HK1237335B - Imidazopyridazine compounds - Google Patents

Description

imidazopyridazine compounds

Field of the Invention

The present invention relates to imidazopyridazine compounds of formula I, which are inhibitors of PDE4 isozymes, particularly having 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

Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave the phosphodiester bond in the second messenger molecules adenosine 3',5'-cyclic monophosphate (cGMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP serve as second messengers in a variety of cellular pathways.

cAMP acts as a second messenger regulating multiple intracellular processes in the body. An example is neurons in the central nervous system, where activation of cAMP-dependent kinases and subsequent protein phosphorylation are involved in the acute regulation of synaptic transmission and neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is shown by the molecular diversity of enzymes involved in the synthesis and degradation of cAMP. There are at least ten adenylate cyclase families and eleven phosphodiesterase families. In addition, different types of neurons are known to express multiple isozymes of each of these types, and there is sufficient evidence for compartmentalization and functional specificity of different isozymes within a given neuron.

The main mechanism for regulating cyclic nucleotide signaling is cyclic nucleotide catabolism catalyzed by phosphodiesterases. Eleven known PDE families are encoded by 21 different genes; each gene typically produces multiple splice variants, which further contribute to isozyme diversity. PDE families differ in function based on cyclic nucleotide substrate specificity, regulatory mechanisms, and sensitivity to inhibitors. In addition, PDEs are expressed differently throughout the organism (including in the central nervous system). Due to these different enzymatic activities and locations, different PDE isozymes can be used for different physiological functions. In addition, compounds that selectively inhibit different PDE isozymes can provide specific therapeutic effects, fewer side effects, or both (Deninno, M., Future Directions in Phosphodiesterase Drug Discovery. Bioorganic and Medicinal Chemistry Letters 2012, 22, 6794-6800).

The present invention relates to compounds having binding affinity for the fourth family of PDEs (PDE4A, PDE4B, PDE4C and PDE4D), and in particular for the PDE4B isoforms.

The PDE4 isoenzyme selectively and highly hydrolyzes the second messenger adenosine 3',5'-cyclic monophosphate (cAMP). The beneficial pharmacological effects caused by this inhibition have been shown in multiple disease models. In recent years, a variety of PDE4 inhibitors have been discovered. For example, roflumilast (sold by Forest Pharmaceuticals, Inc.) is approved for use in severe chronic obstructive pulmonary disease (COPD) to reduce the number of sudden attacks or prevent the worsening of COPD symptoms. Apremilast has been approved by the U.S. Food and Drug Administration for the treatment of adults with active psoriatic arthritis.

Although PDE4 inhibitors have shown beneficial pharmacological activity, a common side effect of these treatments is the induction of gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which are currently believed to be related to the inhibition of the PDE4D isoform. Attempts have been made to develop compounds that have affinity for the PDE4B isoform relative to the PDE4D isoform (see: Donnell, A.F. et al., Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20, 2163-7; and Naganuma, K. et al., Discovery of selective PDE4B inhibitors. Bioorganic and Medicinal Chemistry Letters 2009, 19, 3174-6). However, there remains a need to develop selective PDE4 inhibitors, particularly selective PDE4 inhibitors that have affinity for the PDE4B isoform. In particular, compounds with enhanced binding affinity for PDE4B isoforms relative to PDE4D isoforms are expected to be useful in treating various diseases and disorders of the central nervous system (CNS). Selected compounds of the present invention have been found to address this ongoing need and provide additional therapies for treating 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 reduce gastrointestinal side effects such as nausea, vomiting, and diarrhea, which are thought to be associated with the inhibition of PDE4D isoforms (Robichaud, A. et al., Deletion of Phosphodiesterase 4D in Mice Shortens α2-Adrenoreceptor-Mediated Anesthesia, A Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, 110, 1045-1052).

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from -(CH ₂ ) _m -(C ₃ -C ₈ )cycloalkyl, -(CH ₂ ) _m -(4- to 10-membered)heterocycloalkyl, -(CH ₂ ) _m -(C ₆ -C ₁₀ )aryl and -(CH ₂ ) _m -(5- to 14-membered)-heteroaryl, and where chemically permitted, said (C ₃ -C ₈ )cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C ₆ -C ₁₀ )aryl and (5- to 14-membered)heteroaryl moieties are optionally substituted with 1 to 5 R ² ;

When present, each R ² is independently selected from halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C ₆ )alkenyl, optionally substituted (C ₂ -C 6 )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ )(R ⁵ ), -C(＝O) ^{—R 4} , -C(＝O)—OR ⁴ , and optionally substituted (C ₃ -C ₈ )cycloalkyl;

When present, each R ³ is independently selected from halogen, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C ₂ -C ₆ )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ ) ⁽ R ⁵ ), -C(＝O)—R ⁴ and -C(＝O)—OR ⁴ ;

R ⁴ and R ⁵ are each independently selected from hydrogen and optionally substituted (C ₁ -C ₆ )alkyl;

^R6 and ^R7 are each independently selected from hydrogen, optionally substituted ( _C1 - _C6 )alkyl, -( _CH2 ) _n- ( _C3 - _C8 )cycloalkyl, -( _CH2 ) _n- (4- to 10-membered)heterocycloalkyl, -( _CH2 ) _n- ( _C6 - _C10 )aryl, and -( _CH2 ) _n- (5- to 10-membered)heteroaryl, and where chemically permitted, said ( _C3 - _C8 )cycloalkyl, (4- to 10-membered)heterocycloalkyl, ( _C6 - _C10 )aryl, and (5- to 10-membered)heteroaryl are optionally substituted with one to five ^R8 ; or

R ⁶ and R ⁷ together with the nitrogen to which they are attached form a (4- to 10-membered) heterocycloalkyl, and said (4- to 10-membered) heterocycloalkyl is optionally substituted with one to five R ⁹ when chemically permitted;

When present, each R ⁸ is independently selected from halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C ₆ )alkenyl, optionally substituted (C ₂ -C 6 )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ )(R ⁵ ), -C(＝O) ^{—R 4} , and -C(＝O)—OR ⁴ ;

When present, each R ⁹ is independently selected from halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C ₆ )alkenyl, optionally substituted (C ₂ -C 6 )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ )(R ⁵ ), -C(＝O) ^{—R 4} , and -C(＝O)—OR ⁴ ;

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 present invention include Examples 1-104 as described herein, or pharmaceutically acceptable salts thereof.

The compounds of formula I are inhibitors of PDE4B isoforms.

The compounds of formula I are useful for treating or preventing diseases and/or disorders of the central nervous system (CNS), pain, trauma, cardiac, thrombotic, metabolic, autoimmune and inflammatory diseases or disorders and disorders associated with increased endothelial activity/impaired endothelial barrier function.

The present invention also relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a condition susceptible to modulation of the PDE4B gene family (ie, PDE4B enzyme).

The present invention also relates to pharmaceutically acceptable formulations comprising a mixture of a compound of the present invention and at 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., depots), aerosols for inhalation, and solutions/suspensions for oral ingestion.

Detailed Description of the Invention

The headings of this document are intended only to facilitate quick reference to the reader and should not be construed as limiting the scope of the invention or the claims in any way.

Definition and Examples

As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically stated otherwise.Plural and singular terms are to be regarded as interchangeable except when indicating numerical values.

As used herein, the term "n-membered," where n is an integer, generally describes the number of ring atoms in a group, where the number of ring 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 this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. It is specifically intended that the present invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "(C ₁ -C ₆ ) alkyl" is specifically intended to include C ₁ alkyl (methyl), C ₂ alkyl (ethyl), C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl. For another example, the term "(5-10 membered) heterocycloalkyl" is specifically intended to include any 5-, 6-, 7-, 8-, 9-, and 10-membered heterocycloalkyl.

As used herein, the term "(C ₁ -C ₆ )alkyl" refers to a saturated, branched or straight-chain alkyl group containing 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.

As used herein, the term “optionally substituted (C ₁ -C ₆ )alkyl” refers to a (C ₁ -C ₆ )alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF ₅ , nitro, —N(R ⁴ )(R ⁵ ), —N(R ⁴ )(C(═O)R ⁵ ), —N(R ⁴ )C(═O)—OR ⁵ , —C(═O)—N(R ⁴ )(R ⁵ ), —C(═O)—ON(R ⁴ )(R ⁵ ), —C(═O)—R ⁴ , —C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl. For example, a (C ₁ -C ₆ )alkyl moiety may be substituted with one or more halogen atoms to form a “halo(C ₁ -C ₆ )alkyl.” Representative examples of halo(C ₁ -C ₆ )alkyl include, but are not limited to, fluoromethyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

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

The term “optionally substituted (C ₂ -C ₆ )alkenyl” refers to a (C ₂ -C ₆ )alkenyl group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl.

The term "(C ₂ -C ₆ )alkynyl" refers to an aliphatic hydrocarbon having two to six carbon atoms and having at least one carbon-carbon triple bond, including straight or branched chains having at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “optionally substituted (C ₂ -C ₆ )alkynyl” refers to a (C ₂ -C ₆ )alkynyl group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl.

As used herein, the term "(C ₁ -C ₆ )alkoxy" refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Representative examples of (C ₁ -C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

As used herein, the term “optionally substituted (C ₁ -C ₆ )alkoxy” refers to a (C ₁ -C ₆ )alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl. For example, a (C ₁ -C ₆ )alkoxy group may be substituted with one or more halogen atoms to form a “halo(C ₁ -C ₆ )alkoxy group.” Representative examples of halo(C ₁ -C ₆ )alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

As used herein, the term "(C ₁ -C ₆ )alkylthio" refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom. Representative examples of (C ₁ -C ₆ )alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, and the like.

As used herein, the term “optionally substituted (C ₁ -C ₆ )alkylthio” refers to a (C ₁ -C ₆ )alkylthio group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl.

As used herein, the term "( _C3 - _C8 )cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule in which the cyclic framework has 3 to 8 carbon atoms. "( _C3 - _C6 )cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule having 3 to 6 carbon atoms. "Cycloalkyl" can be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Also included in the definition 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 "( _C4 - _C8 )bicycloalkyl". The term "( _C4 - _C8 )bicycloalkyl" refers to a bicyclic ring system containing 4 to 8 carbon atoms. The bicycloalkyl group may be a fused group such as bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[2.2.0]hexane, bicyclo[3.1.0]hexane, bicyclo[3.2.0]heptane and bicyclo[3.3.0]octane. The term "bicycloalkyl" also includes bridged bicycloalkyl systems such as, but not limited to, bicyclo[2.2.1]heptane and bicyclo[1.1.1]pentane.

The term “optionally substituted (C ₃ -C ₈ )cycloalkyl” refers to a (C ₃ -C ₈ )cycloalkyl group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl.

As used herein, "heterocycloalkyl" refers to a cycloalkyl group as defined above in which at least one ring carbon atom is replaced by a heteroatom selected from nitrogen, oxygen, or sulfur. The term "(4-6 membered)heterocycloalkyl" means a heterocycloalkyl substituent containing a total of 4 to 6 ring atoms, at least one of which is a heteroatom. The term "(4-8 membered)heterocycloalkyl" means a heterocycloalkyl substituent containing a total of 4 to 8 ring atoms, at least one of which is a heteroatom. "(4-10 membered)heterocycloalkyl" means a heterocycloalkyl substituent containing a total of 4 to 10 ring atoms. "(6 membered)heterocycloalkyl" means a heterocycloalkyl substituent containing a total of 6 ring atoms, at least one of which is a heteroatom. "(5 membered)heterocycloalkyl" means a heterocycloalkyl substituent containing a total of 5 ring atoms, at least one of which is a heteroatom. A heterocycloalkyl group may be a monocyclic ring having up to a total of 10 members. Alternatively, Heterocycloalkyl as defined above can comprise 2 or 3 rings fused together, wherein at least one such ring contains heteroatoms as ring atoms (i.e. nitrogen, oxygen or sulphur). The Heterocycloalkyl substituent can be connected to the imidazopyridazine core of the compound of the present invention by a nitrogen-atom with appropriate valence or by any ring carbon atom. The Heterocycloalkyl substituent can also be connected to the nitrogen of the amide moiety on the imidazopyridazine core. The Heterocycloalkyl moiety can optionally be replaced by one or more substituents at the nitrogen-atom with appropriate valence or at any available carbon atom.

Also included within the definition of "heterocycloalkyl" are heterocycloalkyl groups fused to a phenyl or naphthyl ring, or a heteroaryl ring such as, but not limited to, a pyridyl or 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, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxolyl, benzodioxolyl, benzoxazinyl, indolinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, isochromyl, dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like. Other 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-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4- Oxazepan-1-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazin-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinone, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), and the like.

The term "optionally substituted heterocycloalkyl" [e.g., optionally substituted (4- to 10-membered)heterocycloalkyl] refers to a heterocycloalkyl as defined above wherein, where chemically permitted, one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, _-SF5 , 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 - _C8 )cycloalkyl, wherein ^R4 and ^R5 are each independently hydrogen or optionally substituted ( _C1 - _C6 )alkyl.

"(C ₆ -C ₁₀ )aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group containing 6 to 10 carbon atoms and having a conjugated pi-electron system, such as phenyl or naphthyl.

The term “optionally substituted (C ₆ -C ₁₀ )aryl” refers to a (C ₆ -C ₁₀ )aryl group as defined above, wherein one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF ₅ , nitro, -N(R ⁴ )(R ⁵ ), -N(R ⁴ )(C(═O)R ⁵ ), -N(R ⁴ )C(═O)—OR ⁵ , -C(═O)—N(R ⁴ )(R ⁵ ), -C(═O)—ON(R ⁴ )(R ⁵ ), -C(═O)—R ⁴ , -C(═O)—OR ⁴ and (C ₃ -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl.

