PHOSPHODIESTERASE 4 INHIBITORS

This application claims the benefit of US Patent Application 61/077,625, filed July 2, 2008.

This application is related to U.S. Patent No. 6,699,890, U.S Patent No. 7,205,320 (divisional of US 6,699,890), and copending Application Serial No. 11/602,283, filed

November 21, 2007 (divisional of US 7,205,320), the disclosures of each of which are hereby incorporated by reference in their entirety.

This application is also related to copending U.S. Application Serial No. 10/622,833, filed July 21, 2003, the disclosure of which is hereby incorporated by reference in their entirety.

This application is also related to U.S. Patent No. 7,087,625, and copending U.S. Application Serial No. 11/378,615, filed March 20, 2006 (continuation of US 7,087,625), the disclosures of each of which are hereby incorporated by reference in their entirety.

This application is also related to copending U.S. Application Serial No. 11/008,775, filed December 10, 2004, the disclosure of which is hereby incorporated by reference in their entirety.

This application is also related to copending U.S. Application Serial No. 11/449,868, filed June 9, 2006, the disclosure of which is hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role. PDE enzymes can be grouped into eleven families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, PDE 1 is stimulated by Ca ²⁺ /calmodulin. PDE 2 is cGMP-dependent, and is found in the heart and adrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme creates positive inotropic activity. PDE is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity. PDE 5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE 5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation.

PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al., Expression, Purification, and Characterization of human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320- 324 (1997)] . In addition, various splice variants of each PDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5 '-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP- 840 and ariflo are powerful antiinflammatory agents and therefore may be useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms.

rolipram piclamilast

In addition to such compounds as rolipram, and xanthine derivatives such as pentoxifylline, denbufylline, and theophylline, inhibit PDE4 and have received considerable attention for their cognition enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body.

Rolipram, previously in development as an anti-depressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has subsequently been extended to include indications such as dementia, [see "The PDE IV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, IU, et al, Drugs of the

Future, 1992, 17(9):799-807 for a general review]. Further clinical developments of rolipram and other first-generation PDE4 inhibitors were terminated due to the side effect profile of these compounds. The primary side effect in primates is emesis, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotrophic effects, increased gastric acid secretion and stomach erosion.

SUMMARY OF THE INVENTION

The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically the present invention relates to novel compounds, e.g., novel N- substituted aniline and diphenylamine compounds, that inhibit PDE4 enzymes, and especially have improved side effect profiles, e.g., are relatively non-emetic, (e.g., as compared to the previously discussed prior art compounds). Preferably, the compounds selectively inhibit PDE4 enzymes. The compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system.

Still further, the present invention provides methods for synthesizing compounds with such activity and selectivity as well as methods of (and corresponding pharmaceutical compositions for) treating a patient, e.g., mammals, including humans, requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is due in part to catabolism of intracellular c AMP levels by PDE 4 enzymes, or where such memory impairment may be improved by effectively inhibiting PDE4 enzyme activity.

In a preferred aspect, the compounds of the invention improve such diseases by inhibiting PDE4 enzymes at doses which do not induce emesis.

The present invention includes compounds that fall within the scope of the genus defined by Formula I:

wherein

R ¹ is Ci_ ₄ -alkyl, which is branched or unbranched _A and which is unsubstituted or substituted one or more times by halogen (e.g., CH ₃ , C ₂ H ₅ , CHF ₂ , CF ₃ ,

CH ₂ CF ₃ , etc.),

or

C ₃ -io-cycloalkyl, preferably C ₃ _ ₆ -cycloalkyl, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, C _1-4 -alkyl, C ₁ . 4-alkoxy, or combinations thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl);

R , 2 is H, C _1-12 -alkyl, preferably Ci- ₈ -alkyl, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci- ₄ -alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH ₂ CH ₂ - groups is replaced in each case by -CH=CH- or -C≡C- (e.g., methyl, ethyl, isopropyl, butyl, CHF ₂ , CF ₃ , CH ₂ CF ₃ , etc.),

C ₃ -io-cycloalkyl, preferably C ₃ _g-cycloalkyl, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, Ci- ₄ -alkyl, Ci- 4-alkoxy, or combinations thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl),

C ₄ _i ₆ -cycloalkylalkyl, preferably C ₄ _ ₁₂ -cycloalkylalkyl, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci- ₄ -alkyl, Ci- ₄ -alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

C _ό - ₁₄ -aryl which is unsubstituted or substituted one or more times by halogen, CF _3, OCF ₃ , Ci- ₈ -alkyl, hydroxy, Ci- ₈ -alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

C ₆ -i ₄ -aryl-Ci- ₅ -alkyl, in which the alkyl portion is branched or unbranched, which is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF ₃ OCF ₃ , Q-g-alkyl, hydroxy, Crg-alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH ₂ CH ₂ - groups are each optionally replaced by - CH=CH- or -C≡C-, and one or more -CH ₂ - groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., benzyl, phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc., especially benzyl),

a partially unsaturated Cs-^-carbocyclic group, which is unsubstituted or substituted one or more times by halogen, Ci- ₈ -alkyl, Ci- ₈ -alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy,

C ₆ "i ₄ -aryl, Crg-alkyl, Crg-alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-pyrrolyl, 3-thienyl, and particularly tetrahydrofuranyl such as tetrahydrofuran-3-yl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least

1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF ₃ , hydroxy, C ₆ -i ₄ -aryl, Ci- ₈ -alkyl, Ci- ₈ -alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH ₂ CH ₂ - groups are each optionally replaced by -CH=CH- or -C≡C- , and one or more -CH ₂ - groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);

is H,

Ci-g-alkyl, preferably Ci- ₄ -alkyl, which is branched or unbranched, and which is unsubstituted or substituted one or more times with halogen, hydroxyl, cyano, Ci- ₄ -alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, 2- hydroxyethyl, 2-hydroxy-2-methyl-propyl, 2-hydroxypropyl, 3- hydroxypropyl, etc.),

a partially unsaturated Cs-w-carbocycle-Crs-alkyl group wherein the alkyl portion which is branched or unbranched, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, Ci-g- alkyl, Ci-g-alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci- ₄ -alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.),

Cγ-ig-arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, and which is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF ₃ O, nitro, amino, Ci-g-alkyl, Ci-g-alkoxy, Ci-g-alkylamino, di-(Ci-g-alkyl)amino, and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc., particularly benzyl), or

a heterocycle-Ci- ₅ -alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroarylalkyl), wherein the heterocyclic portion has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched, the heterocycle- Ci- ₅ -alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, Ci- ₈ -alkyl, Ci- ₈ -alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, Ci-8-alkylamino, (Ii-(C ₁ -S- alkyl)amino, aminocarbonyl (i.e., carbamoyl, NH ₂ -CO-), C ₆ -i ₄ -aryl which is unsubstituted or substituted (e.g., aryl substituted one or more times by C _1-4 - alkyl, Ci_ ₄ -alkoxy, halogenated Ci_ ₄ -alkyl, and/or halogenated Ci_ ₄ -alkoxy, such as 4-difluoromethoxy-3-ethoxyphenyl), or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyrazinylmethyl, pyridylmethyl, 1-pyridylethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, pyrazolylmethyl, methylpyrazolylmethyl, oxazolylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, tetrahydrofuranylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, pyrimidinylmethyl, pyradizinylmethyl, thiadiazolylmethyl, etc.);

is H,

Ci-g-alkyl, preferably Ci- ₄ -alkyl, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, carboxy, cyano, Cr ₄ -alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, 3- carboxypropyl, etc.),

C ₃ - _1(r cycloalkyl, preferably C ₃ -g-cycloalkyl, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, carboxy, cyano, Cr ₄ - alkyl, Cr ₄ -alkoxy, or combinations thereof (e.g., cyclopentyl, cyclohexyl, carboxycyclohexyl),

C ₆ - ₁₄ -aryl and which is unsubstituted or substituted one or more times by halogen, Ci- ₈ -alkyl, C ₂ - ₈ -alkenyl, C ₂ - ₈ -alkynyl, hydroxy, Crs-alkoxy, Ci- ₈ - alkoxy-Ci- ₈ -alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, amino-Ci-s-alkyl (e.g., NH ₂ -CH ₂ -), amino-C ₂ -g-alkoxy (e.g., NH ₂ -CH ₂ CH ₂ O-), Crg-alkylamino (e.g., CH ₃ -NH-), di-(Ci- ₈ -alkyl)amino

(e.g., (CHs) ₂ NH-), Ci- ₈ -hydroxyalkyl (e.g., hydroxymethyl, hydroxypropyl, - C(CH ₃ ) ₂ -OH), hydroxamic acid (-C(O)-NHOH), pyrrolyl, tetrazole-5-yl, 2(- heterocycle)tetrazole-5-yl (e.g., 2-(2-tetrahydropyranyl)tetrazole-5-yl), C ₁ - _S - hydroxyalkoxy (e.g., HO-C(CH ₃ ) ₂ -CH ₂ -O-), Ci- ₈ -dihydroxyalkoxy (e.g., OCH ₂ CH(OH)CH ₂ OH), carboxy, Ci- ₈ -alkoxy-carbonyl (e.g., tert- butoxycarbonyl, ethoxycarbonyl), cyano, acyl, Ci-g-alkylthio (e.g., methylthio, ethylthio), Ci-g-alkylsulfinyl, Ci-g-alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), phenoxy, tri-Crg-alkylsilyloxy (e.g. tert- butyldimethylsilyloxy), R ⁵ -L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or

a heterocyclic group, which is fully saturated, partially saturated or unsaturated (e.g., heteroaryl), having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, Ci-g-alkyl, hydroxy, Ci-g-alkoxyl, oxo, Ci-g-alkoxy-Ci-g- alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, amino- Crg-alkyl, Crg-alkylamino, amino-C ₂ -g-alkoxy, di-Crg-alkylamino, C ₁ - _S - hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C (O) -NHOH), tetrazole-5-yl, Ci-g-hydroxyalkoxy, carboxy, Ci-g-alkoxy-carbonyl (e.g., tert- butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Crg-alkylthio (e.g., methylthio, ethylthio), Crg-alkylsulfinyl, Crg-alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), phenoxy, tri-Crg-alkylsilyloxy (e.g. tert- butyldimethylsilyloxy), R ⁵ -L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, benzisoxazolyl, etc.);

is H,

Q-g-alkyl, preferably Ci- ₄ -alkyl, which is unsubstituted or substituted one or more times with halogen, Ci- ₄ -alkyl, Ci- ₄ -alkoxy, oxo, hydroxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), Ci-g-alkylamino or di-Crg-alkylamino, preferably Ci- ₄ -alkylamino or CU-Cr ₄ - alkylamino (e.g., dimethylamino, etc.),

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.),

C ₃ -io-cycloalkyl, preferably C ₃ - ₈ -cycloalkyl, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, Ci- ₄ -alkoxy, Q- ₄ -alkyl, or combinations thereof (e.g., cyclopentyl),

C ₄ - ₁₆ -cycloalkylalkyl, preferably C ₄ - ₁₂ -cycloalkylalkyl, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

C _ό - ₁₄ -aryl which is unsubstituted or substituted one or more times by halogen,

Ci- ₈ -alkyl, hydroxy, Ci- ₈ -alkoxy, Crg-alkoxy-Crg-alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, amino-Crg-alkyl, amino-C ₂ - ₈ -alkoxy, Crg-alkylamino, di-Crg-alkylamino, Crg-hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, C ₁ -S- hydroxyalkoxy, carboxy, Crg-alkoxy-carbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Crg-alkylthio (e.g., methylthio, ethylthio), C ₁ - _S - alkylsulfinyl, Crg-alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), phenoxy, C ₃ -io-cycloalkyl, C _ό - ₁₄ -aryl, heteroaryl or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

C ₇ -i ₉ -arylalkyl wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, and which is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF ₃ O, nitro, amino, Crg-alkyl, Crg-alkoxy, amino, Q-g-alkylamino, or di-Crg-alkylamino, and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, Ci- ₈ -alkyl, hydroxy, Ci- ₈ -alkoxy, Crg-alkoxy-Crg-alkoxy, oxo, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, amino-Crg-alkyl, amino-C ₂ -g-alkoxy, Q-g-alkylamino, di-Crg-alkylamino, Crg-hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, C ₁ -S- hydroxyalkoxy, carboxy, Crg-alkoxy-carbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Crg-alkylthio, Crg-alkylsulfinyl, C ₁ - _S - alkylsulfonyl, phenoxy, C ₃ -io-cycloalkyl, C ₆ -i ₄ -aryl, heteroaryl or combinations thereof (e.g., pyrrolidinyl, 1,3-oxazoldiny, 1,3-dioxanyl, pyrazolyl, pyranyl, 1,2,4-triazolyl, imidazolidinyl, pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle- alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, Crg-alkyl, Crg-alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, Crg-alkylamino, di-Crg-alkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, morpholinylethyl, pyrrolidinylmethyl, etc.);

is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH ₂ - groups are each optionally replaced by -O-, -S-, - SO-, -SO ₂ -, -NR ⁶ -, -SO ₂ NH-, -NHSO ₂ -, -SO ₂ NR ⁶ -, -NR ⁶ SO ₂ -, -CHOH-, -

CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, - SCSNH-, or -NHCSNH- (e.g., -0-, CH ₂ -, -CO-, -CO-O-, -0-C0-, -CH ₂ -CO- O-, -CH ₂ CH ₂ -CO-O-, -CH ₂ CH ₂ CH ₂ -CO-O-, -CO-NH-, -NH-CO-, -CO-NH-O- , -NCH ₃ -CH ₂ -CO-, -CH ₂ CH ₂ CH ₂ -NH-CO-, -CH ₂ -CH ₂ -O-, -SO ₂ -NH-CH ₂ CH ₂ - 0-, -0-CH ₂ CH ₂ -O-, -0-CH ₂ -CO-O-, -CH ₂ -NH-CO-, -CO-NH-CH ₂ -, -SO ₂ - NH-, -NH-SO ₂ -, -CH ₂ -NH-SO ₂ -, -CH ₂ CH ₂ CH ₂ -SO ₂ -NH-, -NH-CH ₂ CH ₂ -SO ₂ -, -SO ₂ -, -CO-NH-SO ₂ -, etc.); and

is H,

Ci- ₈ -alkyl, preferably Ci- ₄ -alkyl, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci- ₄ -alkyl, C ₁ - ₄ -alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.);

Cγ-ig-arylalkyl wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, and which is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF ₃ O, nitro, amino, Crg-alkyl, Crg-alkoxy, C ₁ - _S - alkylamino, or di-Ci-g-alkylamino, and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.);

C ₆ -i ₄ -aryl which is unsubstituted or substituted one or more times by halogen, C ₁ - ₈ -alkyl, hydroxy, Crg-alkoxy, Crg-alkoxy-Crg-alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, amino-Crg-alkyl, amino-C ₂ -g-alkoxy, C ₁ - g-alkylamino, di-Crg-alkylamino, Crg-hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, Crg-hydroxyalkoxy, carboxy, Ci-g-alkoxy-carbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Ci-g-alkylthio, Crg-alkylsulfinyl, or Crg-alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

wherein at least one of R ³ and R ⁴ is other than H. Some compounds encompassed by the genus of Formula I are disclosed in U.S. Patent No. 6,699,890, U.S Patent No. 7,205,320, copending Application Serial No. 11/602,283, copending U.S. Application Serial No. 10/622,833, U.S. Patent No. 7,087,625, copending U.S. Application Serial No. 11/378,615, filed March 20, 2006, copending U.S. Application Serial No. 11/008,775, filed December 10, 2004, and copending U.S. Application Serial No. 11/449,868, filed June 9, 2006.

According to a further aspect of the invention, the compounds are of Formula (I) in which:

R ¹ is cycloalkyl having 3 to 10, preferably 3 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, Ci- ₄ -alkyl, Ci- ₄ -alkoxy, or combinations thereof, e.g., cyclopropyl, cyclobutyl, cyclopentyl (such as 3-[[4-(cyclopropyloxy)-3- ethoxyphenyl](pyrimidin-5-ylmethyl)amino]benzoic acid, compound 272); and/or

R ³ is alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is substituted one or more times with hydroxyl, e.g., 2- hydroxyethyl, 2-hydroxy-2-methyl-propyl, 2-hydroxypropyl, 3-hydroxypropyl (such as 2-[[3,4bis(difluoromethoxy)phenyl](phenyl)amino]-ethanol, compound 266 ; 1 - [ [3 ,4-bis (difluoromethoxy)phenyl] (3-chlorophenyl)amino] - 2-methylpropan-2-ol, compound 267; l-[[3,4-bis(difluoromethoxy)phenyl](3- chlorophenyl)amino]propan-2-ol, compound 268; and 3-[[3,4- bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]propan-l-ol , compound 269), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroarylalkyl) and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heterocycle- alkyl group is substituted one or more times in the heterocycle portion by at least aminocarbonyl (i.e., carbamoyl, NH ₂ -CO-), unsubstituted aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms and which is substituted

(e.g., aryl substituted one or more times by Ci- ₄ -alkyl, Ci- ₄ -alkoxy, halogenated Ci_ ₄ -alkyl, and/or halogenated C^-alkoxy), or combinations thereof, and is optionally substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., 4-difluoromethoxy-3-ethoxyphenyl), etc.) (such as 3-{ { [l-(aminocarbonyl)-piperidin-3-yl]methyl}[3- (cyclopentyloxy)-4-methoxyphenyl] amino Jbenzoic acid, compound 234; and

4- [ [4- (difluoromethoxy) -3 -ethoxyphenyl] ( { 2- [4- (difluoromethoxy) -3 - ethoxyphenyl]-l,3-oxazol-5-yl}methyl)amino]benzoic acid, compound 273); and/or

is alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, carboxy, cyano, Ci- ₄ -alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, 3-carboxypropyl, etc.) (such as 4-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]but anoic acid, compound 270), or

cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is substituted one or more times by carboxy, e.g., carboxycyclohexyl (such as cis-4-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]cyc lohexane- carboxylic acid, compound 271), or

aryl having 6 to 14 carbon atoms and which is substituted one or more times by at least (substituted-C ₁ _ ₈ -alkoxy)-C ₁ _ ₈ -alkoxy (see R -L) (e.g., (alkoxy substituted one or more times by halogen, hydroxy, carboxy, and/or cyano)- alkoxy such as hydroxyalkoxy)-alkoxy (e.g., OCH ₂ CH(OH)CH ₂ OCH ₃ ), dihydroxyalkoxy (e.g., OCH ₂ CH(OH)CH ₂ OH), or combinations thereof (such as (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]-phenoxy}propane-l,2-diol, compound 233; (2R)-3-{3-[[3-

(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}propane-l,2-diol, compound 238; (2R)-3-{4-[[3,4- bis (difluoromethoxy )phenyl] (pyridin- 3 -ylmethyl) amino] phenoxy } propane- 1,2-diol, compound 240; (2R)-3-{4-[[3-(cyclopentyloxy)-4- methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino] -phenoxy Jpropane- 1 ,2-diol, compound 241; (2R)-3-{4-[(3,4-dimethoxyphenyl)(pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol, compound 244; 5-[[3,4- bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino]-2-{ [(2R)-2,3- dihydroxypropyl]oxy} benzoic acid, compound 246; (2R)-3-{3-[[3,4- bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenoxy } propane- 1,2-diol, compound 255; (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3- thiazol-5-ylmethyl)amino]phenoxy}propane-l,2-diol, compound 258; (2R)-3-

{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmeth yl)amino]- phenoxy}propane-l,2-diol, compound 259; and l-{3-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]phe noxy}-3- methoxypropan-2-ol, compound 265), or

a heterocyclic group, which is fully saturated or partially saturated, having 5 to

10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, Ci- ₈ -alkyl, hydroxy, Cμg-alkoxy, oxo, Ci.g-alkoxy-Ci.g-alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, amino-Crg-alkyl, amino-C ₂ -g-alkoxy, Ci-g-alkylamino, di-Ci-g-alkylamino, (substituted-Ci-g-alkyl)amino (see R ⁵ -L)

(e.g., the alkyl group is substituted one or more times by halogen, hydroxy, carboxy and/or cyano, for example, -NHCH(CH ₃ )CH ₂ OH, NHCH(CH ₂ OH)CH ₂ CH ₃ , NHCH ₂ CH(OH)CH ₂ CH ₃ , NHCH ₂ CH ₂ CH(OH)CH ₃ , NHCH ₂ CH(OH)CH ₃ , NHCH ₂ C(OH)(CH ₃ ) ₂ , etc.), Ci- ₈ -alkyl(substituted-Ci- ₈ - alkyl)amino (See R -L) (e.g., alkyl(alkyl substituted one or more times by halogen, hydroxy, carboxy and/or cyano)-amino such as - N(CH ₃ )CH ₂ CH(OH)-CH ₂ OH), Ci- ₈ -hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, Ci-g-hydroxyalkoxy, carboxy, Ci-g-alkoxy-carbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Ci.g-alkylthio, Ci_g-alkylsulfinyl, Cμg-alkylsulfonyl, phenoxy, tri-Ci_g- alkylsilyloxy (e.g. tert-butyldimethylsilyloxy), R ⁵ -L-, or combinations thereof (such as 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]pyridin-2(lH)-one, compound 235; 5-[[3-(cyclopentyloxy)-4- methoxyphenyl] (pyridin-3-ylmethyl)amino] -2-methyl- 1 ,2-benzisoxazol- 3(2H)-one, compound 242; 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-

3-ylmethyl)amino]-l,2-benzisoxazol-3(2H)-one, compound 243; 5-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]-l, 2-benzisoxazol- 3(2H)-one, compound 261; and 6-[[3,4-bis(difTuoromethoxy)phenyl](l,3- thiazol-5-ylmethyl)amino]-l,2-benzisoxazol-3(2H)-one, compound 263), or

a heterocyclic group, which is unsaturated (i.e., heteroaryl) (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is substituted one or more times by at least oxo, (substituted-Ci- ₈ -alkyl)amino (See R ⁵ -L) (e.g., the alkyl group is substituted one or more times by halogen, hydroxy, carboxy and/or cyano, for example, - NHCH(CH ₃ )CH ₂ OH, NHCH(CH ₂ OH)CH ₂ CH ₃ , NHCH ₂ CH(OH)CH ₂ CH ₃ , NHCH ₂ CH ₂ CH(OH)CH ₃ , NHCH ₂ CH(OH)CH ₃ , NHCH ₂ C(OH)(CH ₃ ) ₂ , etc.), or Ci-g-alky^substituted-Ci-g-alky^amino (See R ⁵ -L) (e.g., alkyl(alkyl substituted one or more times by halogen, hydroxy, carboxy and/or cyano)- amino such as -N(CH ₃ )CH ₂ CH(OH)CH ₂ OH), or combinations thereof (such as 5-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridin-3- ylmethyl)amino]pyridin-2(lH)-one, compound 235; 2-({5-[[3-

(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amin o]pyridin-2- yl}amino)propan-l-ol, compound 236; 3-[{5-[[3-(cyclopentyloxy)-4- methoxyphenyl](pyridin-3-ylmethyl)amino]pyridin-2- yl}(methyl)amino]propane-l,2-diol, compound 237; 2-({5-[[3- (cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amino]p yridin-2- yl}amino)butan-l-ol, compound 247; l-({5-[[3-(cyclopentyloxy)-4- methoxyphenyl] (pyridin-3-ylmethyl)amino]pyridin-2-yl } amino)butan-2-ol, compound 248; 4-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]pyridin-2-yl}amino)butan-2-ol, compound 249; l-({5-[[3- (cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amino]p yridin-2- yl}amino)-2-methylpropan-2-ol trifluoroacetic acid salt, compound 252; 3- [{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]pyridin-2-yl } (methyl)amino]propane- 1 ,2-diol, compound 253; and 3-[{5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]pyridin-2-yl } (methyl)amino]propane- 1 ,2-diol, compound

254); and/or R ⁵ is a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is substituted one or more times by at least oxo (such as (5S)-5-({3-[[3- (cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amino]p henoxy}- methyl)pyrrolidin-2-one, compound 58; 4-{3-[[3,4- bis(difluoromethoxy)phenyl]-(pyridin-3-ylmethyl)amino]phenyl }-2-methyl- l,2-dihydro-3H-pyrazol-3-one, compound 105; 5-{3-[[3-(cyclopentyloxy)-4- methoxyphenyl](pyridin-3-ylmethyl)amino]phenyl}imidazolidine -2,4-dione, compound 239; 5-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl}-imidazolidine-2,4-dione, compound 245; l-({5-[[3-

(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amin o]pyridin-2- yl}amino)propan-2-ol, compound 250; 5-{3-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]phe nyl}- 1,3,5- trimethylimidazolidine-2,4-dione, compound 256; 5-{3-[[3,4- bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione, compound 257; 4-{3-[[3,4- bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino]phenyl} imidazolidin- 2-one, compound 260; 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-l,3-oxazolidin-2-one, compound 262; and 4-{3- [[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino]p henyl}-l,3- oxazolidin-2-one, compound 264);

and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

According to another aspect of the invention, both R ³ and R ⁴ are other than H.

