imidazo[ 1,2-b ]pyridazine-2carboxamide (7)

Step 1. Synthesis of ethyl 3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazine-2carboxylate (C10).

Aqueous sodium carbonate solution (3 M, 8.8 mL, 26 mmol) was added to a mixture of C2 (2.10 g, 6.62 mmol), (4-chloro-3-fluorophenyl)boronic acid (1.73 g, 9.92 mmol), and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(ll) (401 mg, 0.530 mmol) in

1,4-dioxane (34 mL), and the reaction mixture was heated at 85 °C ovemight. It was 15 then diluted with water (75 mL) and extracted with ethyl acetate (4 x 250 mL). The combined organic layers were dried over magnésium sulfate, filtered, and concentrated in vacuo·, purification via chromatography on silica gel (Gradient: 5% to 100% ethyl acetate in heptane) afforded the product. Yield: 1.50 g, 4.69 mmol, 71%. LCMS m/z 320.0, 322.0 [M+H]⁺. ¹H NMR (400 MHz, CDCb) δ 8.43 (br d, J=4.3 Hz, 1 H), 8.11 (br d, 20 J=9.3 Hz, 1H), 7.52-7.58 (m, 2H), 7.46-7.50 (m, 1H), 7.22 (dd, J=9.3, 4.4 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of 3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid, lithium sait (C11).

A mixture of C10 (700 mg, 2.2 mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in methanol (100 mL) and water (30 mL) was stirred at room température for 16 hours. The reaction mixture was concentrated to remove methanol, and the residue was washed with ethyl acetate. Collection of the resulting solid via filtration afforded the product as a yellow solid. Yield: 700 mg, quantitative. ¹H NMR (400 MHz, DMSO-cfe) δ 8.56 (brd, J=4 Hz, 1H), 8.13 (brd, J=9 Hz, 1H), 7.97 (d, J=11 Hz, 1H), 7.79 (d, J=8 Hz, 10 1 H), 7.65 (dd, J=8.5, 8 Hz, 1 H), 7.32 (dd, J=9.3, 4.3 Hz, 1 H).

Step 3. Synthesis of 3-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4yl)imidazo[1,2-b]pyridazine-2-carboxamide (7).

A mixture of C11 (200 mg, 0.67 mmol) and O-(7-azabenzotriazol-1-yl)-/V,/V,A/’,/Vtetramethyluronium hexafluorophosphate (500 mg, 1.3 mmol) in N,Ndimethylformamide (5 mL) and /V,/V-diisopropylethylamine (2 mL) was stirred at room température for 20 minutes. 1 -Methyl-1 /-/-pyrazol-4-amine (200 mg, 2.1 mmol) was added, and the reaction mixture was stirred at 35 °C for 2 hours, whereupon it was diluted with water and fîltered. The collected solid was washed with ethyl acetate and methanol to provide the product as a pink solid. Yield: 130 mg, 0.351 mmol, 52%. LCMS m/z 393.0 [M+Na⁺], ¹H NMR (400 MHz, DMSO-cfe) δ 10.76 (s, 1H), 8.64 (br d, J=4.4 Hz, 1H), 8.26 (br d, J=9.4 Hz, 1H), 8.04 (s, 1H), 7.82 (br d, J=10.7 Hz, 1H), 7.73 (dd, J=8.3, 8.0 Hz, 1H), 7.66 (s, 1H), 7.61 (br d, J=8.4 Hz, 1H), 7.44 (dd, J=9.3, 4.3 Hz,

1H), 3.79 (s, 3H).

Example 8

Azetidin-1-yl[3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone (8)

C12

Step 1. Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5ajpyridine (C12).

A mixture of 6-bromopyrazolo[1,5-a]pyridine (1.5 g, 7.6 mmol), 4,4,4,4,5,5,5^octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.03 g, 7.99 mmol), [1.1’bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.27 g, 0.37 mmol), and potassium acetate (2.2 g, 22 mmol) in 1,4-dioxane (25 mL) was degassed for 10 minutes, and then heated at 100 °C overnight. After removal of solvent in vacuo, the residue was diluted with dichloromethane, mixed with diatomaceous earth (~5 g), and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a green liquid. Yield: 1.35 g, 5.53 mmol, 73%. GCMS m/z 244 [M⁺]. ¹H NMR (400 MHz, CDCh) δ 8.86-8.87 (m, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.8, 1.1 Hz, 1H), 7.37 (dd, J=8.8, 1.1 Hz, 1H), 6.49 (dd, J=2.2, 0.9 Hz, 1H), 1.37 (s, 12H).

Step 2. Synthesis of azetidin-1-yl(3-bromoimidazo[1,2-b]pyridazin-2-yl)methanone (C13).

A mixture of azetidine hydrochloride (1.73 g, 18.5 mmol) and triethylamine (2.57 mL, 18.5 mmol) in anhydrous methanol (18 mL) was stirred at room température for 10 minutes. Compound C8 (500 mg, 1.85 mmol) and calcium chloride (206 mg, 1.86 mmol) were added, the reaction vessel was tightly capped, and the reaction mixture was heated at 50 °C overnight. After removal of solvent in vacuo, the residue was partitioned between water (25 mL) and dichloromethane (100 mL). The organic layer was dried over magnésium sulfate, filtered, and concentrated under reduced pressure;

chromatography on silica gel (Eluent: ethyl acetate) afforded the product as a light yellow solid. Yieid: 357 mg, 1.27 mmol, 69%. LCMS m/z 281.0, 283.0 [M+H]⁺. ¹H NMR (400 MHz, CDCb) δ 8.45 (dd, J=4.4, 1.6 Hz, 1H), 7.87 (dd, J=9.2, 1.6 Hz, 1H), 7.12 (dd,

J=9.2, 4.4 Hz, 1H), 4.59-4.65 (m, 2H), 4.17-4.24 (m, 2H), 2.27-2.37 (m, 2H).

Step 3. Synthesis of azetidin-1 -yl[3-(pyrazolo[ 1,5-a]pyridin-6-yl)imidazo[1,2-bJpyridazin2-yl]methanone (8).

A flask containing a solution of C13 (1.06 g, 3.77 mmol) in toluene (60 mL) was evacuated under high vacuum and then filled with nitrogen. Repeating the évacuation I nitrogen fill after each addition, C12 (2.84 g, 11.6 mmol) was added, followed by a solution of césium fluoride (2.87 g, 18.9 mmol) in water (18 mL), and a solution of bis[ditert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(ll) (335 mg, 0.473 mmol) in 1,2-dichloroethane (9 mL). The reaction mixture was heated at 100 °C for 23 hours, whereupon it was cooled to room température, concentrated in vacuo, and subjected to chromatography on silica gel (Eluents: ethyl acetate, then 5% methanol in dichloromethane). This material was combined with the product from a similar reaction carried out on C13 (200 mg, 0.71 mmol) and purified via supercritical fluid chromatography (Column: Princeton Methanesulfonamide, 5 pm; Mobile phase: 4:1 carbon dioxide / methanol). The resulting material was recrystallized from éthanol to afford the product as a white solid. This material was found to be crystalline via powder X-ray diffraction. Yieid: 540 mg, 1.7 mmol, 38%. LCMS m/z319.1 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) δ 9.07 (br s, 1H), 8.40 (dd, J=4.3, 1.6 Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 8.01 (dd, J=9.3, 1.7 Hz, 1H), 7.63 (d, half of AB quartet, J=Q.3 Hz, 1H), 7.54 (dd, half of

ABX pattern, J=9.2, 1.4 Hz, 1H), 7.16 (dd, J=9.3, 4.4 Hz, 1H), 6.56 (d, J=2.2 Hz, 1H), 4.59-4.65 (m, 2H), 4.20-4.27 (m, 2H), 2.31-2.40 (m, 2H).