As used herein, the term "heteroaryl" refers to a monocyclic or fused-ring polycyclic aromatic heterocyclic group in which one or more heteroatom ring members (ring atoms) in at least one ring are each independently selected from oxygen (O), sulfur (S), and nitrogen (N). A "(5- to 14-membered) heteroaryl" ring refers to a heteroaryl ring having 5 to 14 ring atoms, wherein at least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. A "(5- to 10-membered) heteroaryl" ring refers to a heteroaryl ring having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. A "(5- to 10-membered) nitrogen-containing heteroaryl" ring refers to a heteroaryl ring having 5 to 10 ring atoms, wherein at least one ring atom is nitrogen, and the remaining ring atoms are independently selected from carbon and nitrogen. A "(5- to 6-membered)heteroaryl" ring refers to a heteroaryl ring having 5 to 6 ring atoms, at least one of which is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. A "(5- to 6-membered)nitrogen-containing heteroaryl" refers to a heteroaryl ring having 5 to 6 ring atoms, wherein all heteroatoms in the ring are nitrogen. A "(6-membered)nitrogen-containing heteroaryl" refers to a heteroaryl ring having 6 ring atoms, wherein all heteroatoms in the ring are nitrogen. A "(5-membered)nitrogen-containing heteroaryl" refers to a heteroaryl ring having 5 ring atoms, wherein all heteroatoms in the ring are nitrogen. A heteroaryl group can be a single ring or two or three fused rings. Examples of heteroaryl groups include, but are not limited to, 6-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered heteroaryl groups such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, isothiazolyl, and pyrazolyl; 6/5-membered fused ring substituents such as indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothienyl, benzothienyl, benzisoxazole, benzothiazolyl, benzothiophenyl ... 1,4-Benzo[1,6,7,8-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 will be appreciated that the heteroaryl group may be optionally fused to a cycloalkyl or heterocycloalkyl group as defined herein.

The heteroaryl substituents may be attached to the imidazopyridazine core of the compounds of the invention through a nitrogen atom with appropriate valence or through any ring carbon atom or to the nitrogen of the amide portion of the imidazopyridazine core. The heteroaryl moiety may optionally be substituted with one or more substituents at the nitrogen atom with appropriate valence or at any available carbon atom.

The terms "optionally substituted (5- to 14-membered)heteroaryl", "optionally substituted (5- to 6-membered)heteroaryl" and "optionally substituted (5- to 6-membered)nitrogen-containing heteroaryl" refer to (5- to 14-membered)heteroaryl, (5- to 6-membered)heteroaryl and (5- to 6-membered)nitrogen-containing heteroaryl as defined above, wherein one or more hydrogen atoms are replaced, where chemically permitted, by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, _-SF5 , 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 -C ₈ )cycloalkyl, wherein R ⁴ and R ⁵ are each independently hydrogen or optionally substituted (C ₁ -C ₆ )alkyl. The substituents may be attached to the heteroaryl moiety at any available carbon atom or to a heteroatom when the heteroatom is nitrogen with appropriate valence.

As used herein, "halo" or "halogen" refers to a chlorine, fluorine, bromine, or iodine atom.

As used herein, "hydroxy" refers to an -OH group.

As used herein, "cyano" refers to a -CN group, which may also be depicted as

As used herein, "nitro" means a _-NO2 group.

As used herein, "oxo" refers to a =O moiety. When an oxo group is substituted on a carbon atom, they together form a carbonyl moiety [-C(=O)-]. When one oxo group 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- ].

As used herein, the term "optionally substituted" means that substitution is optional and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced by a substituent selected from the designated group (up to and including each hydrogen atom on the designated atom or moiety being replaced by a substituent selected from the designated group), provided that the normal valence 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., -CH ₃ ) is optionally substituted, then up to three hydrogen atoms on the carbon atom can be replaced by substituents.

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

When a bond of a substituent is shown to cross a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring (i.e., to one or more hydrogen atoms). For example, as shown in Formula I above, ^R may be bonded to any ring-forming atom of the substitutable pyridazine ring.

A "therapeutically effective amount" refers to that amount of the compound being administered which relieves to some extent one or more of the symptoms of the condition being treated.

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

Unless otherwise indicated, as used herein, the term "treat" means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition. Unless otherwise indicated, as used herein, the term "treatment" means to act as a treatment in the form of "treatment" as defined immediately above. The term "treatment" also includes adjuvant and neo-adjuvant treatment of an individual.

"Pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal to be treated therewith.

"Isoform" means any of several different forms of the same protein.

"Isozymes" means closely related variants of an enzyme that differ in their amino acid sequence but catalyze the same chemical reaction.

"Isomers" means "stereoisomers" and "geometric isomers" as defined below.

"Stereoisomers" refer to compounds with one or more chiral centers, each of which can exist in the R or S configuration. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof.

"Geometric isomers" refer to compounds that can exist in cis, trans, anti, hetero (E) and homo (Z) forms, as well as mixtures thereof.

[0046] This specification uses the terms "substituent," "radical," and "group" interchangeably.

If substituents are described as being "independently selected" from a group, each instance of the substituent is selected independently of the other substituents. Thus, each substituent may be the same as or different from the other substituents.

As used herein, the term "Formula I" may hereinafter be referred to as a "compound of the present invention". Such terms are also defined to include all forms of the compounds of the present invention, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof. For example, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound (such as in channel solvates and hygroscopic compounds), the water/solvent content will depend on humidity and drying conditions. In such cases, the non-stoichiometric amount will prevail.

The compounds of the present invention may exist in the form of clathrates or other complexes. Included within the scope of the present invention are complexes such as clathrates, drug-host containing complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the present invention containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or unionized. For a review of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288, Haleblian (August 1975).

Some compounds of the present invention have asymmetric carbon atoms. In this article, the carbon-carbon bonds of the compounds of the present invention can be depicted using solid lines, solid wedges, or dashed wedges. The use of solid lines to depict bonds connected to asymmetric carbon atoms is intended to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) about the carbon atom are included. The use of solid lines or dashed wedges to depict bonds connected to asymmetric carbon atoms means that the stereoisomers shown are present. When present in a racemic compound, solid lines and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Racemic compounds with such indications are marked with (+/-). Unless otherwise indicated, it is expected that the compounds of the present invention can exist in the form of stereoisomers, including cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, geometric isomers, rotational isomers, configurational isomers, atropisomers, and mixtures thereof (such as racemates and diastereoisomer pairs). The compounds of the present invention may exhibit more than one isomerism. Also included are acid addition salts or base addition salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

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

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Depending on the specific compound, salts of the compound may be advantageous due to one or more physical properties of the salt (such as enhanced drug stability at different temperatures and humidities or suitable solubility in water or oil). In some cases, salts of the compound may also aid in the separation, purification, and/or analysis of the compound.

When the salt is intended for administration to a patient (as opposed to, for example, in vitro), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of the invention with an acid or base, wherein the anion of the acid or the cation of the base is generally considered suitable for mammalian consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the invention because they are more water soluble than the parent compound.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include, where possible, acid addition salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid; and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, and trifluoroacetic acid. Suitable organic acids generally include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids.

Specific 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, aspartate, glutamate, benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate , pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminoethanesulfonate, alginate, beta-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

In addition, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. In another embodiment, base salts are formed from bases that form non-toxic salts, including aluminum salts, arginine salts, benzathine penicillin salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, meglumine salts, ethanolamine salts, tromethamine salts, and zinc salts.

Organic salts can be prepared from monoamine, tertiary amine, or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl ( _C1 - _C6 ) halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, myristyl, and octadecyl), arylalkyl halides (e.g., benzyl and phenethyl bromides), and the like.

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

Some compounds of the present invention may exist as geometric isomers. The compounds of the present invention may have one or more asymmetric centers and therefore exist in two or more stereoisomeric forms. The present invention includes all individual stereoisomers and geometric isomers of the compounds of the present invention and mixtures thereof. Individual enantiomers may be obtained by chiral separation or by using related enantiomers in synthesis.

In addition, the compounds of the present invention can exist in the form of non-solvates and solvates with pharmaceutically acceptable solvents (such as water, ethanol, etc.). In general, for the purposes of the present invention, it is believed that solvated forms are equivalent to non-solvated forms. The compound can also exist in one or more crystalline states, i.e., polymorphs, or it can exist in an amorphous solid form. The claims cover all such forms.

So-called "prodrugs" of the compounds of the present invention also fall within the scope of the present invention. Thus, certain derivatives of the compounds of the present invention, which may themselves have minimal or no pharmacological activity, can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity upon administration to or on the body. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACSSymposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs according to the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with specific moieties known to those skilled in the art as "pro-moieties," as described, for example, in H. Bundgaard (Elsevier, 1985), "Design of Prodrugs."

The present invention also encompasses compounds of the present invention that contain protecting groups. Those skilled in the art will also appreciate that the compounds of the present invention can also be prepared with specific protecting groups suitable for purification or storage and that can be removed prior to administration to a patient. The protection and deprotection of functional groups are described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd edition, by T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds equivalent to the compounds described herein, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, the following isotopes: hydrogen, such as ^2H , ^3H ; carbon, such as ^11C , ^13C , and ^14C ; chlorine, such as ^36Cl ; fluorine, such as ^18F ; iodine, such as ^123I and ^125I ; 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 present invention (e.g., by incorporation of radioactive isotopes) are useful in drug and/or substrate tissue distribution studies (e.g., analysis). The radioactive isotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly suitable for this purpose due to their ease of incorporation and readily available means of detection. Substitution with heavier isotopes, such as deuterium (i.e., ² H), may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Substitution with positron-emitting isotopes, such as ¹¹ C, ¹⁵ F, ¹⁸ F, ¹⁵ O, and ¹³ N, may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying schemes and/or the examples and preparations, using an appropriately isotopically labeled reagent in place of the unlabeled reagent previously used. Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, such as D ₂ O, acetone-d ₆ , or DMSO-d ₆ . Compounds of the present invention, including those exemplified in Examples 1-104 below, include isotopically labeled forms of these compounds, such as, but not limited to, deuterated and tritiated isotopes, and all other isotopes described above.

Compound

The compounds of Formula I described above contain an imidazo[1,2-b]pyridazine core, wherein the core is substituted at the ³ -position with ^{an R1} moiety optionally substituted with 1 to 3 R2s; optionally substituted at the 5, 6 and/or ⁷ positions with an R3 moiety; and the nitrogen of the amide moiety attached to the 2-position of the imidazo[1,2-b]pyridazine core is substituted with ^R6 and ^R7 .

In one embodiment, in the above formula I, m is 0, and R ¹ is (4- to 10-membered) heterocycloalkyl optionally substituted with 1 to 3 R ² .

In certain embodiments, when ^R is optionally substituted (4-10 membered) heterocycloalkyl, the heterocycloalkyl is selected from azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydro benzoxazinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, isochromanyl, dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl, 3-azabicyclo[3.1.0]hexanyl and 3-azabicyclo[4.1.0]heptanyl.

In certain other embodiments, when R ¹ is optionally substituted (4- to 10-membered) heterocycloalkyl, the heterocycloalkyl is selected from dihydrobenzofuranyl, benzodioxolyl, or dihydrobenzodioxinyl.

In another embodiment, in the above formula I, R ¹ is (C ₆ -C ₁₀ )aryl optionally substituted with 1 to 3 R ² .

In certain embodiments, when R ¹ is optionally substituted (C ₆ -C ₁₀ )aryl, the aryl group is selected from phenyl or naphthyl.

In certain other embodiments, when R ¹ is optionally substituted (C ₆ -C ₁₀ )aryl, the aryl is phenyl.

In another embodiment, in the above formula I, R ¹ is (5- to 14-membered) heteroaryl optionally substituted with 1 to 3 R ² .

In certain embodiments, R ¹ is optionally substituted (5- to 10-membered) heteroaryl.

In certain other embodiments, when R ¹ is optionally substituted (5- to 10-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, thienyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothiophenyl, benzoxazolyl, benzofuranyl ... oxadiazolyl, benzothiazolyl, isobenzothiophenyl, benzothiophenyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and 1,4-benzoxazinyl.

In certain other embodiments, ^R is optionally substituted (5-10 membered) nitrogen-containing heteroaryl. For example, when ^R is optionally substituted (5-10 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, quinolyl, cinnolinyl, quinazolinyl, isoquinolyl, or quinoxalinyl.

In certain other embodiments, when R ¹ is optionally substituted (5- to 10-membered) nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, or quinoxalinyl.

In certain other embodiments, R ¹ is an optionally substituted (6-membered) nitrogen-containing heteroaryl. For example, when R ¹ is an optionally substituted (6-membered) nitrogen-containing heteroaryl, the heteroaryl is selected from pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In certain embodiments, when R ¹ is an optionally substituted (6-membered) nitrogen-containing heteroaryl, the heteroaryl is selected from pyrimidinyl or pyridinyl.

In certain other embodiments, R ¹ is an optionally substituted (5-membered) nitrogen-containing heteroaryl. For example, when R ¹ is an optionally substituted (5-membered) nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, imidazolyl or pyrazolyl.

In any of the foregoing embodiments, where chemically permitted, when R ¹ is substituted with 1 to 3 R ² , each R ² is independently selected from halogen, oxo, cyano, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain embodiments, when R ² is halogen, said halogen is selected from fluorine and chlorine.

In certain other embodiments, when ^R is an optionally substituted (C ₁ -C ₆ ) alkyl group, the alkyl group is selected from methyl, ethyl, or propyl, and the methyl, ethyl, and propyl groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like.

In another embodiment, when ^R is an optionally substituted (C ₁ -C ₆ )alkoxy group, the alkoxy group is selected from methoxy, ethoxy, or propoxy, and the methoxy, ethoxy, and propoxy groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

It will be appreciated that any of the above subtypes of R ¹ can be combined with any of the embodiments of R ³ , R ⁶ , and R ⁷ described above and below. For example, in one embodiment, when R ¹ is optionally substituted (C ₆ -C ₁₀ ) aryl and the aryl is phenyl, b can be 0 (R ³ is absent); and one of R ⁶ and R ⁷ can be hydrogen and the other can be optionally substituted (C ₃ -C ₈ ) cycloalkyl, such as cyclopropyl.