In the compounds of Formula I, R ¹ preferably is Ci_ ₄ -alkyl, halogenated C^-alkyl preferably fluorinated and/or chlorinated, or C ₃ _io-cycloalkyl, especially C ₃ _ ₆ -cycloalkyl, which is optionally substituted. Suitable examples of R ¹ include, but are not limited to, methyl, ethyl, isopropyl, difluoromethyl, trifluoroethyl, trifluoromethyl, or cyclopropyl, in particular CH ₃ , C ₂ H ₅ , CHF ₂ , CF ₃ , CH ₂ CF ₃ , and cyclopropyl, especially methyl and difluoromethyl. In the compounds of Formula I, R ² is preferably (i) Ci.g-alkyl, especially C _1-4 -alkyl, or halogenated Cμg-alkyl, especially halogenated Ci_ ₄ -alkyl, preferably fluorinated and/or chlorinated, (ii) C ₃ _ ₈ -cycloalkyl, especially C ₃ _ ₆ -cycloalkyl, which is unsubstituted or substituted, (iii) C ₄ -i ₂ -cycloalkylalkyl which is unsubstituted or substituted, (iv) arylalkyl which is unsubstituted or substituted, especially benzyl, or (v) tetrahydrofuranyl, especially tetrahydrofuran-3-yl. Suitable examples of R ² include, but are not limited to, methyl, ethyl, isopropyl, butyl, difluoromethyl, trifluoroethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, and benzyl, in particular methyl, ethyl, cyclopentyl, and difluoromethyl.

In the compounds of Formula I, R ³ is preferably

(i) Ci- ₄ -alkyl which is branched or unbranched and which is unsubstituted or substituted one or more times by, for example, hydroxyl and/or carboxy (such as, but not limited to, methyl, ethyl, n-propyl, n-butyl, (CH ₂ ) ₂ OH, CH ₂ C(CH ₃ ) ₂ OH, CH ₂ CH(CH ₃ )OH, (CH ₂ ) ₃ OH or (CH ₂ ) ₃ COOH;

(ii) C _7- i ₉ -arylalkyl, which may be substituted or unsubstituted in the alkyl and/or the aryl portions, such as, but not limited to, substituted or unsubstituted benzyl (e.g., fluorobenzyl, difluorobenzyl, cyanobenzyl),

(iii) a heterocyclic-alkyl group, which may be substituted or unsubstituted in the alkyl and/or heterocyclic portions, wherein the heterocyclic portion is saturated or partially unsaturated. Suitable examples include, but not limited to, substituted or unsubstituted pyridinylmethyl (e.g., pyridin-3-ylmethyl, pyridin-4-ylmethyl, 5-methoxypyridin-3- ylmethyl), substituted or unsubstituted dihydropyridinylmethyl (e.g., 6-oxo-l,6- dihydropyridin-3-yl)methyl), substituted or unsubstituted oxazolylmethyl (e.g., l,3-oxazol-5- ylmethyl, 4-methyl-l,3-oxazol-5-ylmethyl, 2-[4-(difluoromethoxy)-3-ethoxyphenyl]-l,3- oxazol-5-yl}methyl), substituted or unsubstituted pyrazolylmethyl (e.g., lH-pyrazol-4- ylmethyl, l-methyl-lH-pyrazol-4-yl)methyl), substituted or unsubstituted thiazolylmethyl (e.g., l,3-thiazol-5-ylmethyl), substituted or unsubstituted pyrimidinylmethyl (e.g., pyrimidin-5-ylmethyl, 2-(dimethylamino)pyrimidin-5-ylmethyl), substituted or unsubstituted pyridazinylmethyl (e.g., pyridazin-4-ylmethyl), and substituted or unsubstituted pyrazinylmethyl (e.g., pyrazin-2-ylmethyl); (iv) a heterocyclic-alkyl group, which may be substituted or unsubstituted, wherein the heterocyclic portion is fully saturated. Suitable examples include, but not limited to, substituted or unsubstituted piperidinylmethyl (e.g., piperidin-3-ylmethyl, 1-aminocarbonyl piperidin-3-ylmethyl, and piperidin-4-ylmethyl).

In the compounds of Formula I, examples of further preferred R ³ groups include, but are not limited to, benzyl, pyrazolylmethyl, pyridinylmethyl, oxazolylmethyl, thiazolylmethyl, pyrimidinylmethyl, pyridizinylmethyl, pyrazinylmethyl, and thiadiazolylmethyl, which in each case is unsubstituted or substituted (e.g., substituted one or more times by halogen). Examples of such R ³ groups are pyridin-3-ylmethyl, l,3-oxazol-5- ylmethyl, l,3-thiazol-5-ylmethyl, and pyrimidin-5-ylmethyl.

In the compounds of Formula I, R ⁴ is preferably aryl or heteroaryl, especially phenyl, pyridinyl, or benzisoxazole, more preferably phenyl and pyridinyl, which in each case is unsubstituted or is substituted one or more times. Preferred substituents include, but are not limited to, OH, F, Cl, CF ₃ , alkyl (such as methyl or ethyl), oxo, alkoxy (such as methoxy and ethoxy), hydroxyalkoxy, (dihydroxy)alkoxy, NHCOCH ₃ , (substituted-alkyl)amino, alkyl(substituted-alkyl)amino, CN, CONHOH, CONHCH ₂ CH ₂ OH, COOH, CH ₂ COOH, (CH ₂ ) ₂ COOH, COOalkyl, and combinations thereof.

Thus, for example, R ⁴ can be phenyl or pyridinyl (especially phenyl) which is substituted one or more times and at least one of the substituents is a R ⁵ -L- group selected from the following: -COOH, -CO-NH ₂ , -CO-NH-C 1-4-alkyl, -CO-N(C ₁ . ₄ -alkyl) ₂ ,-CO-NH- SO ₂ -Ci_ ₄ -alkyl, ,-CO-N(Ci_ ₄ -alkyl)-SO ₂ -Ci_ ₄ -alkyl, -NH-SO ₂ -Ci_ ₄ -alkyl, -N(d_ ₄ -alkyl)-SO ₂ - Ci_ ₄ -alkyl, -SO ₂ -NH ₂ , -SO ₂ -NH-Ci_ ₄ -alkyl, -SO ₂ -N(Ci_ ₄ -alkyl) ₂ , -O-Ci_ ₄ -alkylene-COO-Ci_ ₄ - alkyl (e.g., -0-CH ₂ -COO-C i- ₄ -alkyl), -0-CH ₂ -CHOH-CH ₂ -O-CH ₃ , -O-Ci. ₄ -alkylene-OH (e.g., -0-CH ₂ CH ₂ -OH), -O-C^-alkylene-heterocycle (e.g., -O-CH^heterocycle), -NH-CH ₂ - aryl, -N(C ₁ _ ₄ -alkyl)-CH ₂ -aryl, -d_ ₄ -alkylene-OH, -d_ ₄ -alkylene-COOH, -NH-heterocycle, - NH-C^-alkylene-heterocycle, -S-Ci_ ₄ -alkyl, -SO ₂ -Ci_ ₄ -alkyl, -NH-C ₁ _ ₄ -alkylene-SO ₂ -C ₁ _ ₄ - alkyl, -N(Ci-4-alkyl)-Ci-4-alkylene-CO-N(Ci-4-alkyl) ₂ , -CO-NH-OH, -CO- Ci-4-alkyl, -0-C ₁ . ₄ -alkylene-C(OH)(CH ₃ ) ₂ , -NH-Ci-4-alkylene-OH, -N(Ci _-4 - alkyl)-CH ₂ -CHOH-CH ₂ -CHOH, -0-CH ₂ -CHOH-CH ₂ -CHOH, and -NH-C _M -alkylene- CHOH-Ci-4-alkyl. R ⁴ can also preferably be substituted or unsubstituted cycloalkyl, e.g., carboxycyclohexyl.

In addition, when R ⁴ is aryl, especially, phenyl, preferred substituents include R ⁵ -L-, e.g., R ⁵ -, R ⁵ -O-, R ⁵ -CO-, R ⁵ -NH-CO-, R ⁵ -SO ₂ -NH-, R ⁵ -SO ₂ -NR ⁶ -, R ⁵ -NHR ⁶ -SO ₂ -, R ⁵ -SO ₂ - NH-alkylene-O-, NH ₂ -alkyl-NH-CO-, R ⁵ -alkylene-NH-CO-, alkyl-CO-NH-alkyl, as well as methyl, ethyl, Cl, F, CN, OCH ₃ , CF ₃ , amino, nitro, HOCH ₂ and COOH.

In R ⁵ -SO ₂ -NR ⁶ -, R ⁵ -NHR ⁶ -SO ₂ -, R ⁶ is preferably aryl or arylalkyl, e.g., substituted or unsubstituted phenyl or benzyl.

When R ⁴ is aryl substituted by R ⁵ -SO ₂ -NH- it is preferably a substituted phenyl group and R ⁵ is preferably methyl, ethyl, propyl or phenyl.

When R ⁴ is aryl substituted by R ⁵ -SO ₂ -NH-alkylene-O- it is preferably a substituted phenyl. In such cases, R is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -.

When R ⁴ is aryl substituted by R ⁵ -L- it is preferably substituted phenyl. In such cases, preferred R ⁵ groups include benzyl, tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L is preferably a single bond, -O-, -CO-, -CH ₂ -, -CH ₂ CH ₂ -, - CH ₂ CH ₂ CH ₂ -, -CH ₂ -O-, -CH ₂ CH ₂ -O-, -CH ₂ CH ₂ CH ₂ -O-, -CH ₂ -NH-CH ₂ CH ₂ -O-, -CO-NH-, - NH-CO-, -SO ₂ -NR ⁶ -, -NHR ⁶ -SO ₂ -, -SO ₂ -, or -CONHSO ₂ -.

According to a further aspect of the invention, the compounds of Formula I are selected from:

1) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-N- (methylsulfonyl)benzamide

2) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-N- (ethylsulfonyl)benzamide

3) 3-{ (3-fluorobenzyl)[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl] amino Jbenzoic acid

4) 3-[(3,4-dimethoxyphenyl)(3-fluorobenzyl)amino]benzoic acid

5 ) 3 - [ (3 -ethoxy-4-methoxyphenyl) (3 -fluorobenzyl) amino] benzoic acid

6) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid 7) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid

8) 3-[(2,6-difluorobenzyl)(3,4-dimethoxyphenyl)amino]benzoic acid

9) 3-[(2,6-difluorobenzyl)(3-ethoxy-4-methoxyphenyl)amino]benzo ic acid

10) 3-[(2,6-difluorobenzyl)(3-isopropoxy-4-methoxyphenyl)amino]b enzoic acid 11) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](2,6-difluorobenzyl)am ino]benzoic acid

12) 3-((2,6-difluorobenzyl) { 4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl}amino)benzoic acid

13) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethyl)a mino]benzoic acid

14) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid 15) 3-[[3,4-bis(difluoromethoxy)phenyl](2,6-difluorobenzyl)amino ]benzoic acid

16) 3-[[3,4-bis(difluoromethoxy)phenyl](3-fluorobenzyl)amino]ben zoic acid

17) 3-{ (2,6-difluorobenzyl)[4-(difluoromethoxy)-3-methoxyphenyl]ami no}benzoic acid

18) 3-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

19) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](3-fluorobenzyl)amin o]benzoic acid 20) 3-[[3,4-bis(difluoromethoxy)phenyl](2-fluorobenzyl)amino]ben zoic acid

21) 3-[[3,4-bis(difluoromethoxy)phenyl](4-fluorobenzyl)amino]ben zoic acid

22) 3-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl } amino)benzonitrile

23) N-(3-fluorobenzyl)-4-methoxy-N-[4-(methylsulfonyl)phenyl]-3- [(3R)- tetrahydrofuran- 3 -yloxy] aniline

24) N-ethyl-N-[4-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrof uran-3- yloxy]phenyl } amino)phenyl] ethanesulf onamide

25) 3-{ (3-cyanobenzyl)[3-(cyclopentyloxy)-4-methoxyphenyl]amino}ben zoic acid

26) 3-{ [3-(cyclopentyloxy)-4-methoxyphenyl] [(6-OXO- l,6-dihydropyridin-3- yl)methyl] amino Jbenzoic acid

27) 5-bromo-N-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(pyridin-3- ylmethyl)pyridin-2- amine

28) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (piperidin-3-ylmethyl)amino]benzoic acid

29) 4-{ [3-(cyclopentyloxy)-4-methoxyphenyl][(6-oxo-l,6-dihydropyrid in-3- yl)methyl] amino Jbenzoic acid 30) Ethyl {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy } acetate

31) 2-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}ethanol

32) 3-(cyclopentyloxy)-N-(4-{ [(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy}phenyl)-4- methoxy-N- (pyridin- 3 -ylmethyl) aniline

33) N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-m ethyl-N(5)-(pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

34) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylmethy l)amino]benzoic acid

35) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid

36) {3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]phenyl}acetic acid

37) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-ethylbenzoic acid

38) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-4- methylbenzoic acid

39) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylmethy l)amino]benzoic acid

40) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

41) N-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(pyridin-3-ylmethyl )-6-pyrrolidin-l- ylpyridin- 3 - amine

42) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-(2-morpholin- 4-ylethyl)-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

43) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

44) N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-( pyridin-3- ylmethyl)pyridine-2,5-diamine

45) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-4-ylmethyl)amino]benzoic acid

46) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

47) 4- [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (pyridazin- 3 -ylmethyl) amino] benzoic acid

48) 3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (pyridazin- 3 -ylmethyl) amino] benzoic acid

49) {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]phenyl}acetic acid 50) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (piperidin-4-ylmethyl)amino]benzoic acid

51) 4-([3-(cyclopentyloxy)-4-methoxyphenyl] { [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid

52) 3-([3-(cyclopentyloxy)-4-methoxyphenyl] { [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid

53) 3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl Jpropan- 1 -ol

54) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]nicotinic acid

55) 3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl}propanoic acid

56) 3-(cyclopentyloxy)-4-methoxy-N-[3-(2-methyl-l,3-thiazol-4-yl )phenyl]-N-(pyridin-3- ylmethyl)aniline

57) {3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amin o]phenyl}acetic acid

58) (5S)-5-({3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}methyl)pyrrolidin-2-one

59) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid

60) 3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid

61) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-[2-(methylsul fonyl)ethyl]-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine 62) 3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyridin -3-ylmethyl)aniline

63) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr idin-3- ylmethyl)aniline

64) 2-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } (methyl)amino] -N,N-dimethylacetamide 65) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-(pyridin-3-yl methyl)-N(2)- (tetrahydro-2H-pyran-4-yl)pyridine-2,5-diamine

66) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyr idin-3- ylmethyl)aniline

67) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-N,2- dihydroxybenzamide

68) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-3- methylbenzoic acid

69) {4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amin o]phenyl}acetic acid 70) 3-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid

71) 4-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid 72) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid

73) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid

74) 4-[[3,4-bis(difluoromethoxy)phenyl] (pyridazin-3-ylmethyl)amino]benzoic acid 75) 3-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl)ami no]benzoic acid

76) 3,4-bis(difluoromethoxy)-N-[4-(ethylthio)phenyl]-N-(pyridin- 3-ylmethyl)aniline

77) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline

78) 3,4-bis(difluoromethoxy)-N-[4-(ethylsulfonyl)phenyl]-N-(l,3- thiazol-5- ylmethyl)aniline

79) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline

80) 4-[[3,4-bis(difluoromethoxy)phenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

81) 5-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino] nicotinic acid

82) 3-[[3,4-bis(difluoromethoxy)phenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

83) 5-[[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]nicotinic acid

84) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]-2- hydroxyphenyl } ethanone 85) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2,2,2- trifluoroethanone

86) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}ethanone

87) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]phenol

88) 1 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } ethanone 89) 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}propan-2- ol

90) 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2,3-difluorophenol 91) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid

92) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid 93) l-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]pyridin-3- yljethanone

94) 1 - { 5 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] pyridin-3 - yljethanone

95) N-[3,4-bis(difluoromethoxy)phenyl]-5-(2-methyl-l,3-dioxolan- 2-yl)-N-(pyridin-3- ylmethyl)pyridin-3-amine

96) 3,4-bis(difluoromethoxy)-N-[3-(lH-pyrazol-3-yl)phenyl]-N-(py ridin-3- ylmethyl)aniline

97) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

98) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]nicotinic acid 99) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid

100) {4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid

101) 3,4-bis(difluoromethoxy)-N-(PFi ^din -3-ylmethyl)-N-[3-(lH-l,2,4-triazol-5- yl)phenyl] aniline 102) 4-{3-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 -ylmethyl) amino] phenyl } - 1 - methyl- lH-pyrazol-5-ol

103) {3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid

104) 4-[[3- (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid

105) 4- { 3- [[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2-methyl- 1 ,2-dihydro-3H-pyrazol-3-one

106) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid 107) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid

108) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid

109) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid 110) 3-[[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl](l,3-thiazo l-5- ylmethyl)amino]benzoic acid

111) 4-methoxy-N-[4-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline 112) l-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanone

113) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyr imidin-5- ylmethyl)aniline

114) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr imidin-5- ylmethyl)aniline

115) 4-methoxy-N-[3-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline

116) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid 117) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5- ylmethyl)amino]phenyl}ethanone

118) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr azin-2- ylmethyl)aniline

119) 1 - { 4- [ [3 ,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]phenyl } ethanone 120) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid

121) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-th iazol-5- ylmethyl)amino]benzoic acid

122) l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenoxy}-2- methylpropan-2-ol

123) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-2- methylpropan-2-ol

124) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

125) 3-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid 126) 3-[[3-butoxy-4-(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]benzoic acid

127) 3-{ [3,4-bis(difluoromethoxy)phenyl][(l-methyl-lH-pyrazol-4- yl)methyl] amino Jbenzoic acid

128) 4-[[3-butoxy-4-(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]benzoic acid

129) 4-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid 130) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]b enzoic acid

131) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)ami no]benzoic acid

132) 3-(cyclopropylmethoxy)-4-methoxy-N-[4-(methylsulfonyl)phenyl ]-N-(l,3-thiazol-5- ylmethyl)aniline 133) l-{4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]phenyl}ethanone

134) 3,4-bis(difluoromethoxy)-N-methyl-N-[4-(methylsulfonyl)pheny l]aniline

135) 4- [ [3 - (cyclopropylmethoxy)-4- (difluoromethoxy)phenyl] (pyridin- 3 - ylmethyl)amino]benzoic acid 136) 3,4-bis(difluoromethoxy)-N-[4-methyl-3-(methylsulfonyl)pheny l]-N-(l,3-thiazol-5- ylmethyl)aniline

137) {4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid

138) 4-[(3,4-dimethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoi c acid 139) {3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid

140) {4- [ [3 ,4-bis (difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]phenyl } acetic acid

141) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-oxazol-5-ylmethyl)am ino]benzoic acid

142) 4-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid 143) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

144) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid

145) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzenesulfonamide

146) 4- [ [3 ,4-bis (difluoromethoxy)phenyl] ( 1 ,3-thiazol-5- ylmethyl)amino]benzenesulfonamide

147) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyrazin-2-ylmethyl)amino]benzoic acid

148) 3-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid

149) 3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 150) 4-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 151) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzamide

152) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzamide

153) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrimidin-5-ylmethy l)amino]benzoic acid

154) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrazin-2-ylmethyl) amino]benzoic acid

155) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid

156) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid

157) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid

158) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzamide 159) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid

160) 5-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]nicotinic acid

161) 4-[[3-(difluoromethoxy)-4-methoxyphenyl](pyrazin-2-ylmethyl) amino]benzoic acid 162) N-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2- methylphenyl } methanesulf onamide

163) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}methanesulfonamide

164) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanesulfonamide

165) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzenesulfonamide

166) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid 167) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid

168) 4- [ [3 - (cyclopropylmethoxy)-4- (difluoromethoxy)phenyl] (pyrimidin- 5 - ylmethyl)amino]benzoic acid 169) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

170) 4-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid

171) 3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] ( 1 -pyridin- 3 -ylethyl) amino] benzoic acid 172) 3-[(3,4-dimethoxyphenyl)(l-pyridin-3-ylethyl)amino]benzoic acid

173) 4- [ (4-ethoxy- 3 -methoxyphenyl) ( 1 ,3 - thiazol- 5 -ylmethyl) amino] benzoic acid

174) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-thiazol-5- ylmethyl)aniline

175) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl} acetic acid

176) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-oxazol-5- ylmethyl)aniline

177) {4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid 178) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5- ylmethyl)amino]phenyl } acetic acid

179) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid

180) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid 181) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid

182) 4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid

183) 4- [ [3 - (cyclopropylmethoxy)-4-methoxyphenyl] (l,3-oxazol-5 -ylmethyl) amino] benzoic acid 184) 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid

185) 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid

186) 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](pyrimidin-5-y lmethyl)amino]benzoic acid 187) 4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(5-methoxypyridin-3- yl)methyl] amino Jbenzoic acid

188) 4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(4-methyl-l,3-oxazol-5- yl)methyl] amino Jbenzoic acid 189) 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid

190) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-4-ylmethy l)amino]benzoic acid

191) 4-[(3,4-diethoxyphenyl)(pyrimidin-5-ylmethyl)amino]benzoic acid

192) 4-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid 193) 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl) amino]benzoic acid

194) 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

195) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

196) 4-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid 197) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid

198) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid

199) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid 200) 3-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid

201) 3-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid

202) 4-[(4-ethoxy-3-isopropoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid

203) 3-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid 204) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid

205) 4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5 - ylmethyl)amino]benzoic acid

206) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid 207) 4-[(3-ethoxy-4-isopropoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid

208) 4-[(4-ethoxy-3-isopropoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid

209) 4-[(4-ethoxy-3-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid

210) 3-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid

211) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrimi din-5- ylmethyl)amino]benzoic acid 212) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

213) 3-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid

214) 4-[[3-(benzyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5-ylm ethyl)amino]benzoic acid

215) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid

216) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid

217) 4-[[3-ethoxy-4-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid 218) 3-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

219) 4-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid

220) 4-[(3,4-diethoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]benzoic acid

221) 4-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid

222) 3-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid 223) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

224) 3-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid

225) 4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(2-methyl-l,3-thiazol-5 - yl)methyl] amino Jbenzoic acid 226) 3-[(4-ethoxy-3-methoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]b enzoic acid

227) 3-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid

228) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

229) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](tetrahydrofuran-3-yl methyl)amino]benzoic acid 230) 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl] (pyrimidin-5- ylmethyl)amino]benzoic acid

231) 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid,

232) 4- [ [4-methoxy-3 - (trifluoromethoxy)phenyl] (l,3-oxazol-5 -ylmethyl) amino] benzoic acid,

233) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy } propane- 1 ,2-diol 234) 3-{ { [l-(aminocarbonyl)piperidin-3-yl]methyl}[3-(cyclopentyloxy)- 4- methoxyphenyl] amino Jbenzoic acid

235) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]pyridin-2(lH)- one 236) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)propan- 1 -ol

237) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } (methyl)amino]propane- 1 ,2-diol

238) (2R)-3-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}propane-l,2-diol

239) 5-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione

240) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol 241) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol- 5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

242) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-methyl-l,2- benzisoxazol-3(2H)-one

243) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-l,2- benzisoxazol-3(2H)-one

244) (2R)-3-{4-[(3,4-dimethoxyphenyl)(pyridin-3-ylmethyl)amino]ph enoxy}propane-l,2- diol

245) 5-{4-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione 246) 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2-{ [(2R)-2,3- dihydroxypropyl]oxy Jbenzoic acid

247) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)butan- 1 -ol

248) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)butan-2-ol

249) 4-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)butan-2-ol

250) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)propan-2-ol 251) 5 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione

252) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)-2-methylpropan-2-ol trifluoroacetic acid salt 253) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-yl methyl)amino]pyridin- 2-yl } (methyl)amino]propane- 1 ,2-diol

254) 3-[{5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]pyridin-2- yl } (methyl)amino]propane- 1 ,2-diol

255) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy}propane-l,2-diol

256) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenyl}- 1,3,5- trimethylimidazolidine-2,4-dione

257) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione 258) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

259) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

260) 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidin-2-one

261) 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one

262) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-l,3- oxazolidin-2-one 263) 6-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one

264) 4- { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } - 1 ,3 - oxazolidin-2-one

265) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-3- methoxypropan-2-ol

266) 2-[[3,4-bis(difluoromethoxy)phenyl] (phenyl)amino]ethanol

267) l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]-2- methylpropan-2-ol

268) l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-2-ol

269) 3-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-l-ol 270) 4-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]butanoic acid

271) cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino] cyclohexanecarboxylic acid

272) 3-[[4-(cyclopropyloxy)-3-ethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid, 273) 4- [ [4- (difluoromethoxy) -3 -ethoxyphenyl] ( { 2- [4- (difluoromethoxy) -3 -ethoxyphenyl] - l,3-oxazol-5-yl}methyl)amino]benzoic acid

279) 3-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid,

280) 4-[[3-(difluoromethoxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid, 281) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,2,3-thiadiazol-5-y lmethyl)amino]benzoic acid,

282) 4-[[3-hydroxy-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid,

283) 3-[[4-ethoxy-3-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid,

284) 3-[[3,4-diethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid, 285) 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid,

286) 3-[[3-cyclopropyloxy-4-methoxyphenyl](l,3-oxazol-5-ylmethyl) amino]benzoic acid,

287) 3-[[3-cyclobutyloxy-4-difluoromethoxyphenyl](pyrimidin-5-ylm ethyl)amino]benzoic acid, and

288) 3-[[3-cyclopropyloxy-4-difluoromethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to further aspect of the invention, the compounds of Formula I are selected from:

233) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol 234) 3-{ { [l-(aminocarbonyl)piperidin-3-yl]methyl}[3-(cyclopentyloxy)- 4- methoxyphenyl] amino Jbenzoic acid

235) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]pyridin-2(lH)- one

236) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)propan-l-ol

237) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } (methyl)amino]propane- 1 ,2-diol

238) (2R)-3-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol 239) 5-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione

240) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

241) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol- 5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

242) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-methyl-l,2- benzisoxazol-3(2H)-one

243) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-l,2- benzisoxazol-3(2H)-one 244) (2R)-3-{4-[(3,4-dimethoxyphenyl)(pyridin-3-ylmethyl)amino]ph enoxyJpropane-l,2- diol

245) 5-{4-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione

246) 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2-{ [(2R)-2,3- dihydroxypropyl]oxy J benzoic acid

247) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl J amino)butan- 1 -ol

248) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl J amino)butan-2-ol 249) 4-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)butan-2-ol

250) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)propan-2-ol 251) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione

252) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)-2-methylpropan-2-ol trifluoroacetic acid salt

253) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-yl methyl)amino]pyridin- 2-yl } (methyl)amino]propane- 1 ,2-diol

254) 3-[{5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]pyridin-2- yl } (methyl)amino]propane- 1 ,2-diol

255) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol 256) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenyl}-l,3,5- trimethylimidazolidine-2,4-dione

257) 5- { 3- [[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione

258) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

259) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

260) 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidin-2-one 261) 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one

262) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenylJ-l,3- oxazolidin-2-one

263) 6-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one

264) 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenylJ-l,3- oxazolidin-2-one

265) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-3- methoxypropan-2-ol 266) 2-[[3,4-bis(difluoromethoxy)phenyl](phenyl)amino]ethanol 267) l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]-2- methylpropan-2-ol

268) l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-2-ol

269) 3-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-l-ol

270) 4-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]butanoic acid 271) cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino] cyclohexanecarboxylic acid

272) 3-[[4-(cyclopropyloxy)-3-ethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid, and

273 ) 4- [ [4- (difluoromethoxy) -3 -ethoxyphenyl] ( { 2- [4- (difluoromethoxy) -3 -ethoxyphenyl] - l,3-oxazol-5-yl}methyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to further aspect of the invention, the compounds of Formula I are selected from:

3) 3-{ (3-fluorobenzyl)[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl] amino Jbenzoic acid, 4) 3-[(3,4-dimethoxyphenyl)(3-fluorobenzyl)amino]benzoic acid,

5 ) 3 - [ (3 -ethoxy-4-methoxyphenyl) (3 -fluorobenzyl) amino] benzoic acid,

6) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid,

7) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid, 8) 3-[(2,6-difluorobenzyl)(3,4-dimethoxyphenyl)amino]benzoic acid,

9) 3-[(2,6-difluorobenzyl)(3-ethoxy-4-methoxyphenyl)amino]benzo ic acid,

10) 3-[(2,6-difluorobenzyl)(3-isopropoxy-4-methoxyphenyl)amino]b enzoic acid,

11) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](2,6-difluorobenzyl)am ino]benzoic acid, 12) 3-((2,6-difluorobenzyl) { 4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl}amino)benzoic acid,

15) 3-[[3,4-bis(difluoromethoxy)phenyl](2,6-difluorobenzyl)amino ]benzoic acid,

16) 3-[[3,4-bis(difluoromethoxy)phenyl](3-fluorobenzyl)amino]ben zoic acid,

17) 3-{ (2,6-difluorobenzyl)[4-(difluoromethoxy)-3-methoxyphenyl]ami no}benzoic acid, 19) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](3-fluorobenzyl)amin o]benzoic acid,

20) 3-[[3,4-bis(difluoromethoxy)phenyl] (2-fluorobenzyl)amino]benzoic acid,

21) 3-[[3,4-bis(difluoromethoxy)phenyl](4-fluorobenzyl)amino]ben zoic acid,

22) 3-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl } amino)benzonitrile, 23) N-(3-fluorobenzyl)-4-methoxy-N-[4-(methylsulfonyl)phenyl]-3- [(3R)- tetrahydrofuran-3-yloxy]aniline,

24) N-ethyl-N-[4-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrof uran-3- yloxy]phenyl}amino)phenyl]ethanesulfonamide, and

25) 3-{ (3-cyanobenzyl)[3-(cyclopentyloxy)-4-methoxyphenyl]amino}ben zoic acid,

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

In addition, preferred compounds of formula I are those of the subformulae II and III:

wherein R ¹ , R ² , and R ⁴ are as defined in Formula I, one or two of A, B, D and E are N, and the others are CH, and X is O or S; and

pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof..

In subformulas II and in, preferably, A is N, and B, D and E are CH; or

A and B are both N, and D and E are CH; or

A and E are both N, and D and B are CH; or

A and D are both N, and B and E are CH.

In subformulas II and in, R ⁴ is preferably aryl, more preferably phenyl, which is substituted or unsubstituted. Prefered substituents when R ⁴ is susbtituted phenyl include carboxy (e.g., 4-carboxyphenyl).

In subformulas II and IH, preferably R ¹ is halogenated alkyl (e.g., such as CF ₃ , or CHF ₂ , espcecially CHF ₂ ), and R ² is alkyl (e.g., such as methyl, ethyl) or halogenated alkyl (e.g., such as CF ₃ , CHF ₂ , espcecially CHF ₂ ).

In particular, in subformulas II and HI, R ¹ is preferably CHF ₂ , R ² is preferably methyl, ethyl, or CHF ₂ , A is N, B is CH orN, D is CH, X is O or S, and R ⁴ is substituted phenyl (especially carboxy substituted phenyl, e..g., 4-carboxyphenyl).

Suitable compounds of subformulas II and HI include: 14) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethyl)a mino]benzoic acid,

59) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid,

120) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid,

124) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3- ylmethyl)amino]benzoic acid,

143) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyrimidin-5- ylmethyl)amino]benzoic acid, and

144) 4-[[4-(difTuoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid,

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula II are selected from the following compounds wherein only one of A, B, D, and E is N:

1) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-N- (methylsulfonyl)benzamide

2) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-N- (ethylsulfonyl)benzamide 13) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethyl)a mino]benzoic acid

14) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

18) 3-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

26) 3-{ [3-(cyclopentyloxy)-4-methoxyphenyl] [(6-OXO- l,6-dihydropyridin-3- yl)methyl] amino Jbenzoic acid

27) 5-bromo-N-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(pyridin-3- ylmethyl)pyridin-2- amine

30) Ethyl {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy } acetate 31) 2-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}ethanol

32) 3-(cyclopentyloxy)-N-(4-{ [(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy}phenyl)-4- methoxy-N- (pyridin- 3 -ylmethyl) aniline

33) N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-m ethyl-N(5)-(pyridin- 3-ylmethyl)pyridine-2,5-diamine

36) {3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]phenyl}acetic acid

37) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-ethylbenzoic acid 38) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-4- methylbenzoic acid

41) N- [3-(cyclopentyloxy)-4-methoxyphenyl] -N-(pyridin-3-ylmethyl)-6-pyrrolidin- 1 - ylpyridin- 3 -amine

42) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-(2-morpholin- 4-ylethyl)-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

44) N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-( pyridin-3- ylmethyl)pyridine-2,5-diamine

49) {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]phenyl}acetic acid 53) 3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl Jpropan- 1 -ol

54) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]nicotinic acid

55) 3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl Jpropanoic acid 56) 3-(cyclopentyloxy)-4-methoxy-N-[3-(2-methyl-l,3-thiazol-4-yl )phenyl]-N-(pyridin-3- ylmethyl)aniline

57) {3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amin o]phenyl}acetic acid

58) (5S)-5-({3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}methyl)pyrrolidin-2-one

61) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-[2-(methylsul fonyl)ethyl]-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

62) 3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyridin -3-ylmethyl)aniline

63) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr idin-3- ylmethyl)aniline

64) 2-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } (methyl)amino] -N,N-dimethylacetamide

65) N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-(pyridin-3-yl methyl)-N(2)- (tetrahydro-2H-pyran-4-yl)pyridine-2,5-diamine 66) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyr idin-3- ylmethyl)aniline

67) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-N,2- dihydroxybenzamide

68) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-3- methylbenzoic acid

69) {4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amin o]phenyl}acetic acid 76) 3,4-bis(difluoromethoxy)-N-[4-(ethylthio)phenyl]-N-(pyridin- 3-ylmethyl)aniline

83) 5-[[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]nicotinic acid

84) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]-2- hydroxyphenyljethanone

85) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2,2,2- trifluoroethanone

86) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}ethanone

87) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]phenol 88) 1 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } ethanone

89) 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}propan-2- ol

90) 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2,3-difluorophenol 94) 1 - { 5 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] pyridin-3 - yljethanone

95) N-[3,4-bis(difluoromethoxy)phenyl]-5-(2-methyl-l,3-dioxolan- 2-yl)-N-(pyridin-3- ylmethyl)pyridin- 3 -amine 96) 3,4-bis(difluoromethoxy)-N-[3-(lH-pyrazol-3-yl)phenyl]-N-(py ridin-3- ylmethyl)aniline

101) 3,4-bis(difluoromethoxy)-N-(pyridin-3-ylmethyl)-N-[3-(lH-l,2 ,4-triazol-5- yl)phenyl] aniline

102) 4-{3-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 -ylmethyl) amino] phenyl } - 1 - methyl- lH-pyrazol-5-ol

105) 4- { 3- [[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2-methyl- 1 ,2-dihydro-3H-pyrazol-3-one

107) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid

108) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid 122) l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenoxy}-2- methylpropan-2-ol

124) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid 126) 3-[[3-butoxy-4-(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]benzoic acid 128) 4-[[3-butoxy-4-(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]benzoic acid 135) 4- [ [3 - (cyclopropylmethoxy)-4- (difluoromethoxy)phenyl] (pyridin- 3 - ylmethyl)amino]benzoic acid

171) 3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] ( 1 -pyridin- 3 -ylethyl) amino] benzoic acid

172) 3-[(3,4-dimethoxyphenyl)(l-pyridin-3-ylethyl)amino]benzoic acid 221) 4-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid 222) 3-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid

233) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

235) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]pyridin-2(lH)- one 236) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)propan- 1 -ol

237) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } (methyl)amino]propane- 1 ,2-diol 238) (2R)-3-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

239) 5-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione 240) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

242) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-methyl-l,2- benzisoxazol-3(2H)-one

243) 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-l,2- benzisoxazol-3(2H)-one

244) (2R)-3-{4-[(3,4-dimethoxyphenyl)(pyridin-3-ylmethyl)amino]ph enoxy}propane-l,2- diol

245) 5-{4-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione 246) 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2-{ [(2R)-2,3- dihydroxypropyl]oxy} benzoic acid

247) 2-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)butan- 1 -ol

248) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)butan-2-ol

249) 4-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)butan-2-ol

250) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl } amino)propan-2-ol 251) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione

252) l-({5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]pyridin-2- yl}amino)-2-methylpropan-2-ol trifluoroacetic acid salt

254) 3-[{5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]pyridin-2- yl}(methyl)amino]propane-l,2-diol

255) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

260) 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}imidazolidin-2-one 262) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-l,3- oxazolidin-2-one

264) 4-{3- [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } - 1 ,3 - oxazolidin-2-one, and 280) 4-[[3-(difluoromethoxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula II are selected from the following compounds wherein A and B are N:

43) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

46) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid 80) 4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)ami no]benzoic acid

82) 3-[[3,4-bis(difluoromethoxy)phenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

113) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyr imidin-5- ylmethyl)aniline

114) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr imidin-5- ylmethyl)aniline

117) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5- ylmethyl)amino]phenyl}ethanone

137) {4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid 139) {3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid

143) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

144) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid 153) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrimidin-5-ylmethy l)amino]benzoic acid

168) 4- [ [3 - (cyclopropylmethoxy)-4- (difluoromethoxy)phenyl] (pyrimidin- 5 - ylmethyl)amino]benzoic acid

169) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

186) 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid

191) 4-[(3,4-diethoxyphenyl)(pyrimidin-5-ylmethyl)amino]benzoic acid

192) 4-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid 193) 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl) amino]benzoic acid

194) 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

195) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

196) 4-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid 199) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid 202) 4-[(4-ethoxy-3-isopropoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid

205) 4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5 - ylmethyl)amino]benzoic acid

209) 4-[(4-ethoxy-3-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid 210) 3-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid

211) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrimi din-5- ylmethyl)amino]benzoic acid

212) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid 213) 3-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid

214) 4-[[3-(benzyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5-ylm ethyl)amino]benzoic acid 218) 3 - [ [3 - (cyclopropyloxy)-4-methoxyphenyl] (pyrimidin- 5 -ylmethyl) amino] benzoic acid

223) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

228) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid 230) 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl] (pyrimidin-5- ylmethyl)amino]benzoic acid

272) 3-[[4-(cyclopropyloxy)-3-ethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid,

283) 3-[[4-ethoxy-3-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid,

284) 3-[[3,4-diethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid, 285) 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid, and

287) 3-[[3-cyclobutyloxy-4-difluoromethoxyphenyl](pyrimidin-5-ylm ethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula II are selected from the following compounds wherein E and B are N:

47) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridazin-3-ylmethyl )amino]benzoic acid,

48) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridazin-3-ylmethyl)amino]benzoic acid,

74) 4-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl)ami no]benzoic acid, and

75) 3-[[3,4-bis(difluoromethoxy)phenyl] (pyridazin-3-ylmethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula II are selected from the following compounds wherein A and E are N:

118) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(pyr azin-2- ylmethyl)aniline, 119) l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)am ino]phenyl}ethanone,

140) {4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)amin o]phenyl}acetic acid,

142) 4-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid,

147) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] (pyrazin-2-ylmethyl)amino]benzoic acid,

148) 3-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid, 154) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrazin-2-ylmethyl) amino]benzoic acid,

155) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid,

156) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid, 157) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid,

159) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid, and

161) 4-[[3-(difluoromethoxy)-4-methoxyphenyl](pyrazin-2-ylmethyl) amino]benzoic acid wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula HI are selected from the following compounds wherein X is S:

35) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid, 40) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

59) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid,

60) 3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid,

70) 3-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid,

71) 4-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid,

72) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid, 73) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid,

77) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline,

78) 3,4-bis(difluoromethoxy)-N-[4-(ethylsulfonyl)phenyl]-N-(l,3- thiazol-5- ylmethyl)aniline, 79) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline,

81) 5-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino] nicotinic acid, 91) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid,

92) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid,

93) l-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]pyridin-3- yljethanone,

97) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

98) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]nicotinic acid,

99) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

100) {4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid,

103) {3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid,

104) 4-[[3- (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid, 106) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

109) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid,

110) 3-[[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl](l,3-thiazo l-5- ylmethyl)amino]benzoic acid,

111) 4-methoxy-N-[4-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline,

112) l-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanone, 115) 4-methoxy-N-[3-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline,

116) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid, 120) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

121) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-th iazol-5- ylmethyl)amino]benzoic acid, 123) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-2- methylpropan-2-ol,

125) 3-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

129) 4-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

130) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]b enzoic acid, 131) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)ami no]benzoic acid,

132) 3-(cyclopropylmethoxy)-4-methoxy-N-[4-(methylsulfonyl)phenyl ]-N-(l,3-thiazol-5- ylmethyl)aniline,