3-(4-Chloro-2, S-difluorophenyl)-^ -cyclopropylimidazo[ 1,2-b]pyridazine-2-carboxamide

Example 9

HN-<]

Potassium phosphate (80%, 1.42 g, 5.35 mmol) was added to a degassed solution of C9 (500 mg, 1.78 mmol) in 2-methyltetrahydrofuran (20 mL) and water (5 mL), and the mixture was heated to 80 °C. [1,TBis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex (97%,

90.1 mg, 0.107 mmol) was introduced, and after 2 minutes, 2-(4-chloro-2,διό difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (635 mg, 2.31 mmol) was added. The reaction mixture was maintained at 80 °C overnight, whereupon it was cooled to room température and fïltered through diatomaceous earth. The filter pad was rinsed with ethyl acetate, and the combined filtrâtes were washed with water; the organic layer was concentrated in vacuo and purified via silica gel chromatography 15 (Gradient: 50% to 100% ethyl acetate in heptane). Recrystallization from methanol afforded the product as an off-white solid. Yield: 217 mg, 0.622 mmol, 35%. LCMS m/z 349.1, 351.1 [M+H]⁺. ¹H NMR (400 MHz, CDCI3) δ 8.40 (dd, J=4.4, 1.7 Hz, 1H), 7.98 (dd, J=9.3, 1.6 Hz, 1H), 7.53 (br s, 1H), 7.50 (dd, J=8.9, 5.9 Hz, 1H), 7.31 (dd, J=8.6,

6.1 Hz, 1H), 7.21 (dd, J=9.3, 4.4 Hz, 1H), 2.86-2.93 (m, 1H), 0.84-0.89 (m, 2H), 0.66-

0.71 (m, 2H).

Using the methodology described above for Examples 1-9, Examples 10-25 were synthesized. See Table 1 for spécifie methods employed, as well as characterization data for these Examples.

Table 1

Method of préparation, structure, and physicochemical data for

Examples 10 -25.

Example Number	Method of Synthesis: Example Number; Source of Noncommerci al Starting Materials	Structure	1H NMR (400 MHz, CDCb) δ (ppm); Mass spectrum, observed ion m/z [M+H]+ or HPLC rétention time; Mass spectrum m/z [M+H]+ (unless otherwise indicated)
10	Example 1; C11	Cl L'-N-yJ1 ΗΝ-<]	1H NMR (400 MHz, CD3OD) δ 8.48 (dd, J=4.3, 1.4 Hz, 1H), 8.07 (dd, J=9.3, 1.4 Hz, 1H), 7.64- 7.69 (m, 1 H), 7.53-7.59 (m, 2H), 7.33 (dd, J=9.3, 4.4 Hz, 1H), 2.79-2.87 (m, 1H), 0.78-0.85 (m, 2H), 0.63- 0.69 (m, 2H); 331.1,333.1
11	Example 41; C8	Cl r^a HN~<]	8.40 (dd, J=4.4, 1.6 Hz, 1 H), 7.96 (dd, J=9.3, 1.6 Hz, 1 H), 7.93 (d, J=1.9 Hz, 1H), 7.70 (dd, half of ABX pattern, J=8.3, 2.1 Hz, 1H), 7.60 (br s, 1H), 7.58 (d, half of AB quartet, J=8.4 Hz, 1H), 7.19 (dd, J=9.3, 4.4 Hz, 1 H), 2.86-2.94 (m, 1H), 0.83-0.90 (m, 2H), 0.64- 0.71 (m, 2H); 346.9

12	Example 5; C9	Cl HN-<]	1H NMR (400 MHz, DMSOcfe) δ 8.54 (dd, J=4.4, 1.6 Hz, 1H), 8.48 (br d, J=4.9 Hz, 1H), 8.19 (dd, J=9.3, 1.6 Hz, 1H), 7.45-7.47 (m, 1H), 7.37 (dd, J=9.3, 4.4 Hz, 1H), 7.33-7.35 (m, 2H), 2.76-2.84 (m, 1H), 1.99- 2.00 (m, 3H), 0.62-0.65 (m, 4H); 327.1,329.1
13	Example 7; C11	Cl f^rF	1H NMR (400 MHz, DMSOdg) δ 8.62 (dd, J=4.3, 1.5 Hz, 1H), 8.25 (dd, J=9.3, 1.5 Hz, 1H), 7.81 (dd, J=10.8, 1.9 Hz, 1H), 7.71 (dd, J=8.3, 8.0 Hz, 1H), 7.59 (br dd, J=8.3,1.4 Hz, 1H), 7.39 (dd, J=9.3, 4.4 Hz, 1 H), 4.47-4.53 (m, 2H), 4.00-4.07 (m, 2H), 2.21- 2.32 (m, 2H); 330.8
14	Example 42; C1	N==\ Cl Çr HN—<]	1H NMR (400 MHz, DMSOd6) δ 8.85 (d, J=1.6 Hz, 1 H), 8.70 (d, J=2.4 Hz, 1 H), 8.64 (dd, J=4.4, 1.5 Hz, 1 H), 8.62 (brd, J=4.6 Hz, 1H), 8.30 (dd, J=2.1,2.0 Hz, 1H), 8.23 (dd, J=9.3, 1.5 Hz, 1H), 7.44 (dd, J=9.3, 4.4 Hz, 1H), 2.81- 2.90 (m, 1H), 0.63-0.70 (m, 4H), 313.9

15	Example 3; CI	N-\ Cl Çr N-y	1H NMR (400 MHz, DMSOd6) δ 8.83 (d, J=1.9 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.64 (dd, J=4.4, 1.5 Hz, 1H), 8.30 (dd, <7=2.4, 1.9 Hz, 1H), 8.28 (dd, J=9.3, 1.5 Hz, 1 H), 7.42 (dd, J=9.3, 4.4 Hz, 1H), 4.57- 4.62 (m, 2H), 4.02-4.08 (m, 2H), 2.24-2.33 (m, 2H); 313.9
16	C13	N-, 0·	9.22 (brs, 1H), 8.40-8.44 (m, 2H), 7.98-8.07 (m, 2H), 7.86 (brd, J=9 Hz, 1H), 7.21 (dd, J=9.4, 4.3 Hz, 1H), 4.68-4.75 (m, 2H), 4.21-4.28 (m, 2H), 2.34- 2.44 (m,2H); 319.8
17	Example 44; C1	CN 0-N-O ^>^N HN—<]	2.55 minutes5; 336.2
18	Example 44; C1	CN F-0^ N // Vy	2.46 minutes5; 336.2
19	Example 26; C1	CN 0Ν'Ν·<ζ^0 HN—0	2.52 minutes5; 336.1