In another embodiment, in the above formula I, n is an integer selected from 0, 1 or 2; and ^R6 and ^R7 are each independently selected from hydrogen, optionally substituted ( _C1 - _C6 ) alkyl, -(CH2) _n- ( _{C3 - C8} ) cycloalkyl, -( _CH2 ) _n- ( _C6 - _C10 ) aryl and -( _CH2 ) _n- (5- to 6-membered) heteroaryl, and when chemically permitted, the ( _C3 - _C8 ) cycloalkyl, ( _C6 - _C10 ) aryl and (5- to 6-membered) heteroaryl are optionally substituted with 1 to 3 ^R8 ; or

R ⁶ and R ⁷ together with the nitrogen to which they are attached form (4- to 6-membered) heterocycloalkyl, and (4- to 6-membered)-heterocycloalkyl is optionally substituted with 1 to 3 R ⁹ when chemically permitted;

When present, each R ⁸ is independently selected from halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C ₆ )alkenyl, optionally substituted (C ₂ -C 6 )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ )(R ⁵ ), -C(＝O) ^{—R 4} , and -C(＝O)—OR ⁴ ; and

When present, each R ⁹ is independently selected from halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C 2 -C ₆ )alkenyl, optionally substituted (C ₂ -C 6 )alkynyl, optionally substituted (C ₁ -C ₆ )alkylthio, optionally substituted (C _{1 -C 6} )alkoxy, -N(R ₄ )(R ⁵ ), -N(R ⁴ )(C＝(O)R ⁵ ), -C(＝O)N(R ⁴ )(R ⁵ ), -C(＝O)—ON(R ⁴ )(R ⁵ ), -C(＝O) ^{—R 4} , and -C(＝O)—OR ⁴ .

In certain embodiments, in the above formula I, one of R ⁶ and R ⁷ is hydrogen and the other is optionally substituted (C ₁ -C ₆ )alkyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₁ -C ₆ ) alkyl, the alkyl is selected from 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 ^R and ^R is an optionally substituted (C ₁ -C ₆ ) alkyl group, the alkyl group is selected from methyl, ethyl, or propyl, and the methyl, ethyl, and propyl groups are optionally substituted with 1 to 3 fluorine atoms. For example, the optionally substituted (C ₁ -C ₆ ) alkyl group is selected from fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.

In another embodiment, in the above formula I; n is an integer selected from 0, 1 or 2; and one of R ⁶ and R ⁷ is hydrogen and the other is -(CH ₂ ) _n -(C ₃ -C ₈ )cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 3 R ⁸ .

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₃ -C ₈ )cycloalkyl, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, or bicyclo[1.1.1]pentyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₃ -C ₈ )cycloalkyl, the cycloalkyl is selected from cyclopropyl or bicyclo[1.1.1]pentyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₃ -C ₈ )cycloalkyl, the cycloalkyl is cyclopropyl.

In another embodiment, in the above formula I; n is selected from 0, 1 or 2; and one of R ⁶ and R ⁷ is hydrogen and the other is -(CH ₂ ) _n -(C ₆ -C ₁₀ )aryl, wherein said aryl is optionally substituted with 1 to 3 R ⁸ .

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₆ -C ₁₀ )aryl, the (C ₆ -C ₁₀ )aryl is selected from phenyl or naphthyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (C ₆ -C ₁₀ )aryl, the (C ₆ -C ₁₀ )aryl is phenyl.

In another embodiment, in the above formula I; one of R ⁶ and R ⁷ is hydrogen and the other is -(CH ₂ ) _n -(5- to 6-membered)heteroaryl, wherein said heteroaryl is optionally substituted with 1 to 3 R ⁸ .

In certain embodiments, when one of ^R and R is 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, thienyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (5-6 membered) heteroaryl, said heteroaryl is oxazolyl.

In certain embodiments, when one of R ⁶ and R ⁷ is optionally substituted (5- to 6-membered) heteroaryl, the heteroaryl is a (5- to 6-membered) nitrogen-containing heteroaryl.

In certain embodiments, when one of R ⁶ and R ⁷ 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 R ⁶ and R ⁷ is an optionally substituted (5- to 6-membered) nitrogen-containing heteroaryl, the heteroaryl is selected from triazolyl, pyrazolyl, or pyrimidinyl.

In any of the foregoing embodiments, when one of ^R6 and ^R7 is ( _C3 - _C8 )cycloalkyl, ( _C6 - _C10 )aryl, or (5- to 6-membered)heteroaryl substituted with 1 to 3 ^R8 , each ^R8 is independently selected from halogen, oxo, cyano, hydroxy, optionally substituted ( _C1 - _C6 )alkyl, and optionally substituted ( _C1 - _C6 )alkoxy.

In certain embodiments, when R ⁸ is halogen, said halogen is selected from fluoro and chloro.

In certain other embodiments, when ^R is an optionally substituted (C ₁ -C ₆ ) alkyl group, the alkyl group is selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl and the like.

In another embodiment, when ^R is an optionally substituted (C ₁ -C ₆ )alkoxy group, the alkoxy group is selected from methoxy, ethoxy, or propoxy, and the methoxy, ethoxy, and propoxy groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

In another embodiment, in the above formula I, R ⁶ and R ⁷ together with the nitrogen to which they are attached form a (4- to 6-membered) heterocycloalkyl optionally substituted with 1 to 3 R ⁹ .

In certain embodiments, when ^R and ^R, 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 R ⁶ and R ⁷ are taken together with the nitrogen to which they are attached to form a (4- to 6-membered) heterocycloalkyl, the heterocycloalkyl is azetidinyl.

In any of the foregoing embodiments, when R ⁶ and R ⁷ , together with the nitrogen to which they are attached, form a (4- to 6-membered) heterocycloalkyl substituted with 1 to 3 R ⁹ , each R ⁹ is independently selected from halogen, oxo, cyano, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain embodiments, when R ⁹ is halogen, said halogen is selected from fluoro and chloro.

In certain other embodiments, when ^R is an optionally substituted (C ₁ -C ₆ ) alkyl group, the alkyl group is selected from methyl, ethyl or propyl, and the methyl, ethyl and propyl groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl and the like.

In another embodiment, when ^R is an optionally substituted (C ₁ -C ₆ )alkoxy group, the alkoxy group is selected from methoxy, ethoxy, or propoxy, and the methoxy, ethoxy, and propoxy groups are optionally substituted with 1 to 3 fluorine atoms. For example, optionally substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and the like.

It will be appreciated that any of the above subclasses of ^R and ^R can be combined with any of the embodiments of ^R and ^R described above and below. For example, in one embodiment, when one of ^R and ^R is hydrogen and the _{other is optionally substituted (C-C )} cycloalkyl (such as cyclopropyl), ^R can be optionally substituted (C- _{C )} aryl, wherein the aryl is phenyl, and b can be 0 ( ^R is absent).

In another embodiment, in the above Formula I, when present, each R ³ is independently selected from halogen, cyano, hydroxy, -SF ₅ , nitro, optionally substituted (C ₁ -C ₆ )alkyl, and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain embodiments, when R ³ is halogen, said halogen is selected from fluorine and chlorine.

In certain other embodiments, when R ³ is optionally substituted (C ₁ -C ₆ )alkyl and/or optionally substituted (C ₁ -C ₆ )alkoxy, the (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy are as described above in any of the preceding embodiments.

It will be appreciated that any of the above subtypes of R ³ may be combined with any of the above embodiments of R ¹ , R ⁶ , and R ⁷ .

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 in treating PDE4B-mediated disorders, which comprises administering to a mammal (preferably a human) in need thereof a therapeutically effective amount of a compound of the present invention that effectively inhibits PDE4B activity; more preferably, administering an amount of a compound of the present invention that has improved binding affinity for PDE4B while having less inhibitory activity against PDE4D.

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

In certain embodiments, the compounds of the present invention have an enhanced binding affinity for the PDE4B isoform relative to the PDE4D isoform, such that the compound exhibits an enhanced binding affinity of about 2-fold to about 325-fold relative to the PDE4D isoform for the PDE4B isoform. In certain other embodiments, the compounds of the present invention exhibit an enhanced binding affinity of about 5-fold to about 50-fold relative to the PDE4D isoform for the PDE4B isoform. In certain other embodiments, the compounds of the present invention exhibit an enhanced binding affinity of about 51-fold to about 100-fold relative to the PDE4D isoform for the PDE4B isoform. In certain other embodiments, the compounds of the present invention exhibit an enhanced binding affinity of about 101-fold to about 200-fold relative to the PDE4D isoform for the PDE4B isoform. In certain other embodiments, the compounds of the present invention exhibit an enhanced binding affinity of about 201-fold to about 250-fold relative to the PDE4D isoform for the PDE4B isoform. In certain other embodiments, the compounds of the present invention exhibit about 251-fold to about 300-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit about 301-fold to about 325-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain embodiments, the compounds of the present invention exhibit at least about 5-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 10-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain embodiments, the compounds of the present invention exhibit at least about 20-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 40-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 50-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 75-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 100-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 200-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit at least about 300-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. In certain other embodiments, the compounds of the present invention exhibit up to about 325-fold binding affinity for the PDE4B isoform relative to the PDE4D isoform. The binding affinities of the compounds of the present invention for PDE4B and PDE4D isoforms are shown in Table 3 in the Experimental section below.

In another embodiment, the present invention provides a pharmaceutical composition comprising a mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In another embodiment, administration of the compounds of the present invention to patients in need thereof may also reduce gastrointestinal discomfort (such as vomiting, diarrhea, and nausea) currently thought to be associated with the administration of compounds having binding affinity for other PDE4 isoforms, particularly the PDE4D isoform, thereby improving patient compliance and overall treatment outcomes.

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

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

Pharmacology

Phosphodiesterases (PDEs) of the PDE4 family are characterized by their selective, high-affinity hydrolytic degradation of the second messenger cyclic nucleotide adenosine 3',5'-cyclic monophosphate (cAMP). PDE4A, PDE4B, and PDE4D isoforms are known to be widely expressed throughout the brain, with PDE4A, PDE4B, and PDE4D isoforms varying in their local and intracellular distribution, while the PDE4C isoform 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 deficient in the phosphodiesterase-4B (PDE4B) enzyme, Psychopharmacology (2007) 192:415-424). The location of PDE4 isoforms makes them attractive targets for novel therapeutics 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 inschizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness, J. Physiol. 584 (2007) pp. 401-405).

The PDE4 inhibitor rolipram has been shown to be effective in treating or reversing Aβ-induced memory deficits by reducing neuronal inflammation and apoptosis-mediated cAMP/CREB signaling; therefore, PDE4 is a potential target for treating cognitive deficits associated with AD (see Wang, C. et al., The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats, International Journal of Neuropsychopharmacology (2012), 15, 749-766).

PDE4 inhibitors may also have antidepressant effects by normalizing the cAMP cascade (see: Fujita, M. et al., Downregulation of Brain Phosphodiesterase Type IV Measured with ¹¹ C-(R)-Rolipram Positron Emission Tomography in Major Depressive Disorder, Biological Psychiatry, 72, 2012, 548-554).

Furthermore, PDE4 inhibitors have been shown to have therapeutic activity and are therefore speculated to be useful in treating multiple sclerosis (see: Sun, X. et al., Rolipram promotes remyelination possibly via MEK-ERK signaling pathway in cuprizone-induced demyelination mouse, Experimental Neurology 2012; 237: 304-311).

In view of the foregoing, in certain embodiments, the compounds of the present invention have broad therapeutic applications for treating conditions or diseases of the central nervous system, including neurological, neurodegenerative and/or psychiatric disorders. Neurological, neurodegenerative and/or psychiatric disorders include, but are not limited to, (1) mood [emotional] disorders; (2) neurological, stress-related and somatoform psychiatric disorders, including anxiety disorders; (3) disorders in mammals (including humans) comprising symptoms of cognitive deficits; (4) disorders comprising attention deficits, executive function deficits (operating memory deficits), impulse control dysfunction, extrapyramidal symptoms, which are disorders based on basal ganglia dysfunction; (5) behavioral and emotional disorders whose onset typically occurs in childhood and adolescence; (6) psychological developmental disorders; (7) primary Generalized atrophy affecting the central nervous system; (8) extrapyramidal and movement disorders; (9) behavioral syndromes related to physiological disturbances and physical factors; (10) personality and behavioral disorders in adults; (11) schizophrenia and other psychotic disorders; (12) mental and behavioral disorders caused by the use of neuroactive substances; (13) sexual dysfunction including hypersexuality; (14) mental retardation; (15) factitious disorders, such as acute hallucinogenic mania; (16) intermittent and paroxysmal disorders, epilepsy; (17) narcolepsy; and (18) dementia.

Examples of mood disorders that can be treated according to the present invention include, but are not limited to, bipolar I disorder, hypomania (manic and mixed forms), bipolar II disorder; depression, such as a single depressive episode or recurrent major depressive disorder, chronic depression, psychotic depression, minor depression, postpartum onset depression, depression with psychotic symptoms; persistent mood disorders, such as bipolar cyclothymia, dysthymia, euphoria; premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

Examples of neurological, stress-related, and somatoform psychiatric 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, specific phobia, social phobia, chronic anxiety disorder; obsessive-compulsive disorder; response and adjustment disorders to severe stress, such as post-traumatic stress disorder (PTSD), acute stress disorder; other neurological disorders, such as depersonalization-derealization syndrome.

The phrase "cognitive deficit" as used herein in the context of a "disorder comprising symptoms of cognitive deficit" refers to subnormal or suboptimal functioning in one or more aspects of cognition (such as memory, intelligence, learning and logical ability), or attention and executive function (operating memory) in a particular individual compared to other individuals of the same general age population.

Examples of "disorders comprising symptoms of cognitive deficits" that can be treated according to the present invention include, but are not limited to, cognitive deficits primarily, but not exclusively, associated with amnesia, psychosis (schizophrenia), Parkinson's disease, Alzheimer's disease, multi-infarct dementia, senile dementia, dementia with Lewy bodies, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington's disease, HIV disease (HIV-associated dementia), brain trauma, and substance abuse; mild cognitive disorder ADHD, Asperger's syndrome, and age-related memory impairment; cognitive decline or worsening following surgery or associated with intensive care therapy.