133) l-{4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]phenyl}ethanone, 136) 3,4-bis(difluoromethoxy)-N-[4-methyl-3-(methylsulfonyl)pheny l]-N-(l,3-thiazol-5- ylmethyl)aniline,

138) 4-[(3,4-dimethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoi c acid,

145) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzenesulfonamide, 146) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]benzenesulfonamide,

149) 3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

150) 4-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid,

151) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzamide,

152) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzamide,

158) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzamide,

160) 5-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]nicotinic acid,

162) N-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2- methylphenyl } methanesulf onamide, 163) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}methanesulfonamide,

164) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanesulfonamide, 165) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzenesulfonamide,

170) 4-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid,

173) 4- [ (4-ethoxy- 3 -methoxyphenyl) ( 1 ,3 - thiazol- 5 -ylmethyl) amino] benzoic acid,

174) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-thiazol-5- ylmethyl)aniline,

178) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5- ylmethyl)amino]phenyl } acetic acid,

207) 4-[(3-ethoxy-4-isopropoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid, 226) 3 - [ (4-ethoxy- 3 -methoxyphenyl) ( 1 ,3 -thiazol- 5 -ylmethyl) amino] benzoic acid, 227) 3-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid,

241) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol- 5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol,

253) 3-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-yl methyl)amino]pyridin- 2-yl } (methyl)amino]propane- 1 ,2-diol, 256) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenyl}-l,3,5- trimethylimidazolidine-2,4-dione,

257) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione,

258) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol,

259) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol,

261) 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one, 263) 6-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-l,2- benzisoxazol-3(2H)-one,

265) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-3- methoxypropan-2-ol,

270) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]butanoic acid, and 271) cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino] cyclohexanecarboxylic acid wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect of the invention, the compounds of Formula HI are selected from the following compounds wherein X is O:

141) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-oxazol-5-ylmethyl)am ino]benzoic acid,

144) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid,

166) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid,

167) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid,

175) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid,

176) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-oxazol-5- ylmethyl)aniline, 177) {4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid,

179) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid,

180) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid, 181) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid, 182) 4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid,

183) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid, 184) 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid,

185) 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid,

189) 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid, 190) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-4-ylmethy l)amino]benzoic acid,

197) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid,

198) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid, 200) 3-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

201) 3-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid,

203) 3-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid,

204) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid, 206) 3-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid,

208) 4-[(4-ethoxy-3-isopropoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid,

215) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid, 216) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid,

217) 4-[[3-ethoxy-4-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid,

219) 4-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

220) 4-[(3,4-diethoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]benzoic acid,

224) 3-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid, 231) 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid, 232) 4-[[4-methoxy-3-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylmet hyl)amino]benzoic acid,

279) 3-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid, 282) 4-[[3-hydroxy-4-methoxyphenyl](l,3-oxazol-5-ylmethyl)amino]b enzoic acid,

285) 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid,

286) 3-[[3-cyclopropyloxy-4-methoxyphenyl](l,3-oxazol-5-ylmethyl) amino]benzoic acid, and

288) 3-[[3-cyclopropyloxy-4-difluoromethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect, the compounds of the invention are of subformula IV:

wherein

R ¹ is Ci- ₄ -alkyl or halogenated Ci- ₄ -alkyl,

R ² is Ci- ₄ -alkyl, halogenated Ci- ₄ -alkyl, or C- ₃ -io-cycloalkyl, R ⁹ is halogen, Ci- ₄ -alkyl, hydroxy, Ci- ₄ -alkoxy, Ci- ₄ -alkoxy-Ci-g-alkoxy, nitro, trifluoromethyl, OCF ₃ , amino, Ci- ₄ -alkylamino, di-(Cr ₄ -alkyl)amino, Crg-hydroxyalkyl, Cr ₄ - hydroxyalkoxy, Ci- ₄ -dihydroxyalkoxy, carboxy, carboxy-Ci- ₄ -alkyl, Ci- ₄ -alkoxy-carbonyl, Cr ₄ - alkylsulfonyl, aminosulfonyl, aminocarbonyl, Cr ₄ -alkylaminocarbonyl, di-Cr ₄ - alkylaminocarbonyl, Cr ₄ -alkyl-NH-SO ₂ -, or cyano, and

R ¹⁰ is H or Ci- ₄ -alkyl,

and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

According to a further aspect of the invention, the compounds of Formula I are selected from:

34) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( lH-pyrazol-4-ylmethyl)amino]benzoic acid, and

39) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( lH-pyrazol-4-ylmethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect, the compounds of the invention are of subformulae Va or Vb:

wherein

E is N or CH,

R ¹ is Ci- ₄ -alkyl or halogenated Ci_ ₄ -alkyl,

R is Ci- ₄ -alkyl, halogenated Ci- ₄ -alkyl, C- ₃ -io-cycloalkyl, C ₄ _i ₂ -cycloalkylalkyl (e.g., cyclopropylmethyl), or tetrahydrofuranyl (e.g., (3R)-tetrahydrofuran-3-yl),

R ⁹ is halogen, Ci- ₄ -alkyl, hydroxy, Ci- ₄ -alkoxy, Ci- ₄ -alkoxy-Ci-g-alkoxy, nitro, trifluoromethyl, OCF ₃ , amino, Ci- ₄ -alkylamino, di-(Ci- ₄ -alkyl)amino, Ci- ₈ -hydroxyalkyl, Cr ₄ - hydroxyalkoxy, Ci- ₄ -dihydroxyalkoxy, Ci^-alkoxy-Ci^-hydroxyalkoxy, carboxy, carboxy-Ci- ₄ - alkyl, Ci- ₄ -alkoxy-carbonyl, Ci- ₄ -alkylsulfonyl, aminosulfonyl, aminocarbonyl, Cr ₄ - alkylaminocarbonyl, di-Ci- ₄ -alkylaminocarbonyl, Cr ₄ -alkyl-SO ₂ -NH-, Cr ₄ -alkyl-NH-SO ₂ -, cyano, trimethylimidazolidinedione, or imidazolidinedione, and

R ¹⁰ is H or Ci- ₄ -alkyl,

and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

According to a further aspect of the invention, the compounds of Formulas Va and Vb are selected from:

35) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid, 40) 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

45) 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-4-ylmethyl)amino]benzoic acid

59) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid,

60) 3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid, 70) 3-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid,

71) 4-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3-th iazol-5- ylmethyl)amino]benzoic acid, 72) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid,

73) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid,

77) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline,

78) 3,4-bis(difluoromethoxy)-N-[4-(ethylsulfonyl)phenyl]-N-(l,3- thiazol-5- ylmethyl)aniline,

79) 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(l,3 -thiazol-5- ylmethyl)aniline, 81) 5-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino] nicotinic acid,

91) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid,

92) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid,

93) l-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]pyridin-3- yljethanone,

97) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

98) 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]nicotinic acid, 99) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid,

100) {4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid,

103) {3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid, 104) 4-[[3- (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid,

106) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid, 109) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid,

110) 3-[[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl](l,3-thiazo l-5- ylmethyl)amino]benzoic acid, 111) 4-methoxy-N-[4-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline,

112) l-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanone,

115) 4-methoxy-N-[3-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydrofur an-3-yloxy]-N-(l,3- thiazol-5-ylmethyl)aniline,

116) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid,

120) 4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid, 121) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-th iazol-5- ylmethyl)amino]benzoic acid,

123) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-2- methylpropan-2-ol,

125) 3-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid, 129) 4-[[3-butoxy-4-(difluoromethoxy)phenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid,

130) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]b enzoic acid,

131) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)ami no]benzoic acid,

132) 3-(cyclopropylmethoxy)-4-methoxy-N-[4-(methylsulfonyl)phenyl ]-N-(l,3-thiazol-5- ylmethyl)aniline, 133) l-{4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]phenyl}ethanone,

136) 3,4-bis(difluoromethoxy)-N-[4-methyl-3-(methylsulfonyl)pheny l]-N-(l,3-thiazol-5- ylmethyl)aniline,

138) 4-[(3,4-dimethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoi c acid, 145) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzenesulfonamide,

146) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]benzenesulfonamide, 149) 3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid,

150) 4-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid, 151) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzamide,

152) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzamide,

158) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N,N- dimethylbenzamide, 160) 5-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-thiazol-5-yl methyl)amino]nicotinic acid,

162) N-{5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2- methylphenyl } methanesulf onamide,

163) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}methanesulfonamide,

164) N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanesulfonamide,

165) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzenesulfonamide, 170) 4-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid,

173) 4- [ (4-ethoxy- 3 -methoxyphenyl) ( 1 ,3 - thiazol- 5 -ylmethyl) amino] benzoic acid,

174) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-thiazol-5- ylmethyl)aniline,

178) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5- ylmethyl)amino]phenyl} acetic acid,

207) 4-[(3-ethoxy-4-isopropoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid,

226) 3 - [ (4-ethoxy- 3 -methoxyphenyl) ( 1 ,3 -thiazol- 5 -ylmethyl) amino] benzoic acid,

227) 3-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid,

241) (2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol- 5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol,

256) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenyl}- 1,3,5- trimethylimidazolidine-2,4-dione,

257) 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione, 258) (2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol,

259) (2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol, 261) 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one,

263) 6-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one,

265) l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-3- methoxypropan-2-ol,

270) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]butanoic acid, and

271) cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino] cyclohexanecarboxylic acid wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect, the compounds of the invention are of subformula VI:

wherein one of A, B, D and E is N and the others are CH (or CR ⁸ if the carbon atom carries the R ⁸ substituent),

R ¹ is Ci- ₄ -alkyl or halogenated Ci- ₄ -alkyl,

R ² is Ci- ₄ -alkyl, halogenated Ci- ₄ -alkyl, C- ₃ -io-cycloalkyl, or C ₄ _i ₂ -cycloalkylalkyl,

R ⁸ is amino, Ci- ₄ -alkylamino, or di-(Ci- ₄ -alkyl)amino, and

R ⁹ is halogen, Ci- ₄ -alkyl, hydroxy, Ci- ₄ -alkoxy, Ci- ₄ -alkoxy-Ci-g-alkoxy, nitro, trifluoromethyl, OCF ₃ , amino, Ci- ₄ -alkylamino, di-(Ci- ₄ -alkyl)amino, Ci- ₈ -hydroxyalkyl, Cr ₄ - hydroxyalkoxy, Ci- ₄ -dihydroxyalkoxy, carboxy, carboxy-Ci- ₄ -alkyl (HOOC-CH ₂ -), Ci- ₄ -alkyl- carbonyl, Ci- ₄ -alkoxy-carbonyl, Ci- ₄ -alkylsulfonyl, aminosulfonyl, aminocarbonyl, Cr ₄ - alkylaminocarbonyl, di-Ci- ₄ -alkylaminocarbonyl, Ci- ₄ -alkyl-SO ₂ -NH-, Cr ₄ -alkyl-NH-SO ₂ -, or cyano,

and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

According to a further aspect, the compounds of the invention are of subformula Via which corresponds to subformula VI wherein A is N.

According to a further aspect, the compounds of the invention are of subformula VIb which corresponds to subformula VI wherein B is N.

According to a further aspect, the compounds of the invention are of subformula VIc which corresponds to subformula VI wherein D is N.

According to a further aspect, the compounds of the invention are of subformula VId which corresponds to subformula VI wherein E is N.

According to a further aspect of the invention, the compounds of Formula VI are selected from:

51) 4-([3-(cyclopentyloxy)-4-methoxyphenyl] { [2-(dimethylamino)pyrimidin-5- yl]methyl}amino)benzoic acid, and

52) 3-([3-(cyclopentyloxy)-4-methoxyphenyl] { [2-(dimethylamino)pyrimidin-5- yl]methyl}amino)benzoic acid wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect, the compounds of the invention are of subformula VII:

wherein

R ¹ is Ci- ₄ -alkyl or halogenated Ci- ₄ -alkyl,

R is H, Ci_ ₄ -alkyl, halogenated C^-alkyl, C- ₃ _io-cycloalkyl, or C- ₄ _ ₁₂ -cycloalkylalkyl,

R ⁹ is halogen, Ci- ₄ -alkyl, hydroxy, Ci- ₄ -alkoxy, Ci- ₄ -alkoxy-Ci-g-alkoxy, nitro, trifluoromethyl, OCF ₃ , amino, Ci- ₄ -alkylamino, di-(Ci- ₄ -alkyl)amino, Ci- ₈ -hydroxyalkyl, Cr ₄ - hydroxyalkoxy, Cr ₄ -dihydroxyalkoxy, carboxy, carboxy-Ci- ₄ -alkyl, Ci- ₄ -alkoxy-carbonyl, Cr ₄ - alkylsulfonyl, aminosulfonyl, aminocarbonyl, Ci- ₄ -alkylaminocarbonyl, di-Ci- ₄ - alkylaminocarbonyl, Cr ₄ -alkyl-SO ₂ -NH-, Cr ₄ -alkyl-NH-SO ₂ -, or cyano, and

R ¹⁰ is H or Ci- ₄ -alkyl, and pharmaceutically acceptable salts or solvates (e.g., hydrates) or N-oxides thereof, or solvates of pharmaceutically acceptable salts or N-oxides thereof.

According to a further aspect of the invention, the compounds of Formula VII are selected from:

141) 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-oxazol-5-ylmethyl)am ino]benzoic acid,

144) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid,

166) 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid,

167) 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid,

175) {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid,

176) 4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl]-N- (l,3-oxazol-5- ylmethyl)aniline, 177) {4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid,

179) 4-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid,

180) 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid, 181) 4-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

182) 4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid,

183) 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid, 184) 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid,

185) 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid,

189) 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid, 190) 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-4-ylmethy l)amino]benzoic acid,

197) 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid, 198) 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid,

200) 3-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

201) 3-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid,

203) 3-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amin o]benzoic acid,

204) 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid,

206) 3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid, 208) 4-[(4-ethoxy-3-isopropoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid,

215) 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid,

216) 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid,

217) 4-[[3-ethoxy-4-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid, 219) 4-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

220) 4-[(3,4-diethoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]benzoic acid,

224) 3-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid,

231) 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid, 232) 4-[[4-methoxy-3-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylmet hyl)amino]benzoic acid,

279) 3-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid,

282) 4-[[3-hydroxy-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid, 285) 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid,

286) 3-[[3-cyclopropyloxy-4-methoxyphenyl](l,3-oxazol-5-ylmethyl) amino]benzoic acid, and

288) 3-[[3-cyclopropyloxy-4-difluoromethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to another aspect of the invention there is provided a genus of novel compounds according to the formulas VIII and IX:

wherein R ¹ , R ² , R ³ , and R ⁴ are as defined above. The compounds of these subgenera of formula I not only have PDE4 inhibitory activity, but may also be useful as intermediates for preparing compounds of Formula I in which R ³ and R ⁴ are both other than H.

Intermediate compounds according to formulas VIII and IX include:

289) 3-{ [3,4-bis(difluoromethoxy)phenyl]amino}benzoic acid,

290) 2-methoxy-4-[(pyridin-3-ylmethyl)amino]benzamide,

291) 3,4-bis(difluoromethoxy)-N-(l,3-thiazol-5-ylmethyl)aniline,

292) 3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]aniline , 293) 4-{ [4-(difluoromethoxy)-3-methoxyphenyl]amino}benzoic acid,

294) 4-{ [4-(difluoromethoxy)-3-ethoxyphenyl]amino}benzoic acid, and

295) 4-{ [3,4-bis(difluoromethoxy)phenyl]amino}benzoic acid.

The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in patients, e.g., mammals, especially humans. These compounds exhibit neurological activity, especially where such activity affects cognition, including long term memory. These compounds will also be effective in treating diseases where decreased cAMP levels are involved. This includes, but is not limited to, inflammation and inflammatory diseases. These compounds may also function as antidepressants, or be useful in treating cognitive and negative symptoms of schizophrenia.

Assays for determining PDE inhibiting activity as well as selectivity of PDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known within the art. See, e.g., U.S. Patent No. 6,136,821, the disclosure of which is incorporated herein by reference.

According to a further aspect of the invention there are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g., PDE4 inhibitors of Formula I) and/or useful for the synthesis of radio-labeled analogs of the PDE4 inhibitors within this application.

Thus, there are provided intermediate compounds which correspond to compounds of Formula I, wherein R ² , R ³ , and R ⁴ are as previously defined for Formula I, R ¹ is R ⁶ , and R ⁶ is H, te/t-butyldimethylsilyl-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example, in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radio-labeled compounds, such as where R ⁶ is ³ H ₃ C-, ¹⁴ CH ₃ - or ¹¹ CH ₃ -, for example, by removing the protecting group and reacting the resultant compound in which R ⁶ is H with suitable radio-labeled reagents. Such radio-labeled compounds are useful for determining compound tissue distribution in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies.

Also provided are intermediate compounds which correspond to compounds of Formula I, wherein R ¹ , R ³ , and R ⁴ are as previously defined for Formula I, R ² is R ⁷ , and R ⁷ is H, tert-butyldimethylsilyloxy-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example, in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 246-293. Compounds in which R ⁷ is H are useful as intermediates, for example, as scaffolds for parallel or combinatorial chemistry applications. Further, these compounds are useful for the introduction of radio-labels such as ³ H, ¹⁴ C, or ¹¹ C. As previously described, compounds according to Formula VIII, wherein R ¹ , R ² and R ⁴ are as previously described are useful intermediates for the production of compounds according to formula I wherein R ³ is other than H.

Also, as previously described, compounds according to Formula IX, wherein R ¹ , R ² and R ³ are as previously described are useful intermediates for the production of compounds according to formula I wherein R ⁴ is other than H.

Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the alkyl portion can be substituted by halogen, alkyl, aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the aryl portion can be substituted by, for example, halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.

Alkyl, as a group or substituent per se or as part of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight-chain or branched- chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include, but are not limited to, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.

Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions by, for example, halogens, oxo, hydroxyl, Ci_ ₄ -alkoxy, and/or cyano. Halogens are preferred substituents, especially F and Cl.

Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH ₂ -CH ₂ - structures are each replaced by -CH=CH-. Suitable alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and 2-pentenyl.

Alkynyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH ₂ -CH ₂ - structures are each replaced by -C≡C-. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, and 2- butynyl.

Alkoxy means alkyl-O- groups and alkoxyalkoxy means alkyl-O-alkyl-0- groups in which the alkyl portions are in accordance with the previous discussion. Suitable alkoxy and alkoxyalkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl -O-CO- in which the alkyl portion is in accordance with the previous discussion. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and te/t-butoxycarbonyl.

Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by, for example, halogen, alkyl, fluorinated alkyl, hydroxy, alkoxy, fluorinated alkoxy (e.g., OCF ₃ , OCHF ₂ ), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and phenoxy.

Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include, but are not limited to, benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl.

Substituted arylalkyl refers to an aryl- alkyl- group wherein the aryl and alkyl portions are in accordance with the previous discussions.

Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant- 1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, by one or more halogens and/or alkyl groups.

Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include, but are not limited to, cyclopropylmethyl and cyclopentylmethyl.

Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.

Heteroaryl refers to an aromatic heterocyclic group having one or two rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is a heteroatom. Preferably, the heteroaryl group contains 1 to 3, especially 1 or 2, hetero-ring atoms which are selected from N, O and S. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.

Substituted heteroaryl refers to the heteroaryl groups described above which are substituted in one or more places by, for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

Heterocycles include heteroaryl groups as described above as well as non-aromatic cyclic groups (i.e., saturated and partially saturated heterocyclic groups) containing at least one hetero-ring atom, preferably selected from N, S and O, for example, but not limited to, tetrahydrofuranyl, piperidinyl, dithianyl, oxathianyl, dioxazolyl, oxathiazolyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and pyrrolidinyl.

Heterocycle-alkyl refers to a heterocyclic group which is attached to the remainder of the molecule via an alkyl bridge group wherein the heterocyclic and alkyl portions are in accordance with the previous discussions. Suitable examples include, but are not limited to, pyridylmethyl, thiazolylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl. Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring structure(s) contains at least one C=C bond. Suitable examples include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.

Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents.

Additional aspects of the present invention include pharmaceutical compositions comprising a compound of Formulae I - VII and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating neurological syndrome, e.g., loss of memory, especially long- term memory, cognitive impairment or decline, memory impairment, etc. a method of treating a disease state modulated by PDE4 activity, in a mammal, e.g., a human, e.g., those mentioned herein.

The compounds of the present invention may be prepared conventionally. Some of the processes which can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials.

The reaction schemes shown below are for illustrative purposes only and should not be viewed as limiting the scope of the synthetic methods available for the production of the compounds described within this application. Note that alternative methods, reagents, solvents, bases, acids etc., which are considered standard in the art, can be utilized in addition or can rep

Starting nitrophenols of the type 1 are either commercially available (e.g., R ¹ = CH ₃ ) or prepared by published procedures (e.g., R ¹ = CHF ₂ or both R ¹ and R ² = CHF ₂ , see Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN: EPXXDW EP 626361A1; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokyo Koho (1999), 6 pp. CODEN: JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor. Int. Symp. Wood. Pulping Chem., 1995, 8th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 Al 19960808). For example, as seen in Scheme 1, aniline intermediates 3 are produced in two steps; first, an addition reaction provides intermediate 2, followed by reduction of the nitro group. Intermediate nitro compounds 2 can be prepared by numerous published procedures, such as by Mitsunobu reactions or standard alkylation reactions. Compounds where R ₂ is aryl or heteroaryl can be prepared by copper catalyzed reactions with aryl or heteroaryl iodides under Ullman conditions or by coupling aryl-, vinyl-, or heteroaryl- boronic acids with phenol 2 in the presence of a copper catalyst (e.g., Cu(OAc) ₂ ) and base such as TEA. Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using an azodicarboxylate (e.g., DEAD, DIAD), and a suitable phosphine (e.g., Ph ₃ P, Bu ₃ P) provides nitroaryl ethers of structure 2. Mitsunobu reactions are general performed in aprotic solvents such as dichloromethane or THF. Alternatively, alkylation can be achieved by the reaction between an appropriately substituted nitrophenol and an alkyl halide in the presence of a base (e.g., K ₂ CO ₃ or NaH) in a polar aprotic solvent (e.g., DMF or CH ₃ CN).