20	Example 87; C13	CN	1H NMR (400 MHz, CDsOD) δ 8.48 (dd, 7=4.3, 1.4 Hz, 1H), 8.14 (dd, 7=9.3, 1.4 Hz, 1H), 7.74 (d, 7=6.5 Hz, 1H), 7.39 (d, 7=9.7 Hz, 1 H), 7.35 (dd, 7=9.3,4.5 Hz, 1 H), 4.73- 4.80 (m, 2H), 4.12-4.20 (m, 2H), 2.36-2.45 (m, 2H), 2.08 (s, 3H); 335.9
21	Example 7; C11	Cl zN-<]	1H NMR (400 MHz, DMSOde), characteristic peaks: δ 8.68 (brd, 7=4.4 Hz, 1H), 8.27 (brd, 7=9 Hz, 1H), 7.87 (brd, 7=11 Hz, 1H), 7.76 (dd, 7=8.3, 8.2 Hz, 1H), 7.57 (brd, 7=9 Hz, 1H), 7.42 (dd, 7=9.3, 4.4 Hz, 1H), 2.99 and 2.80 (2 brs, total 3H), [0.31-0.42, 0.63-0.70 and 0.75-0.83 (3 m, total 4H)]8; 345.1

22	Example 8; C9, C12	d1 fSrO HN—0	1H NMR (400 MHz, CD3OD)Ô9.01 (brs, 1H), 8.53 (dd, J=4.2,1.6 Hz, 1 H), 8.12 (dd, J=9.3, 1.6 Hz, 1 H), 8.04 (d, J=2.4 Hz, 1H), 7.74 (brd, J=9.0 Hz, 1H), 7.54 (dd, J=Q.2, 1.4 Hz, 1H), 7.36 (dd, J=9.2, 4.4 Hz, 1 H), 6.67-6.70 (m, 1H), 2.81-2.88 (m, 1H), 0.79-0.86 (m, 2H), 0.65- 0.71 (m,2H); 341.0 [M+Na+]
23	Example 61; C13	CN (V rN'N	8.42 (dd, J=4.3, 1.6 Hz, 1H), 8.03 (dd, J=9.3, 1.6 Hz, 1 H), 7.78-7.84 (m, 2H), 7.72 (dd, J=8.4, 6.3 Hz, 1H), 7.21 (dd, J=9.2, 4.3 Hz, 1 H), 4.60-4.66 (m, 2H), 4.21-4.27 (m, 2H), 2.33- 2.42 (m, 2H); 322.2
24	Example 5; C13	CN P-Ç^	8.41 (dd, J=4.3, 1.6 Hz, 1H), 8.04 (dd, J=9.3, 1.6 Hz, 1 H), 7.64 (dd, J=8.8, 5.3 Hz, 1 H), 7.45 (dd, J=8.2, 5.0 Hz, 1H), 7.22 (dd, J=9.3, 4.4 Hz, 1H), 4.73-4.80 (m, 2H), 4.20- 4.26 (m, 2H), 2.36-2.45 (m, 2H); 339.9

				Cl
	25	Example		V-F	2.64 minutes10; 319
	59; C8	rN'N5	0
				HN—
1.	In this	case, the catalyst	used	for the Suzuki reaction was

dichlorobis(tricyclohexylphosphine)palladium(ll).

2. The requisite ethyl 3-(5-chloropyridin-3-yl)imidazo[1,2-b]pyridazine-2-carboxylate was synthesized from C1 and 3-bromo-5-chloropyridine, using the method described for conversion of C1 to C5 in Example 3.

3. Compound C1 was converted to azetidin-1-yl(imidazo[1,2-b]pyridazin-2yl)methanone using the method described for transformation of C8 to C13 in Example

8. Further élaboration to Example 16 was effected using the chemistry described for conversion of C1 to C5 in Example 3.

ίο 4. Reaction of C1 with 4-bromo-5-fluoro-2-methylbenzonitrile at elevated température, in the presence of allylpalladium chloride dimer and tetrabutylammonium acetate, afforded the requisite ethyl 3-(4-cyano-2-fluoro-5-methylphenyl)imidazo[1,2b]pyridazine-2-carboxylate.

5. 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.

6. 3-(4-Cyano-5-fluoro-2-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid was prepared from C1 and 4-bromo-2-fluoro-5-methylbenzonitrile using the chemistry described in footnote 4, followed by ester hydrolysis with lithium hydroxide.

7. The requisite aryl boronate dérivative was prepared from the corresponding aryl bromide via reaction with 4,4,4',4^,,5,5,5',5^,-octamethyl-2,2'-bi-1,3,2-dioxaborolane in the presence of [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) and potassium acetate.

8. A ¹H NMR spectrum obtained at elevated température (80 °C) provided the following data: ¹H NMR (400 MHz, DMSO-cfe), characteristic peaks: 5 8.66 (br d, J=4 Hz, 1H),

8.23 (br d, J=Q Hz, 1H), 7.85 (br d, J=11 Hz, 1H), 7.73 (dd, J=Q, 8 Hz, 1H), 7.62 (br d,

J=8 Hz, 1 H), 7.40 (dd, J=9, 4 Hz, 1 H), 2.88-3.02 (br s, 3H), 0.28-0.61 (br s, 4H).

9. In this case, the catalyst used for the Suzuki reaction was [1,1 '-bis(di-fertbutylphosphino)ferrocene]dichloropalladium(ll).

10. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 x 50 mm, 5 pm;

Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 1% to 5% B over 0.6 minutes; 5% to 100%

B over 3.4 minutes; Flow rate: 0.8 mL/minute.

Table 2

Examples 26-104 were prepared using methods analogous to those employed for Examples 1 - 25, or via methodology known to those skilled in the art.

Structure and mass spectrometry data for Examples 26 - 104.