Examples of conditions that are typically first diagnosed in infancy, childhood, and adolescence and that can be treated according to the present invention include, but are not limited to, hyperactivity disorders, including activity and attention disorders, attention-deficit/hyperactivity disorder (ADHD), and comorbid ADHD with conduct disorder; attention deficit disorder (ADD); conduct disorders, including, but not limited to, depressive conduct disorder; tics, including brief tics, chronic motor or vocal tics, combined vocal and multiple motor tics (Tourette syndrome), substance-induced tics; autism; Batten disease, excessive masturbatory behavior, nail biting, nose picking, and thumb sucking.

Examples of mental development disorders that can be treated according to the present invention include, but are not limited to, pervasive developmental delays, including, but not limited to, Asperger's syndrome and Rett syndrome, autism, childhood autism associated with mental retardation and stereotyped movements, and attention deficit hyperactivity disorder, specific motor developmental disorders, and specific learning skill developmental disorders.

Examples of systemic atrophies that primarily affect the central nervous system and that can be treated according to the present invention include, but are not limited to, multiple sclerosis, systemic atrophy that primarily affects the basal ganglia, including Huntington's disease, and amyotrophic lateral sclerosis.

Examples of extrapyramidal and movement disorders with basal ganglia dysfunction and/or degeneration that can be treated according to the present invention include, but are not limited to, Parkinson's disease; secondary Parkinson's disease, such as postencephalitic Parkinson's disease; Parkinson's disease included among other conditions; Niemann-Pick disease, Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal and movement disorders, including tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced tics and organic tics, drug-induced acute dystonia, drug-induced tardive dyskinesia, muscle cramps and conditions associated with muscle spasticity or weakness (including tremor); mental deficits (including spasticity, Down syndrome and fragile X syndrome), levodopa-induced dyskinesia; restless legs syndrome and stiff-person syndrome.

Other examples of movement disorders with basal ganglia dysfunction and/or degeneration that can be treated according to the present invention include, but are not limited to, dystonias, including, but not limited to, focal dystonia, multiple focal or segmental dystonia, torsion dystonia, hemispheric, generalized, and tardive dystonia (induced by psychopharmacological drugs). Focal dystonias include cervical dystonia (torticollis), blepharospasm (spasm of the eyelids), appendicular dystonia (spasm in the extremities, such as writer's cramp), or mandibular dystonia and spasmodic dysphonia (spasm of the vocal cords); neuroleptic-induced movement disorders, including, but not limited to, neuroleptic malignant syndrome (NMS), neuroleptic-induced Parkinson's disease, neuroleptic-induced early onset or acute movement disorders, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, and neuroleptic-induced tremor.

Examples of behavioral syndromes associated with physiological disorders and physical factors according to the present invention include, but are not limited to, non-organic sleep disorders, including, but not limited to, non-organic hypersomnia, non-organic sleep-wake cycle disorders (circadian rhythm sleep disorders), insomnia, parasomnias, and sleep deprivation; mental and behavioral disorders associated with the puerperium, including postpartum and postpartum depression; eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, binge eating disorder, excessive eating, obesity, compulsive eating disorder, and pagophagia.

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

Examples of schizophrenia and other psychotic disorders that can be treated according to the present invention include, but are not limited to, different types of persistent or intermittent schizophrenia (e.g., delusional disorder, adolescent dementia, catatonic disorder, undifferentiated type, sequelae type, and schizophrenia-like disorder); schizoaffective disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic, pseudopsychotic, and schizotypal personality disorder); persistent delusional disorder; acute, transient, and persistent psychotic disorders; induced delusional disorder; different types of schizoaffective disorders (e.g., manic-depressive or mixed types); postpartum psychosis and other and unspecified non-organic psychoses.

Mental and behavioral disorders caused by the use of neuroactive substances that can be treated according to the present invention include (but are not limited to) mental and behavioral disorders caused by the use of alcohol, opioids, cannabinoids, sedatives or hypnotics, cocaine; mental and behavioral disorders caused by the use of other stimulants (including caffeine); mental and behavioral disorders caused by drug dependence and abuse (such as narcotic dependence, alcoholism, amphetamine and methamphetamine dependence, opioid dependence, cocaine addiction, nicotine dependence and drug withdrawal syndrome and relapse prevention), the use of hallucinogens, tobacco (nicotine), volatile solvents; and mental and behavioral disorders caused by multiple drug use and the use of other neuroactive substances, including the following subtypes: harmful use, dependence syndrome, withdrawal state and withdrawal state accompanied by delirium.

Examples of dementias that may be treated according to the present invention include, but are not limited to, vascular dementia; dementia due to Creutzfeld-Jacob disease, HIV, head trauma, Parkinson's disease, Huntington's disease, Pick's disease; and Alzheimer's dementia.

In certain embodiments, the present invention relates to a method of treating schizophrenia by administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In certain other embodiments, the present invention also relates to methods of treating cognitive impairment associated with schizophrenia by administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In addition to the above-mentioned central nervous system disorders, there are a large number of documents in the art describing the effects of PDE inhibitors on a variety of autoimmune and inflammatory cell responses, which, in addition to increasing cAMP, also include inhibiting superoxide production, degranulation, chemotaxis, and tumor necrosis factor (TNF) release in eosinophils, neutrophils, and monocytes. Therefore, the compounds of the present invention may be suitable for treating autoimmune and inflammatory diseases. (See: Schett, G. et al., Apremilast: A novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases, Ther. Adv. Musculoskeletal Dis. 2010; 2(5): 271-278). For example, the compounds of the present invention may be suitable for treating oral ulcers associated with Behcet's disease. The compounds of the present invention may also be suitable for treating pain associated with 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 treating 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). Therefore, the compounds of the present invention may also be suitable for treating ankylosing spondylitis [see: Patan, E. et al., Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis, Ann. Rheum. Dis. (Sept. 14, 2012)]. Other conditions that may be treated by administration of the compounds of the present invention include, but are not limited to, acute and chronic respiratory diseases such as, but not limited to, asthma, chronic or acute bronchoconstriction, chronic bronchitis, bronchiectasis, small airway obstruction, emphysema, obstructive or inflammatory airway disease, acute respiratory distress syndrome (ARDS), COPD, pneumoconiosis, seasonal or perennial allergic rhinitis or sinusitis, and acute lung injury (ALI).

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

In another embodiment, the compounds of the present invention may be useful in treating cancer. For example, the compounds of the present invention may be useful in treating 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 in 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 present invention may be useful in treating leukemias, such as 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, 2484-2494). In other embodiments, the compounds may be useful in treating brain or eye tumors.

In certain other embodiments, the compounds of the present invention may be useful for treating diabetes or diabetes-related diseases (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 of the Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism in Patients with Newly Diagnosed Type 2 Diabetes 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 diabetes (non-insulin-dependent diabetes mellitus), metabolic syndrome, glucose intolerance, urinary incontinence (e.g., overactive bladder), diabetic macular edema, kidney disease, and related health risks, symptoms, or conditions. Thus, the compounds may also be used to reduce body fat or weight in overweight or obese individuals.

In certain other embodiments, the compounds of the present invention may be useful in the prevention and treatment of conditions associated with increased endothelial activity, impaired endothelial barrier function and/or increased angiogenesis, such as septic shock; angioedema, peripheral edema, communicating or non-communicating hydrocephalus, angioedema, cerebral edema; reduced natriuretic disorders; inflammatory diseases, including asthma, rhinitis, arthritis and rheumatoid and autoimmune diseases; acute kidney or liver injury, liver dysfunction; psoriasis, irritable bowel disease (IBD), Crohn's disease, and benign/malignant neoplasia.

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

In certain other embodiments, the compounds described herein are further useful in the prevention and treatment of conditions associated with thrombotic, embolic, or ischemic conditions, including but not limited to thrombotic-induced tissue infarction in coronary artery disease, cerebrovascular disease (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, and cerebral hypoxic-ischemic disease), and/or peripheral vascular disease; stable and unstable angina, transient ischemic attack, stroke, atherosclerosis, myocardial infarction, cerebral infarction, reperfusion injury (brain/myocardium), traumatic brain injury, subdural, epidural, or subarachnoid hemorrhage, migraine, cluster and tension headaches, placental insufficiency, thrombosis following surgical procedures such as bypass, angioplasty, stenting, and heart valve replacement.

In certain other embodiments, the compounds described herein are also useful for treating painful conditions and disorders. Examples of such painful conditions and disorders include, but are not limited to, inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, postoperative pain, non-inflammatory pain, neuralgia, subtypes of neuralgia (including peripheral neuralgia syndrome), chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuralgia syndrome, central post-stroke pain, multiple sclerosis pain, Parkinson's disease pain, and spinal cord injury pain.

In certain other embodiments, the compounds described herein are also useful for treating wounds (or promoting wound healing), burning pain, scars, and related conditions.

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

In certain other embodiments, the compounds described herein are also useful in treating transplant rejection, allograft rejection, renal and liver failure, and restless leg syndrome.

preparation

The compounds of the present invention can be administered orally. Oral administration can include swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be used so that the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the present invention can also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

In another embodiment, the compounds of the present invention may also be formulated so that the compound is systemically absorbed by topical (i.e., transdermal) administration to the skin or mucous membranes. In another embodiment, the compounds of the present invention may also be formulated so that the compound is systemically absorbed by intranasal or inhalation administration. In another embodiment, the compounds of the present invention may be formulated so that the compound is systemically absorbed by rectal or vaginal administration.

The dosage regimen of the compound and/or the composition containing the compound is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimen can be very different. A dosage level of about 0.01 mg to about 100 mg per kilogram of body weight per day is suitable for treating the conditions shown above. In one embodiment, the total daily dose of the compound of the present invention (administered in a single dose or divided doses) is generally about 0.01 mg/kg to about 100 mg/kg. In another embodiment, the total daily dose of the compound of the present invention is about 0.1 mg/kg to about 50 mg/kg, and in another embodiment, about 0.5 mg/kg to about 30 mg/kg (i.e., milligrams of the compound of the present invention per kilogram of body weight). In one embodiment, the dosage is 0.01 to 10 mg/kg/day. In another embodiment, the dosage is 0.1 to 1.0 mg/kg/day. The unit dose composition may contain these amounts or submultiples thereof to constitute a daily dose. In many cases, the compound will be administered repeatedly multiple times a day (usually no more than 4 times). Multiple daily doses can generally be used to increase the total daily dose, if necessary.

For oral administration, the composition is 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 or 500 mg of active ingredient, with the dosage to be adjusted according to the symptoms. The drug typically contains from about 0.01 mg to about 500 mg of active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. For intravenous administration, the dosage can be in the range of from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects for the present invention include mammalian subjects. Mammals for the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects can be of either sex and at any stage of development.

In another embodiment, the present invention includes the use of one or more compounds of the present invention in the preparation of a medicament for the treatment of a condition described herein.

For the treatment of the above-mentioned conditions, the compounds of the present invention may be administered as the compounds themselves. Alternatively, pharmaceutically acceptable salts are suitable for medical use due to their greater water solubility relative to the parent compound.

In another embodiment, the present invention includes pharmaceutical compositions. The pharmaceutical compositions comprise a compound of the present invention provided together with a pharmaceutically acceptable carrier. The carrier can be solid, liquid, or both and can be formulated with the compound into a unit dose composition, such as a tablet, which can contain 0.05% to 95% by weight of the active compound. The compound of the present invention can be coupled with a suitable polymer as a targetable drug carrier. Other pharmacologically active substances may also be present.

The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for that route and in a dose effective for the intended treatment. The active compounds and compositions can be administered, for example, orally, rectally, parenterally or topically (e.g., intranasally or ophthalmically).

Oral administration of a solid dosage form can be presented, for example, as discrete 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 can be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual form, such as a lozenge. In such solid dosage forms, the compounds of the present invention are typically combined with one or more adjuvants. Such capsules or tablets can contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form can also contain a buffer or can be prepared with an enteric coating.

In another embodiment, oral administration can be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (e.g., water) commonly used in the art. Such compositions may also include adjuvants, such as wetting agents, emulsifiers, suspending agents, flavorings (e.g., sweeteners), and/or aromatics.

In another embodiment, the present invention includes parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous or oily suspensions) can be prepared according to known techniques using suitable dispersants, wetting agents, and/or suspending agents, and include reservoir formulations.

In another embodiment, the present invention includes topical dosage forms. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device; intraocular administration; or intranasal or inhaled administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered via a transdermal device, administration will be achieved using a reservoir and porous membrane type or solid matrix type patch. Representative formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Representative carriers include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, eg, Finnin and Morgan, J. Pharm. Sci., 88(10), 955-958 (1999).

Preparations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present invention is dissolved or suspended in a suitable carrier. Representative preparations suitable for administration to the eye or ear can be in the form of drops of micronized suspensions or solutions in isotonic sterile saline with adjusted pH. Other preparations suitable for administration to the eye and ear include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, contact lenses, and microparticles or cystic systems such as niosomes or liposomes. Polymers (such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) can be incorporated with preservatives (such as benzalkonium chloride). Such preparations can also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the active compounds of the invention are preferably delivered as a solution or suspension from a pump spray container (which the patient squeezes or pumps), or as an aerosol spray presentation using a suitable propellant from a pressurized container or nebulizer. Formulations suitable for intranasal administration are typically administered as a dry powder (alone; as a mixture, for example, dry blended with lactose, or as mixed component particles, for example, mixed with a phospholipid (such as lecithin)) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, sprayer, nebulizer (preferably one that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without 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 contain a bioadhesive, such as polyglucosamine or cyclodextrin.

In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form can be in the form of a suppository, for example. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Other carrier materials and modes of administration known in the pharmaceutical field may also be used. The pharmaceutical compositions of the present invention can be prepared by any well-known technique in pharmacy, such as effective formulation and administration procedures. The above matters regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. The formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used alone or in combination with other therapeutic agents to treat a variety of conditions or disease states. The compounds of the present invention can be administered simultaneously with other therapeutic agents (in the same dosage form or in separate dosage forms) or sequentially. Exemplary therapeutic agents can be, for example, metabotropic glutamate receptor agonists.