Nitrocatechols 2 are subsequently reduced to the corresponding anilines 3 by methods standard in the art such as by hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., MeOH or EtOH) under an atmosphere of hydrogen. Alternatively, nitrocatechols 3 can be reduced by using a hydride source (e.g., NaBH ₄ ) and a transition metal catalyst (e.g., NiCl ₂ , Pd on carbon) or by using metals (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HCl) to produce the corresponding anilines. Generally polar protic solvents such as ethanol or methanol are used in these reactions.

N-Arylalkylanilines 4 are synthesized by standard methods in the art such as by reductive amination reaction, alkylation reaction, or by reduction of corresponding amides. For example, the reductive amination reaction of an aryl or arylalkyl aldehyde with appropriately substituted anilines in the presence of a borohydride reducing agent such as NaBH ₄ , NaBH ₃ CN or Na(OAc) ₃ BH with an acid catalyst such as acetic acid or/?TsOH provides desired N-arylalkylanilines. These reactions generally take place in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like, or in chlorinated solvents such as dichloroethane.

N-Arylalkylanilines 4 readily undergo N-arylation by methods standard to the art including Ullman coupling reaction, metal-catalyzed coupling, or aromatic nucleophilic substitution reaction. For example, the metal catalyzed reaction between an N-benzylaniline and an aryl halide using a palladium catalyst, (e.g., Pd ₂ (dba) _z , a bulky electron rich phosphine ligand (e.g., tributylphosphine or "X-Phos"), and suitable base (e.g., NaOtBu, NaOH, Cs ₂ CO ₃ ) provides N-Arylalkyldiphenylamines. Nickel and copper catalysts have been employed as well. Solvents useful in this reaction include non-polar aprotic solvents such as toluene, benzene, xylenes, tetrahydrofuran, ether, dimethoxyethane. When synthesizing compounds of the type 5 wherein R ₄ is an alkoxycarbonylphenyl, it is advantageous that amine 4 is coupled with 1.1 equivalents of tert-butyl 3-iodobenzene and that 22 mol % of (^Bu) ₃ P, 5.5 mol % of Pd ₂ (dba) ₃ and 1.3 equivalents of ΦuONa are used.

SCHEME 1

R ² Br, K ₂ CO ₃ , DMF or

Alternatively, targets of general formula I, represented as structure 5 in the following Scheme 2A, can be prepared by N-arylation reaction between catechol ether halides of general structure 7 and N-substituted anilines of general structure 9 under conditions standard to the art (see Scheme 1). Intermediates 7 and 9 can be synthesized by numerous methods standard in the art, or as represented in Scheme 2.

SCHEME 2A

R ² Br, K ₂ CO ₃ , DMF or

R ² OH, PPh ₃ , DIAD, THF

9

Carboxylic ester intermediates 10 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7, as shown in Scheme 2B. For example, an ethyl ester (R ⁵ = Et, Me) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOH, LiOH) and a water miscible solvent (e.g., EtOH, THF). While /-butyl esters (R ⁵ = /-butyl) can be hydrolyzed using an aqueous acid (e.g., HCl, formic acid, TFA) in a water miscible organic solvent. If necessary, microwave heating can be used.

SCHEME 2B

10 11

Coupling of protected tetrazole bromo or iodobenzenes (e.g., 5-(3-iodophenyl)-2-(2- tetrahydropyran)tetrazole) with N- substituted aniline derivatives 9 produce THP-protected tetrazoles 12. As shown in Scheme 3, hydrolysis of THP-protected tetrazoles 12 can be accomplished by using an aqueous acid, such as HCl in water and a miscible solvent such as THF or EtOH to provide tetrazoles 12. Further, THP tetrazoles 12 can also be oxidatively cleaved using reagents such as CAN and DDQ in halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and the like to yield tetrazoles 13.

SCHEME 3

Alternatively, tetrazole analogs 13 can be prepared from the corresponding nitriles by treatment with azide ion (e.g., KN ₃ , NaN ₃ , etc.) and a proton source (e.g., NH ₄ Cl) in a polar aprotic solvent such as DMF. They also may be prepared by treatment with an azide ion and a Lewis acid (e.g., ZnBr ₂ ) in water, using a water miscible co-solvent such as isopropanol if necessary. Another method of preparation is by treatment of a nitrile with tin or silicon azides (e.g., Me ₃ SiN3, Bu ₃ SnN ₃ ) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.

As illustrated in Scheme 4, diphenylamines 14 can be prepared by coupling appropriately substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyaniline, with arylboronic acids in the presence of a base such as triethylamine and a copper catalyst such as copper acetate (as described by Chan et al, Tetrahedron Lett., 39, 2933-2936 (1998)). In general, halogenated solvents such as dichloromethane, chloroform, dichloroethane, and the like as well as nonpolar aprotic solvents such as benzene, toluene, or xylene are utilized. Such diphenylamines (e.g., 14) can more preferably be synthesized by metal catalyzed amination reactions. For example, reaction of an appropriately substituted aniline 3 with an arylhalide in the presence of a base (e.g., K ₃ PO ₄ , CsCO ₃ , or NaOtBu) and a palladium or nickel catalyst, for example Pd(dppf)Cl ₂ , a ligand (e.g., dppf) and a base (e.g., NaOtBu) (JACS. 1996, 118, 7217) or with Pd ₂ dba ₃ , a bulky electron rich phosphine such as P(tBu) ₃ , and a base (e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired diphenylamines 14. Solvents most commonly utilized in this type of reaction include non- polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.

Diphenylamines 14 can then be alkylated with various alkyl halides or arylalkyl halides such as, but not limited to iodomethane, ethylbromide, benzylchloride, 3- (chloromethyl)pyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4-(bromomethyl)- benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide to provide N- substituted diphenylamines 5. Solvents useful in this reaction include aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like.

SCHEME 4

KN(TMS) ₂ , R ³ I, R ⁴ B(OH) ₂₁ Cu(OAc) ₂ ,

or

R ₄ Br, Pd(dppf)l ₂ , dppf, ¹⁴

NaOtBu, THF

Carboxylic acids 15 can be further manipulated to form carboxamides 16 using methods standard in the art. For example, as shown in Scheme 5, a carboxylic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC, and a base such as Et ₃ N or DIEA to yield a carboxamide. These reactions generally take place in non-polar aprotic solvents such as dichloromethane, chloroform, or dichloroethane.

Carboxylic esters 10 or acids 15 can be reduced using methods standard in the art to give the corresponding carboxaldehyde or hydroxymethyl analogs. For example, an aryl ethyl ester (e.g., Scheme 2 structure 10, R ⁵ = ethyl) can be treated with an appropriate reducing agent (e.g., LAH, DIBAL, etc.) in an aprotic solvent such as ether or THF, to produce the corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and alcohols can be further derivatized by methods standard in the art. Similarly carboxamides (e.g., structure 16) and nitriles can be reduced using methods standard in the art to provide the corresponding substituted amines or aminomethyl analogs. For example, an aryl carboxamide 16 can be reduced with an appropriate reducing agent (e.g., LAH) in an aprotic solvent (e.g., benzene, toluene, ether, THF, etc.) to give the corresponding substituted aminomethyl analog. Whereas reduction of an aryl nitrile yields the corresponding primary aminomethyl analog.

SCHEME 5

16

15

Nitrobenzene compounds 17 can be reduced to the corresponding anilines 13 by methods standard in the art such as hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 17 can also be reduced using a hydride source (e.g., NaBH ₄ ) and a transition metal catalyst (e.g., NiCl ₂ , Pd on carbon) in polar protic solvents such as EtOH, to produce the corresponding anilines 18, as shown in Scheme 6. These anilines can then be further substituted by methods standard in the art. For example, anilines of the type 13 can be alkylated, acylated, or sulfonylated to give the corresponding iV-alkyl amines, carboxamides (e.g., structure 20) or sulfonamides (e.g., structure 19) respectively. For example, a sulfonamide can be prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (e.g., MeSO ₂ Cl, EtSO ₂ Cl, BnSO ₂ Cl, PhSO ₂ Cl, etc.) in the presence of a base (e.g., Et ₃ N, pyridine, DIEA, etc.). Suitable solvents for this reaction include non-polar aprotic solvents such as dichloromethane, chloroform, ether, and the like. SCHEME 6

19 20

Trialkylsilylethers of the type 21 (Scheme 1, structure 5, where R = TBDMS) are prepared in the manner shown in Scheme 1. The tert-butyldimethylsilyl protected catechol intermediates 21 are readily deprotected by numerous literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 273-276.) such as by using a fluoride ion source (e.g., Bu ₄ NF) in an aprotic solvent such as ether or THF; or under acidic conditions (e.g., KF, 48% HBr, DMF), as illustrated in Scheme 7.. The resultant phenol 22, which is a very useful synthetic intermediate, can then be alkylated by methods standard in the art and in a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1, and further illustrated in Scheme 7. For example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by Ullman type aryl coupling or by reaction with vinyl-, aryl- or heteroaryl- boronic acids in the presence of a copper catalyst.

SCHEME 7

21 22

Haloalkoxy intermediates 23, prepared by alkylation of the corresponding phenol, can be alkylated by reactions with substituted amines, alcohols, or thiols in the presence of a base to provide analogs such as 24, as illustrated in Scheme 8. For example, an alkyl halide can be aminated with an appropriate primary or secondary amine and a base such as K ₂ CO ₃ , in a polar aprotic solvent such as THF, DMF, or CH ₃ CN. SCHEME 8

23 24

Many of these synthetic procedures are described more fully in the examples set forth below.

One of ordinary skill in the art will recognize that some of the compounds of

Formulae I - IX, including the specific compounds listed above, can exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures inter alia. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids include tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formulae I - IX can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of ² H, ³ H, ¹¹ C and/or

¹⁴ C.

The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all the compounds of the present invention. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by, for example, reacting a compound of the invention with the appropriate base via a variety of known methods.

The following are further non-limiting examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. For example, the pharmaceutically acceptable salt can be a hydrochloride, a hydrobromide, a hydroformate, or a maleate.

With regards to pharmaceutically acceptable salts, see also the list of FDA approved commercially marketed salts listed in Table I of Berge et al., Pharmaceutical Salts, J. of Phar. ScL, vol. 66, no. 1, January 1977, pp. 1-19, the disclosure of which is incorporated herein by reference.

Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.

One of ordinary skill in the art will also recognize that some of the compounds of Formulae I - IX can exist in different polymorphic forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.

One of ordinary skill in the art will further recognize that compounds of Formulae I -

IX can exist in different solvate forms. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.

The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of Formulae I - VII, and the specific compounds listed above, containing, for example, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

In view of their high degree of PDE4 inhibition, the compounds of the present invention can be administered to anyone requiring or desiring PDE4 inhibition, and/or enhancement of cognition. Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.

Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art. For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.

Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant.

The present invention further includes methods of treatment that involve inhibition of PDE4 enzymes. Thus, the present invention includes methods of selective inhibition of PDE4 enzymes in animals, e.g., mammals, especially humans, wherein such inhibition has a therapeutic effect, such as where such inhibition may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory. Such methods comprise administering to a patient in need thereof, especially a mammal, most especially a human, an inhibitory amount of a compound, alone or as part of a formulation, as disclosed herein.

The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.

Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeldt-Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B 12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.

The present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline. The present invention includes methods of treatment for memory impairment as a result of disease. In another application, the invention includes methods for dealing with memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention.

The compounds of the present invention may be used to treat psychiatric conditions including schizophrenia, bipolar or manic depression, major depression, and drug addiction and morphine dependence. These compounds may enhance wakefulness. PDE4 inhibitors can be used to raise cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of anti-apoptotic and anti-inflammatory properties make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy (MSA).

Thus, in accordance with a preferred embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Rubenstein-Taybi syndrome (RSTS), depression, aging, head trauma, stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetes associated cognitive impairment, memory deficits from early exposure of anesthetic agents, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formulae I - VII, and the specific compounds listed above, or pharmaceutically acceptable salts thereof.

The compounds of the present invention can also be used in a method of treating patients suffering from disease states characterized by decreased NMDA function, such as schizophrenia. The compounds can also be used to treat psychosis characterized by elevated levels of PDE 4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders.

The compounds of the present invention can also be used in methods of treating patients suffering from obesity and in treatment methods for neuronal regeneration or neurogenesis.

A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.

As mentioned, the compounds of the invention also exhibit anti-inflammatory activity. As a result, the inventive compounds are useful in the treatment of a variety of allergic and inflammatory diseases, and the inflammation associated therewith, particularly disease states characterized by decreased cyclic AMP levels and/or elevated phosphodiesterase 4 levels. Thus, in accordance with a further embodiment of the invention, there is provided a method of treating allergic and inflammatory disease states, comprising administering an effective amount of a compound according to Formulae I - VII, and the specific compounds listed above, or a pharmaceutically acceptable salt thereof. Such disease states include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Behcet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.

PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor are known within the art. See, e.g., WO 98/58901, JPl 1-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, and US 5,935,978. These references also describe assays for determining PDE4 inhibition activity, and methods for synthesizing such compounds. The entire disclosures of these documents are hereby incorporated by reference.

PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as an antibiotic, for treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term inhibition of mesenchymal-cell proliferation after transplantation, for treatment of urinary obstruction secondary to benign prostatic hyperplasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (B-CLL), for inhibition of uterine contractions, to attenuate pulmonary vascular ischemia-reperfusion injury (IRI) , for corneal hydration , for inhibition of IL- 2R expression and thereby abolishing HIV-I DNA nuclear import into memory T cells, for augmentation of glucose-induced insulin secretion, in both the prevention and treatment of colitis, and to inhibit mast cell degranulation.

The compounds of Formulae I - VII, and the specific compounds listed above, can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine), typical and atypical antipsychotics (e.g., haloperidol, risperidone, and zyprexia) and selective serotonin reuptake inhibitors (SSRIs). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range. The compounds of Formulae I - VII, and the specific compounds listed above, can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of allergic and/or inflammatory conditions, e.g. respiratory conditions. Suitable examples of other pharmaceutical agents which may be used in combination with the compounds of the present invention include, but are not limited to, other PDE-4 inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, leukotriene antagonists (LTRAs) including antagonists Of LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ , histaminic receptor antagonists including Hl and H3 antagonists, CC ₁ and CC ₂ adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use (e.g., propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride), muscarinic receptor (Ml, M2, and M3) antagonists (e.g., ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine), anticholinergic agents, βi to β ₄ (e.g. β ₂ ) adrenoceptor agonists (e.g., isoprenaline, albuterol, salbutamol, formoterol, salmeterol), COX-I inhibitors (NSAIDs), COX-2 selective inhibitors, nitric oxide NSAIDs, oral or inhaled glucocorticosteroids (e.g., prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone diproprionate), and adenosine A2a receptor agonists. Further examples of suitable other pharmaceutical agents which may be used in combination with the compounds of the present invention are disclosed in U.S. Patent Nos. 6,559,168 and 6,756,392, which are hereby incorporated by reference in their entireties. In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range.

The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.

The compounds of the invention are typically administered at dosage levels and in a manner customary for PDE4 inhibitors such as those known compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.001-100 mg/kg/day, preferably 0.01-70 mg/kg/day, especially 0.01-10 mg/kg/day. Unit dosage forms can contain, for example, 0.1- 50 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of active compound.

In carrying out the procedures of the present invention it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.

The present invention will now be further described by way of the following non- limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference.

EXPERMENTAL EXAMPLES

EXAMPLE 1

Synthesis of (3,4-Bis-difluoromethoxy-phenyl)-thiazol-5ylmethyl-amine

A mixture of 3,4-bis-difluoromethoxy-phenylamine (1.008 g, 4.5 mmol), thiazole-5- carbaldehyde (0.506 g, 4.5 mmol), dichloroethane (25 mL) and acetic acid (3 drops) was stirred for 1 hour at room temperature. Na(OAc) ₃ BH (1.90 g, 9.0 mmol) was then added, and the reaction was stirred overnight; then quenched by the addition of water and aqueous sodium hydroxide (1 M). The mixture was stirred for 30 minutes at room temperature, and the product was extracted three times using dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified via flash chromatography (hexanes/ethyl acetate) to 924 mg (64%) of (3,4-bis-difluoromethoxy- phenyl)-thiazol-5ylmethyl-amine as a colorless oil.

The following compounds were prepared in a similar manner, but with different starting materials:

[4-methoxy-(2,2,2-trifluoroethoxy)phenyl]-3-fluorobenzyl- amine

(3,4-dimethoxyphenyl)-3-fluorobenzyl-amine

(3-ethoxy-4-methoxyphenyl)-3-fluorobenzylamine

(3-cyclobutyloxy-4-methoxyphenyl)-3-fluorobenzylamine

(3-cyclopentyloxy-4-methoxyphenyl)-3-fluorobenzylamine

(3,4-dimethoxyphenyl)-2,6-difluorobenzyl-amine

(3-ethoxy-4-methoxyphenyl)-2,6-difluorobenzyl-amine

(3-isopropoxy-4-methoxyphenyl)-2,6-difluorobenzyl-amine

(3-cyclobutyl-4-methoxyphenyl-2,6-difluorobenzyl-amine

[4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl]-2,6-di fluorobenzyl-amine

(4-difluoromethoxy-3 -ethoxyphenyl) -pyridin- 3 -ylmethyl- amine

(3,4-Bis-difluoromethoxy-phenyl)-2,6-difluorobenzyl-amine

(3,4-Bis-difluoromethoxy-phenyl)-3-fluorobenzyl-amine

(4-difluoromethoxy-3-methoxyphenyl)-2,6-difluorobenzyl-am ine (4-difluoromethoxy-3-methoxyphenyl)-pyridin-3-ylmethyl-amine

(4-difluoromethoxy-3-methoxyphenyl)-3-fluorobenzyl-amine

(3,4-Bis-difluoromethoxy-phenyl)-2-fluorobenzyl-amine

(3,4-Bis-difluoromethoxy-phenyl)-4-fluorobenzyl-amine

[4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl]-3-fluo robenzyl-amine

(3-cyclopentyloxy-4-methoxyphenyl)-3-cyanobenzyl-amine

(3-cyclopentyloxy-4-methoxyphenyl)-(6-oxo-l,6-dihydropyri din-3-yl)methyl-amine

(3-cyclopentyloxy-4-methoxyphenyl)-pyridin-3-ylmethyl-ami ne

(3-cyclopentyloxy-4-methoxyphenyl)(lH-pyrazol-4-ylmethyl) amine

(3-cyclopentyloxy-4-methoxyphenyl)-thiazol-5-ylmethyl-ami ne

(3-cyclopentyloxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-a mine

(3-cyclopentyloxy-4-methoxyphenyl)-pyridazin-3-ylmethyl-a mine

(3-cyclopentyloxy-4-methoxyphenyl)-[2-(dimethylamino)pyri midin-5-yl]methyl- amine

(3,4-Bis-difluoromethoxy-phenyl)-pyridin-3-ylmethyl-amine

(3 ,4-dimethoxy-phenyl) -pyridin- 3 -ylmethyl- amine

[4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl]-thiazo l-5-ylmethyl-amine

(3-cyclopropylmethoxy-4-methoxy-phenyl)-thiazol-5-ylmethy l-amine

(3,4-Bis-difluoromethoxy-phenyl)-pyridazin-3-ylmethyl-ami ne

(3,4-Bis-difluoromethoxy-phenyl)-pyrimidin-5-ylmethyl-ami ne

(4-difluoromethoxy-3-ethoxyphenyl)-thiazol-5-ylmethyl-ami ne

(3-cyclopentyloxy-4-difluoromethoxy-phenyl)-thiazol-5-ylm ethyl-amine (4-difluoromethoxy-3-isopropoxyphenyl)-thiazol-5-ylmethyl-am ine (4-difluoromethoxy-3-isopropoxyphenyl)-pyridin-3-ylmethyl-am ine (4-difluoromethoxy-3-methoxyphenyl)-thiazol-5-ylmethyl-amine [3,4-bis(difluoromethoxyphenyl)]-pyrazin-2-ylmethyl-amine (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-thiazol-5-yl methyl-amine

(4-difluoromethoxy-3 -methoxyphenyl) -pyridin- 3 -ylmethyl- amine [3-( 1 -butyloxy)-4-difluoromethoxy-phenyl] -thiazol-5-ylmethyl-amine [3-(l-butyloxy)-4-difluoromethoxy-phenyl]-pyridin-3-ylmethyl -amine [3,4-bis(difluoromethoxy)phenyl]-(l-methyl-lH-pyrazol-4-yl)m ethyl]amine (3-ethoxy-4-methoxyphenyl)-thiazol-5-ylmethyl-amine

(3-isopropoxy-4-methoxyphenyl)-thiazol-5-ylmethyl-amine

(3-cyclopropylmethoxy-4-methoxy— phenyl)-thiazol-5-ylmethyl-amine

(3 -cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyridin- 3 -ylmethyl- amine

(3,4-dimethoxy-phenyl)-thiazol-5-ylmethyl-amine [3,4-bis(difluoromethoxy)phenyl]-oxazol-5-ylmethyl-amine

(4-difluoromethoxy-3 -ethoxyphenyl) -pyrimidin- 5 -ylmethyl- amine (4-difluoromethoxy-3-ethoxyphenyl)-oxazol-5-ylmethyl-amine (4-difluoromethoxy-3-ethoxyphenyl)-pyrazin-2-ylmethyl-amine (3-difluoromethoxy-4-methoxyphenyl)-thiazol-5-ylmethyl-amine (4-difluoromethoxy-3-methoxyphenyl)-pyrimidin-3-ylmethyl-ami ne

(4-difluoromethoxy-3-methoxyphenyl)-pyrazin-2-ylmethyl-am ine (4-difluoromethoxy-3-isopropoxyphenyl)-pyrazin-2-ylmethyl-am ine (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-pyrazin-2-ylm ethyl-amine (3-difluoromethoxy-4-methoxyphenyl)-pyrazin-2-ylmethyl-amine (4-difluoromethoxy-3-isopropoxyphenyl)-oxazol-5-ylmethyl-ami ne (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-oxazol-5-ylme thyl-amine