Example Number	Structure	Mass spectrum, observed ion m/z [M+H]+, unless otherwise indicated
26	Cl 0 ΔΑ/	314.9
27	Cl , ό ΓΝ~ΐ / \°	326.9

28	Cl._ ÇA /‘N-ÇjO HN—	348.8
29	Cl (V Λν^Ρ HN-\_	354.9 [M+Na+]
30	Cl 0 HN-<^	326.9
31	Cl 0 0N'Ny^° o—	343.1,345.1
32	Cl 0 - x > 0^	326.9
33	Cl	327.0

34	ryci HN—	333.0
35	R __ W'0' Αή^0 VS HN—<]	330.9
36	(Λ- Λν^0 HN--<j	312.9
37	Cl θΒ°κ HN-Yt2^	339.1
38	nAo Λ f ^N-y^0	320.1
39	/°1 ryN HN-<|	320.1
40	Cl HN—<]	331.0,333.1

41	ÇrF r*N'N-Ç_^° HN—\]	311.1
42	r--N ^r- /Γ y-cf3 ^~'N HN-<]	347.9
43	ζΛτΟρ3 A^o ^^Ssl N-j	347.9
44	Cl dr fN'N-Vf J.F HN-<J	367.0
45	Cl AΑ^Γ /P J HN~<J	349.1
46	Cl 0^° -J HN^<j	353.0 [M+Na+]
47	F\ucl fjrF	348.9

48	N^yc| HN~	315.9
49	frC!	327.1,329.1
50	r~\ o.___zZ7 o.X y Ο-Λ ΰ	321.1
51	Cl ^N'N'y^0	327.1,329.0
52	Cl pX5 0 r* N \ y	330.9
53	F fN'N-Ç_^°	325.1

54	Λν''^0	310.9
55	0 [*ν'νΧΧ°	326.9
56	Cl /Λ p N /f	327.2
57	Cl yjf · HCOOH \ N^\ // HN-^ £y°H	393
58	Cl Vj7 · cf3cooh Ô^°7'° ΗΝ-<ζΥ	354
59	Cl Vj/ · CF3C00H /Ν.-,Χ o C N'N- HN-< J. \^N	354

60	Cl 0 A y-f ^Am F	331.1,333.1
61	U- r-f-u. i Wz ü	349.0,351.0
62	drN AN'n-^Ç__^° A/Al N-y •HCOOH	331
63	0 f-QA N·^ •HCOOH	339
64	A>CI a^°	327
65	Cl CI-^Ca rN'N v?	347

66	CL/ • HCOOH	341
67	çP •HCOOH	337
68	Cl F-0 r^'N-^Ç /P J HN—<f	348.9
69	^'A-CI ^n'n-^_^° F HN-<J	331.9
70	Cl /A r^N'N^Ç /P F HN—<f	344.8
71	Cl\^7 O f^N'N y-^° J HN—<]	344.8

72	FV F	328.9
73	0 F-ό Λ	326.9
74	O [»N-n^^°	319.8
75	F. r-N ,4 Cj ί^Ν'Ν-γ^° HN—<|	346.1
76	R <N V rv°	346.0
77	Ν=η & ΓΝ'Τ / \° N-J	320.1

78	N^N Λ N rN'Nv€ HN-<l	320.1
79	CN /N'n^L° H N—<j	343.9 [M+Na+]
80	/TV-CN rN'N-5_^° hn—<]	318.2
81	Cl fN'NV€ HN--\	319.0
82	Cl dr wlzy \^N	357.1
83	Cl Æ-CI rN'N vf	346.9
84	0rcl ΛνΛ^°	312.9

85	CX.z^ H Z /> \\ //	300.8
86	F 0^F Çr° An'n y_^° N-J	359.1
87	F oAr 0 ^'N'y^0 VS HN~<)	346.1
88	Ν=η A aY° SS HN-<|	320.1
89	Æjn'n ΛνΑ^ζ0 H N—<]	333.9
90	CN cVf Υ/Ύ HN~<]	322.2

91	Cl F0~F	349.2
92	CN [*n-n-G° HN~<]	340.1
93	Cl HN—	323
94	Cl C / F I N AzP HN-	305
95	Cl -O ΛΝ-543 H N-\	315
96	Cl f-0'F ΛΝ-Çf	337

97	Cl Av? HN-·	347
98	CN AA? ΗΝ-ξ	324
99	CN AÎA A'N^° hn?	338.1
100	Cl V [*Ν·νΆ VSjhN-^	351
101	Cl O Av? N ΑΆ hn-x7	350.9
102	Cl _ ό Ay--? AA ΗΆ^>	348.9 [M+Na+]

The PDE4A, PDE4B, PDE4C and PDE4D binding affinity for the compounds of the present invention was determined utilizing the following biological assay(s):

Bioloqical Assays

Human PDE4A3 coding sequence (amino acids 2 to 825 from the sequence with accession number NP_001104779) was cloned into the baculovirus expression vector pFastBac (Invitrogen) engineered to include an N-terminal His6 affinity tag and a cterminal FLAG affinity tag to aid in purification. 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. Insect cell paste was lysed and after centrifugation, the supematant was batch bound to Ni-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. This eluate was diluted with FLAG buffer (50mM Tris HCL pH 7.5, 100 mM NaCI, 5% Glycerol, 1 mM TCEP with protease inhibitors) and batch bound to antFLAG M2 agarose (Sigma) overnight at 4 °C. The agarose was packed into a column, washed with buffer and eluted with buffer containing elute using 250ug/ml Flag-peptide. Fractions were analyzed using SDS-PAGE Coomassie blue staining and pooled based on purity. Pooled fractions were chromatographed on a S200 120ml column (GE Healthcare) in 50mM Tris HCL pH 7.5, 150 mM NaCI, 10% Glycerol, 2mM TCEP with protease inhibitors. PDE4A3 fractions were analyzed by SDS-PAGE Coomassie blue staining, pooled based on purity, dialyzed against 50mM Tris HCL pH 7.5, 100 mM NaCI, 20% Glycerol, 2mM TCEP, 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 pFastBac (Invitrogen) engineered to include a N-terminal His6 affinity 5 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 paste was lysed and after centrifugation, the supematant 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 NaCl to -100 mM and loaded on a Source 15Q (GE Healthcare) column. After washing with Q buffer A/10% buffer B to baseline,

PDE4D was eluted with a gradient from 10% to 60% of Buffer B (20 mM Tris HCl pH 8, 1 M NaCl, 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.

Human PDE4C1 coding sequence (amino acids 2 to 712 from the sequence with accession number NP_000914.2) was cloned into the baculovirus expression vector 20 pFastBac (Invitrogen) engineered to include an N-terminal His6 affinity tag and a cterminal FLAG affinity tag to aid in purification. 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. Insect cell paste was lysed and after centrifugation, the supematant was batch bound to Ni-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. This eluate was diluted with FLAG buffer (50mM Tris HCL pH 7.5, 100 mM NaCl, 5% Glycerol, 1 mM TCEP with protease inhibitors) and batch bound to antFLAG M2 agarose (Sigma) ovemight at 4 °C. The agarose was packed into a column, washed with buffer and eluted with buffer containing elute using 250ug/ml Flag-peptide.

Fractions were analyzed using SDS-PAGE Coomassie blue staining and pooled based on purity. Pooled fractions were chromatographed on a S200 120ml column (GE Healthcare) in 50mM Tris HCL pH 7.5,150 mM NaCl, 10% Glycerol, 2mM TCEP with protease inhibitors. PDE4C1 fractions were analyzed by SDS-PAGE Coomassie blue staining, pooled based on purity, dialyzed against 50mM Tris HCL pH 7.5, 100 mM

NaCl, 20% Glycerol, 2mM TCEP, frozen and stored at -80 °C.

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 5 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 12. hours after infection. Insect cell paste was lysed and after 10 centrifugation, the supematant 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 (50 mM Tris HCl pH 8, 4% glycerol, 100 mM NaCl, 1 mM TCEP, Protease inhibitors EDTA-free (Roche)) to reduce NaCl to -200 mM, and loaded on a Q Sepharose (GE Healthcare) column. 15 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 NaCl, 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.

