WO2011119694A1 - Trpv4 antagonists - Google Patents

Abstract

The present invention relates to naphthyridine analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

Description

TRPV4 ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to naphthyridine analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

BACKGROUND OF THE INVENTION

TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al., 2002. J Neurosci 22: 6408-6414). Consistent with its polymodal activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure (Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens et al., 2004. Proc Natl Acad Sci U S A 101 : 396-401 ), In addition, amongst other mechanisms proposed, tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33).

Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dialation. This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood pressures. This places the septal barrier, which separates the circulatory aqueous environment and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung

edema/congestion, as is observed in patients with congestive heart failure.

TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics 4: 165-174) and has been shown to mediate Ca²⁺ entry in isolated endothelial cells and in intact lungs (Jian et al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466- 74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and hemorrage (Alvarez et al., 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38: 386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion. Additional benefit is suggested in inhibiting TRPV4 function in pulmonary-based pathologies presenting with symptoms including lung edema/congestion, infection,

inflammation, pulmonary remodeling and/or altered airway reactivity. A genetic link between TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation in treatment of COPD with or without coincident emphysema. Enhanced TRPV4 activity is also a key driver in ventilator-induced lung injury (Hamanaka et al., 2007. Am J Physiol 293: L923- 32) and it is suggested that TRPV4 activation may underlie pathologies involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004. Am j Physi ol 287: 269-71 ). A potential clinical benefit for TRPV4 blockers in the treatment of sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am J Rhinol 22:7-12).

In addition, TRPV4 channels have recently been implicated in urinary bladder function (Thorneloe et al., 2008. J Pharmacol Exp Ther 326 : 432-42) and are likely to provide therapeutic benefit for conditions of bladder overactivity, characterized by an increased urge to urinate and an enhancement of micturition frequency. These data suggest a clinically beneficial effect of inhibiting TRPV4, located on multiple cell types, on urinary bladder function that is likely to be effective in bladder disorders such as overactive bladder, interstitial cystitis and painful bladder syndrome.

Furthermore TRPV4 has in recent years been implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733; Alessandri-Haber et al., 2006. J Neurosci 26: 3864-3874), genetic motor neuron disorders (Auer-Grumbach et al., 2009. Nat Genet. PMID: 20037588; Deng et al., 2009. Nat Genet PMID: 20037587; Landoure et al., 2009. Nat Genet PMID: 20037586), cardiovascular disease (Earley et al., 2005. Circ Res 97: 1270-9; Yang et al., 2006. Am. J Physiol. 290:L1267-L1276), and bone related disorders;

including osteoarthritis (Muramatsu et al., 2007. J. Biol. Chem. 282: 32158-67), genetic gain-of function mutations (Krakow et al., 2009. Am J Hum Genet 84: 307-15; Rock et al., 2008 Nat Genet 40: 999-1003) and osteoclast differentiation (Masuyama et al. 2008. Cell Metab 8: 257- 65). SUMMARY OF THE INVENTION

In one aspect this invention provides for naphthyridine analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.

In a second aspect, this invention provides for the use of the compounds of Formula (I) as TRPV4 antagonists.

In another aspect, this invention provides for the use of the compounds of Formula (I) for treating and preventing conditions associated with TRPV4 imbalance.

In yet another aspect, this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, postsurgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.

The TRPV4 antagonist may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, antihistamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β- adrenoceptor and a-| -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.

Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for compounds of Formula (I):

(I)

wherein:

Ri is phenyl, cyclohexyl, or thiophenyl all of which may be unsubstituted or substituted by one or two substituents independently chosen from: halo, Ci_-3 alkoxy, Ci_-3 alkyl or CF₃;

R₂ is independently hydrogen, Ci_-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl;

R₃ is phenyl or thiophenyl, both of which are substituted by one to three substituents

independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃;

R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, CF₃, or OH;

R₅ is independently OH, OC^ alkyl, alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H;

R₆ is H , OH, OCi-4 alkyl, alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H;

n is 0 or 1 ;

m is 0 or 1 ;

i is independently 0, 1 or 2;

X is N or CH; and

Y is O or CH₂;

or a pharmaceutically acceptable salt thereof.

"Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms. For example, C-M alkyl refers to an alkyl group having from 1 to 4 member atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), and butyl (n-butyl, isobutyl, and t-butyl).

"Alkoxy" as used herein refers to an -0-Ci_-3 alkyl group wherein Ci_-3 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, and the like.

When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

"Substituted" in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively. In certain embodiments, compounds according to Formula (I) may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2- hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine,

diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methanesulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

Representative Embodiments

In one embodiment:

Ri is phenyl, cyclohexyl, or thiophenyl all of which may be unsubstituted or substituted by one or two substituents independently chosen from: halo, Ci_-3 alkoxy, Ci_-3 alkyl or CF₃;

R₂ is independently hydrogen, Ci_-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl;

R₃ is phenyl or thiophenyl, both of which are substituted by one to three substituents

independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃;

R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, CF₃, or OH;

R₅ is independently OH, OC^ alkyl, alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H;

R₆ is H , OH, OC₁-4 alkyl, C₁- alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H;

n is 0 or 1 ;

m is 0 or 1 ;

i is independently 0, 1 or 2;

X is N or CH; and

Y is O or CH₂;

In another embodiment:

Ri is phenyl;

R₂ is independently C_1-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl;

R₃ is phenyl which is substituted by one to three substituents independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃; R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, OH, or CF₃;

R₅ is independently C_1-3 alkyl, C_1-3 alkoxy, halo, OH, or C_1-3 alkyl-OH;

R₆ is hydrogen;

n is 1;

m is 0;

i is independently 0, 1 or 2;

X is N or CH; and

YisOorCH₂;

In another embodiment:

Ri is phenyl;

R₂ is independently C_1-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl;

R₃ is phenyl which is substituted by one to three substituents independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃;

R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, OH, or CF₃;

R₅ is independently C_1-3 alkyl, C_1-3 alkoxy, halo, OH, or C_1-3 alkyl-OH;

R₆ is hydrogen;

n is 1;

m is 0;

i is independently 0, 1 or 2;

X is N; and

YisOorCH₂.