(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-pyrimidin- 5-ylmethyl-amine (4-difluoromethoxy-3-isopropoxyphenyl)-pyrimidin-5-ylmethyl- amine (3,4-diethoxyphenyl)-thiazol-5-ylmethyl-amine (3-cyclopentyloxy-4-methoxyphenyl)-( 1 -pyridin-3-ylethyl)amine (3,4-dimethoxyphenyl)-(l-pyridin-3-ylethyl)amine

(4-ethoxy-3-methoxyphenyl)-thiazol-5-ylmethyl-amine (4-difluoromethoxy-3-methoxyphenyl)-oxazol-5-ylmethyl-amine (3-isopropyloxy-4-methoxyphenyl)-oxazol-5-ylmethyl-amine (3-ethoxy-4-methoxyphenyl)-oxazol-5-ylmethyl-amine (3-cyclobutyloxy-4-difluoromethoxyphenyl)-oxazol-5-ylmethyl- amine

(3-cyclopropylmethoxy-4-methoxyphenyl)-oxazol-5-ylmethyl- amine (3-cyclobutyloxy-4-methoxyphenyl)-oxazol-5-ylmethyl-amine [3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-oxazol-5-ylmethy l-amine [3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl]-pyrimidin-5-ylme thyl-amine (4-difluoromethoxy-3-ethoxyphenyl)-(5-methoxypyridin-3-yl)me thyl-amine

(4-difluoromethoxy-3-ethoxyphenyl)-(4-methyloxazol-5-yl)m ethyl-amine (3-cyclopropyloxy-4-methoxyphenyl)-oxazol-5-ylmethyl-amine (3,4-diethoxyphenyl)-pyrimidin-5-ylmethyl-amine (3-isopropoxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-amine (3-cyclobutyloxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-amine (3-cyclopropyloxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-amin e

(3-cyclopropylmethoxy-4-methoxyphenyl)-pyrimidin-5-ylmeth yl-amine (3-ethoxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-amine (4-ethoxy-3-isopropoxyphenyl)-pyrimidin-5-ylmethyl-amine (3-cyclobutyloxy-4-difluoromethoxyphenyl)-pyrimidin-5-ylmeth yl-amine (3-ethoxy-4-isopropoxyphenyl)-thiazol-5-ylmethyl-amine

(4-ethoxy-3-isopropoxyphenyl)-oxazol-5-ylmethyl-amine (4-ethoxy-3 -methoxyphenyl) -pyrimidin- 5 -ylmethyl- amine (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-pyrimidin-5-y lmethyl-amine (3-cyclopropylmethoxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl- amine (3-benzyloxy-4-difluoromethoxyphenyl)-pyrimidin-5-ylmethyl-a mine

(3-cyclopropylmethoxy-4-methoxyphenyl)-oxazol-5-ylmethyl- amine (3-cyclobutyloxy-4-methoxyphenyl)-oxazol-5-ylmethyl-amine (3-ethoxy-4-trifluoromethoxyphenyl)-oxazol-5-ylmethyl-amine (3-cyclopropyloxy-4-methoxyphenyl)-pyrimidin-5-ylmethyl-amin e (4-ethoxy-3-methoxyphenyl)-oxazol-5-ylmethyl-amine

(3,4-diethoxyphenyl)-oxazol-5-ylmethyl-amine (4-ethoxy-3 -methoxyphenyl) -pyridin- 5 -ylmethyl- amine

(4-cyclopropyloxy-3-ethoxyphenyl)-pyrimidin-5-ylmethyl-am ine

[4-methoxy-3-(methylthio)phenyl]-thiazol-5-ylmethyl-amino

(4-difluoromethoxy-3-ethoxyphenyl)-(2-methylthiazol-5-yl) methyl-amine

(4-difluoromethoxy-3-ethoxyphenyl)-tetrahydrofuran-3-ylme thyl-amino

(3-cyclopropyloxy-4-difluoromethoxyphenyl)-pyrimidin-5-yl methyl-amine

(3-cyclopropyloxy-4-difluoromethoxyphenyl)-oxazol-5-ylmet hyl-amine

(4-methoxy-3-trifluoromethoxyphenyl)-oxazol-5-ylmethyl-am ine

(3-difluoromethoxy-4-methoxyphenyl)-oxazol-5-ylmethyl-ami ne

(3-difluoromethoxy-4-methoxyphenyl)-pyridin-3-ylmethyl-am ine

(4-difluoromethoxy-3-ethoxyphenyl)-(l,2,3-thiadiazol-5-yl )methyl-amine.

EXAMPLE 2

Synthesis of 4-r(3,4-Bis-difluoromethoxy-phenyl)-thiazol-5ylmethyl-amino1 -benzoic acid tert-butyl ester

A Schlenk tube was loaded under an atmosphere of argon with (3,4-bis- difluoromethoxy-phenyl)-thiazol-5ylmethyl-amine (924 mg, 2.86 mmol), 4-bromo-benzoic acid tert-butyl ester (1.52 g, 5.91 mmol), Pd ₂ (dba) ₃ (134 mg, 0.146 mmol) and dimethylamine (20 mL). P(t-Bu) ₃ (10% in hexane, 1.5 mL, 0.573 mmol) was then added and the reaction was stirred at 80 ⁰ C under an atmosphere of argon overnight. The reaction mixture was then cooled to room temperature and filtered trough celite. The filtrate was concentrated in vacuo and the residue was purified via flash chromatography (hexane/ethyl acetate) to give 1.215 g (85 %) of the crude product as an oil, which was further purified by stirring overnight at room temperature with MP-TMT (macroporous polystyrene-2,4,6- trimercaptotriazine) resin (600 mg) in dichloromethane (20 mL). The mixture was filtered through celite and the filtrate was concentrated, to afford 1.13 g (79%) of 4-[(3,4-Bis- difluoromethoxy-phenyl)-thiazol-5ylmethyl-amino] -benzoic acid tert-butyl ester.

The following compounds were synthesized in a similar manner, but using different startin ¹ gO materials:

3-{(3-fluorobenzyl)[4-methoxy-3-(2,2,2-trifluoroethoxy)ph enyl]amino}benzoic acid tert-butyl ester

3-[[3,4-bis(difluoromethoxy)phenyl]amino]benzoic acid, tert-butyl ester

3-[(3,4-dimethoxyphenyl)(3-fluorobenzyl)amino]benzoic acid tert-butyl ester

3-[(3-ethoxy-4-methoxyphenyl)(3-fluorobenzyl)amino]benzoi c acid tert-butyl ester

3-[[3-(cyclobutyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid tert- butyl ester

3-[[3-(cyclopentyloxy)-4-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid tert- butyl ester 3-[(2,6-difluorobenzyl)(3,4-dimethoxyphenyl)amino]benzoic acid tert-butyl ester

3-[(2,6-difluorobenzyl)(3-ethoxy-4-methoxyphenyl)amino]be nzoic acid tert-butyl ester

3-[(2,6-difluorobenzyl)(3-isopropoxy-4-methoxyphenyl)amin o]benzoic acid tert-butyl ester 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](2,6-difluorobenzyl)am ino]benzoic acid tert- butyl ester

3-((2,6-difluorobenzyl) { 4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl}amino)benzoic acid tert-butyl ester

3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethy l)amino]benzoic acid tert-butyl ester 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethyl)a mino]benzoic acid tert-butyl ester

3-[[3,4-bis(difluoromethoxy)phenyl] (2,6-difluorobenzyl)amino]benzoic acid tert- butyl ester 3-[[3,4-bis(difluoromethoxy)phenyl](3-fluorobenzyl)amino]ben zoic acid tert-butyX ester

3-{(2,6-difluorobenzyl)[4-(difluoromethoxy)-3-methoxyphen yl]amino}benzoic acid tert-butyX ester

3-[[4-(difluoromethoxy)-3-methoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid tert-butyλ ester

3-[[4-(difluoromethoxy)-3-methoxyphenyl] (3-fluorobenzyl)amino]benzoic acid tert- butyl ester

3-[[3,4-bis(difluoromethoxy)phenyl] (2-fluorobenzyl)amino]benzoic acid tert-butyX ester 3-[[3,4-bis(difluoromethoxy)phenyl](4-fluorobenzyl)amino]ben zoic acid tert-butyλ ester

3-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl } amino)benzonitrile

N-(3-fluorobenzyl)-4-methoxy-N-[4-(methylthio)phenyl]-3-[ (3R)-tetrahydrofuran-3- yloxy] aniline

N-[4-((3-fluorobenzyl){4-methoxy-3-[(3R)-tetrahydrofuran- 3-yloxy]phenyl})-N-(4- nitrophenyl)-amine

3-{ (3-cyanobenzyl)[3-(cyclopentyloxy)-4-methoxyphenyl]amino}ben zoic acid ethyl ester 3-{ [3-(cyclopentyloxy)-4-methoxyphenyl] [(6-oxo- 1, 6-dihydropyridin-3- yl)methyl] amino Jbenzoic acid ethyl ester

5-bromo-N-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(pyridin -3-ylmethyl)pyridin-2- amine

3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (piperidin- 3 -ylmethyl) amino] benzoic acid tert-butyl ester

4-{ [3-(cyclopentyloxy)-4-methoxyphenyl] [(6-oxo- 1, 6-dihydropyridin-3- yl)methyl] amino Jbenzoic acid ethyl ester

Ethyl {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy } acetate 1 - { 4- [[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]phen-3- yloxyjpropene

2-Chloropyridin-5-yl-4-(3-cyclopenyloxy-4-methoxyphenyl)- 3-pyridylmethylamine

N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2 )-methyl-N(5)-(pyridin- 3-ylmethyl)pyridine-2,5-diamine

3-{ { [l-(aminocarbonyl)piperidin-3-yl]methyl}[3-(cyclopentyloxy)- 4- methoxyphenyl] amino Jbenzoic acid tert butyl ester

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylme thyl)amino]benzoic acid tert-butyl ester 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiazol-5-ylmeth yl)amino]benzoic acid tert-butyl ester

{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]phenyl}acetic acid tert-butyl ester

5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]-2-ethylbenzoic acid methyl ester

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]-4- methylbenzoic acid ethyl ester

4-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylme thyl)amino]benzoic acid ethyl ester 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid ethyl ester

N-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(pyridin-3-ylmet hyl)-6-pyrrolidin-l- ylpyridin- 3 -amine

N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-(2,3-dihyd roxypropyl)-N(2)- methyl)-N(5)-(pyridin-3-ylmethyl)pyridine-2,5-diamine

N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-(2-morphol in-4-ylethyl)-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid ethyl ester N(2)-benzyl-N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-( pyridin-3- ylmethyl)pyridine-2,5-diamine

3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-4-ylmethyl)amino]benzoic acid ethyl ester

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid ethyl ester 4- [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (pyridazin- 3 -ylmethyl) amino] benzoic acid ethyl ester

3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (pyridazin- 3 -ylmethyl) amino] benzoic acid ethyl ester {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl) amino]phenyl}acetic acid ethyl ester

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](piperidin-4-ylmet hyl)amino]benzoic acid tert-butyl ester

4-([3-(cyclopentyloxy)-4-methoxyphenyl]{ [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid ethyl ester

3-([3-(cyclopentyloxy)-4-methoxyphenyl]{ [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid ethyl ester

3 - { 4- [ [3 - (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl Jpropan- 1 -ol 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]nicotinic acid ethyl ester

3 - { 4- [ [3 - (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}propanoic acid ethyl ester

3-(cyclopentyloxy)-4-methoxy-N-[3-(2-methyl-l,3-thiazol-4 -yl)phenyl]-N-(pyridin-3- ylmethyl)aniline l-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]phen-3- yloxyjpropene

{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]phenyl}acetic acid ethyl ester (5S)-5-({3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy}methyl)pyrrolidin-2-one

5 - { 3 - [ [3 - (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione

4-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid ethyl ester l-{4-[[3,4-bis(difluoromethoxy)phenyl](3-pyridylmethyl)amino ]phen-4- yloxyjpropene

3-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid tert- butyl ester N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(2)-[2-(methylsul fonyl)ethyl]-N(5)- (pyridin- 3 -ylmethyl)pyridine-2, 5 -diamine

3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyri din-3-ylmethyl)aniline

3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-( pyridin-3- ylmethyl)aniline

1 - { 4- [3-cyclopentyloxy-4-methoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]phen-4- yloxyjpropene

2-[{5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylm ethyl)amino]pyridin-2- yl } (methyl)amino] -N,N-dimethylacetamide N(5)-[3-(cyclopentyloxy)-4-methoxyphenyl]-N(5)-(pyridin-3-yl methyl)-N(2)-

(tetrahydro-2H-pyran-4-yl)pyridine-2,5-diamine

3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyri din-3-ylmethyl)aniline

5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]-N,2- dihydroxybenzamide 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-3- methylbenzoic acid methyl ester

{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]phenyl}acetic acid ethyl ester

3-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3 -thiazol-5- ylmethyl)amino]benzoic acid tert-butyl ester

4-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3 -thiazol-5- ylmethyl)amino]benzoic acid ethyl ester

4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]benzoic acid ethyl ester 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5- ylmethyl)amino]benzoic acid tert-butyl ester

4-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl) amino]benzoic acid tert- butyl ester

3-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl) amino]benzoic acid tert- butyl ester

3,4-bis(difluoromethoxy)-N-[4-(ethylthio)phenyl]-N-(pyrid in-3-ylmethyl)aniline 3,4-bis(difluoromethoxy)-N-[4-(methylthio)phenyl]-N-(l,3-thi azol-5-ylmethyl)aniline 3,4-bis(difluoromethoxy)-N-[4-(ethylthio)phenyl]-N-(l,3-thia zol-5-ylmethyl)aniline 3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(l,3-thi azol-5-ylmethyl)aniline 4-[[3,4-bis(difluoromethoxy)phenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid tert- butyl ester

5-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino] nicotinic acid tert-butyl ester 3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)ami no]benzoic acid tert- butyl ester

5-[[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]nicotinic acid tert butyl ester l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]-2-?er?- butyldimethylsilyloxyphenyl } ethanone

1 - { 4- [[3,4-bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2,2,2- trifluoroethanone

1 - { 4- [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } ethanone 1 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } ethanone 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2,3-difluoro-l-?ert- butyldimethylsilyloxyphenyl

5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2-tert- butyldimethylsilyloxybenzoic acid tert-butyl ester

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2-tert- butyldimethylsilyloxybenzoic acid methyl ester

3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]benzaldehyde

1 - { 5 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridine- 3 -ylmethyl) amino] pyridin-3 - yl} ethanone

N- [3 ,4-bis (difluoromethoxy)phenyl] - 5 - (2-methyl- l,3-dioxolan-2-yl)-N- (pyridin- 3 - ylmethyl)pyridin-3-amine

3,4-bis(difluoromethoxy)-N-[3-(lH-(l-triphenylmethyl)pyra zol-3-yl)phenyl]-N- (pyridin- 3 -ylmethyl) aniline

3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]nicotinic acid tert- butyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester {4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid ethyl ester

3 [3 ,4-bis (difluoromethoxyphenyl) -N- (pyridin- 3 -ylmethyl) amino] benzonitrile

{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmeth yl)amino]phenyl}acetic acid ethyl ester

4- [ [3 - (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid tert-butyl ester

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid tert-butyl ester 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid tert-butyl ester

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylm ethyl)amino]benzoic acid tert-butyl ester

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

3 - [ [3 - (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 , 3 -thiazol- 5 - ylmethyl)amino]benzoic acid tert-butyl ester

4-methoxy-N-[4-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydro furan-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline l-{4-[[3,4-bis(difhioromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}ethanone l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-3- methoxypropan-2-ol

3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyri midin-5-ylmethyl)aniline 3,4-bis(difluoromethoxy)-N-[4-(methylthio)phenyl]-N-(pyrimid in-5-ylmethyl)aniline

4-methoxy-N-[3-(methylsulfonyl)phenyl]-3-[(3R)-tetrahydro furan-3-yloxy]-N-(l,3- thiazol- 5 -ylmethyl) aniline

3-[[4-(difluoromethoxy)-3-methoxyphenyl](l,3-thiazol-5-yl methyl)amino]benzoic acid tert-butyl ester 1- { 4-[[3,4-bis(difluoromethoxy)phenyl] (pyrimidin-5- ylmethyl)amino]phenyl}ethanone

3 ,4-bis (difluoromethoxy)-N- [4- (methylsulf onyl)phenyl] -N-(pyrazin-2- ylmethyl)aniline l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)am ino]phenyl}ethanone 4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3 -thiazol-5- ylmethyl)amino]benzoic acid tert-butyl ester 1 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenoxy } -2- methylpropan-2-ol l-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenoxy}-2- methylpropan-2-ol

4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid tert-butyl ester

3-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

3-[[3-butoxy-4-(difluoromethoxy)phenyl](pyridin-3-ylmethy l)amino]benzoic acid tert-butyl ester 3-{ [3,4-bis(difluoromethoxy)phenyl][(l-methyl-lH-pyrazol-4- yl)methyl] amino Jbenzoic acid tert-butyl ester

4-[[3-butoxy-4-(difluoromethoxy)phenyl](pyridin-3-ylmethy l)amino]benzoic acid tert-butyl ester

4-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

4-[(3-ethoxy-4-methoxyphenyl)( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

4-[(3-isopropoxy-4-methoxyphenyl)( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert- butyl ester 3 - (cyclopropylmethoxy) -4-methoxy-N- [4- (methylsulf onyl)phenyl] -N- ( 1 , 3 -thiazol-5 - ylmethyl)aniline l-{4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]phenyl}ethanone

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr idin-3- ylmethyl)amino]benzoic acid tert-butyl ester

3,4-bis(difluoromethoxy)-N-[4-methyl-3-(methylsulfonyl)ph enyl]-N-(l,3-thiazol-5- ylmethyl)aniline

{4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl )amino]phenyl}acetic acid ethyl ester 4-[(3,4-dimethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoi c acid tert-butyl ester {3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid ethyl ester

{4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)a mino]phenyl}acetic acid ethyl ester 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-oxazol-5-ylmethyl)am ino]benzoic acid tert- butyl ester

4-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid tert- butyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid tert-butyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

Methyl 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]- benzenesulphonate 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrazin-2-ylmethyl)a mino]benzoic acid tert-butyX ester

3-[[3,4-bis(difluoromethoxy)phenyl] (pyrazin-2-ylmethyl)amino]benzoic acid tert- butyl ester

2-[[3,4-bis(difluoromethoxy)phenyl](phenyl)amino]-l-((te/ t- butyldimethyl)silyloxy)ethane

3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyλ ester

4-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyX ester 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrimidin-5-ylmethy l)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid tert-butyX ester

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylm ethyl)amino]benzoic acid tert-butyλ ester

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylm ethyl)amino]benzoic acid tert-butyX ester

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr azin-2- ylmethyl)amino]benzoic acid tert-butyλ ester 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid tert-butyl ester

5-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]nicotinic acid tert-butyl ester 4-[[3-(difluoromethoxy)-4-methoxyphenyl] (pyrazin-2-ylmethyl)amino]benzoic acid tert-butyl ester

N-[3,4-bis(difluoromethoxy)phenyl]-N-(l,3-thiazol-5-ylmet hyl)]-4-methyl-3- nitroaniline

N-[3,4-bis(difluoromethoxy)phenyl]-N-(l,3-thiazol-5-ylmet hyl)]-3-nitroaniline 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid tert-butyl ester

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3 -oxazol-5- ylmethyl)amino]benzoic acid tert-butyl ester

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr imidin-5- ylmethyl)amino]benzoic acid tert-butyl ester

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-y lmethyl)amino]benzoic acid tert-butyl ester

4-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benz oic acid tert-butyl ester

3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] ( 1 -pyridin- 3 -ylethyl) amino] benzoic acid tert-butyl ester

3-[(3,4-dimethoxyphenyl)(l-pyridin-3-ylethyl)amino]benzoi c acid tert-butyl ester

4-[(4-ethoxy-3-methoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid tert-butyl ester

4-(difluoromethoxy)-3-ethoxy-N-[4-(methylsulfonyl)phenyl] -N-(l,3-thiazol-5- ylmethyl)aniline

{ 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5- ylmethyl)amino]phenyl} acetic acid ethyl ester

3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]butyric acid tert- butyl ester { 4- [[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5- ylmethyl)amino]phenyl} acetic acid ethyl ester

{ 3- [[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-thiazol-5- ylmethyl)amino]phenyl} acetic acid ethyl ester 4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyX ester

4-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)a mino]benzoic acid tert- butyl ester 4-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid tert-butyX ester

4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxaz ol-5- ylmethyl)amino]benzoic acid tert-butyX ester

4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid tert-butyX ester

4-[[3-(cyclobutyloxy)-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyX ester

4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid tert-butyX ester 4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](pyrimidin-5-y lmethyl)amino]benzoic acid tert-butyX ester

4-{ [4-(difluoromethoxy)-3-ethoxyphenyl] [(5-methoxypyridin-3- yl)methyl] amino Jbenzoic acid tert-butyX ester

4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(4-methyl-l,3-oxazol-5- yl)methyl] amino Jbenzoic acid tert-butyX ester

4-[[3-(cyclopropyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylme thyl)amino]benzoic acid tert-butyX ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-4-ylmethyl)amino]benzoic acid methyl ester cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]cyclohexanecarboxylic acid ethyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-4-ylmethyl)amino]benzoic acid tert-butyX ester

4-[(3,4-diethoxyphenyl)(pyrimidin-5-ylmethyl)amino]benzoi c acid tert-butyX ester 4-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid tert- butyl ester

4-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmeth yl)amino]benzoic acid tert-butyX ester

4-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid tert-butyX ester 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid tert-butyl ester

4-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid tert-butyl ester 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid tert-butyl ester

3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3 -oxazol-5- ylmethyl)amino]benzoic acid tert-butyl ester

3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid methyl ester

3-[(3-ethoxy-4-methoxyphenyl)( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