The PDE4A3, PDE4B1, PDE4C1 and PDE4D3 assays use the Scintillation 20 Proximity Assay (SPA) technology to measure the inhibition of human recombinant PDE4A1, PDE4B3, PDE4C1, and PDE4D3 enzyme activity by compounds in vitro. The PDE4A1, PDE4B3, PDE4C1, and PDE4D3 assays are run in parallel using identical parameters, except for the concentration of enzyme (80 pM PDE4A3, 40 pM PDE4B3, 40 pM PDE4C1 and 10 pM PDE4D). The assays are performed in a 384-well format 25 with 50uL assay buffer (50mM TRIS pH7.5; 1.3mM MgCI2; .01% Brij) containing enough PDE4A3, PDE4B1, PDE4C1, and PDE4D to convert -20% of substrate (1 μΜ cAMP consisting of 20nM 3H-cAMP + 980uM cold cAMP) and a range of inhibitors. Reactions are incubated for 30 min at 25 °C. The addition of 20uL of 8mg/ml yitrium silicate SPA beads (Perkin Elmer) stops the reaction. The plates are sealed (TopSeal, 30 Perkin Elmer) and the beads are allowed to settle for 8 hrs, after which they are read on the Trilux Microbeta overnight.

Table 3

Biological data for Examples 1 - 104.

Example Number	Human PDE4A FL; IC50 (nM)b	Human PDE4B FL; IC50 (nM)b	Human PDE4C FL; IC50 (nM)b	Human PDE4D FL; IC50 (nM)b	IUPAC Name
1	38.6	35.5e	130	10300e	azetidin-1-yl[3-(4chlorophenyl)imidazo[1, 2-b]pyridazin-2yl]methanone
2	10.7	17.7	27.9	4340e	3-(4-chlorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
3	12.7	29.1	51.9	2410	azetidin-1-yl[3-(3,5difluoro-4methoxyphenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone
4	187	380e	561	>27100e	A/-cyclopropyl-3-(2methoxypyrimidin-5yl)imidazo[1,2b]pyridazine-2carboxamide
5	40.2	89.5	208	>26600	3-(6-cyanopyridin-3-yl)- Ncyclopropylimidazo[1,2b]pyridazine-2carboxamide

6	64.4	49.3	326	4890e	A/-cyclopropyl-3([1,2,4]triazolo[1,5a]pyridin-6yl)imidazo[1,2b]pyridazine-2carboxamide
7	2.77	<1.89	2.35	34.5	3-(4-chloro-3fluorophenyl)-/V-(1methyl-1 H-pyrazol-4yl)imidazo[1,2b]pyridazine-2carboxamide
8	20.0	41.3e	64.9	5440e	azetidin-1 -yl[3(pyrazolo[1,5-a]pyridin6-yl)imidazo[1,2b]pyridazin-2yl]methanone
9	3.83	10.5	40.9	1490	3-(4-chloro-2,5difluorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
10	1.51	3.80e	6.84	590e	3-(4-chloro-3fluorophenyl)-A/cyclopropylimidazo[1,2b]pyridazine-2carboxamide
11	ND	1.60	ND	334e	A/-cyclopropyl-3-(3,4dichlorophenyl)imidazo[ 1,2-b]pyridazine-2carboxamide

12	14.4	35.8e	89.6	5220e	3-(4-chloro-2methylphenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
13	5.13	4.63e	17.3	669e	azetidin-1 -yl[3-(4-chloro- 3fluorophenyl)imidazo[1,2 -b]pyridazin-2yl]methanone
14	73.7	79.1e	108	>8010e	3-(5-chloropyridin-3-yl)- Ncyclopropylimidazo[1,2b]pyridazine-2carboxamide
15	264	252e	421	>23700°	azetidin-1 -yl[3-(5chloropyridin-3yl)imidazo[1,2b]pyridazin-2yl]methanone
16	ND	552	ND	>27500	azetidin-1-yl[3([1,2,4]triazolo[1,5a]pyridin-6- yl)imidazo[1,2b]pyridazin-2yl]methanone
17	89.9	175e	216	>18200e	3-(4-cyano-2-fluoro-5methylphenyl)-A/cyclopropylimidazo[1,2b]pyridazine-2carboxamide

18	55.0	150	147	8200	4-[2-(azetidin-1ylcarbonyl)imidazo[1,2b]pyridazin-3-yl]-5fluoro-2methylbenzonitrile
19	16.9	13.6	98.4	645	3-(4-cyano-5-fluoro-2methylphenyl)-/Vcyclopropylimidazo[1,2ô]pyridazine-2carboxamide
20	6.70	5.74e	74.8	490e	4-[2-(azetidin-1ylcarbonyl)imidazo[1,2b]pyridazin-3-yl]-2fluoro-5methylbenzonitrile
21	53.7	91.3e	170	>12300e	3-(4-chloro-3fluorophenyl)-/\/cyclopropyl-A/methylimidazo[1,2b]pyridazine-2carboxamide
22	27.6	58.9	71.2	1890	/V-cyclopropyl-3(pyrazolo[1,5-a]pyridin6-yl)imidazo[1,2b]pyridazine-2carboxamide
23	15.1	30.5	45.8	4130	4-[2-(azetidin-1ylcarbonyl)imidazo[1,2b]pyridazin-3-yl]-2fluorobenzonitrile

49120

24	5.04	19.1	59.7	>2150	4-[2-(azetidin-1 ylcarbonyl)imidazo[1,2b]pyridazin-3-yl]-2,5difluorobenzonitrile
25	38.6	140	150	4970	3-(4-chloro-5-fluoro-2methylphenyl)-/Vmethylimidazo[1,2b]pyridazine-2carboxamide
26	85.5	114	111	3800e	3-(4-chlorophenyl)-/Vpropylimidazo[1,2b]pyridazine-2carboxamide
27	742	609	768	5620e	[3-(4chlorophenyl)imidazo[1, 2-b]pyridazin-2yl](pyrrolidin-1 yl)methanone
28	15.6	31.7	49.0	393e	3-(3,5-dichlorophenyl)- A/-propylimidazo[1,2b]pyridazine-2carboxamide
29	3.48	5.05	13.8	409e	3-(4-chloro-3fluorophenyl)-/Vpropylimidazo[1,2b]pyridazine-2carboxamide
30	11.6	55.0	24.5	4000e	3-(4-chlorophenyl)-A/-(2methylcyclopropyl)imida zo[1,2-b]pyridazine-2carboxamide