It is to be understood that the present invention covers all combinations of particular groups described hereinabove.

Specific examples of compounds of the present invention include the following:

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-V-[(1R)-2,2,2-trifluoro-1 -phenylethyl]- 1,5-naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-V-[(1S)-1-phenylethyl]-1,5- naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-V-(1-phenylcyclopropyl)-1,5- naphthyridine-4-carboxamide; 3-(1 ^'-bipiperidin-1 '-ylmethyl)^

naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phen

phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-[(1 S^

1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-A/-(1-phenylcycloprop

naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-(1-phenylcyclopropyl)-2-[3-(trffl

1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-(4-chloro-3-fluo^

naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)^

naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-(4-chloro-3-fluorophenyl)- V-[(1 R)-2,2,2-trifluoro-1-phenylethyl]- 1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-7-bromo-A/-[(1 S)-1-phenylethyl]-2-[3-(trifluorometh

naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-A/-(1-phenylcyclopropyl)-2-[3-(trifluorometh

1 ,5-naphthyridine-4-carboxamide;

7-bromo-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}- V-(1-phenylcyclopropyl)-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

7-bromo-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}- V-[(1 S)-1-phenylethyl]-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-6-(methyloxy^

1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-A/-[(1R

phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-A/-(1-ph^

1 ,5-naphthyridine-4-carboxamide;

6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]m

2,2,2-trifluoro-1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-(1-phenylcyclopropyl)-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide; 6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-[(1 S)-1-phen

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1'-ylmethyl)-6-(methyloxy)- V-(1-phenylcyclopropyl)-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-hydroxy-2-[3-^

phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluorometh

trifluoro-1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-(1-phenylcyclopropyl)-2

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl^

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-hydroxy-A/-(1-phenylcyclopropyl)-2-[3-(trifluorom

1 ,5-naphthyridine-4-carboxamide; and

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-A/-[(1 S)-1-phenylethyl]-2-[3-(trifluorom

naphthyridine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

Compound Preparation

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these

circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

The synthesis of the compounds of the general formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1 - 3. In the following description, the groups are as defined above for compounds of formula (I) unless otherwise indicated. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

Scheme 1

Target molecules can be prepared from 2-bromo-3-pyridinamine. The pyridinyl amine can be protected with a BOC group under conditions common to the art such as LiHMDS and BOC anhydride to provide intermediate 1 . Subsequent lithiation and trapping by diethyl oxalate provides intermediate 2, which under alkaline conditions such as potassium hydroxide in alcohol with appropriate propiophenones result in intermediate 3. Benzylic, radical bromination of intermediate 3 using NBS and an initiator such as benzoyl peroxide followed by a solvent swap from carbon tetrachloride to acetonitrile and nucleophilic displacement of the bromide affords intermediate 4. The carboxylic acid in 4 can then be coupled to an appropriate amine under conditions common to the art such as EDC in the presence of a base such as DIEA, and a coupling modifier such as, but not limited to, HOBT to provide the compound of Formula I.

Scheme 2

Modification of the naphthyridine core originates at intermediate 3. Conversion of the carboxylic acid to the methyl ester 5 can be accomplished under conditions common to the art such as treatment with oxalyl chloride and catalytic DMF followed by methanol trapping to yield the methyl ester intermediate 5. Regioselective halogenation of intermediate 5 under conditions common to the art such as bromine in fert-butanol and water affords intermediate 6. Benzylic radical bromination of 6 using NBS and an initiator such as benzoyl peroxide followed by a solvent swap from carbon tetrachloride to acetonitrile and nucleophilic displacement of the bromide affords intermediate 7. The methyl ester intermediate 7 can then be hydrolyzed under conditions common to the art such as hydrochloric acid in THF to provide the free carboxylic acid 8, which can then be coupled to an appropriate amine under conditions common to the art such as T3P in the presence of a base such as diisopropylethylamine or EDC in the presence of a base such as TEA, and a coupling modifier such as, but not limited to, HATU to provide the compound of Formula I. Scheme 3

Additional methods for modifying the naphthyridine ring include chlorination of the initial 3-amino-2-bromopyridine to form chlorinated intermediate 9. Boc-protection of 9 using conditions common to the art provides intermediate 10. Lithium-halogen exchange and trapping of the aryllithium with diethyloxalate provides ketoester intermediate 11 , which under alkaline conditions such as potassium hydroxide in alcohol with appropriate propiophenones result in intermediate 12 (R₄ is -OMe when MeOH is used or R₄ is -OEt when EtOH is used).