3-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxaz ol-5- ylmethyl)amino]benzoic acid tert-butyl ester 4-[(4-ethoxy-3-isopropoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid tert- butyl ester

3-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)a mino]benzoic acid tert- butyl ester

3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

4- [ [3 - (cyclobutyloxy) -4- (difluoromethoxy)phenyl] (pyrimidin-5 - ylmethyl)amino]benzoic acid tert-butyl ester

3-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyl ester 4-[(3-ethoxy-4-isopropoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid tert- butyl ester

4-[(4-ethoxy-3-isopropoxyphenyl)(l,3-oxazol-5-ylmethyl)am ino]benzoic acid tert- butyl ester

4- [(4-ethoxy-3-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]benzo ic acid tert-butyl ester

3-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid methyl ester

3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr imidin-5- ylmethyl)amino]benzoic acid tert-butyl ester 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid tert-butyλ ester

3-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)am ino]benzoic acid tert- butyl ester 4-[[3-(benzyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5-ylm ethyl)amino]benzoic acid tert-butyλ ester

3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid tert-butyλ ester

3-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmet hyl)amino]benzoic acid tert-butyλ ester

4-[[3-ethoxy-4-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid ethyl ester

3-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid tert-butyλ ester 4-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid tert-butyλ ester

4-[[4-(difluoromethoxy)-3-methoxyphenyl]amino]benzoic acid tert-butyλ ester 4-[[4-(difluoromethoxy)-3-ethoxyphenyl]amino]benzoic acid tert-butyλ ester 4-[[3,4-bis(difluoromethoxy)phenyl]amino]benzoic acid tert-butyλ ester 4-[(3,4-diethoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyλ ester

4-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]be nzoic acid tert-butyλ ester

3-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]be nzoic acid tert-butyλ ester 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid tert-butyλ ester

3 - [ [4- (cyclopropyloxy)- 3 -ethoxyphenyl] (pyrimidin- 5 -ylmethyl) amino] benzoic acid methyl ester

3-[(4-ethoxy-3-methoxyphenyl)( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid tert-butyλ ester

4-[[4-methoxy-3-(methylthio)phenyl](l,3-thiazol-5-ylmethy l)amino]benzoic acid tert- butyλ ester

4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(2-methyl-l,3-thiazol-5 - yl)methyl] amino Jbenzoic acid tert-butyλ ester 3-[(4-ethoxy-3-methoxyphenyl)( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid tert-butyl ester

3-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benz oic acid tert-butyl ester

3-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmeth yl)amino]benzoic acid tert-butyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl](tetrahydrofuran-3 -ylmethyl)amino]benzoic acid tert-butyl ester

4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](pyrimid in-5- ylmethyl)amino]benzoic acid tert-butyl ester 4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid, tert-butyl ester

4-[[4-methoxy-3-(trifluoromethoxy)phenyl](l,3-oxazol-5-yl methyl)amino]benzoic acid, tert-butyl ester

3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid, tert-butyl ester

4-[[3-(difluoromethoxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid, tert-butyl ester

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,2,3-thiadiazol-5-ylmethyl)amino]benzoic acid, tert-butyl ester 4-[[3-hydroxy-4-methoxyphenyl](l,3-oxazol-5-ylmethyl)amino]b enzoic acid, tert- butyl ester

3- [[4-ethoxy-3-methoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid, tert-butyl ester

3-[[3,4-diethoxyphenyl](pyrimidin-5-ylmethyl)amino]benzoi c acid, tert-butyl ester 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid, tert-butyl ester

3-[[3-cyclopropyloxy-4-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid, tert-butyl ester

3-[[3-cyclobutyloxy-4-difluoromethoxyphenyl](pyrimidin-5- ylmethyl)amino]benzoic acid, tert-butyl ester and 3-[[3-cyclopropyloxy-4-difluoromethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid, tert-butyl ester.

EXAMPLE 3

Synthesis of 4-r(3,4-Bis-difluoromethoxy-phenyl)-thiazol-5ylmethyl-amino1 -benzoic acid

A mixture of 4-[(3,4-bis-difluoromethoxy-phenyl)-thiazol-5ylmethyl-amino] -benzoic acid tert-butyl ester (1.13 g, 2.3 mmol) and trifluoroacetic acid (0.7 rnL, 9.09 mmol) in dichloromethane (12 rnL) was heated at 100 ⁰ C in a microwave oven at 75 Watts for 1 hour. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified via flash chromatography

(dichloromethane/methanol)) to afford 692 mg (68%) of the desired product as an off-white foam. Recrystallization from ethyl acetate afforded 4-[(3,4-Bis-difluoromethoxy-phenyl)- thiazol-5ylmethyl-amino]-benzoic acid as a white crystalline solid. Mp = 144.3-145.7 °Cτ

mp 144.3-145.7 ⁰ C; ¹ H NMR (DMSOd ₆ ) δ 12.49 (bs, IH), 8.98 (s, IH), 7.86 (s, IH), 7.79 (m, 2H), 7.39-7.14 (m, 5H), 7.03-6.97 (m, 2H), 5.30 (s, 2H); MS (ESI, [M+H ⁺ ]) m/z 443; Anal. Calcd for C ₁₉ Hi ₄ F ₄ N ₂ O ₄ S: C, 51.59; H, 3.19; N, 6.33. Found: C, 51.37; H, 3.07; N, 6.35.

The following compounds were prepared in a similar manner starting with the corresponding tert-butyl ester:

3-{(3-fluorobenzyl)[4-methoxy-3-(2,2,2-trifluoroethoxy)ph enyl]amino}benzoic acid

3- [ [3 ,4-bis (difluoromethoxy)phenyl] amino]benzoic acid

3-[(3,4-dimethoxyphenyl)(3-fluorobenzyl)amino]benzoic acid

3 - [ (3 -ethoxy-4-methoxyphenyl) (3 -fluorobenzyl) amino] benzoic acid

3-[[3-(cyclobutyloxy)-4-methoxyphenyl](3-fluorobenzyl)ami no]benzoic acid 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](3-fluorobenzyl)amino ]benzoic acid 3-[(2,6-difluorobenzyl)(3,4-dimethoxyphenyl)amino]benzoic acid 3-[(2,6-difluorobenzyl)(3-ethoxy-4-methoxyphenyl)amino]benzo ic acid 3-[(2,6-difluorobenzyl)(3-isopropoxy-4-methoxyphenyl)amino]b enzoic acid 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](2,6-difluorobenzyl)am ino]benzoic acid

3-((2,6-difluorobenzyl) { 4-methoxy-3-[(3R)-tetrahydrofuran-3- yloxy]phenyl}amino)benzoic

3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethy l)amino]benzoic acid 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyridin-3-ylmethyl)a mino]benzoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](2,6-difluorobenzyl)amino ]benzoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](3-fluorobenzyl)amino]ben zoic acid 3-{ (2,6-difluorobenzyl)[4-(difluoromethoxy)-3-methoxyphenyl]ami no}benzoic acid

3-[[4-(difluoromethoxy)-3-methoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid 3-[[4-(difluoromethoxy)-3-methoxyphenyl](3-fluorobenzyl)amin o]benzoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](2-fluorobenzyl)amino]ben zoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](4-fluorobenzyl)amino]ben zoic acid 3-{ { [l-(aminocarbonyl)piperidin-3-yl]methyl}[3-(cyclopentyloxy)- 4- methoxyphenyl] amino Jbenzoic acid

3-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

3-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3 -thiazol-5- ylmethyl)amino]benzoic acid 3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid

5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]nicotinic acid 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid

4- [ [3 - (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid 4-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylm ethyl)amino]benzoic acid 3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyridin-3-ylmeth yl)amino]benzoic acid

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 3 - [ [3 - (cyclopentyloxy) -4- (difluoromethoxy)phenyl] ( 1 ,3 - thiazol- 5 - ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 4-[[4-(difluoromethoxy)-3-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

3-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 3-[[3-butoxy-4-(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]benzoic acid

3-{ [3,4-bis(difluoromethoxy)phenyl][(l-methyl-lH-pyrazol-4- yl)methyl] amino Jbenzoic acid 4-[[3-butoxy-4-(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]benzoic acid

4-[[3-butoxy-4-(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid 4-[(3-ethoxy-4-methoxyphenyl)( 1 ,3-miazol-5-ylmethyl)amino]benzoic acid 4-[(3-isopropoxy-4-methoxyphenyl)(l,3-thiazol-5-ylmethyl)ami no]benzoic acid 4-[(3,4-dimethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoi c acid 3-[[3-(difluoromethoxy)-4-methoxyphenyl](l,3-thiazol-5-ylmet hyl)amino]benzoic acid

4-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylm ethyl)amino]benzoic acid

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrazin-2-ylm ethyl)amino]benzoic acid

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr azin-2- ylmethyl)amino]benzoic acid 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrazi n-2- ylmethyl)amino]benzoic acid

4-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benz oic acid 3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] ( 1 -pyridin- 3 -ylethyl) amino] benzoic acid 3-[(3,4-dimethoxyphenyl)(l-pyridin-3-ylethyl)amino]benzoic acid 4-[(4-ethoxy-3-methoxyphenyl)( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

3-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]butyric acid 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid

4-{ [4-(difluoromethoxy)-3-ethoxyphenyl] [(5-methoxypyridin-3- yl)methyl] amino Jbenzoic acid 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid

3-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid 4-[(3-ethoxy-4-isopropoxyphenyl)(l,3-thiazol-5-ylmethyl)amin o]benzoic acid 4-[(4-ethoxy-3-isopropoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid 4-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid 4-[[4-(difluoromethoxy)-3-methoxyphenyl]amino]benzoic acid

4-[[4-(difluoromethoxy)-3-ethoxyphenyl]amino]benzoic acid 4- [ [3 ,4-bis (difluoromethoxy)phenyl] amino]benzoic acid 4-[(3,4-diethoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]benzoic acid 4-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid 3-[(4-ethoxy-3-methoxyphenyl)(pyridin-3-ylmethyl)amino]benzo ic acid

3-[(4-ethoxy-3-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid 3-[(4-ethoxy-3-methoxyphenyl)( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 3-[(3,4-diethoxyphenyl)(l,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](l,3-oxa zol-5- ylmethyl)amino]benzoic acid

4-[[4-methoxy-3-(trifluoromethoxy)phenyl](l,3-oxazol-5-yl methyl)amino]benzoic acid

3-[[4-ethoxy-3-methoxyphenyl](pyrimidin-5-ylmethyl)amino] benzoic acid 3-[[3,4-diethoxyphenyl] (pyrimidin-5-ylmethyl)amino]benzoic acid 3-[[3,4-diethoxyphenyl](l,3-oxazol-5-ylmethyl)amino]benzoic acid

3-[[3-cyclopropyloxy-4-methoxyphenyl](l,3-oxazol-5-ylmeth yl)amino]benzoic acid, and

3-[[3-cyclopropyloxy-4-difluoromethoxyphenyl](l,3-oxazol- 5- ylmethyl)amino]benzoic acid. EXAMPLE 4 Synthesis of 4-Bromo-2-ethoxy-phenol

A mixture of 2-ethoxyphenol (30.0 g, 217 mmol) and TBAB [(tri-n-butylamino tribromide) ((W-Bu ₄ )NBr ₃ )] (104.7 g, 217 mmol) in a 10:1 mixture of dichloromethane/methanol (385 mL) was allowed to warm from -78 ⁰ C to 0 ⁰ C over a period of 2.5 hr. The reaction was quenched by the addition of Na ₂ S ₂ O ₃ (8 g in 80 mL of water) and the reaction mixture was concentrated in vacuo. The residue was extracted with diethyl ether and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to a volume of 400 mL. The mixture was then warmed slightly and filtered by gravity. The filtrate was concentrated, taken up in diethylether/hexanes (1:2), heated, and the mixture was) filtered while it was hot to remove the inorganic by-product. The filtrate was concentrated to afford 37.04 g of 4-bromo-2- ethoxy-phenol as a slightly colored solid. A second crop of lower purity was isolated from the filtrate, affording an additional 9.41 g of product.

EXAMPLE 5

Synthesis of 4-Bromo-l-difluoromethoxv-2-ethoxy-benzene

Powdered potassium hydroxide (5.17 g, 92. 1 mmol) was added to a stirring solution of 4-bromo-2-ethoxy-phenol (20.0 g, 92.1 mmol) in N-methylpyrrolidinone (400 mL) at room temperature. The dark colored solution was stirred for 30 minutes, then difluorochloromethane was bubbled through the reaction mixture until saturation occurred. The reaction was stirred for an additional 30 minutes, then potassium hydroxide (10.3 g in 10 mL of water) was added dropwise maintaining the temperature below 31 ⁰ C. The resulting mixture was stirred for 3 hours. Nitrogen was then bubbled through the mixture for 25 minutes, and the reaction mixture was poured into a 1:1 mixture of diethylether/water. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organics were washed with water and brine, then dried over sodium sulfate, filtered and evaporated. The resulting crude material was purified via flash chromatography (hexane/ethyl acetate) to afford 16.7 g of 4-bromo-l-difluoromethoxy-2-ethoxy-benzene as colorless oil.

EXAMPLE 6

Synthesis of 4-r(Pyrimidin-5-ylmethyl)-aminol-benzoic acid tert-hutyλ ester

A mixture of 4-amino-benzoic acid ester (3.93 g, 20.4 mmol), pyrimidine-5- carboxaldehyde (2.00 g, 18.5 mmol), Na(OAc) ₃ BH (5.88 g, 27.8 mmol) and methanol (3 drops) in dichloroethane (75 mL) was stirred at room temperature for 16 hr. The reaction mixture was then diluted with dichloromethane, washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The resulting crude material was purified via flash chromatography (hexane/ethyl acetate), to afford 4.02 g of 4-[(pyrimidin-5-ylmethyl)-amino]-benzoic acid tert-butyX ester.

EXAMPLE 7

Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-pyrimidin-5-ylmethyl- amino1- benzoic acid fert-butyl ester

A mixture of toruene/dimethoxyethane (10 mL/3 rnL) was added to a mixture of 4- [(pyrimidin-5-ylmethyl)-amino]-benzoic acid tert-butyl ester (1.42 g, 4.91 mmol), 4-bromo- l-difluoromethoxy-2-ethoxy-benzene (2.00 g, 7.49 mmol), sodium hydroxide (589 mg, 14.7 mmol), and Pd(I-Bu ₃ P) ₂ (251 mg, 0.49 mmol) under an atmosphere of argon. The resulting mixture was stirred at room temperature for 15 minutes, then heated at 40 ⁰ C for 15 minutes, followed by heating at 60 ⁰ C for 3.5 hr. The reaction mixture was then cooled to room temperature and MP-TMT (macroporous polystyrene-2,4,6-trimercaptotriazine) resin (1.0 g) was added. The mixture was gently stirred overnight, then filtered through celite. The filtrate was evaporated in vacuo and the residue was purified via flash chromatography (hexane/ethyl acetate) to afford 2.45 g of 4-[(4-Difluoromethoxy-3-ethoxy-phenyl)- pyrimidin-5-ylmethyl-amino]-benzoic acid tert-butyl ester as a syrup.

EXAMPLE 8

Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-pyrimidin-5-ylmethyl- amino1- benzoic acid

A mixture of 4-[(4-difluoromethoxy-3-ethoxy-phenyl)-pyrimidin-5-ylmethyl- amino]- benzoic acid tert-butyl ester (2.30 g, 4.88 mmol) and potassium hydroxide (2.00 g, 35.6 mmol) in ethanol (85 niL) was heated at reflux for 4 hr, then cooled to room temperature and concentrated in vacuo. The resulting residue was taken up in water and washed with dichloromethane (5 mL). Toluene (120 mL) was then added and the mixture was adjusted to pH 6.5 by the addition of 6M hydrochloric acid, then heated to 70 ⁰ C until homogeneous. The reaction mixture was allowed to cool slowly overnight during which time a light tanned solid formed. The needle-like crystals were collected by filtration and washed with toluene and water. The crystals were dried under vacuum at 50 ⁰ C for 3 days, then purified through a short silica column. The resulting solid was recrystallized from ethyl acetate to afford 1.42g of 4- [(4-Difluoromethoxy-3-ethoxy-phenyl)-pyrimidin-5-ylmethyl-am ino] -benzoic acid as fine white crystals, mp = 165.3-165.9 ⁰ C.

mp 165.3-165.9 ⁰ C; ¹ H NMR (DMSOd ₆ ) δ 12.36 (bs, IH), 9.07 (s, IH), 8.74 (s, 2H), 7.77- 7.74 (m, 2H), 7.30-6.80 (m, 6H), 5.12 (s, 2H), 4.03 (q, J = 7 Hz, 2H), 1.29 (t, J = 7 Hz, 3 H); MS (ESI, [M+H ⁺ ]) m/z 416; Anal. Calcd for C ₂ IH ₁₉ F ₂ N ₃ O ₄ : C, 60.72; H, 4.61; N, 10.12. Found: C, 60.69; H, 4.55; N, 10.20.

The following compounds were prepared in a similar fashion starting with the corresponding tert-butyX esters:

Ester hydrolysis with KOH

3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (piperidin- 3 -ylmethyl) amino] benzoic acid

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylme thyl)amino]benzoic acid

3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[[3-(cyclopentyloxy)-4-methoxyphenyl](lH-pyrazol-4-ylme thyl)amino]benzoic acid

4-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid 3-[[3-(cyclopentyloxy)-4-methoxyphenyl] ( 1 ,3-thiazol-4-ylmethyl)amino]benzoic acid

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid 3 - [ [3 - (cyclopentyloxy) -4-methoxyphenyl] (pyridazin- 3 -ylmethyl) amino] benzoic acid 3-[[3-(cyclopentyloxy)-4-methoxyphenyl](piperidin-4-ylmethyl )amino]benzoic acid

4-([3-(cyclopentyloxy)-4-methoxyphenyl]{ [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid 3-([3-(cyclopentyloxy)-4-methoxyphenyl]{ [2-(dimethylamino)pyrimidin-5- yl] methyl }amino)benzoic acid

4-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}(l,3 -thiazol-5- ylmethyl)amino]benzoic acid

4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]benzoic acid

3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino]benzoic acid 4-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl)ami no]benzoic acid

3-[[3,4-bis(difluoromethoxy)phenyl](pyridazin-3-ylmethyl) amino]benzoic acid 4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)ami no]benzoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)ami no]benzoic acid 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid 4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrimidin-5-ylmethy l)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-methoxyphenyl](pyrazin-2-ylmeth yl)amino]benzoic acid

5-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-miazol-5-ylmethyl)amino]nicotinic acid 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrimi din-5- ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-y lmethyl)amino]benzoic acid

4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](pyrimidin- 5-ylmethyl)amino]benzoic acid

4- [ (3 ,4-diethoxyphenyl) (pyrimidin- 5 -ylmethyl) amino] benzoic acid 4-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino ]benzoic acid 4-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl) amino]benzoic acid 4-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid 4-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

4-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid 4-[(4-ethoxy-3-isopropoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid

4- [ [3 - (cyclobutyloxy) -4- (difluoromethoxy)phenyl] (pyrimidin-5 - ylmethyl)amino]benzoic acid

4-[(4-ethoxy-3-methoxyphenyl)(pyrimidin-5-ylmethyl)amino] benzoic acid 3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyrimi din-5- ylmethyl)amino]benzoic acid

4-[[3-(benzyloxy)-4-(difluoromethoxy)phenyl](pyrimidin-5- ylmethyl)amino]benzoic acid

3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-oxazol-5- ylmethyl)amino]benzoic acid, and

3-[[3-cyclobutyloxy-4-difluoromethoxyphenyl](pyrimidin-5- ylmethyl)amino]benzoic acid.

EXAMPLE 9

Synthesis of 4-r(Pyridin-3-ylmethyl)-amino1-benzoic acid fert-butyl ester

A mixture of 4-amino-benzoic acid tert-butyl ester (6.63 g, 34.3 mmol), pyridine-5- carboxaldehyde (3.34 g, 31.2 mmol) and Na(OAc) ₃ BH (9.91 g, 46.8 mmol) in dichloroethane (75 mL) was stirred at room temperature for 16 hr. The reaction mixture was then diluted with dichloromethane and washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered, and evaporated. The resulting crude material was purified via flash chromatography (hexane/ethyl acetate) to affording 8.64 g of 4- [(Pyridin-3-ylmethyl)-amino] -benzoic acid tert-butyl ester as a white solid.

EXAMPLE 10

Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-pyridin-3-ylmethyl-am ino1- benzoic acid tert-butyl ester

A mixture of toluene/dimethoxyethane (10 mL/3 mL) was added to a mixture of 4- [(pyridin-3-ylmethyl)-amino]-benzoic acid tert-butyl ester (1.39 g, 4.91 mmol), 4-bromo-l- difluoromethoxy-2-ethoxy-benzene (2.00 g, 7.49 mmol), sodium hydroxide (589 mg, 14.7 mmol), and Pd(t-Bu ₃ P) ₂ (251 mg, 0.49 mmol) under an atmosphere of argon. The resulting mixture was stirred at room temperature for 15 minutes, then heated at 40 ⁰ C for 15 minutes, followed by heating to 60 ⁰ C for 3.5 hr. The reaction was then cooled to room temperature and MP-TMT (macroporous polystyrene-2,4,6-trimercaptotriazine) resin (1.0 g) was added. The mixture was gently stirred overnight, then filtered through celite. The filtrate was evaporated in vacuo and the residue was purified via flash chromatography (hexane/ethyl acetate) to afford 2.50 g of 4-[(4-Difluoromethoxy-3-ethoxy-phenyl)-pyridin-3-ylmethyl- amino] -benzoic acid tert-butyl ester as an oil.