31	2820	2670	5810	>26200	[3-(4chlorophenyl)imidazo[1, 2-b]pyridazin-2-yl](3methoxyazetidin-1yl)methanone
32	1030	419e	469	>30000°	3-(4-chlorophenyl)-/Vcyclopropyl-/Vmethylimidazo[1,2b]pyridazine-2carboxamide
33	58.6	53.6	127	2330	3-(4-chlorophenyl)-/V-(1 methylcyclopropyl)imida zo[1,2-b]pyridazine-2carboxamide
34	29.5	83.2e	47.0	2110e	3-(3-chloro-5fluorophenyl)-/Vpropylimidazo[1,2b]pyridazine-2carboxamide
35	35.7	48.0	37.0	1220	3-(3-chloro-5fluorophenyl)-A/cyclopropylimidazo[1,2b]pyridazine-2carboxamide
36	23.7	6.99	21.0	254	3-(3-chlorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
37	127	75.3	161	2570	A/-(b icyclo[ 1.1.1 ]pent-1 yl)-3-(4chlorophenyl)imidazo[1, 2-b]pyridazine-2carboxamide

38	ND	268	ND	11200	/V-cyclopropyl-3(furo[3,2-b]pyridin-6yl)imidazo[1,2b]pyridazine-2carboxamide
39	14.8	26.5	67.8	3820b	3-(1,3-benzoxazol-5-yl)Ncyclopropylimidazo[1,2b]pyridazine-2carboxamide
40	19.6	65.3	58.1	9020	3-(4-chloro-2fluorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
41	3.13	8.05	16.8	467	A/-cyclopropyl-3-(3fluoro-4methylphenyl)imidazo[1, 2-b]pyridazine-2carboxamide
42	415	393e	357	>12200e	A/-cyclopropyl-3-[2(trifluoromethyl)pyridin4-yl]imidazo[1,2b]pyridazine-2carboxamide
43	ND	270	ND	>16900	azetidin-1-yl{3-[2(trifluoromethyl)pyridin4-yl]imidazo[1,2b]pyridazin-2yl}methanone

44	ND	3.92	ND	320	3-(4-chloro-3fluorophenyl)-/V-(2,2difluorocyclopropyl)imida zo[1,2-b]pyridazine-2carboxamide
45	2.91	1.97	11.7	159	3-(4-chloro-3fluorophenyl)-/V- [(1 R,2S)-2fluorocyclopropyl]imidaz o[1,2-b]pyridazine-2carboxamide
46	15.2	12.3	39.3	971	3-(4-chlorophenyl)-/V[(1 R,2S)-2fluorocyclopropyl]imidaz o[1,2-b]pyridazine-2carboxamide
47	7.37	3.90e	23.9	334e	azetidin-1 -yl[3-(4-chloro- 3,5difluorophenyl)imidazo[1 ,2-b]pyridazin-2yl]methanone
48	768	322	212	>7670	3-(5-chloropyridin-3-yl)- A/-propylimidazo[1,2b]pyridazine-2carboxamide
49	4.16	13.3	19.0	535b	azetidin-1 -yl[3-(3-chloro- 4- methylphenyl)imidazo[1, 2-b]pyridazin-2yl]methanone

..................19120

50	28.1	116	235	3140	azetidin-1 -yl[3-(2,3dihydro-1 -benzofuran-5yl)imidazo[1,2b]pyridazin-2yl]methanone
51	ND	42.9	ND	2810	azetidin-1 -yl[3-(4-chloro- 3- methylphenyl)imidazo[1, 2-ô]pyridazin-2yl]methanone
52	24.3	37.3	113	5510	azetidin-1 -yl[3-(4-chloro2fluorophenyl)imidazo[1,2 -b]pyridazin-2yl]methanone
53	17.8	63.3	153	3110	azetidin-1 -yl[3-(4-fluoro- 3,5dimethylphenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone
54	103	107e	136	>20000c	azetidin-1 -yl[3-(2-fluoro- 4- methylphenyl)imidazo[1, 2-b]pyridazin-2yl]methanone
55	176	200	>1550	>20900c	azetidin-1 -yl[3-(3-fluoro- 4methoxyphenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone

56	22.7	43.1e	84.5	3930e	azetidin-1 -yl[3-(4-chloro- 2- methylphenyl)imidazo[1, 2-b]pyridazin-2yl]methanone
57	ND	236	ND	>21800	3-(4-chlorophenyl)-A/-[2(2hydroxyphenyl)ethyl]imid azo[1,2-b]pyridazine-2carboxamide, formate sait
58	ND	43.3	ND	831	3-(4-chlorophenyl)-/V-(5methyl-1,2-oxazol-3yl)imidazo[1,2b]pyridazine-2carboxamide, trifluoroacetate sait
59	ND	58.5	ND	749	3-(4-chlorophenyl)-/V-(2methyl-2H-1,2,3-triazol4-yl)imidazo[1,2d]pyridazine-2carboxamide, trifluoroacetate sait
60	269	196	287	>4930	[3-(4chlorophenyl)imidazo[1, 2-b]pyridazin-2-yl](3fluoroazetidin-1yl)methanone

61	144	184	126	1930	[3-(4chlorophenyl)imidazo[1, 2-b]pyridazin-2-yl](3,3difluoroazetidin-1yl)methanone
62	ND	275	ND	11000	azetidin-1-yltSiquinoxalin-eyl)imidazo[1,2b]pyridazin-2yl]methanone, formate sait
63	ND	17.7	ND	394	1 -{3-[2-(azetidin-1 ylcarbonyl)imidazo[1,2b]pyridazin-3-yl]-4fluorophenyl}ethanone, formate sait
64	ND	24.2	ND	844	azetidin-1 -yl[3-(5-chloro2methylphenyl)imidazo[1, 2-b]pyridazin-2yl]methanone
65	ND	71.9	ND	3720	azetidin-1-yl[3-(2,4dichlorophenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone
66	ND	41.0	ND	3390	azetidin-1 -yl[3-(3-chloro- 2,4dimethylphenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone, formate sait

67	ND	59.8	ND	2260	azetidin-1-yl[3-(2,3dihydro-1,4-benzodioxin6-yl)imidazo[1,2b]pyridazin-2yl]methanone, formate sait
68	10.6	35.4	25.1	2620	3-(4-chloro-2fluorophenyl)-/V[(1 R,2S)-2fluorocyclopropyl]imidaz o[1,2-b]pyridazine-2carboxamide
69	ND	116	ND	3330	3-(5-chloropyridin-3-yl)A/-[(1fî,2S)-2fluorocyclopropyljimidaz o[1,2-b]pyridazine-2carboxamide
70	36.4	31.0e	90.0	5760e	3-(4-chloro-2methylphenyl)-/V[(1 R,2S)-2fluorocyclopropyl]imidaz o[1,2-b]pyridazine-2carboxamide
71	<0.669	2.82	2.00	113	3-(3-chloro-4methylphenyl)-/V[(1fî,2S)-2fluorocyclopropyl]imidaz o[1,2-b]pyridazine-2carboxamide

72	ND	192	ND	6590	A/-[(1H,2S)-2- fluorocyclopropyl]-3-(2fluoro-4methylphenyl)imidazo[1, 2-b]pyridazine-2carboxamide
73	165	495	1440	>24700	azetidin-1 -yl[3-(2-fluoro- 4- methoxyphenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone
74	ND	225	ND	10500	azetidin-1-yl[3(pyrazolo[1,5- a] pyrimidin-6yl)imidazo[1,2- b] pyridazin-2yl]methanone
75	10.5	5.99e	24.9	104e	A/-cyclopropyl-3-[2(difluoromethoxy)pyridin4-yl]imidazo[1,2b]pyridazine-2carboxamide
76	7.09	5.43e	22.2	94.5e	azetidin-1 -yl{3-[2(difluoromethoxy)pyridin4-yl]imidazo[1,2b]pyridazin-2yljmethanone
77	46.1	80.4e	186	>16600e	azetidin-1 -yl[3-(1,3benzoxazol-6yl)imidazo[1,2b]pyridazin-2yl]methanone