Conversion of the carboxylic acid to the methyl ester using conditions common to the art followed by benzylic, radical bromination of intermediate 13 using NBS and an initiator such as benzoyl peroxide followed by a solvent swap from carbon tetrachloride to acetonitrile and nucleophilic displacement of the bromide affords intermediate 14. Basic hydrolysis of the methyl ester followed by coupling to an appropriate amine under conditions common to the art such as EDC in the presence of a base such as DIEA, and a coupling modifier such as, but not limited to, HOBT compound of Formula I. A compound of Formula I can be converted to another compound of Formula I. For example, alkoxynaphthyridine 15 can be converted to the corresponding hydroxylnaphthyridine using standard demethylation conditions common to the art including but not limited to hydrobromic acid or boron tribromide. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallization, chromatography, H.P.L.C. or SCF of a stereoisomeric mixture. Pure stereoisomer of the agent may also be prepared from the corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the

corresponding racemate using a suitable chiral support or by fractional crystallization of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Biological Activity

As stated above, the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis,

sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.

The biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist, as well as tissue and in vivo models.

The biological activity of the compounds of Formula (I) are demonstrated by the following tests.

Liqand-qated assay:

TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies). Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of an agonist and inhibition of the agonist-induced activation is recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK-293-MSR-II) and transduced with 1 % BacMam (J. P. Condreay, S.M. Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127-132) virus expressing the human TRPV4 gene are plated at 15000 cells/well in a volume of 50 uL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 hours at 37 degrees and 5% C0₂. Media is then aspirated using a Tecan Plate-washer and replaced with 20 uL of dye loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates are then incubated in the dark at room temperature for 1-1.5 hours. 10 uL of test compound diluted in HBSS + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark and then 10 uL of agonist is added at a final cone, equal to the agonist EC80. Calcium release is measured using the FLIPRtetra (MDS Analytical Technologies).

All examples described herein possessed TRPV4 biological activity with IC₅₀s ranges from 1 nM - 10 uM.

Hypotonicity assay (BHK cells):

BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells are transduced with 2% BacMam virus expressing the human TRPV4 gene and are plated at 10K cells per well in a volume of 50 uL in 384 well poly-D-lysine coated plates. Cells are incubated for 18-24 hours at 37 degrees and 5% C0_2. The following day, the media is aspirated using a Tecan Plate-washer and replaced with 20 uL of dye loading buffer: HBSS buffer, 2.5 mM Probenecid, 500 uM Brilliant Black, 2 uM Fluo-4. The dye loaded cells are incubated for 1-1.5 hours at room temperature in the dark. 10 uL of test compound diluted in HBSS/H₂0 (-1 :2.3) + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark, and then 10 uL of hypotonic buffer (H₂0 + 1.5mM CaCI₂ + -68 mM NaCI; 140 mOsm stock/260mOsm FAC) is used to test the inhibition of the hypotonicity-induced activation. Reaction is measured on a heated stage (37 degrees) using the FLIPRtetra.

Methods of Use

The compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, Crohn's disease, colitis, diarrhea, intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, flatulence, and osteoarthritis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

As used herein, "treat" in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine,

"prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

As used herein, "patient" refers to a human or other animal.

The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal

administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.

Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art. Compositions

The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain

pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American

Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable

disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

The compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, antihistamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective β- adrenoceptor and a-| -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad). Flash column chromatography was performed on silica gel.

The naming program used is ACD Name Pro 6.02.

The following abbreviations and terms had the indicated meanings throughout:

BOC (fert-butyloxycarbonyl);

Br₂ (bromine);

nBuLi (n-butyl lithium);

tBuOH (terf-butanol);

CBz (carbobenzoxy);

CH₂CI₂ (dichloromethane);

CCU (carbon tetrachloride);

DIEA (A/, V-diisopropylethylamine);

DMF (/V, V-dimethylformamide);

EDC (1-[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride);

EtOH (ethanol);

H₂ (hydrogen);

HATU (2-(1 /-/-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uranium hexafluorophosphate methanaminium);

HCI (hydrochloric acid);

HOBT (1-hydroxybenzotriazole);

KOH (potassium hydroxide);

LiHMDS (lithium bis(trimethylsilyl)amide);

MeCN (acetonitrile)

MeOH (methanol);

Na₂S0₄ (sodium sulfate);

NaHC0₃ (sodium bicarbonate);

Na₂C0₃ (sodium carbonate);

NaOH (sodium hydroxide);

Na₂S0₄ (sodium sulphate);

NBS (W-bromosuccinimide); NH₄CI (ammonium chloride);

NMM ( V-methyl morpholine);

Pd/C (palladium on carbon);

TEA (triethylamine);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran).

T3P (1-propanephosphonic acid cyclic anhydride)

3-n^'-biDiDeridin-1'-ylmethvn-2-r3-arifluoromethvnDhenyll-A/-rnffl-2.2.2-trifluoro-1-DhenylethylV

1 ,5-naphthyridine-4-carboxamide

Intermediate A: 1 , 1-Dimethylethyl (2-bromo-3-pyridinyl)carbamate

To a 0°C solution of 2-bromo-3-pyridinamine (1.00 g, 5.78 mmol) and di-fert-butyl dicarbonate (1.26 g, 5.78 mmol) in THF (15 mL) was added LiHMDS (1.0 M in THF, 1 1.56 mL, 1 1.56 mmol) slowly. The mixture was stirred at 0°C until completion at which point it was warmed to room temperature and quenched by the addition of saturated NH₄CI. After stirring at room

temperature for one hour, the mixture was extracted three times with ethyl acetate and the combined organic extracts were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. Silica gel column chromatography (8:1 petroleum ether:ethyl acetate) afforded 950 mg (61 %) of the title compound. LCMS (m/z): 273.1/275.1 (M⁺/M+2).