Administration of two or more compounds "in combination" means that the two compounds are administered close enough in time that the presence of one compound modifies the biological effect of the other. The two or more compounds can be administered simultaneously, concurrently, or sequentially. Additionally, simultaneous administration can be achieved by mixing the compounds prior to administration, or by administering the compounds at the same time point but at different anatomical sites or using different routes of administration.

The phrases "concurrent administration," "co-administration," and "simultaneous administration" mean that the compounds are administered in combination.

The present invention encompasses the use of a PDE4 inhibitor compound of the present invention in combination with one or more other pharmaceutically active agents. If a combination of active agents is administered, they may be administered sequentially or simultaneously in separate dosage forms or combined in a single dosage form. Thus, the present invention also encompasses pharmaceutical compositions comprising amounts of: (a) a first agent comprising a compound of the present invention or a pharmaceutically acceptable salt of such a compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle, or diluent.

A variety of pharmaceutically active agents may be selected for use in combination with the compounds of the present 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 present invention include, but are not limited to:

(i) acetylcholinesterase inhibitors such as donepezil hydrochloride (Aricept, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine bromide (MESTINON), ambenonium chloride (MYTELASE), demarcarium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (Exelon), ladostigid, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A; NeuroHitech), phenserine, edrophonium chloride (ENLON, TENSILON), and INM-176;

(ii) amyloid-β (or fragments thereof), such as Aβ _1-15 conjugated to an epitope that binds to pan-HLA DR (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24, AN-1792, Affitope AD-01, CAD106, and V-950;

(iii) antibodies to amyloid-β (or fragments thereof), such as ponezumab, sulanizumab, bapinezumab (also known as AAB-001), AAB-002 (Wyeth/Elan), ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized chem266; Lilly), R1450 (Roche), ACU-5A5, huC091, and International Patent Publication No. WO04/0328 68, WO05/025616, WO06/036291, WO06/069081, WO06/118959, U.S. Patent Publication Nos. US2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, European Patent Publication Nos. EP0994728 and 1257584, and U.S. Patent No. 5,750,349;

(iv) Agents that reduce or inhibit amyloid (including agents that reduce amyloid production, accumulation and fibrillation), such as dimebon, dafnetide, erosartan, 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 R-enantiomer taflurbiprofen (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (Advil, Merlin, NUROFEN), ibuprofen lysine, meclofenamic acid, meclofenamic acid sodium (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (Voltaren tablets), diclofenac potassium, sulindac (Qinoli), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulinase (also known as insulinolysin), Ginkgo biloba extract EGb-761 (ROKAN, TEBONIN), tramisart (CEREBRIL, ALZHEMED), irosart (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), KLVF F-(EEX)3, SKF-74652, ibuprofen mesylate, BACE inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609, and TTP-854; gamma secretase modulators such as ELND-007; and RAGE (receptor for advanced glycation end products) inhibitors such as TTP488 (Transtech) and TTP4000 (Transtech), and substances disclosed in U.S. 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 phenylephrine), methoxamine, cilazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armofenil (NUVIGIL);

(vi) beta-adrenergic receptor blockers (beta blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propranolol (INDERAL), sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (Tianormin), butaxamine, and SR 59230A (Sanofi);

(vii) Anticholinergics such as amitriptyline (ELAVIL, ENDEP), butritriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolamine bromide (PARMINE), dicyclomine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL), XL, OXYTROL), pentothiabendium, 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 (Deridol, CARBATROL), oxcarbazepine (Trileptal), phenytoin (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (Lyrica), topirimate (TOPAMAX), valproic acid (DEPAKENE), valproate sodium (DEPACON), 1-benzyl-5-bromouracil, progabamide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);

(ix) Antipsychotics such as fluphenazine hydrochloride (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), ilopirazone (FANAPTA), flupentixol decanoate (DEPIXOL, Fulansu), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHR IS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone (Risperidone), paliperidone (Rida), 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 (Pendil), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound nimodipine (Nimotop), nisoldipine (SULAR), nitrendipine, lacidipine (Lexip, MOTENS), lercanidipine (Zanipam), lifarizine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R18565 (AstraZeneca), and enecadin;

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

(xii) central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamine (Glucoenergan, Reactivan), phenethylphylline (Captagone), meretran, diarol (also known as dimethylaminoethanol), methylphenidate (Daytran), methylphenidate hydrochloride (Ritalin), dexmethylphenidate (Focalin), amphetamines (alone or in combination with other CNS stimulants, e.g., Adderall (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (Dexedrine, Destrostat), methamphetamine (Desoxyn), rivoamphetamine (Vyvanse), and benzphetamine (Didrex);

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

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

(xv) dopamine receptor antagonists such as chlorpromazine, fluphenazine, haloperidol, loxapine, risperidone, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A, SCH-23390, ecopipan, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxetine (also known as GBR-12909) and its decanoate DBL-583, and ameptine;

(xvii) gamma-aminobutyric acid (GABA) receptor agonists, such as baclofen (Leo Lesotho, KEMSTRO), siclofen, pentobarbital (NEMBUTAL), progabamide (Halogab), and clomethiazole;

(xviii) histamine 3 (H3) antagonists, such as ciproxifan, tilorexant, S-38093, irdabisant, tilorexant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-cyclobutanecarboxamide (PF-3654746, and U.S. Patent Publication Nos. US2005-0043354, US2005-0267095, and US2 Nos. 005-0256135, 008-0096955, 2007-1079175, and 2008-0176925; International Patent Publication Nos. WO2006/136924, WO2007/063385, WO2007/069053, WO2007/088450, WO2007/099423, WO2007/105053, WO2007/138431, and WO2007/088462; and U.S. Pat. No. 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), linomide, laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (Noxolin), mycophenolate mofetil (Cyclic), mycophenolate sodium (Mifu), azathioprine (AZASAN, Imuran), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (Leukoran), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H,1'H-2,2'-bipyrrole (also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, Libiruzin) 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), benserazide (Madopa), alpha-methyldopa, monofluoromethyldopa, difluoromethyldopa, bromocrisine, or m-hydroxyphenylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine (NAMENDA, AXURA, IBESAN), amantadine (SYMMETREL), acamprosate (CAMPRAL), besonprodil, ketamine (KETALAR), dexamethasone, dextromethorphan, dextrorphan, trexolotide, CP-283097, himantane, idantadol, ipexazone, L-701252 (Merck ), lancicemine, levorphanol (DROMORAN), LY-233536 and LY-235959 (both from Lilly), methadone (DOLOPHINE), neramexane, perginfortep, phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogaine, selenomethrin, tiletamine, riluzole (Rilutek), acetaminophen (CERESOTAT), galvistinide, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors such as selegiline (EMSAM), selegiline hydrochloride (l-deprenyl, imidopyril, ZELAPAR), dimethylselegiline, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), niaramide (NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), difemelane, desoxypeganine, halamine (also known as telepathine or banasterine), harmine, linezolid (SVO, ZYVOXID), and pargyline (EUDATIN, SUPIRDYL);

(xxv) muscarinic receptor (particularly M1 subtype) agonists such as cevimeline, levetiracetam, bethanechol (DUVOID, URECHOLINE), itamerine, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furethonium iodide (FURAMON, FURANOL), furethonium besylate, furethonium toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MEST, CARBOPTIC);

(xxvi) Neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprim, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H-carbazole-3-imide, dermoplastase, aticibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both from Allon Therapeutics), neurostrol, perampenel, isopycine, bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyl tartrate (also known as dactylorhin B or DHB), formobactin, Xaprila, lactacystin, dimeboline hydrochloride hydrochloride)(DIMEBON), disufenton (CEROVIVE), alendic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both from 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), ancrodase (VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220 (17-beta-hydroxyepiandrosterone; Newron Pharmaceuticals), Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin, S-18986, pyclozotan, NP031112, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory Biomedical 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 from Targacept), and RJR-2403;

(xxviii) norepinephrine (NE) reuptake inhibitors such as atomoxetine (Zestar), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, Ludiomet, PSYMION), bupropion (WELLBUTRIN), and radaxafine;

((xxix) phosphodiesterase (PDE) inhibitors, including but not limited to (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and substances disclosed in U.S. Pat. No. 6,235,742), (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550 and substances described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, pagrelili and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piramilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oliminast (also known as GRC3886), 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 (Ailida, VIVANZA), Udenafil, Avanafil, Dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, Zaprinast, iodenafil, Milonafil, DA-8159 and substances disclosed in International Patent Applications WO2002/020521, WO2005/049616, WO2006/120552, WO2006/126081, WO2006/126082, WO2006/126083 and WO2007/122466), (f) PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (e.g., BAY 73-6691 (Bayer AG) and substances disclosed in U.S. 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)-1H-pyrazol-3-yl]phenoxy}methyl)quinolin-3(4H)-one and SCH-1518291; and (j) PDE11 inhibitors;

(xxx) Quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, hydrogen sulfate and gluconate), chloroquine, methylchloroquine, 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, (+)-pheserin tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), 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), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-N-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT _1A ) receptor antagonists, such as spiperone, levopindolol, BMY7378, NAD-299, S-(-)-UH-301, NAN 190, and lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT _2c ) receptor agonists such as valcaserin and zilonapine;

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

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT ₆ ) receptor antagonists, such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiothepine (also known as methyltepine), ritanserin, ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S) and PRX-07034 (Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors, such as alapropylate, citalopram (CELEXA, CIPRAMIL), escitalopram (Lexapro, CIPRALEX), clomipramine (Anafranil), duloxetine (Cymbalta), femoxetine (MALEXIL), fenfluramine (PONDIMIN), desethylfenfluramine, fluoxetine (Prozac), fluvoxamine (Lavoxet), indalpine, milnacipran (IXEL), paroxetine (PAXIL, Seroxat), sertraline (Zoloft, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), busulfan, vilazodone, cariprazine, neuralstem, and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; erthofamine), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, taenia, and glial cell-derived neurotrophic factor (GDNF), and agents that stimulate the 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, JNJ-17305600 and ORG-26041;

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

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

The present invention also includes kits suitable for practicing the above-described methods of treatment. In one embodiment, the kit comprises a first dosage form comprising one or more compounds of the present invention and a quantity of administration containers sufficient to practice the methods of the present invention.

In another embodiment, the kits of the invention comprise one or more compounds of the invention.

The compounds of the present invention or their pharmaceutically acceptable salts can be prepared by a variety of methods similarly known in the art. The following reaction schemes, along with synthetic methods known in the art of organic chemistry or modifications and derivatizations familiar to those skilled in the art, illustrate methods for preparing the compounds. Other methods (including modifications thereof) will be readily apparent to those skilled in the art.

The starting materials used herein are either commercially available or can be prepared by conventional methods known in the art, such as those disclosed in standard reference books such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vols. I-XII (published by Wiley-Interscience). Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by 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 incorporated by reference.

The compounds of the present invention or pharmaceutically acceptable salts of the compounds or tautomers and radioisotopes can be prepared according to the reaction schemes described below. Unless otherwise indicated, the substituents in the schemes are as defined above. Isolation and purification of the products are achieved by standard procedures known to chemists of ordinary skill.

Those skilled in the art will recognize that in some cases, the compounds in Scheme 1 are produced as mixtures of diastereomers and/or enantiomers; which can be separated at various stages of the synthetic route using conventional techniques or combinations of such techniques (such as, but not limited to, crystallization, normal phase chromatography, reverse phase chromatography, and chiral chromatography) to provide the individual enantiomers of the present invention.

It will be understood by those skilled in the art that the various symbols, superscripts, and subscripts used in the routes, methods, and examples are used for ease of presentation and/or to reflect the order in which they are introduced into the routes and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. The routes represent methods suitable for synthesizing the compounds of the present invention. They do not limit the scope of the present invention in any way.

Scheme 1 shows a general synthetic method for preparing compounds of Formula I. The preparation of compounds of Formula A, where R = lower alkyl, has been previously described. Some examples include: Journal of Heterocyclic Chemistry 1968, 5(1), 35-39; II Farmaco-Ed. Sci. 1977, 36(6), 430-437; Journal of Heterocyclic Chemistry 2002, 39, 737-742. Direct installation of the ^R1 substituent to provide compounds of Formula B can be achieved via a C-H insertion/direct arylation reaction. These transformations can be carried out by treatment with an appropriate aryl halide, a metal source (palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), copper iodide), a ligand (triphenylphosphine, bis(adamantan-1-yl)(butyl)phosphine, 1,10-phenanthroline), and a base (potassium carbonate, cesium carbonate, potassium tert-butoxide) in an appropriate solvent, typically heated to a temperature above 50°C (RSC Advances 2012, 2(14), 5972-5975; Organic Letters 2012, 14(7), 1688-1691; PCT International Application No. 2011075643). During this step, the (R ³ ) _b and R ¹ moieties should be represented by the same moieties as desired in the final product. For example, in the compound of Example 1, b is 0, and R ¹ is a 4-chlorophenyl moiety. The intermediate of formula B can then be converted to a compound of formula I by treating the ester with an appropriate amine using heat and a Lewis acid (such as magnesium methoxide or calcium chloride) in an appropriate solvent (see Tetrahedron Letters 2010, 51, 3879-3882). During this step, the ^R6 and ^R7 moieties should be represented by the same moieties as desired in the final product. For example, in Example 4, ^R6 is cyclopropyl and ^R7 is hydrogen. Alternatively, the conversion of the ester of Formula B to the amide of Formula I can be carried out in a two-step process, wherein the ester is first hydrolyzed to the acid by acidic or basic treatment in water and a cosolvent; the acid is then converted to the amide by treatment with an appropriate amine in the presence of an amide coupling/dehydrating agent (such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide (T3P), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc.) at a temperature in the range of -20°C to 100°C to provide the compound of Formula I. During any of these steps, the ^R1 moiety should be represented by the same moiety as that desired in the final product. For example, in Example 1, ^R1 should be represented by a 4-chlorophenyl moiety.