78	ND	364	ND	6490	/V-cyclopropyl-3(pyrazolo[1,5- a] pyrimidin-6yl)imidazo[1,2- b] pyridazine-2carboxamide
79	48.8	190e	297	>25400e	3-(4-cyano-2fluorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
80	ND	344	ND	>25400	3-(5-cyano-2methylphenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
81	7.86	9.34e	25.8	853e	3-(4-chloro-3fluorophenyl)-/Vethylimidazo[1,2b]pyridazine-2carboxamide
82	12.0	5.14	43.4	56.5	3-(4-chloro-3fluorophenyl)-A/-(1 Hpyrazol-4-yl)imidazo[1,2b]pyridazine-2carboxamide
83	6.21	5.39	40.0	495	azetidin-1 -yl[3-(3,4dichlorophenyl)imidazo[ 1,2-b]pyridazin-2yl]methanone

102

84	16.7	7.84e	44.4	977°	azetidin-1-yl[3-(3chlorophenyl)imidazo[1, 2-h]pyridazin-2yl]methanone
85	25.6	87.3°	47.2	6700e	3-(4-chlorophenyl)-/Vethylimidazo[1,25]pyridazine-2carboxamide
86	5.83	7.72	25.0	179	azetidin-1-yl[3-(2,2difluoro-1,3-benzodioxol5-yl)imidazo[1,2h]pyridazin-2yl]methanone
87	240	173	397	6790	A/-cyclopropyl-3-[6(difluoromethoxy)pyridin3-yl]imidazo[1,2d]pyridazine-2carboxamide
88	45.0	39.2e	136	10400e	3-(1,3-benzoxazol-6-yl)Ncyclopropylimidazo[1,25]pyridazine-2carboxamide
89	829	333	3760	>17200	A/-cyclopropyl-3-(7methyl[1,2,4]triazolo[1,5a]pyridin-6yl)imidazo[1,25]pyridazine-2carboxamide

90	21.4	43.7	25.5	2620	3-(4-cyano-3fluorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
91	12.6	36.9	80.0	2250	azetidin-1 -yl[3-(4-chloro- 2,5difluorophenyl)imidazo[1 ,2-b]pyridazin-2yl]methanone
92	5.52	21.0	42.5	>1440	3-(4-cyano-2,5difluorophenyl)-/Vcyclopropylimidazo[1,2b]pyridazine-2carboxamide
93	62.9	276	134	4110	3-(4-chloro-2,5difluorophenyl)-/Vmethylimidazo[1,2b]pyridazine-2carboxamide
94	24.9	253	65.0	5380	3-(4-chloro-3fluorophenyl)-/Vmethylimidazo[1,2b]pyridazine-2carboxamide
95	ND	306	ND	14800	3-(4-chloro-2methylphenyl)-/Vethylimidazo[1,2b]pyridazine-2carboxamide

104

96	4.58	33.2	29.2	908	3-(4-chloro-2,5difluorophenyl)-A/ethylimidazo[1,2b]pyridazine-2carboxamide
97	5.48	23.3	20.0	>1850	3-(4-chloro-5-fluoro-2methylphenyl)-/V(propan-2yl)imidazo[1,2b]pyridazine-2carboxamide
98	26.6	62.7	107	3320	3-(4-cyano-5-fluoro-2- methylphenyl)-/Vethylimidazo[1,2b]pyridazine-2carboxamide
99	19.8	36.2	138	1550	3-(4-cyano-5-fluoro-2methylphenyl)-/V(propan-2yl)imidazo[1,2b]pyridazine-2carboxamide
100	ND	49.1	ND	766	3-(4-chloro-2,5difluorophenyl)-/V(propan-2yl)imidazo[1,2b]pyridazine-2carboxamide

105

101	268a	861	1179a	>25900	3-(4-chlorophenyl)-A/(pyrimidin-2yl)imidazo[1,2b]pyridazine-2carboxamide
102	59.9	103	76.0	5010	3-(4-chlorophenyl)-/V(cyclopropylmethyl)imida zo[1,2-b]pyridazine-2carboxamide
103	62.7	249	203	1550	3-(4-chlorophenyl)-A/(1 H-pyrazol-5yl)imidazo[1,2b]pyridazine-2carboxamide
104	<0.488	1.59	4.69	145	3-(4-chloro-3,5difluorophenyl)-A/cyclopropylimidazo[1,2b]pyridazine-2carboxamide

a. Values represents 1 détermination

b. Values represent the géométrie mean of 2 - 9 déterminations, unless otherwise indicated.

c. Value represents the géométrie mean of 2:10 déterminations

ND. Value not determined

Claims (29)

1. What is claimed:

   1. A compound of Formula I:

   or a pharmaceutically acceptable sait thereof, wherein:

   R¹ is selected from the group consisting of -(CH2)m-(C3-C8)cycloalkyl, -(CH2)m(4- to 10-membered)heterocycloalkyl, -(CH2)m-(C6-Cw)aryl and -(CH2)m-(5- to 14membered)heteroaryl, and, where chemically permissible, the (Cs-Cejcycloalkyl, (4- to 10-membered)heterocycloalkyl, (Ce-Cio)aryl and (5- to 14-membered)heteroaryl 5 moieties are optionally substituted with one to five R²;

   when présent, each R² is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (Ci-Cejalkylthio, optionally substituted (Ci-C6)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=0)-R⁴, -C(=O)-OR⁴, and optionally 10 substituted (Cs-Cejcycloalkyl;

   when présent, each R³ is independently selected from the group consisting of halogen, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (Ca-Cejalkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-C6)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), 15 -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

   R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and optionally substituted (Ci-Ce)alkyl;

   R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, optionally substituted (C-i-Cejalkyl, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-(4- to 10-membered) heterocycloalkyl, -(CH2)n-(C6-Cio)aryl, and -(CH2)n-(5- to 1020 membered)heteroaryl, and where chemically permissible, the (Cs-Csjcycloalkyl, (4- to

   10-membered)heterocycloalkyl, (C6-Cio)aryl, and (5- to 10-membered)heteroaryl are optionally substituted with one to five R⁸; or

   R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4to 10-membered)heterocycloalkyl, and where chemically permissible, the (4- to 10membered)-heterocycloalkyl is optionally substituted with one to five R⁹;

   when présent, each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-C6)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

   when present, each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-Cejalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-Cs)alkynyl, optionally substituted (Ci-Csjalkylthio, optionally substituted (Ci-Ce)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴;

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

   m is represented by an integer selected from 0, 1, or 2; and n is represented by an integer selected from 0, 1,2, 3 or 4.
2. 2. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein m is 0 and R¹ is a (4- to 10-membered)heterocycloalkyl optionally substituted with one to three R², wherein the optionally substituted heterocycloalkyl is selected from the group consisting of azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octaohydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl, dihydro1 H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl, 3-azabicyclo[3.1.0]hexanyl, and 3azabicyclo[4.1.0]heptanyl.