Intermediate B: Ethyl Γ3-(ΙΓ(1 -dimethylethyl)oxylcarbonyl)amino)-2-pyridinyll(oxo)acetate To a -78°C solution of 1 ,1-dimethylethyl (2-bromo-3-pyridinyl)carbamate (965 mg, 3.55 mmol) in THF (15 ml.) was added dropwise nBuLi (2.5 M in hexanes, 3 ml_, 7.45 mmol). After one hour, diethyl oxalate (621 mg, 4.26 mmol) was added dropwise and the reaction was warmed to room temperature. The reaction mixture was then diluted with ethyl acetate, washed with saturated NaHC0₃, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. Silica gel column chromatography (15:1 petroleum ether:ethyl acetate) afforded 790 mg (76 %) of the title compound. LCMS (m/z): 373.2/375.2 (M7M+2).

Intermediate C: 3-Methyl-2-r3-(trifluoromethyl)phenyll-1 ,5-naphthyridine-4-carboxylic acid To a solution of ethyl [3-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-2-pyridinyl](oxo)acetate (940 mg, 3.20 mmol) in ethanol (10 mL) was added KOH (1.31 g, 19.18 mmol) in water (3 ml_). The reaction was then heated to reflux overnight before being cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in water, washed with diethyl ether, acidified with acetic acid, and extracted three times with CH₂CI₂. The combined organic extracts were dried over Na₂S0₄, filtered, and concentrated to give 600 mg (56 %) of the crude product. LCMS (m/z): 333.2 (M+H).

Intermediate D: 3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-2-r3-(trifluoromethyl)phenyll-1 ,5-naphthyridine-

4-carboxylic acid

3-Methyl-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylic acid (2.75 g, 8.28 mmol) was dried azeotropically with benzene three times. NBS (1.92 g, 10.76 mmol), benzoyl peroxide (0.2 g, 0.83 mmol), and CCI₄ (50 mL) were then added sequentially. The reaction was heated to reflux overnight before being cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeCN (50 mL) and 1 ,4'-bipiperidine (1.74 g, 10.35 mmol) were added. The reaction was stirred at room temperature until completion before being concentrated. Purification was performed by reverse-phase chromatography followed by amine scavenging using a SCX cartridge to yield 1.6 g (44 %) of the title compound. LCMS (m/z): 499.2 (M+H).

3-n .4'-biDiDeridin-1 lmethvn-2-r3-qrifluorom

1 ,5-naphthyridine-4-carboxamide

3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylic acid (100 mg, 0.20 mmol), (1 R-2,2,2-trifluoro-1-phenylethyl)amine (53 mg, 0.25 mmol), HOBT (31 mg, 0.20 mmol), EDC (1 15 mg, 0.60 mmol) and DIEA (0.18 ml_, 1.00 mmol) were dissolved in CH₂CI₂ (4 ml_). The reaction was heated to 60°C until complete. The reaction was then cooled to room temperature before saturated Na₂C0₃ (50 ml_), water (50 ml_), and CH₂CI₂ (50 ml.) were added and the mixture stirred for 30 min. The aqueous layer was extracted three times with CH₂CI₂ and the combined organic extracts were passed through a phase separator and subsequently concentrated under reduced pressure. The crude material was purified by preparative HPLC [Sunfire C18 Column, 30x150mm, 50 mL/min, A: 0.1 % TFA in water, B: 0.1 % TFA in acetonitrile, B: 10-50% over 10 minutes with holding at 100 % for 3 min] to obtain 24 mg (18 %) of the title compound as a white solid. LCMS (m/z): 656.3 (M+H); ¹H NMR (400 MHz, DMSO-c ₆) ppm 0.88 (m, 2H), 1.27-1.43 (m, 8H), 1.50 (m, 1 H), 1.63 (m, 1 H), 1.86 (m, 1 H), 2.26 (m, 4H), 2.38 (m, 2H), 3.46 (s, 2H), 6.14 (m, 1 H), 7.42-7.47 (m, 3H), 7.66 (m, 2H), 7.71 (t, J = 7.9 Hz, 1 H), 7.82 (d, J = 8.5 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.97 (s, 1 H), 8.48 (dd, J=8.5, 1.5 Hz, 1 H), 8.98 (dd, J = 4.3, 1.5 Hz, 1 H), 9.80 (d, J = 9.5 Hz, 1 H).

Examples 2-11

The examples in Table 1 (Scheme 1 ) were prepared by a method similar to the one described for the preparation of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]- V-(2,2,2- trifluoro-1-phenylethyl)-1 ,5-naphthyridine-4-carboxamide. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reagents and reaction conditions. Table 1

3-(1 ,4'-Bipiperidin-1 lmethyl)-7-bromo-A/-r(1 S)-1-ph

Intermediate E: Methyl 3-methyl-2-r3-(trifluoromethyl)phenyll-1 ,5-naphthyridine-4-carboxylate 3-Methyl-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylic acid (4.25 g, 12.79 mmol) was dissolved in CH₂CI₂ (30 ml.) and DMF (0.05 ml_, 0.64 mmol). Oxalyl chloride (1.98 ml_, 22.57 mmol) was then added dropwise and the reaction was stirred at room temperature for one hour before MeOH (10 ml.) was added. The pH of the solution was then adjusted to ~7 using saturated NaHC0₃ and the mixture was extracted using CH₂CI₂. The combined organic extracts were dried over Na₂S0₄, filtered, and concentrated. Silica gel column chromatography (20-30 % ethyl acetate:hexane) afforded 3.97 g (82 %) of the desired product. LCMS (m/z): 347.1 (M+H).