Alternatively, the compound of formula A is halogenated by treating it with an electrophilic halogen reagent (such as N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), iodine monochloride (ICl), iodine (I ₂ ), bromine (Br ₂ ), etc.) in an inert solvent at room temperature to 100° C., optionally under acid catalysis, to obtain a compound of formula C, wherein X is represented by bromine or iodine. The compound of formula C can be converted to the compound of formula I in two ways. The first approach employs substitution of the halogenated imidazopyridazine of formula C by the 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 borate in the presence of a base, a transition metal catalyst [possibly palladium(II) acetate or tris(dibenzylideneacetone)dipalladium(0)], and a metal chelating ligand (typically a phosphine system) in a suitable solvent installs the appropriate ^R moiety and provides formula B. Compounds of formula B are then converted to compounds of formula I as previously described. In a second approach, intermediates of formula C can be converted to amides D by treating the ester with an appropriate amine in the presence of heat and a Lewis acid such as magnesium methoxide or calcium chloride. Alternatively, conversion of intermediates of formula C to compounds of formula D can be carried out in a two-step process in which the ester is hydrolyzed to the acid by treatment with basic or acidic water in a suitable cosolvent. The resulting acid is then converted to a compound of formula D by treatment with an appropriate amine in the presence of an amide coupling/dehydrating agent such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc. at a temperature in the range of -20°C to 100°C. The intermediate of formula D can then be converted to a compound of formula I by 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 borate in the presence of a base, a transition metal catalyst [possibly palladium(II) acetate or tris(dibenzylideneacetone)dipalladium(0)] and a metal chelating ligand (generally a phosphine-based) in a suitable solvent to install the desired ^R1 moiety.

Route 1

Experimental operation

The following describes the synthesis of several compounds of the present invention. Other compounds within the scope of the present invention can be prepared using the methods described in these examples alone or in combination with techniques generally known in the art.

Experiments were generally performed under an inert atmosphere (nitrogen or argon), particularly when using oxygen- or moisture-sensitive reagents or intermediates. Commercially available solvents and reagents were generally used without further purification. Anhydrous solvents were used where appropriate, typically products from Acros Organics or EMD Chemicals. Otherwise, commercial solvents were passed through a column packed with molecular sieves until the following QC standards for water were achieved: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, the solvents were further treated with sodium metal, calcium hydride, or molecular sieves and distilled immediately prior to use. The products were typically dried under vacuum before performing other reactions or submitting for biological testing. Mass spectral data were reported by liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI), or gas chromatography-mass spectrometry (GCMS) instruments. Chemical shifts in nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to the residual peak from the deuterated solvent used. In some embodiments, chiral separations are performed to separate the enantiomers of a particular compound of the invention (in some embodiments, the separated enantiomers are referred to as ENT-1 and ENT-2 based on their elution order). In some embodiments, the optical rotation of the enantiomers is measured using a polarimeter. Based on the observed optical rotation data (or its specific optical rotation data), the enantiomer that rotates clockwise is referred to as the (+)-enantiomer and the enantiomer that rotates counterclockwise is referred to as the (-)-enantiomer.

Typically, LCMS is performed after reacting by a detectable intermediate, and the reaction is continued until complete conversion, followed by subsequent reagent addition. For the synthetic reference operation in other embodiments or methods, reaction conditions (reaction time and temperature) may vary. Generally speaking, thin layer chromatography or mass spectrometry is performed after the reaction, and aftertreatment is performed when appropriate. Purification between experiments may vary: typically, solvents and solvent ratios are selected for eluent/gradient to provide appropriate R _f or retention time.

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 pyridazine-3-amine (20 g, 210 mmol) and ethyl 3-bromo-2-oxopropanoate (82 g, 420 mmol) in ethanol (300 mL) was heated under reflux for 16 hours. After removing the solvent by distillation, the residue was dissolved in 2M hydrochloric acid (100 mL) and washed with ethyl acetate. The aqueous layer was basified to approximately pH 8 by adding aqueous sodium bicarbonate solution and then extracted with chloroform; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 20% ethyl acetate in petroleum ether) gave the product as a brown solid. Yield: 8.0 g, 42 mmol, 20%. LCMS m/z 192.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.53(s,1H),8.39(dd,J＝4.4,1.6Hz,1H),8.01-8.04(m,1H),7.12(dd,J＝9.3,4.4Hz,1H),4.48(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H).

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

N-iodosuccinimide (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 temperature for 24 hours. Additional N-iodosuccinimide (1 equivalent after every 24 hours) was introduced and stirring was continued for another 48 hours (72 hours in total) until analysis by thin layer chromatography showed complete consumption of the starting material. After removing the solvent in vacuo, the residue was dissolved in dichloromethane and washed with 1 M hydrochloric acid and 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) gave the product as an off-white solid. Yield: 14.5 g, 45.7 mmol, 46%. LCMS m/z 318.0 [M+H] ⁺ . ¹ H NMR (300MHz, DMSO-d ₆ )δ8.74(dd,J＝4.3,1.3Hz,1H),8.18(dd,J＝9.2,1.4Hz,1H),7.41(dd,J＝9.3,4.4Hz,1H),4.35(q,J＝7.0Hz,2H),1.36(t,J＝7.1Hz,3H).

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

Aqueous sodium carbonate (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]palladium(II) dichloride (382 mg, 0.505 mmol) in 1,4-dioxane (32 mL). The reaction mixture was heated at 90°C overnight before being 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 magnesium sulfate, filtered, and concentrated in vacuo. Purification by 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] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.39(dd,J＝4.3,1.5Hz,1H),8.09(dd,J＝9.3,1.5Hz,1H),7.65(br d,J＝8.5Hz,2H),7.50(br d, J＝8.5Hz, 2H), 7.17 (dd, J＝9.3, 4.3Hz, 1H), 4.42 (q, J＝7.1Hz, 2H), 1.38 (t, J＝7.1Hz, 3H).

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

A solution of C3 (1.75 g, 5.80 mmol) in methanol (25 mL) and tetrahydrofuran (25 mL) was added to a 2 M aqueous sodium hydroxide solution (25 mL), and the reaction mixture was stirred at room temperature for 4 hours. The resulting solid was collected by filtration and washed with cold water (2 x 25 mL) to give 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-2-yl]methanone (1).

Compound C4 (1.40 g, 4.74 mmol) was combined with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU, 2.92 g, 7.70 mmol) and N,N-diisopropylethylamine (3.56 mL, 20.4 mmol) in N,N-dimethylformamide (75 mL). After 2 minutes, azetidine hydrochloride (957 mg, 10.2 mmol) was added and the reaction mixture was stirred at 50 ° C overnight. After removing the solvent in vacuo, the residue was subjected to silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) and then triturated with ethyl acetate (30 mL) at 50 ° C; this mixture was cooled to 0 ° C and filtered. The collected solid was washed with diethyl ether (50 mL) and cold ethyl acetate (15 mL). It was then recrystallized from ethyl acetate to give the product as an off-white solid. Yield: 980 mg, 3.13 mmol, 66%. LCMS m/z 313.2,315.2[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.41 (dd, J＝4.4, 1.6Hz, 1H), 8.10 (br d, J＝9.2Hz, 1H), 7.75 (br d, J＝8.6Hz, 2H), 7.48 (br d,J＝8.6Hz,2H),7.19(dd,J＝9.2,4.3Hz,1H),4.46-4.57(m,2H),4.17-4.28(m,2H),2.28-2.39(m,2H).

Example 2

3-(4-Chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide (2)

O-Benzotriazol-1-yl-N,N,N',N'-tetramethylurea 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 give the carboxylic acid rather than the sodium salt) (1.50 g, 5.48 mmol) and N,N-diisopropylethylamine (2.86 mL, 16.4 mmol) in tetrahydrofuran (100 mL), and the reaction mixture was stirred at room temperature for 2 minutes. Cyclopropylamine (0.77 mL, 11 mmol) was introduced and stirring was continued at room temperature 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 then purified again by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) to give the product as a solid. Yield: 1.39g, 4.44mmol, 81%. LCMS m/z 313.3,315.2[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.46(dd,J＝4.3,1.6Hz,1H),8.06(dd,J＝9.3,1.7Hz,1H),7.71(br d,J＝8.7Hz,2H),7.48(br d,J＝8.6Hz,2H),7.31(dd,J＝9.3,4.4Hz,1H),2.79-2.86(m,1H),0.78-0.84(m,2H),0.62-0.68(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 ethyl 3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazine-2-carboxylate (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 N,N-dimethylformamide (10 mL) was degassed several times with nitrogen. Palladium (II) acetate (50 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium (0) (30 mg, 26 μmol) were added and the reaction mixture was stirred at 110 ° C overnight. After adding water (50 mL), the mixture was extracted with ethyl acetate (3×30 mL); the combined organic layers were concentrated in vacuo and purified by silica gel chromatography to give 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-2-carboxylic acid (C6).

To a solution of C5 (500 mg, 1.5 mmol) in ethanol (30 mL) was added a solution of lithium hydroxide (2 equivalents) in water (10 mL), and the reaction mixture was stirred at room temperature for 4 hours before being concentrated in vacuo. The residue was diluted with water and acidified to pH 4 with hydrochloric acid. After the mixture was extracted with dichloromethane (3×30 mL), the combined organic layers were concentrated under reduced pressure to give the product as a yellow solid, which was used in the next step without further purification. Yield: 500 mg, quantitative. LCMS m/z 305.9 [M+H] ⁺ .

Step 3. Synthesis of azetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]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)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 186 mg, 0.489 mmol), N,N-diisopropylethylamine (126 mg, 0.975 mmol), and N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated in vacuo and purified by reverse phase HPLC (column: Phenomenex Synergi C18, 4 μm; mobile phase A: 0.225% aqueous formic acid; mobile phase B: acetonitrile; gradient: 33% to 53% B) to give the product as a yellow solid. Yield: 35.7 mg, 0.104 mmol, 32%. LCMS m/z344.9[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.63 (dd, J＝4.4, 1.6Hz, 1H), 8.24 (dd, J＝9.3, 1.6Hz, 1H), 7.56 (br d,J＝9.9Hz,2H),7.39(dd,J＝9.4,4.4Hz,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-2-carboxylate (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. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (30 mg, 40 μmol) 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 by silica gel chromatography gave the product as a yellow solid. Yield: 800 mg, 2.7 mmol, 47%. LCMS m/z 299.7 [M+H] ⁺ .

Step 2. Synthesis of N-cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]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, then diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC (column: Agella Venusil ASB C 18, 5 μm; mobile phase A: 0.225% aqueous formic acid; mobile phase B: acetonitrile; gradient: 29% to 49% B) gave the product as a white solid. Yield: 430.3 mg, 1.39 mmol, 51%. LCMS m/z 311.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.01 (s, 2H), 8.40 (dd, J＝4.4, 1.6Hz, 1H), 7.97 (dd, J＝9.2, 1.7Hz, 1H), 7.60 (br s,1H),7.20(dd,J＝9.3,4.3Hz,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).

N-Bromosuccinimide (25.6 g, 144 mmol) was added to a 0 ° C solution of C1 (25.0 g, 131 mmol) in dichloromethane (250 mL). The reaction mixture was gradually warmed to room temperature and stirred overnight, after which the reactants were quenched with a 10% aqueous sodium bisulfite solution. The resulting mixture was diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration with tert-butyl methyl ether gave the product (25.4 g) as a pink-purple solid. The filtrate was concentrated under reduced pressure and then triturated with tert-butyl methyl ether and hexane 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] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.55(dd,J＝4.4,1.6Hz,1H),8.05(dd,J＝9.3,1.6Hz,1H),7.22(dd,J＝9.3,4.4Hz,1H),4.53(q,J＝7.1Hz,2H),1.49(t,J＝7.1Hz,3H).

Step 2. Synthesis of 3-bromo-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide (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 before being cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane and water, and the organic layer was concentrated under reduced pressure. The residue was triturated with ether and water to give the product as a pink solid. Yield: 24.4 g, 86.8 mmol, 87%. LCMS m/z 281.0, 283.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.52 (dd, J＝4.4, 1.6Hz, 1H), 7.90 (dd, J＝9.3, 1.6Hz, 1H), 7.46 (br s,1H),7.20(dd,J=9.2,4.4Hz,1H),2.91-2.98(m,1H),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-2-carboxamide (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(II) dichloromethane complex (97%, 53.9 mg, 64.0 μmol). After 2 minutes, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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 temperature and filtered through celite; the filter pad was rinsed with ethyl acetate and the combined filtrates were washed with water. After concentrating the organic layer in vacuo, the residue was purified by silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) to give a white solid (196 mg). Recrystallization from methanol gave the product as colorless needles. Yield: 135 mg, 0.444 mmol, 41%. LCMS m/z 305.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.18 (d, J = 1.5 Hz, 1H), 8.41-8.46 (m, 2H), 8.01 (dd, J = 9.2, 1.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.66 (br s,1H),7.26(dd,J＝9.2,4.4Hz,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-2-carboxamide (6)

Compound C9 (1.90 g, 6.76 mmol) was combined with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[1,2,4]triazolo[1,5-a]pyridine (1.82 g, 7.43 mmol), [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (51.4 mg, 68.0 μmol), and 1,4-dioxane (34 mL). Aqueous sodium carbonate (3 M, 9.0 mL, 27 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 temperature and the supernatant was immediately filtered through a pad of Celite, rinsing with 10% methanol in ethyl acetate. The remaining solid was partitioned between half-saturated aqueous sodium chloride (25 mL) and 10% methanol in ethyl acetate with stirring for 5 minutes; this mixture was also filtered through Celite. The combined filtrates were diluted with saturated aqueous sodium chloride (25 mL) and then with 10% methanol in ethyl acetate. The aqueous layer was extracted three times with 10% methanol in ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed onto celite (4 times the weight of the crude product) using dichloromethane and methanol and subjected to silica gel chromatography (gradient: 0% to 20% methanol in ethyl 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 obtain the product as an off-white solid. Powder X-ray diffraction revealed this material to be crystalline. Yield: 1.66 g, 5.20 mmol, 77%. LCMS m/z 320.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.35 (dd, J＝1.4, 1.3Hz, 1H), 8.64 (dd, J＝4.4, 1.6Hz, 1H), 8.61 (br d,J＝5Hz,1H),8.60(s,1H),8.24(dd,J＝9.3,1.6Hz,1H),7.93-7.99(m,2H),7.44(dd,J＝9.3,4.4Hz,1H),2.82-2.90(m,1H),0.64-0.70(m,4H).