   108
3. 3. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein m is 0 and R¹ is a (Ce-Cio)aryl optionally substituted with one to three R², wherein the optionally substituted (Cs-Cio)aryl is phenyl or naphthyl.
4. 4. The compound according to claim 3, or a pharmaceutically acceptable sait thereof, wherein the optionally substituted (Ce-Cio)aryl is phenyl.
5. 5. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein m is 0 and R¹ is a (5- to 14-membered)heteroaryl optionally substituted with one to three R², wherein the optionally substituted (5- to 14-membered)heteroaryl is selected from the group consisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and

   1,4-benzoxazinyl.
6. 6. The compound according to claim 5, or a pharmaceutically acceptable sait thereof, wherein the heteroaryl is a (5- to 10-membered)nitrogen-containing heteroaryl selected from the group consisting of triazolyl, imidazolyl, pyrazolyl pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, or quinoxalinyl.
7. 7. The compound according to claim 6, or a pharmaceutically acceptable sait thereof, wherein the heteroaryl is selected from:

   i) a (5-membered)nitrogen-containing heteroaryl; or ii) a (6-membered)nitrogen-containing heteroaryl.
8. 8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable sait thereof, wherein each R² is independently selected from the group

   109 consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-C6)alkyl, and optionally substituted (Ci-Ce)alkoxy.
9. 9. The compound according to claim 8, or a pharmaceutically acceptable sait thereof, wherein R² is selected from:

   i) a halogen selected from fluoro or chloro;

   ii) an optionally substituted (Ci-Cejalkyl selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl are optionally substituted with one to three fluorine atoms; or iii) an optionally substituted (Ci-Ce)alkoxy selected from methoxy, ethoxy or propoxy and the methoxy, ethoxy and propoxy are optionally substituted with one to three fluorine atoms.
10. 10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable sait thereof, wherein R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, optionally substituted (Ci-C6)alkyl, -(CH2)n-(C3Csjcycloalkyl, -(CH2)n-(C6-Cw)aryl, and -(CH2)n-(5- to 6-membered)heteroaryl, and where chemically permissible, the (C3-Cs)cycloalkyl, (C6-Cio)aryl, and (5- to 6membered)heteroaryl are optionally substituted with one to three R⁸; or

    R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4to 6-membered)heterocycloalkyl, and where chemically permissible, the (4- to 6membered)-heterocycloalkyl is optionally substituted with one to three R⁹;

    when present each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-Cejalkyl, optionally substituted (Cz-Cejalkenyl, optionally substituted (C2-Ce)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-Ce)alkoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴, and -C(=O)-OR⁴; and when present each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, optionally substituted (C2-C₆)alkenyl, optionally substituted (C2-Ce)alkynyl, optionally substituted (Ci-C6)alkylthio, optionally substituted (Ci-Cejaikoxy, -N(R⁴)(R⁵), -N(R⁴)(C=(O)R⁵), -C(=O)N(R⁴)(R⁵), -C(=O)-O-N(R⁴)(R⁵), -C(=O)-R⁴,and -C(=O)-OR⁴.
11. 11. The compound according to claim 10, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is hydrogen and the other is an optionally substituted (Ci-Ce)alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, and the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl is optionally substituted with one or more fluorine atoms.
12. 12. The compound according to claim 10, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(C3-Cs)cycloall<yl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl or bicyclo[1.1.1]pentyl, wherein the cycloalkyl is optionally substituted with one to three R⁸.
13. 13. The compound according to claim 10, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(C6-Cio)aryl, wherein the aryl is optionally substituted with one to three R⁸.
14. 14. The compound according to claim 10, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is hydrogen and the other is -(CH2)n-(5- to 6membered)heteroaryl selected from triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl,

    1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, wherein the heteroaryl is optionally substituted with one to three R⁸.
15. 15. The compound according to any one of claims 10-14, or a pharmaceutically acceptable sait thereof, wherein each R⁸ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-C6)alkyl, and optionally substituted (Ci-C6)alkoxy.
16. 16. The compound according to claim 10, 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 with one to three R⁹, wherein the heterocycloalkyl is selected from azetidinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, or pyrrolidinyl.

    111
17. 17. The compound according to claim 16, or a pharmaceutically acceptable sait thereof, wherein the heterocycloalkyl is azetidinyl.
18. 18. The compound according to any one of claims 16-17, or a pharmaceutically acceptable sait thereof, wherein each R⁹ is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, optionally substituted (Ci-C6)alkyl, and optionally substituted (Ci-Ce)alkoxy.
19. 19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable sait thereof, wherein b is an integer selected from 0, 1 or 2 and, when présent, each R³ is independently selected from the group consisting of halogen, cyano, hydroxy, -SFs, nitro, optionally substituted (Ci-C6)alkyl, and optionally

    5 substituted (Ci-C6)alkoxy.
20. 20. Azetidin-1 -yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone, or a pharmaceutically acceptable sait thereof.
21. 21. 3-(6-Cyanopyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide, or a pharmaceutically acceptable sait thereof.
22. 22. N-Cyclopropyl-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2carboxamide, or a pharmaceutically acceptable sait thereof.
23. 23. 3-(4-Chloro-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2- carboxamide, or a pharmaceutically acceptable sait thereof.
24. 24. A pharmaceutical composition comprising the compound according to any one of claims 1-23, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.
25. 25. A compound of Formula I, or a pharmaceutically acceptable sait thereof, as defined in any one of claims 1 to 23, for use in a method of treating a patient suffering from a disease or condition mediated by the PDE4B isoform, wherein said disease or condition is selected from schizophrenia, dépréssion, anxiety, Alzheimer’s disease,

    112

    Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cérébral vascular disease, and allergie conjunctivitis.
26. 26. Use of a compound of Formula I, or a pharmaceutically acceptable sait thereof, as defined in any one of claims 1 to 23, in the manufacture of a médicament for the

    5 treatment of a patient suffering from a disease or condition mediated by the PDE4B isoform, wherein said disease or condition is selected from schizophrenia, dépréssion, anxiety, Alzheimer's disease, Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cérébral vascular disease, and allergie conjunctivitis.

    10
27. 27. 4-[2-(azetidin-1 -ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2-fluoro-5methylbenzonitrile, or a pharmaceutically acceptable sait thereof.
28. 28. 3-(4-chloro-2-rnethylphenyl)-/V-[(1 F?,2S)-2-fluorocyclopropyl]imidazo[1,2b]pyridazine-2-carboxamide, or a pharmaceutically acceptable sait thereof.
29. 29. 3-(4-chloro-5-fluoro-2-methylphenyl)-A/-(propan-2-yl)imidazo[1,2-b]pyridazine-2-

    15 carboxamide, or a pharmaceutically acceptable sait thereof.