Intermediate F: Methyl 7-bromo-3-methyl-2-r3-(trifluoromethyl)phenyll-1 ,5-naphthyridine-4- carboxylate

Bromine (0.70 ml_, 13.56 mmol) was added dropwise to a suspension of methyl 3-methyl-2-[3- (trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylate (4.27 g, 12.33 mmol) in tert-butanol (25 ml.) and water (25 ml_). The reaction was then heated to 90°C overnight after which it was cooled to room temperature and neutralized using saturated NaHC0₃. The mixture was extracted three times with ethyl acetate and the combined organic extracts were dried over Na₂S0₄, filtered, and concentrated. Purification of the crude material by silica gel column chromatography (10-50 % ethyl acetate:hexanes) afforded 1.42 g (26 %) of the desired product. LCMS (m/z): 425.0/427.0 (M7M+2

Intermediate G: Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-2-r3-(trifluoromethyl)phenyll-

1 ,5-naphthyridine-4-carboxylate

Methyl 7-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylate (180 mg, 0.42 mmol) was azeotropically dried three times with benzene. NBS (98 mg, 0.55 mmol), benzoyl peroxide (10 mg, 0.04 mmol), and CCI₄ (2.8 mL) were added sequentially. The reaction was heated to 100°C until complete. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeCN (4 mL) and 1 ,4'- bipiperidine (89 mg, 0.53 mmol) was added. The reaction was stirred at room temperature until completion before being concentrated. Purification of the crude material by silica gel column chromatography (0-15 % methanol:dichloromethane) afforded 130 mg (49%) of the title compound. LCMS (m/z): 591.2/59

Intermediate H: 3-(1 ,4'-bipiperidin-1'-ylmethyl)-7-bromo-2-r3-(trifluoromethyl)phenyll-1 ,5- naphthyridine-4-carboxylic acid

Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4- carboxylate (935 mg, 1.58 mmol) was dissolved in THF (7.9 mL) and 6M aq HCI (7.9 mL) was added and heated to 80°C overnight. The reaction was cooled to room temperature, diluted with water, and neutralized with saturated NaHC0₃. The mixture was extracted three times with ethyl acetate and the combined organic extracts were dried over Na₂S0₄, filtered, and concentrated under reduced pressure to afford 0.9 g (93 %) of the title compound as crude material. LCMS (m/z): 577.1/579.2 (M⁺/M+2).

3-( 1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-A/-r( 1 S)-1 -phenylethyll-2-r3-(trifluoromethyl)phenyll-1 ,5- naphthyridine-4-carboxamide

To a CH₂CI₂ (0.75 ml.) solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-2-[3- (trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylic acid (130 mg, 0.23 mmol), (S)-(-)-alpha- methylbenzylamine (36 mg, 0.29 mmol), TEA (63 uL, 0.45 mmol), HATU (94 mg, 0.25 mmol) and EDC (48 mg, 0.25 mmol) were added sequentially. The mixture was stirred at room temperature overnight before being concentrated. The residue was purified by preparative HPLC [Sunfire C18 Column, 30x150mm, 50 mL/min, A: 0.1 % TFA in water, B: 0.1 % TFA in acetonitrile, B: 20-60% over 10 minutes with holding at 100 % for 3 min]. Fractions containing the desired compound were concentrated followed by neutralization with saturated NaHC0₃. The aqueous phase was extracted three times with CH₂CI₂ and the combined organic phases were concentrated and subsequently lyophilized to afford 56 mg (35 %) of the title compound as a tan solid. LCMS (m/z): 680.2/682.2 (M7M+2); ¹H NMR (400 MHz, DMSO-c/₆) ppm 0.90 (m, 2H), 1.27-1.43 (m, 8H), 1.46 (d, J = 7.0 Hz, 3H), 1.61 (m, 2H), 1.92 (m, 1 H), 2.23-2.43 (m, 6H), 3.44 (s, 2H), 5.27 (m, 1 H), 7.26 (t, J = 7.4 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.71 (t, J = 7.7 Hz, 1 H), 7.85 (d, J = 12.1 Hz, 1 H), 7.87 (d, J = 11.8 Hz, 1 H), 7.96 (s, 1 H), 8.82 (d, J = 2.3 Hz, 1 H), 8.97 (d, J = 8.0 Hz, 1 H), 9.16 (d, J = 2.3 Hz, 1 H).

Examples 13-15

The compounds in Table 2 (Scheme 2) were prepared by a method similar to the one described for the preparation of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo- V-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide. As is appreciated by those skilled in the art, these analogous examples may involve variations in reagents and reaction conditions. Table 2

3-n .4'-bipiperidin-1 lmethvn-6-(methyloxy)-2-r3-^^

1-phenylethyll-1 ,5-naphthyridine-4-carboxamide

Intermediate I: 2-bromo-6-chloro-3-pyridinamine

A solution of 2-bromo-3-pyridinamine (6 g, 34.7 mmol) and NCS (4.63 g, 34.7 mmol) in MeCN (18 mL) was heated to reflux for 3 h. After cooling to ambient temperature, the reaction was concentrated and purified via silica gel column chromatography (0-60 % CH₂CI₂/hexane) to give the title compound (5.63 g, 78%) as a light brown solid. LCMS (m/z): 206.9 (M+H)

Intermediate J: 1 ,1-dimethylethyl (2-bromo-6-chloro-3-pyridinyl)carbamate A solution of 2-bromo-6-chloro-3-pyridinamine (5.63 g, 27.1 mmol), di-tert-butyl dicarbonate (7.70 g, 35.3 mmol), DMAP (0.663 g, 5.43 mmol), and TEA (7.57 mL, 54.3 mmol) in CH₂CI₂ (13.57 mL) was stirred at RT for 24 h. The reaction was concentrated and purified via silica gel column chromatography (0-15 % CH₂CI₂/hexane) to give the title compound (4.87 g, 58.3%) as a white solid. LCMS (m/z): 308.9 (M+