Example 7

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

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

Aqueous sodium carbonate (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]palladium(II) dichloride (401 mg, 0.530 mmol) in 1,4-dioxane (34 mL), and the reaction mixture was heated at 85°C overnight. The mixture was then diluted with water (75 mL) and extracted with ethyl acetate (4 x 250 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo; the product was purified by silica gel chromatography (Gradient: 5% to 100% ethyl acetate in heptane) to afford the product. Yield: 1.50 g, 4.69 mmol, 71%. LCMS m/z 320.0, 322.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.43 (brd, J = 4.3Hz, 1H), 8.11 (br d,J＝9.3Hz,1H),7.52-7.58(m,2H),7.46-7.50(m,1H),7.22(dd,J＝9.3,4.4Hz,1H),4.44(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).

Step 2. Synthesis of 3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid lithium salt (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 temperature for 16 h. The reaction mixture was concentrated to remove methanol, and the residue was washed with ethyl acetate. The resulting solid was collected by filtration to give the product as a yellow solid. Yield: 700 mg, quantitative. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (br d, J = 4 Hz, 1H), 8.13 (br d, J = 9 Hz, 1H), 7.97 (d, J = 11 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.65 (dd, J = 8.5, 8 Hz, 1H), 7.32 (dd, J = 9.3, 4.3 Hz, 1H).

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

A mixture of C11 (200 mg, 0.67 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (500 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (2 mL) was stirred at room temperature for 20 minutes. 1-Methyl-1H-pyrazol-4-amine (200 mg, 2.1 mmol) was added and the reaction mixture was stirred at 35° C. for 2 hours before being diluted with water and filtered. The collected solid was washed with ethyl acetate and methanol to give the product as a pink solid. Yield: 130 mg, 0.351 mmol, 52%. LCMS m/z 393.0 [M+Na ⁺ ]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.76 (s, 1H), 8.64 (br d, J = 4.4Hz, 1H), 8.26 (br d,J＝9.4Hz,1H),8.04(s,1H),7.82(brd,J＝10.7Hz,1H),7.73(dd,J＝8.3,8.0Hz,1H),7.66(s,1H),7.61(br d, J＝8.4Hz, 1H), 7.44 (dd, J＝9.3, 4.3Hz, 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)

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

A mixture of 6-bromopyrazolo[1,5-a]pyridine (1.5 g, 7.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.03 g, 7.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (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 removing the solvent in vacuo, the residue was diluted with dichloromethane, mixed with celite (approximately 5 g), and concentrated under reduced pressure. Silica gel chromatography (gradient: 0% to 50% ethyl acetate in heptane) provided the product as a green liquid. Yield: 1.35 g, 5.53 mmol, 73%. GCMS m/z = 244 [M ⁺ ]. ¹ H NMR (400MHz, CDCl ₃ )δ8.86-8.87(m,1H),7.99(d,J＝2.2Hz,1H),7.50(dd,J＝8.8,1.1Hz,1H),7.37(dd,J＝8.8,1.1Hz,1H),6.49(dd,J＝2.2,0.9Hz,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 temperature 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 removing the solvent in vacuo, the residue was partitioned between water (25 mL) and dichloromethane (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure; silica gel chromatography (eluent: ethyl acetate) gave the product as a light yellow solid. Yield: 357 mg, 1.27 mmol, 69%. LCMS m/z 281.0, 283.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.45(dd,J＝4.4,1.6Hz,1H),7.87(dd,J＝9.2,1.6Hz,1H),7.12(dd,J＝9.2,4.4Hz,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-b]pyridazin-2-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. The evacuation/nitrogen filling was repeated after each addition, and a solution of C12 (2.84 g, 11.6 mmol), cesium fluoride (2.87 g, 18.9 mmol) in water (18 mL), and a solution of bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) dichloride (335 mg, 0.473 mmol) in 1,2-dichloroethane (9 mL) were added sequentially. The reaction mixture was heated at 100° C. for 23 hours before being cooled to room temperature, concentrated in vacuo, and subjected to silica gel chromatography (eluent: ethyl acetate, followed by 5% methanol in dichloromethane). This material was combined with the product from a similar reaction performed on C13 (200 mg, 0.71 mmol) and purified by supercritical fluid chromatography (column: Princeton methanesulfonamide, 5 μm; mobile phase: 4:1 carbon dioxide/methanol). The resulting material was recrystallized from ethanol to give the product as a white solid. Powder X-ray diffraction revealed this material to be crystalline. Yield: 540 mg, 1.7 mmol, 38%. LCMS m/z 319.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(brs,1H),8.40(dd,J＝4.3,1.6Hz,1H),8.01(d,J＝2.2Hz,1H),8.01(dd,J＝9.3,1.7Hz,1H),7.63(d,half of ABquartet,J＝9.3Hz,1H),7.54(dd,half of ABX pattern,J＝9.2,1.4Hz,1H),7.16(dd,J＝9.3,4.4Hz,1H),6.56(d,J＝2.2Hz,1H),4.59-4.65(m,2H),4.20-4.27(m,2H),2.31-2.40(m,2H).

Example 9

3-(4-Chloro-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide (9)

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. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (97%, 90.1 mg, 0.107 mmol) was introduced, and after 2 minutes, 2-(4-chloro-2,5-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 before being cooled to room temperature and filtered through Celite. The filter pad was rinsed with ethyl acetate and the combined filtrates were washed with water; the organic layer was concentrated in vacuo and purified by silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane). Recrystallization from methanol gave the product as an off-white solid. Yield: 217 mg, 0.622 mmol, 35%. LCMS m/z 349.1, 351.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Examples 10-25 were synthesized using the methods described above for Examples 1-9. See Table 1 for the specific methods used and characterizing data for these Examples.

Table 1

Preparation methods, structures and physicochemical data of Examples 10-25

1. In this case, the catalyst used for the Suzuki reaction is dichlorobis(tricyclohexylphosphine)palladium(II).

2. The desired 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 the conversion of C1 to C5 in Example 3.

3. Compound C1 was converted to azetidin-1-yl(imidazo[1,2-b]pyridazin-2-yl)methanone using the method described for the conversion of C8 to C13 in Example 8. Example 16 was described in further detail using the chemistry described for the conversion of C1 to C5 in Example 3.

4. C1 is reacted with 4-bromo-5-fluoro-2-methylbenzonitrile in the presence of allylpalladium chloride dimer and tetrabutylammonium acetate at elevated temperature to give the desired ethyl 3-(4-cyano-2-fluoro-5-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxylate.

5. Analytical HPLC conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; 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/min.

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 desired boronic acid aryl ester derivatives were prepared from the corresponding aryl bromide by reacting with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and potassium acetate.

8. The ¹ H NMR spectrum obtained at elevated temperature (80° C.) provided the following data: ¹ H NMR (400 MHz, DMSO-d ₆ ), characteristic peaks: δ 8.66 (br d, J=4 Hz, 1 H), 8.23 (br d, J=9 Hz, 1 H), 7.85 (br d, J=11 Hz, 1 H), 7.73 (dd, J=8,8 Hz, 1 H), 7.62 (br d, J=8 Hz, 1 H), 7.40 (dd, J=9,4 Hz, 1 H), 2.88-3.02 (br s, 3 H), 0.28-0.61 (br s, 4 H).

9. In this case, the catalyst used for the Suzuki reaction is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride.

10. Analytical HPLC conditions: Column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; 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 min; 5% to 100% B over 3.4 min; Flow rate: 0.8 ml/min.

Table 2

Examples 26-104 were prepared using methods similar to those used for Examples 1-25 or by methods known to those skilled in the art.

Structure and mass spectrometry data of Examples 26-104

The PDE4A, PDE4B, PDE4C and PDE4D binding affinities of the compounds of the invention were determined using the following biological assays:

Biological analysis

The human PDE4A3 coding sequence (amino acids 2 to 825 of the sequence with accession number NP_001104779) was cloned into the baculovirus expression vector pFastBac (Invitrogen), which was engineered to contain an N-terminal His6 affinity tag and a C-terminal FLAG affinity tag to facilitate purification. The recombinant shuttle vector was isolated and used to transfect insect cells to generate a viral stock. To generate a cell slurry for purification, insect cells were infected with the viral stock and harvested 72 hours post-infection. The insect cell slurry was lysed and, after centrifugation, the supernatant was batch-bound to Ni-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. This eluate was diluted with FLAG buffer (50 mM Tris HCl 7.5, 100 mM NaCl, 5% glycerol, 1 mM TCEP with protease inhibitors) and batch-bound to anti-FLAG M2 agarose (Sigma) overnight at 4°C. Agarose was packed into a column, washed with buffer, and eluted with a buffer containing the eluate obtained using 250 μg/ml Flag peptide. Fractions were analyzed by SDS-PAGE with Coomassie blue staining and pooled according to purity. Pooled fractions were chromatographed on an S2001 20 ml column (GE Healthcare) in 50 mM Tris HCl pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP containing protease inhibitors. PDE4A3 fractions were analyzed by SDS-PAGE with Coomassie blue staining, pooled according to purity, dialyzed against 50 mM Tris HCl pH 7.5, 100 mM NaCl, 20% glycerol, 2 mM TCEP, frozen, and stored at -80°C.

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

The human PDE4C1 coding sequence (amino acids 2 to 712 of the sequence with accession number NP_000914.2) was cloned into the baculovirus expression vector pFastBac (Invitrogen), which was engineered to contain an N-terminal His6 affinity tag and a C-terminal FLAG affinity tag to facilitate purification. The recombinant shuttle vector was isolated and used to transfect insect cells to generate a viral stock. To generate a cell slurry for purification, insect cells were infected with the viral stock and harvested 72 hours post-infection. The insect cell slurry was lysed and, after centrifugation, the supernatant was batch-bound to Ni-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. This eluate was diluted with FLAG buffer (50 mM Tris HCl 7.5, 100 mM NaCl, 5% glycerol, 1 mM TCEP with protease inhibitors) and batch-bound to anti-FLAG M2 agarose (Sigma) overnight at 4°C. Agarose was packed into a column, washed with buffer, and eluted with a buffer containing the eluate obtained using 250 μg/ml Flag peptide. Fractions were analyzed by SDS-PAGE with Coomassie blue staining and pooled according to purity. Pooled fractions were chromatographed on an S2001 20 ml column (GE Healthcare) in 50 mM Tris HCl pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP containing protease inhibitors. PDE4C1 fractions were analyzed by SDS-PAGE with Coomassie blue staining, pooled according to purity, dialyzed against 50 mM Tris HCl pH 7.5, 100 mM NaCl, 20% glycerol, 2 mM TCEP, frozen, and stored at -80°C.

As described in Seeger, T.F. et al., Brain Research 985 (2003) 113-126, a portion of the human PDE4D3 coding sequence (amino acids 50 to 672 of the sequence of accession number Q08499-2) was cloned into the baculovirus expression vector pFastBac (Invitrogen), which was engineered to include a C-terminal His6 affinity tag to aid purification. The recombinant shuttle vector was isolated and used to transfect insect cells to generate a viral stock. To generate a cell slurry for purification, insect cells were infected and harvested 72 hours after infection. The insect cell slurry was lysed and, after centrifugation, the supernatant was chromatographed on Ni-NTA agarose (Qiagen) as described in Seeger, T.F. et al., Brain Research 985 (2003) 113-126. Ni-NTA agarose fractions containing PDE4 were pooled, diluted with Q buffer A (50 mM Tris HCl pH 8, 4% glycerol, 100 mM NaCl, 1 mM TCEP, without the protease inhibitor EDTA (Roche)) to reduce the NaCl to approximately 200 mM and loaded onto a Q agarose (GE Healthcare) column. After washing to baseline with Q buffer A, PDE4D was eluted with a gradient from 10% to 60% buffer B (50 mM Tris HCl pH 8, 1 M NaCl, 4% glycerol, 1 mM TCEP). PDE4D fractions were analyzed by SDS-PAGE with Coomassie blue staining, pooled according to purity, frozen, and stored at -80°C.

The PDE4A3, PDE4B1, PDE4C1, and PDE4D3 assays used scintillation proximity assay (SPA) technology to measure compound inhibition of human recombinant PDE4A1, PDE4B3, PDE4C1, and PDE4D3 enzyme activity in vitro. The PDE4A1, PDE4B3, PDE4C1, and PDE4D3 assays were performed simultaneously using identical parameters, except for enzyme concentration (80 pM PDE4A3, 40 pM PDE4B3, 40 pM PDE4C1, and 10 pM PDE4D). The assay was performed in a 384-well format using 50 μL of assay buffer (50 mM TRIS pH 7.5; 1.3 mM _MgCl ; 0.01% Brij) containing PDE4A3, PDE4B1, PDE4C1, and PDE4D, sufficient to convert approximately 20% of substrate (1 μM cAMP consisting of 20 nM 3H-cAMP + 980 μM cold cAMP) and a range of inhibitors. Reactions were incubated at 25°C for 30 minutes. Reactions were terminated by the addition of 20 μL of 8 mg/ml yttrium silicate SPA beads (Perkin Elmer). The plate was sealed (TopSeal, Perkin Elmer) and the beads were allowed to settle for 8 hours before being read overnight on a Trilux Microbeta.

Table 3

Biological Data of Examples 1-104.

a. Values represent 1 measurement

b. Unless otherwise indicated, values represent the geometric mean of 2-9 determinations.

c. Values represent the geometric mean of ≥10 measurements

ND. Value not determined.