Intermediate K: ethyl r6-chloro-3-({r(1 ,1-dimethylethyl)oxylcarbonyl)amino)-2- pyridinyll(oxo)acetate

n-BuLi (2.5 M, 1 1.93 mL, 29.8 mmol) was added dropwise to a -78 °C solution of 1 ,1- dimethylethyl (2-bromo-4-chloro-3-pyridinyl)carbamate (4.37 g, 14.21 mmol) in THF (47.4 mL). After stirring for 30 minutes at -78°C, diethyl oxalate (2.49 g, 17.05 mmol) was added, and the reaction was stirred at -78°C for 50 minutes. The ice bath was removed and the reaction was diluted with EtOAc. Saturated, aqueous NaHC0₃ and water were added. The layers were separated, and the aqueous layer was washed with EtOAc. The combined organic layers were dried over Na₂S0₄, filtered, and concentrated. The residue was purified via silica gel column chromatography (0-15% CH₂CI₂/hexane) to give the title product (1.88 g, 40.2%) as a white solid. LCMS (m/z): 273.0 (M-56)

Intermediate L: methyl 3-methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-1 ,5-naphthyridine-

4-carboxylate

A solution containing ethyl [6-chloro-3-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-2- pyridinyl](oxo)acetate (4.97 g, 15.12 mmol), 1-[3-(trifluoromethyl)phenyl]-1-propanone (3.06 g, 15.12 mmol) and potassium hydroxide (2.57 g, 45.8 mmol) in methanol (20 ml.) and water (20 ml.) was placed in a pressure tube and stirred at 90°C for 18 h. The reaction was then heated at 120°C for 3 days. After cooling to ambient temperature, the methanol was concentrated. The reaction was acidified with 6N HCI until pH~ 4. The solid precipitate was collected by filtration, washed with H₂0 and air dried. The solid was then dissolved in A/,A/-dimethylformamide (DMF) (30 ml) and treated with potassium carbonate (8.36 g, 60.5 mmol) and iodomethane (4.73 ml, 76 mmol) at 50 °C for 1.5 h. After cooling to ambient temperature, the potassium carbonate was filtered off and washed well with EtOAC. The combined filtrate was partitioned between EtOAc and water. The organic layer was washed with H₂0 (3X), dried over Na₂S0₄, filtered, and concentrated. The residue was purified via silica gel column chromatography (0-20%

EtOAc/hexane) to give the title product (2.1 g, 36.9%) as a yellow solid. LCMS (m/z): 377.1 (M+H)

Intermediate M: methyl 3-(1 ,4'-bipiperidin-1 '-ylnnethyl)-6-(nnethyloxy)-2-r3- (trifluoromethyl)phenyll-1 ,5-naphthyridine-4-carboxylate

A solution containing methyl 3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-1 ,5- naphthyridine-4-carboxylate (0.1 g, 0.266 mmol), NBS (0.052 g, 0.292 mmol), and benzoyl peroxide (0.0064g, 0.027 mmol) in CCI₄ (5 mL) was stirred at 100°C for 18 h. The reaction was cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeCN (5 mL) and treated with 1 ,4'-bipiperidine (0.058 g, 0.345 mmol). After stirring at RT for 2 h, the solvent was removed, and the residue was dissolved in EtOAc. The resulting solution was washed with saturated aqueous NaHC0₃. The organic layer was dried over Na₂S0₄, filtered, and concentrated. The residue was purified via silica gel column chromatography (1-10% MeOH/CH₂CI₂) to give the title product (0.1 15 g, 79%) as a light yellow oil. LCMS (m/z): 543.2 (M+H)

Intermediate N: 3-(1 ,4'-bipiperidin-1'-ylmethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-1 ,5- naphthyridine-4-carboxylic acid

A solution containing methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylate (0.1 11 g, 0.205 mmol) and potassium hydroxide (0.1 15 g, 2.046 mmol) in MeOH (3 mL) and water (1 mL) was heated to reflux for 18 h. After cooling to ambient temperature, the MeOH was concentrated, and the reaction was diluted with EtOAc. The layers were separated, and the water layer was acidified with 2N HCI until pH~5. The reaction was allowed to stand until solid precipitated. The solid was collected by filtration and air dried to afford the title product (0.06 g, 55.5%). LCMS (m/z): 529.1 (M+H)

1-phenylethyll-1 ,5-naphthyridine-4-carboxamide

A suspension containing 3-(1 ,4'-bipiperidin-1'-ylmethyl)-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxylic acid (0.2 g, 0.378 mmol), [(1 f?)-2,2,2- trifluoro-1-phenylethyl]amine (0.086 g, 0.492 mmol), EDC (0.290 g, 1.514 mmol), HOBT (0.058 g, 0.378 mmol) and DIEA (0.330 mL, 1.892 mmol) in THF (1 mL) and DMF (1 mL) was stirred at 50°C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc. The organic layer was washed with H₂0 (3X), dried over Na₂S0₄, filtered and concentrated. The residue was purified via silica gel column chromatography (0-7% MeOH (0.1 M NH₃)/CH₂CI₂) to give the title product (0.172 g, 66.3 %) as a light yellow solid. LCMS (m/z): 686.3 (M+H). ¹H NMR (400 MHz, CDCI₃) ppm 1.05-1.28 (m, 2H), 1 .42 (m, 3H), 1.55 (m, 5H), 1.62-1.78 (m, 4H), 2.36-2.41 (m, 5H), 3.58 (s, 2H), 3.72 (s, 3H), 6.16 (m, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 7.44-7.47 (m, 3H), 7.62-7.54 (m, 3H), 7.74-7.71 (m, 2H), 7.90 (s, 1 H), 8.23 (d, J = 9.2 Hz, 1 H).

Examples 17-22

Examples 17-22 in Table 3 (Scheme 3) were prepared by a method similar to the one described for the preparation of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]- V-[(1 f?)-2,2,2-trifluoro-1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide, example 16. As is appreciated by those skilled in the art, these analogous examples may involve variations in reagents and reaction conditions.

Table 3

Example 23

3-n .4'-bipiperidin-1 lmethvn-6-oxo-2-r3-qrifl^^

phenylethyll-5,6-dihvdro-1 ,5-naphthyridine-4-carboxamide

Boron tribromide (1 mL, 1.000 mmol) was added to a solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)- 6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-A/-[(1 R)-2,2,2-trifluoro-1-phenylethyl]^

naphthyridine-4-carboxamide, Example 16, (19.89 mg, 0.029 mmol) in CH₂CI₂ (1 mL) at -60°C. The reaction was stirred at -60°C for 1 h then at RT for 1 day. Solvent was concentrated, and the reaction was quenched with H₂0 and saturated aqueous NaHC0₃. The product was extracted into CH₂CI₂. The combined organics were dried over Na₂S0₄, filtered, and

concentrated. The residue was purified via silica gel column chromatography (0-10% MeOH (0.1 M NH₃)/ CH₂CI₂) to give the title product (5 mg, 25.75 %) as an off-white solid. LCMS (m/z): 672.3 (M+H). ¹H N MR (400 MHz, MeOD) ppm 1.05-1.15 (m, 1 H), 1.21-1.29 (m, 1 H), 1 .46 (m, 2H), 1.58-1.69 (m, 10H), 2.04-2.06 (m, 1 H), 2.31-2.34 (m, 1 H), 2.45 (m, 4H), 3.50 (d, J = 14 Hz, 1 H), 3.68 (d, J = 14 Hz, 1 H), 6.12-6.18 (m, 1 H), 6.94 (d, J = 9.6 Hz, 1 H), 7.47-7.52 (m, 3H), 7.62 (m, 2H), 7.70-7.74 (m, 1 H), 1.11-1 2 (m, 2H), 7.89 (s, 1 H), 8.08 (d, J = 9.6 Hz, 1 H).

Examples 24-27

The examples in Table 4 (Scheme 3) were prepared by a method similar to the one described for the preparation of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-oxo-2-[3-(trifluoromethyl)phenyl]- V-[(1 f?)- 2,2,2-trifluoro-1-phenylethyl]-5,6-dihydro-1 ,5-naphthyridine-4-carboxamide, Example 23, using examples 19-22 as precursors. As is appreciated by those skilled in the art, these analogous examples may involve variations in reagents and reaction conditions. Table 4

3-n 4'-bipiperidin-1 lmethvn-6^

naphthyridine-4-carboxamide

Intermediate O: 6-chloro-3-methyl-2-r3-(trifluoromethyl)phenylH _^

acid

Ethyl [6-chloro-3-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-2-pyridinyl](oxo)acetate,

Intermediate K, (1.23g, 3.74 mmol), 1-[3-(trifluoromethyl)phenyl]-1-propanone (0.756 g, 3.74 mmol), and NaOH (0.449 g, 1 1.22 mmol) were dissolved in ethanol (7.48 ml.) and water (7.48 ml_). The resulting solution was heated to reflux for 3 h. The reaction mixture was then concentrated and dissolved in DMSO. The DMSO solution was filtered through a 0.2 m filter and purified by preparative HPLC [Sunfire C18 Column, 30x150mm, 50 mL/min, A: 0.1 % TFA in water, B: 0.1 % TFA in acetonitrile, B: 20-60% over 10 minutes with holding at 100 % for 3 min] to afford the desired product (300 367.0 (M+H).

Intermediate P: 3-(1 ,4'-bipiperidin-1'-ylmethyl)-6-chloro-2-r3-(trifluoromethvnphenyll-1 ,5- naphthyridine-4-carboxylic acid

In a 100 mL flask was added 6-chloro-3-methyl-2-[3-(trifluoromethyl)phenyl]-1 ,5-naphthyridine- 4-carboxylic acid (300 mg, 0.818 mmol). Benzene was added, and then removed under reduced pressure. This was repeated three times to remove any water. The resulting residue was treated with V-bromosuccinimide (189 mg, 1.063 mmol) and diphenylperoxyanhydride (19.82 mg, 0.082 mmol) in carbon tetrachloride (10 mL). The flask was fitted with a condenser, and the reaction mixture was heated to reflux for 24 h. The solvents were then removed under reduced pressure to afford a light orange residue. To the residue was added acetonitrile (10.00 mL) and 1 ,4'-bipiperidine (172 mg, 1.023 mmol). After stirring the reaction mixture for 1.5 h, the mixture was concentrated under reduced pressure and dissolved in methanol. The resulting solution was filtered through a 0.2 m filter and purified by preparative HPLC [Sunfire C18 Column, 30x150mm, 50 mL/min, A: 0.1 % TFA in water, B: 0.1 % TFA in acetonitrile, B: 20-60% over 10 minutes with holding at 100 % for 3 min] to afford the desired product (43 mg, 5.3 %). LCMS (m/z): 533.2 (M+H).