Claims (28)

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in: ^R1 is selected from -( _CH2 ) _m- ( _C6 - _C10 )aryl and -( _CH2 ) _m- (5 to 14-membered)heteroaryl, and where chemically permissible, the ( _C6 - _C10 )aryl and (5 to 14-membered)heteroaryl moieties are optionally substituted by one to five ^R2s ; When present, each ^R2 is independently selected from halogen, oxo, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 ) alkyl, (C2-C6) alkenyl, ( _C2 - _C6 ) alkynyl, ( _C1 - _C6 ) alkylthio, ( _C1 - _C6 ) _alkoxy , -N( ^R4 )(R5), -N(R4 ₎ (C=(O) ^R5 ), -C(=O)N( ^R4 )( ^R5 ), -C(=O)-ON( ^R4 ) ^{( R5} ), -C(= ^O ) ^-R4 , -C(=O) ^-OR4 and ( _C3 - _C8 ) cycloalkyl; When present, each ^R3 is independently selected from halogen, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )alkylthio, ( _C1 - _C6 )alkoxy, -N(R4)( ^R5 ), -N( ^R4 )(C＝(O) ^R5 ), -C(＝O) ^{N(R4 )} ( ^R5 ), -C(＝O)-ON( ^R4 )( ^R5 ), -C(＝O) ^-R4 and -C(＝O) ^-OR4 ; ^R4 and ^R5 are each independently selected from hydrogen and ( _C1 - _C6 ) alkyl groups; ^R6 and ^R7 are each independently selected from hydrogen, optionally halogenated ( _C1 - _C6 )alkyl, -( _CH2 ) _n- ( _C3 - _C8 )cycloalkyl, -( _CH2 ) _n- (4 to 10-membered)heterocycloalkyl, -( _CH2 ) _n- ( _C6 - _C10 )aryl and -( _CH2 ) _n- (5 to 10-membered)heteroaryl, and, where chemically permissible, the ( _C3 - _C8 )cycloalkyl, (4 to 10-membered)heterocycloalkyl, ( _C6 - _C10 )aryl and (5 to 10-membered)heteroaryl are optionally substituted by one to five ^R8s ; or ^R6 and ^R7 together with the nitrogen to which they are attached form (4 to 10) heterocyclic alkyl groups, and where chemically permissible, the (4 to 10) heterocyclic alkyl groups are optionally substituted by one to five ^R9 groups; When present, each ^R8 is independently selected from halogen, oxo, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )alkylthio, ( _{C1 - C6} )alkoxy, -N( ^R4 )( ^R5 ), -N( ^R4 )(C＝(O) ^R5 ), -C(＝O)N( ^R4 )( ^R5 ), -C(＝O ⁾ -ON(R4)( ^R5 ), -C(＝O) ^-R4 and -C(＝O) ^-OR4 ; When present, each ^R9 is independently selected from halogen, oxo, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )alkylthio, ( _{C1 - C6} )alkoxy, -N( ^R4 )( ^R5 ), -N( ^R4 )(C＝(O) ^R5 ), -C(＝O)N( ^R4 )( ^R5 ), -C(＝O ⁾ -ON(R4)( ^R5 ), -C(＝O) ^-R4 and -C(＝O) ^-OR4 ; b is represented by an integer selected from 0, 1, 2, or 3; m is 0; and n is represented by an integer selected from 0, 1, 2, 3, or 4. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0, and ^R1 is a ( _C6 - _C10 ) aryl group optionally substituted with 1 to 3 R2 ^groups , wherein the optionally substituted ( _C6 - _C10 ) aryl group is phenyl or naphthyl. 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted ( _C6 - _C10 ) aryl group is phenyl. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0, and ^R1 is a (5- to 14-membered) heteroaryl group optionally substituted with 1 to 3 ^R2 groups, wherein the optionally substituted (5- to 14-membered) heteroaryl group is selected from triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5- or 1,3,4-oxadiazolyl, oxazolyl, thiophene, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, inzolyl, benzofuranyl, benzimidazolyl, benzothiophene, benzoxoxazolyl Diazolyl, benzothiazolyl, isobenzothiaphenyl, benzothiaphenyl, benzoisoxazolyl, benzoxazolyl, benzom-dioxacyclopentenyl, furan-pyridyl, purine, imidazopyridyl, imidazopyrimidinyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, thiophenopyridyl, triazolopyrimidinyl, triazolopyridyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, oxochromenyl, quinoxolinyl, and 1,4-benzoxazinyl. 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group is a nitrogen-containing heteroaryl group selected from the following (5 to 10 quinones): triazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl or quinoxalyl. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group is selected from: i)(5-yuan) nitrogen-containing heteroaryl group; or ii)(6 yuan) contains nitrogen-containing heteroaryl groups. 7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein each ^R2 is independently selected from halogen, oxo, cyano, hydroxyl, optionally halogen-substituted ( _C1 - _C6 ) alkyl and optionally halogen-substituted ( _C1 - _C6 ) alkoxy. 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein ^R2 is selected from: i) Halogens selected from fluorine or chlorine; ii) A ( _C1 - _C6 ) alkyl group optionally substituted with a halogen, said alkyl group being selected from methyl, ethyl, or propyl, and said methyl, ethyl, and propyl groups optionally being substituted with 1 to 3 fluorine atoms; or iii) ( _C1 - _C6 ) alkoxy groups optionally substituted with halogens, wherein the alkoxy group is selected from methoxy, ethoxy, or propoxy, and wherein the methoxy, ethoxy, and propoxy groups are optionally substituted with 1 to 3 fluorine atoms. 9. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein ^R6 and ^R7 are each independently selected from hydrogen, optionally halogen-substituted ( _C1 - _C6 )alkyl, -( _CH2 ) _n- ( _C3 - _C8 )cycloalkyl, -( _CH2 ) _n- ( _C6 - _C10 )aryl and -( _CH2 ) _n- (5 to 6-membered)heteroaryl, and, where chemically permissible, the ( _C3 - _C8 )cycloalkyl, ( _C6 - _C10 )aryl and (5 to 6-membered)heteroaryl are optionally substituted by 1 to 3 ^R8s ; or ^R6 and ^R7 together with the nitrogen to which they are attached form (4 to 6-membered) heterocyclic alkyl groups, and where chemically permissible, the (4 to 6-membered) heterocyclic alkyl groups are optionally substituted by 1 to 3 ^R9s ; When present, each ^R8 is independently selected from halogen, oxo, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )alkylthio, ( _{C1 - C6} )alkoxy, -N( ^R4 )( ^R5 ), -N( ^R4 )(C＝(O) ^R5 ), -C(＝O)N( ^R4 )( ^R5 ), -C(＝O)-ON(R4)( ^R5 ), -C(＝O) ^{-R4 and} -C(＝O) ^-OR4 ; and When present, each ^R9 is independently selected from halogen, oxo, cyano, hydroxyl, _-SF5 , nitro, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )alkylthio, ( _{C1 - C6} )alkoxy, -N( ^R4 )( ^R5 ), -N( ^R4 )(C＝(O) ^R5 ), -C(＝O)N( ^R4 )( ^R5 ), -C(＝O ⁾ -ON(R4)( ^R5 ), -C(＝O) ^-R4 and -C(＝O) ^-OR4 . 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein one of ^R6 and ^R7 is hydrogen and the other is an alkyl group optionally substituted with a halogen ( _C1 - _C6 ), said alkyl group being selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, and said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups are optionally substituted with one or more fluorine atoms. 11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein one of ^R6 and ^R7 is hydrogen and the other is -( _CH2 ) _n- ( _C3 - _C8 )cycloalkyl, said cycloalkyl being selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl or bicyclo[1.1.1]pentyl, wherein said cycloalkyl is optionally substituted by 1 to 3 ^R8s . 12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein one of ^R6 and ^R7 is hydrogen and the other is -( _CH2 ) _n- ( _C6 - _C10 )aryl, wherein the aryl group is optionally substituted with 1 to 3 ^R8s . 13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein one of ^R6 and ^R7 is hydrogen and the other is -( _CH2 ) _n- (5 to 6-membered) heteroaryl, said heteroaryl being selected from triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5- or 1,3,4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein said heteroaryl is optionally substituted by 1 to 3 ^R8s . 14. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein each ^R8 is independently selected from halogen, oxo, cyano, hydroxyl, ( _C1 - _C6 )alkyl and ( _C1 - _C6 )alkoxy. 15. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein ^R6 and ^R7 together with the nitrogen to which they are attached form a (4- to 6-membered) heterocyclic alkyl group optionally substituted with 1 to 3 ^R9s , wherein the heterocyclic alkyl group is selected from aza-butane, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazoalkyl, piperidinyl, piperazinyl, oxazolyl or pyrrolidinyl. 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic alkyl group is an azahexacyclic butyl group. 17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein each ^R9 is independently selected from halogen, oxo, cyano, hydroxyl, ( _C1 - _C6 )alkyl and ( _C1 - _C6 )alkoxy. 18. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein b is an integer selected from 0, 1 or 2, and when ^R3 is present, it is each independently selected from halogen, cyano, hydroxy, _-SF5 , nitro, ( _C1 - _C6 )alkyl and ( _C1 - _C6 )alkoxy. 19. Azacyclobutane-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone or a pharmaceutically acceptable salt thereof. 20.3-(6-cyanopyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide or a pharmaceutically acceptable salt thereof. 21. N-Cyclopropyl-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-carboxamide or a pharmaceutically acceptable salt thereof. 22.3-(4-chloro-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 24. Use of a compound of formula I as defined in any one of claims 1-22, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a patient suffering from a disease or condition mediated by a PDE4B isoform, wherein the disease or condition is selected from schizophrenia, depression, anxiety, Alzheimer's disease, Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cerebrovascular disease, and allergic conjunctivitis. 25. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from: 3-(4-chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; N-Cyclopropyl-3-(2-Methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(4-chloro-3-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-(3,4-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(5-chloropyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(5-chloropyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(4-cyano-2-fluoro-5-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 4-[2-(azacyclobutane-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-5-fluoro-2-methylbenzonitrile; 3-(4-cyano-5-fluoro-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-cyclopropyl-N-methylimidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 4-[2-(azacyclobutane-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile; 4-[2-(azacyclobutane-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2,5-difluorobenzonitrile; 3-(4-chloro-5-fluoro-2-methylphenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chlorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide; [3-(4-chlorophenyl)imidazo[1,2-b]pyridine-2-yl](pyrrolidine-1-yl) methyl ketone; 3-(3,5-dichlorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-Chlorophenyl)-N-(2-methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide; [3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3-methoxyazacyclobutane-1-yl) methyl ketone; 3-(4-chlorophenyl)-N-cyclopropyl-N-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-Chlorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(3-chloro-5-fluorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(3-chloro-5-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(3-Chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; N-(bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-(furano[3,2-b]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(1,3-benzoxazol-5-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-(3-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-[2-(trifluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl{3-[2-(trifluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazin-2-yl} methyl ketone; 3-(4-chloro-3-fluorophenyl)-N-(2,2-difluorocyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chlorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(4-chloro-3,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(5-chloropyridin-3-yl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(3-chloro-4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl] ketone; Azacyclobutane-1-yl[3-(2,3-dihydro-1-benzofuran-5-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(4-chloro-3-methylphenyl)imidazo[1,2-b]pyridazin-2-yl] ketone; Azacyclobutane-1-yl[3-(4-chloro-2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(4-fluoro-3,5-dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(2-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; [3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3-fluorozacriane-1-yl) methyl ketone; [3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3,3-difluoroazacyclobutane-1-yl) methyl ketone; Azacyclobutane-1-yl[3-(5-chloro-2-methylphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(2,4-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(4-chloro-2-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; 3-(5-chloropyridin-3-yl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; 3-(3-chloro-4-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide; N-[(1R,2S)-2-fluorocyclopropyl]-3-(2-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(2-fluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(pyrazolo[1,5-a]pyrimidin-6-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; N-Cyclopropyl-3-[2-(difluoromethoxy)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(4-chloro-2-methylphenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl{3-[2-(difluoromethoxy)pyridin-4-yl]imidazo[1,2-b]pyridazin-2-yl} methyl ketone; Azacyclobutane-1-yl[3-(1,3-benzoxazol-6-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; N-Cyclopropyl-3-(pyrazolo[1,5-a]pyrimidin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-cyano-2-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(5-cyano-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(3,4-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; Azacyclobutane-1-yl[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(4-chlorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(2,2-difluoro-1,3-benzodioxacyclopenten-5-yl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; N-Cyclopropyl-3-[6-(difluoromethoxy)pyridin-3-yl]imidazo[1,2-b]pyridazine-2-carboxamide; 3-(1,3-benzoxazol-6-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; N-Cyclopropyl-3-(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-cyano-3-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; Azacyclobutane-1-yl[3-(4-chloro-2,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl] methyl ketone; 3-(4-cyano-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2,5-difluorophenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2-methylphenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2,5-difluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-5-fluoro-2-methylphenyl)-N-(prop-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-cyano-5-fluoro-2-methylphenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-cyano-5-fluoro-2-methylphenyl)-N-(prop-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chloro-2,5-difluorophenyl)-N-(prop-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chlorophenyl)-N-(pyrimidin-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chlorophenyl)-N-(cyclopropylmethyl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-(4-chlorophenyl)-N-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide; and 3-(4-chloro-3,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide. 26. Compounds selected from: Azacyclobutane-1-yl[3-(3-chloro-2,4-dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl]methyl ketone carboxylate; Azacyclobutane-1-yl[3-(2,3-dihydro-1,4-benzodioxane-6-yl)imidazo[1,2-b]pyridazin-2-yl] ketone carboxylate; Azacyclobutane-1-yl[3-(quinoxalo-6-yl)imidazo[1,2-b]pyridazin-2-yl]methyl ketone formate; 1-{3-[2-(azacyclobutane-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-4-fluorophenyl}acetone carboxylate; 3-(4-chlorophenyl)-N-[2-(2-hydroxyphenyl)ethyl]imidazo[1,2-b]pyridazine-2-carboxamide carboxylate; 3-(4-chlorophenyl)-N-(5-methyl-1,2-oxazol-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide trifluoroacetate; and 3-(4-chlorophenyl)-N-(2-methyl-2H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide trifluoroacetate. 27.3-(4-chloro-2-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide or a pharmaceutically acceptable salt thereof. 28.3-(4-chloro-5-fluoro-2-methylphenyl)-N-(prop-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide or a pharmaceutically acceptable salt thereof.