3-n .4'-biDiDeridin-1 lmethvn-6-chloro-A/-rn S)-1-Dhenylethyll-2-r3-qrifluoromethvnDhenyll-1.5- naphthyridine-4-carboxamide

In a 20 mL vial was added 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-2-[3-(trifluoromethyl)phenyl]- 1 ,5-naphthyridine-4-carboxylic acid (40mg, 0.046 mmol), (1 S)-1-phenylethanamine (0.029 mL, 0.229 mmol), HOBT (7.00 mg, 0.046 mmol), EDC (52.6 mg, 0.274 mmol), DIEA (0.040 mL, 0.229 mmol) and dichloromethane (DCM) (2.0 mL). The reaction mixture was stirred until complete product formation was observed by LCMS and then concentrated under reduced pressure. The residue was dissolved in DMSO and filtered through a 0.2 m filter. The resulting solution was purified by preparative HPLC [Sunfire C18 Column, 30x150mm, 50 mL/min, A: 0.1 % TFA in water, B: 0.1 % TFA in acetonitrile, B: 20-60% over 10 minutes with holding at 100 % for 3 min]. The fractions containing the title compound were added to a separatory funnel and diluted with DCM, water, and saturated aqueous NaHC0₃. The two layers were separated, and the organic layer was passed through a hydrophobic phase separator and concentrated to afford the desired product (29 mg, 35.4 %). LCMS (m/z): 636.3 (M+H).

Claims

A compound of Formula (I):

(I)

wherein:

F is phenyl, cyclohexyl, or thiophenyl all of which may be unsubstituted or substituted by two substituents independently chosen from: halo, Ci_-3 alkoxy, Ci_-3 alkyl or CF₃;

R₂ is independently hydrogen, Ci_-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl;

R₃ is phenyl or thiophenyl, both of which are substituted by one to three substituents independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃;

R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, CF₃, or OH;

R₅ is independently OH, OC^ alkyl, alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H; R₆ is H , OH, OCi-4 alkyl, alkyl, CH₂OH, F, CH₂OCi-4 alkyl, CF₃, or CF₂H;

n is 0 or 1 ;

m is 0 or 1 ;

i is independently 0, 1 or 2;

X is N or CH; and

Y is O or CH₂;

or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein:

Ri is phenyl;

R₂ is independently C_1-2 alkyl, or CF₃;

or the two R₂ groups may be fused to form cyclopropyl; R₃ is phenyl which is substituted by one to three substituents independently chosen from: CF₃, halo, C_1-2 alkoxy, C_1-3 alkyl or OCF₃;

R₄ is independently halo, C_1-3 alkoxy, C_1-3 alkyl, OH, or CF₃;

R₅ is independently C_1-3 alkyl, C_1-3 alkoxy, halo, OH, or C_1-3 alkyl-OH;

R₆ is hydrogen;

n is 1;

m is 0;

i is independently 0, 1 or 2;

X is N or CH; and

YisOorCH₂;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 chosen from the group consisting of:

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-V-[(1R)-2,2,2-trifluoro-1 -phenylethyl]- 1,5-naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-V-[(1S)-1-phenylethyl]-1,5- naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-V-(1-phenylcyclopropyl)-1,5- naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-A/-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1_^ naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-A/-[(1R)-2,2,2-trffl phenylethyl]-1,5-naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-V-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]- 1,5-naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-V-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-1,5- naphthyridine-4-carboxamide;

3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-V-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]- 1,5-naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-(4-chloro-3-fluorophenyl)-V-(1-phenylcyclopropyl)-1,5- naphthyridine-4-carboxamide;

3-(1,4'-bipiperidin-1'-ylmethyl)-2-(4-chloro-3-fluorophenyl)-V-[(1S)-1-phenylethyl]-1,5- naphthyridine-4-carboxamide; 3-(1 ^^,-bipiperidin-1 ^,-ylmethyl)-2-(4-chloro-3-fluorophenyl)-A/-[(1 R)-2,2,2-trifluoro-1-p

1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-7-bromo-A/-[(^

naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-bromo-Ay-(1-phenylcyclopropyl)-2-[3-(trifluorom

1 ,5-naphthyridine-4-carboxamide;

7-bromo-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl^^

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

7-bromo-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-[(1 S)-1-phenylethyl]-2-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phen

1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ^'-bipiperidin-1 '-ylmethyl)-6-(et^

phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-Ay-(1-phenylcyclopropyl)-2-[3-(trifluorom

1 ,5-naphthyridine-4-carboxamide;

6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]m

2,2,2-trifluoro-1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]m

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

6-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-[(1 S)-1-phenylethyl]-2^

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1'-ylmethyl)-6-(methyloxy)-Ay-(1-phenylcyclopropyl)-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-hydroxy-2-[3-^

phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)ph trifluoro-1-phenylethyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-(1-phenylcyclopropyl)-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

6-hydroxy-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-A/-[(1 S)-1-phenylethyl]-2-[3-

(trifluoromethyl)phenyl]-1 ,5-naphthyridine-4-carboxamide;

3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-hydroxy-A/-(1 -phenyl

1 ,5-naphthyridine-4-carboxamide; and 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-A/-[(1 S)-1-phenylethyl]-2-[3-(trffl

naphthyridine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound of Formula (I) of claims 1-3 and a pharmaceutically acceptable carrier or excipient.

5. A method of treating congestive heart failure, overactive bladder, pain, cardiovascular disease, or osteoarthritis, which comprises administering to a human in need thereof, a compound of Formula (I) of claims 1-3.

6. A method according to claim 5 wherein the compound of Formula (I) is administered orally.

7. A method according to claim 5 wherein the compound of Formula (I) is administered by inhalation.

8. A method according to claim 5 wherein the compound of Formula (I) is administered by intravenously.