EXAMPLE 11

Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-pyridin-3-ylmethyl-am ino1- benzoic acid

A mixture of 4-[(4-difluoromethoxy-3-ethoxy-phenyl)-pyridin-3-ylmethyl-am ino]- benzoic acid tert-butyl ester (2.29 g, 4.88 mmol) and potassium hydroxide (2.00 g, 35.6 mmol) in ethanol (85 mL) was heated at reflux for 4 hr, then cooled to room temperature and concentrated in vacuo. The residue was taken up in water and washed with dichloromethane (5 mL). Toluene (120 mL) was then added and the mixture was adjusted to pH 6.5 by the addition of 6M hydrochloric acid, then heated at 70 ⁰ C until homogeneous. The mixture was cooled to (room) temperature slowly overnight, and the resulting solid was collected by filtration, washed with toluene and water, and dried under vacuum at 50 ⁰ C overnight. The solid was purified via elution through silica gel (dichloromethane/hexanes), and the resulting solid was recrystallized from ethyl acetate to give 1.43 g of 4-[(4-difluoromethoxy-3-ethoxy- phenyl)-pyridin-3-ylmethyl-amino]-benzoic acid as a white solid, mp = 177.6-178.9 ⁰ C. mp 177.6-178.9 ⁰ C; ¹ H NMR (DMSO-d ₆ ) δ 12.30 (bs, IH), 8.53 (d, J = 2 Hz, IH), 8.44 (dd, J = 1.5, 4.7 Hz, IH), 7.76-6.80 (m, 3H), 7.30-6.80 (m, 7H), 5.11 (s, 2H), 4.03 (q, J = 7 Hz, 2H), 1.29 (t, J = 7 Hz, 3 H); MS (ESI, [M+H ⁺ ]) m/z 415.

EXAMPLE 12

Synthesis of 4-Bromo-l-difluoromethoxy-2-methoxy-benzene

Powdered KOH (4.65 g, 82.9 mmol) was added to a stirring solution of 4-bromo-2- methoxy-phenol (18.0 g, 82.9 mmol) in NMP (l-methyl-2-pyrrolidinone) (400 mL) at room temperature under an atmosphere of nitrogen. The mixture was heated at 50 ⁰ C for 45 minutes, then cooled to room temperature. Difluorochloromethane was bubbled through the reaction mixture (approximately 20 minutes) until saturation occurred, and the mixture was then stirred for an additional 20 minutes. Potassium hydroxide (9.31 g in 5 mL of water) was then added dropwise maintaining the temperature below 33 ⁰ C, and the mixture was stirred for an additional 40 minutes. Additional potassium hydroxide (4.65 g, in 5 mL of water) was then added dropwise, and the mixture was stirred for one hr. Nitrogen was then bubbled through the reaction, and water was added carefully. The pH of the resulting mixture was adjusted to 8.0 by the addition of potassium hydroxide (aqueous) and the mixture was extracted using diethylether. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The crude material was purified via flash chromatography (hexanes/ethyl acetate) to afford 16.3 g of 4-bromo-l-difluoromethoxy-2- methoxy-benzene as colorless liquid.

EXAMPLE 13

Synthesis of 4-r(4-Difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl-a mino1- benzoic acid fert-butyl ester

A mixture of toruene/dimethoxyethane (5/1, 18 rnL) was added to a mixture of A- [(pyridin-3-ylmethyl)-amino]-benzoic acid tert-butyl ester (2.00 g, 7.03 mmol), 4-bromo-l- difluoromethoxy-2-methoxy-benzene (2.66 g, 10.5 mmol), sodium hydroxide (0.84 g, 21.1 mmol), and Pd(I-Bu ₃ P) ₂ (359 mg, 0.70 mmol) under an atmosphere of argon. The resulting mixture was stirred at room temperature for 15 minutes, then heated at 40 ⁰ C for 15 minutes, then heated to 60 ⁰ C for 3.5 hr. After cooling to room temperature MP-TMT (macroporous polystyrene-2,4,6-trimercaptotriazine) resin (1.0 g) was added, the mixture was gently stirred overnight, then filtered through celite. The filtrate was evaporated in vacuo and the residue was purified via flash chromatography (hexane/ethyl acetate) to afford 3.30 g of 4-[(4- difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl-amino] -benzoic acid te/t-butyl ester as a syrup.

EXAMPLE 14

Synthesis of 4-r(4-Difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl-a mino1- benzoic acid

A mixture of 4-[(4-difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl-a mino]- benzoic acid tert-butyX ester (3.20 g), formic acid (9 mL) and hydrochloric acid (6M, 9 mL) in toluene (10 niL) was heated at reflux for 3 hr, then cooled, and the layers were separated. The aqueous layer was carefully adjusted to pH 6.5 by the addition of an aqueous solution of sodium hydroxide, then extracted using ethyl acetate (100 rnL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was dissolved in hot ethyl acetate and the product was recrystallized overnight affording a white solid, which was collected by filtration and rinsed with cold ethyl acetate. The solid was dried in vacuo at 60 ⁰ C to give 913 mg of 4-[(4- Difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl-amino] -benzoic acid. The mother liquors were evaporated in vacuo and the residue purified via flash chromatography (dichloromethane/methanol). The resulting solid was recrystallized from ethyl acetate to afford a further 1.29 g of 4-[(4-Difluoromethoxy-3-methoxy-phenyl)-pyridin-3-ylmethyl- amino] -benzoic acid as white crystals, mp = 183.7-184.9 ⁰ C.

mp 183.7-184.9 ⁰ C; ¹ H NMR (DMSOd ₆ ) δ 12.39 (bs, IH), 8.55 (d, J = 1.8 Hz, IH), 8.45 (dd, J = 1.6, 4.8 Hz, IH), 7.76-7.72 (m, 3H), 7.37-6.81 (m, 7H), 5.12 (s, 2H), 3.78 (s, 3H); MS (ESI, [M+H ⁺ ]) m/z 401; Anal. Calcd for C _2I Hi ₈ F ₂ N ₂ O ₄ : C, 63.00; H, 4.53; N, 7.00. Found: C, 63.00; H, 4.58; N, 6.97.

The following compounds were prepared in a similar fashion starting with the corresponding tert-butyl ester:

5-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](l,3-thiazol-5 - ylmethyl)amino] nicotinic acid

5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]nicotinic acid

3-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]benzoic acid

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3 -thiazol-5- ylmethyl)amino]benzoic acid

4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](pyr idin-3- ylmethyl)amino]benzoic acid

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-oxazol-5-ylmethyl )amino]benzoic acid 4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)amino ]benzoic acid 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5-ylmethy l)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrazin-2-ylmethy l)amino]benzoic acid 3-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)amino ]benzoic acid 4-[[3-(difluoromethoxy)-4-methoxyphenyl](pyrazin-2-ylmethyl) amino]benzoic acid

4-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid 4-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3-ox azol-5- ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid

4-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)a mino]benzoic acid 4-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino]be nzoic acid

4-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxaz ol-5- ylmethyl)amino]benzoic acid

4-[[3-(cyclobutyloxy)-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid

4-[[3-methoxy-4-(2,2,2-trifluoroethoxy)phenyl](l,3-oxazol -5- ylmethyl)amino]benzoic acid

4-{ [4-(difluoromethoxy)-3-ethoxyphenyl][(4-methyl-l,3-oxazol-5- yl)methyl] amino Jbenzoic acid

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-4-ylmethyl)amino]benzoic acid

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid

3-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl](l,3 -oxazol-5- ylmethyl)amino]benzoic acid

3-[(3-ethoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)amino ]benzoic acid

3-[[3-(cyclobutyloxy)-4-(difluoromethoxy)phenyl](l,3-oxaz ol-5- ylmethyl)amino]benzoic acid

3-[(3-isopropoxy-4-methoxyphenyl)(l,3-oxazol-5-ylmethyl)a mino]benzoic acid

3-[[4-(difluoromethoxy)-3-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid

3-[[3-(cyclobutyloxy)-4-methoxyphenyl](l,3-oxazol-5-ylmet hyl)amino]benzoic acid 4-[[4-methoxy-3-(methylthio)phenyl](l,3-thiazol-5-ylmethyl)a mino]benzoic acid

4- { [4-(difluoromethoxy)-3-ethoxyphenyl] [(2-methyl- 1 ,3-thiazol-5- yl)methyl] amino Jbenzoic acid 4-[[4-(difluoromethoxy)-3-ethoxyphenyl](tetrahydrofuran-3-yl methyl)amino]benzoic acid

3-[[3-(difluoromethoxy)-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid 4-[[3-(difluoromethoxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzoic acid

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,2,3-thiadiazol-5-ylmethyl)amino]benzoic acid, and

4-[[3-hydroxy-4-methoxyphenyl] ( 1 ,3-oxazol-5-ylmethyl)amino]benzoic acid.

EXAMPLE 15

Synthesis of 4-r(2-Triisopropylsilanyl-oxazol-5-ylmethyl)-amino1-benzoic acid tert-butyl ester

Acetic acid (10 drops) was added to a mixture of 4-amino-benzoic acid tert-butyl ester (2.99 g, 15.5 mmol) and 2-triisopropylsilanyl-oxazole-5-carbaldehyde (3.94 g, 15.5 mmol) in dichloroethane (60 rnL), and the resulting mixture was stirred at room temperature for 2.5 h. Na(OAc) ₃ BH (6.56 g, 51.0 mmol) was then added, and the reaction was stirred at room temperature overnight, then quenched by then addition of (aqueous) sodium hydroxide

(IM). The mixture was stirred for 30 minutes and the product was extracted using dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude residue was purified via flash chromatography (hexane/ethyl acetate to afford 4.57 g (69 %) of 4- [(2-triisopropylsilanyl-oxazol-5-ylmethyl)-amino] -benzoic acid tert-butyl ester as a white solid.

EXAMPLE 16 Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-oxazolo-5-ylmethyl-am inol- benzoic acid tert-butyl ester

A mixture of toluene/DME (10/3, 13 rnL) was added to a mixture of 4-[(2- triisopropylsilanyl-oxazol-5-ylmethyl)-amino] -benzoic acid tert-butyl ester (2.00 g, 4.23 mmol), 4-bromo-l-difluoromethoxy-2-ethoxy-benzene (1.69 g, 6.35 mmol), sodium hydroxide (508 mg, 12.7 mmol), and Pd(t-Bu ₃ P) ₂ (216 mg, 0.42 mmol) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 15 minutes, then heated to 40 ⁰ C for 15 minutes and then to 50 ⁰ C for 3.5 hr. After cooling to room temperature, MP- TMT (macroporous polystyrene-2,4,6-trimercaptotriazine) resin (1.0 g) was added. The mixture was stirred overnight, filtered through celite, and the filtrate was evaporated in vacuo. The resulting residue was purified via flash chromatography (hexane/EtOAc) to afford 2.04 g of 4-[(4-difluoromethoxy-3-ethoxy-phenyl)-oxazolo-5-ylmethyl-am ino]- benzoic acid tert-butyl ester as a foamy syrup.

EXAMPLE 17

Synthesis of 4-r(4-Difluoromethoxy-3-ethoxy-phenyl)-oxazolo-5-ylmethyl-am ino1- benzoic acid

A mixture of 4-[(4-difluoromethoxy-3-ethoxy-phenyl)-oxazolo-5-ylmethyl-am ino]- benzoic acid tert-butyl ester (2.35 g), formic acid (3.5 mL) and hydrochloric acid (6M, 3.5 mL) in toluene (5 mL) was heated to 60 ⁰ C for 30 minutes. The reaction mixture was then concentrated in vacuo, and the residue was taken up in water and ethyl acetate. The pH was adjusted to 6.5, the organic and aqueous layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate. (,) filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography (dichloromethane (/) methanol) to afford 1.62 g of the desired product (as a foam), which was recrystallized from ethyl acetate. The resulting white crystals were collected by filtration, washed with cold ethyl acetate, and dried in vacuo at 60 ⁰ C to provide 4-[(4-difluoromethoxy-3-ethoxy-phenyl)-oxazolo-5-ylmethyl-am ino]-benzoic acid. Mp = 111.1-113.0 ⁰ C.

mp 111.1-113.0 ⁰ C; ¹ H NMR (DMSOd ₆ ) δ 12.34 (bs, IH), 8.30 (s, IH), 1.11 -1.1 A (m, 2H), 7.31-6.82 (m, 7H), 5.06 (s, 2H), 4.03 (q, J = 1 Hz, 2H), 1.31 (t, J = 1 Hz, 3H); MS (ESI, [M+H ⁺ ]) m/z 405; Anal. Calcd for C ₂₀ Hi ₈ F ₂ N ₂ O ₅ : C, 59.40; H, 4.49; N, 6.93. Found: C, 59.30; H, 4.37; N, 6.88.

EXAMPLE 18

Synthesis of 4-r(2-Thiazol-5-ylmethyl)-aminol-benzoic acid tert-butyl ester

A mixture of 4-amino-benzoic acid tert-butyl ester (4.13 g, 21.4 mmol), thiazole-5- carboxaldehyde (2.20 g, 19.5 mmol) and Na(OAc) ₃ BH (6.18 g, 29.2 mmol) in dichloroethane (50 mL) was stirred at room temperature for 16 hr. The reaction mixture was then diluted with dichloromethane, washed with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified via flash chromatography (hexane/EtOAc) to afford 5.84 g of 4-[(2-Thiazol-5ylmethyl)-amino]- benzoic acid tert-butyl ester as a white solid.

EXAMPLE 19

Synthesis of 4- r(4-Difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-ami no1 - benzoic acid tert-butyl ester

A mixture of toluene/DME (5/1, 18 mL) was added to a mixture of 4-[(2-thiazol- 5ylmethyl)-amino] -benzoic acid tert-butyl ester (2.00 g, 6.89 mmol), 4-bromo-l- difluoromethoxy-2-methoxy-benzene (2.61 g, 10.3 mmol), sodium hydroxide (826 mg, 20.7 mmol), and Pd(I-Bu ₃ P) ₂ (352 mg, 0.69 mmol) under an atmosphere of argon. The resulting mixture was stirred at room temperature for 15 minutes, then heated at 40 ⁰ C for 15 minutes, finally to 6θ ^α (60)-65 ⁰ C for 3.5 hours. After cooling to room temperature, MP-TMT (macroporous polystyrene-2,4,6-trimercaptotriazine) resin (1.0 g) was added. The mixture was stirred overnight and then filtered through celite. The filtrate was evaporated in vacuo and the residue was purified via flash chromatography (hexane/ethyl acetate) to afford 0.47 g of 4- [(4-Difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-ami no] -benzoic acid tert- butyl ester as a colorless syrup.

EXAMPLE 20

Synthesis of 4- r(4-Difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-ami no1 - benzoic acid

A mixture of 4-[(4-difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-a mino]- benzoic acid tert-butyl ester (2.90 g), formic acid (9 mL) and HCl (6M, 9 mL) in toluene (10 mL) was heated to reflux for 4 hr. The reaction mixture was then cooled, concentrated in vacuo, and the residue was partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via flash chromatography (dichloromethane/methanol) to afford the product as foam. The foam was recrystallized from ethyl acetate to give lightly colored crystals, which were (further) recrystallized from isopropanol/ethyl acetate (1/1) to give 382 mg of 4-[(4- Difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-amino] -benzoic acid as colorless crystals. The mother liquors were concentrated and the residue recrystallized from isopropanol/ethyl acetate (1/1) to afford an additional 879 mg of 4-[(4-Difluoromethoxy-3- methoxy-phenyl)-thiazol-5-ylmethyl-amino]-benzoic acid as colorless crystals. Recrystallization of the mother liquors was then repeated, affording an additional 628 mg of crystalline 4- [(4-Difluoromethoxy-3-methoxy-phenyl)-thiazol-5-ylmethyl-ami no] -benzoic acid. Mp = 164.9-165.3 ⁰ C.

mp 164.9-165.3 ⁰ C; ¹ H NMR (DMSOd ₆ ) δ 12.36 (bs, IH), 8.97 (d, J = 0.8 Hz, IH), 7.87 (s, IH), 1.11 -1.1 A (m, 2H), 7.31-6.80 (m, 6H), 5.23 (s, 2H), 3.78 (s, 3H); MS (ESI, [M+H ⁺ ]) m/z 407; Anal. Calcd for C ₁₉ H ₁₆ F ₂ N ₂ O ₄ S: C, 56.15; H, 3.97; N, 6.89. Found: C, 55.90; H, 3.90; N, 6.91.

EXAMPLE 21

Ester Hydrolysis using LiOH The following compounds were prepared from the corresponding methyl or ethyl esters by base hydrolysis using LiOH. The general procedure involves stirring 1 equivalent of ester in a 1:1 mixture of THF and H ₂ O (20 mL/mmol) with 12 equivalents of LiOH for about 16 hours while heating to reflux. The mixture is cooled to room temperature, acidified with dilute HCl and extracted with EtOAc. The organic fraction is washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 4% MeOH and 0.5% AcOH in CH ₂ Cl ₂ provided the desired acids below.

3-{(3-cyanobenzyl)[3-(cyclopentyloxy)-4-methoxyphenyl]ami no}benzoic acid

3-{ [3-(cyclopentyloxy)-4-methoxyphenyl] [(6-OXO- l,6-dihydropyridin-3- yl)methyl] amino Jbenzoic acid

4-{ [3-(cyclopentyloxy)-4-methoxyphenyl][(6-oxo-l,6-dihydropyrid in-3- yl)methyl] amino Jbenzoic acid

{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]phenyl}acetic acid 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-ethylbenzoic acid

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]-4- methylbenzoic acid

4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid 4-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridazin-3-ylmethyl)amino]benzoic acid

{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmeth yl)amino]phenyl}acetic acid

5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]nicotinic acid

3 - { 4- [ [3 - (cyclopentyloxy)-4-methoxyphenyl] (pyridin- 3 - ylmethyl)amino]phenyl}propanoic acid

{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]phenyl}acetic acid

4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]-3- methylbenzoic acid

{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)a mino]phenyl}acetic acid 5-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-2- hydroxybenzoic acid

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-2- hydroxybenzoic acid {4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl) amino]phenyl}acetic acid

{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmeth yl)amino]phenyl}acetic acid {4-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl)am ino]phenyl}acetic acid

{3-[[3,4-bis(difluoromethoxy)phenyl](pyrimidin-5-ylmethyl )amino]phenyl}acetic acid

{4-[[3,4-bis(difluoromethoxy)phenyl](pyrazin-2-ylmethyl)a mino]phenyl}acetic acid {3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid

{ 4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-5- ylmethyl)amino]phenyl } acetic acid

{3-[[4-(difluoromethoxy)-3-ethoxyphenyl](l,3-thiazol-5- ylmethyl)amino]phenyl} acetic acid

4-[[4-(difluoromethoxy)-3-ethoxyphenyl] ( 1 ,3-oxazol-4-ylmethyl)amino]benzoic acid cis-4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]cyclohexanecarboxylic acid, and

4-[[3-ethoxy-4-(trifluoromethoxy)phenyl](l,3-oxazol-5-ylm ethyl)amino]benzoic acid.

The following compounds were prepared in a similar fashion as describe above, but the NaOH was used instead of LiOH:

3-[[4-(difluoromethoxy)-3-ethoxyphenyl](pyrimidin-5-ylmet hyl)amino]benzoic acid 3-[(3-ethoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)amino]ben zoic acid 3-[[3-(cyclopropylmethoxy)-4-methoxyphenyl](pyrimidin-5-ylme thyl)amino]benzoic acid

3-[(3-isopropoxy-4-methoxyphenyl)(pyrimidin-5-ylmethyl)am ino]benzoic acid 3-[[3-(cyclopropyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl )amino]benzoic acid

3-[[4-(difluoromethoxy)-3-isopropoxyphenyl](pyrimidin-5-y lmethyl)amino]benzoic acid

3 - [ [4- (cyclopropyloxy)- 3 -ethoxyphenyl] (pyrimidin- 5 -ylmethyl) amino] benzoic acid 3-[[3-(cyclobutyloxy)-4-methoxyphenyl](pyrimidin-5-ylmethyl) amino]benzoic acid, and

4-[[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl](pyrimid in-5- ylmethyl)amino]benzoic acid.

EXAMPLE 22

Synthesis of 4-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)amino 1-N-

(methylsulfonyl)benzamide

4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]benzoic acid (50 mg, 0.11 mmol), methanesulfonamide (22 mg, 0.23 mmol), EDCI (44 mg), DMAP (17 mg) and DMF were combined and stirred for 16 hours at room temperature and then at 100°C for 1 hour.

The mixture was cooled, diluted with 40 mL of EtOAc and washed with 10 mL of IM HCl,

10 mL of H ₂ O, 10 mL of brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by HPLC over a reverse phase column using a gradient elution going from 20 to 80% CH ₃ CN in H ₂ O with 0.5% formic acid over 6 minutes with a flow rate of 45 niL/minute to provide 2.3 mg of 4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-N-

(methylsulfonyl)benzamide.

The following compound was prepared in a similar fashion but starting with ethanesulfonaminde rather than methansulfonamide: 4-[[3,4-bis(difluoromethoxy)phenyl]- (pyridin- 3 -ylmethyl) amino] -N- (ethylsulf onyl)benzamide .

EXAMPLE 23

Preparation of 4-rr3-(cvclopentyloxy)-4-methoxyphenyll(pyridin-3- vlmethvDaminolphenol

1. Preparation of (3-cvclopentyloxy-4-methoxy-phenyl)-{4-r((E and Z)-propenyl)oxyl- phenyl I -pyridin-3-ylmethyl-amine

To a mixture of 400 mg (1.53 mmol) of 4-allyloxy-iodobenzene and 371 mg (1.0 mmol) 3- cyclopentyloxy-4-methoxy-phenyl)-pyridin-3-ylmethyl-amine in toluene 5 rnL were added 70 mg of Pd ₂ (dba) ₃ , tri-£-butylphosphine (40μL) and sodium ^-butoxide (500 mg). The reaction mixture was heated for 18 h at 90 °C, after which time the disappearance of the starting amine was observed by TLC. The reaction mixture was cooled and passed through a 1O g column of silica gel, eluting with methylene chloride, then 5% acetone/methylene chloride. The crude material (300 mg), whose MS was consistent with product, was isolated and repurified by flash chromatography, using 20% acetone/hexane as eluent to give 250 mg of material. An analytical sample was obtained by dissolving 100 mg of the material in methylene chloride and stirring with MP-TMT (macroporous polystyrene-2,4,6- trimercaptotriazine) overnight. The resin was removed by filtration and washed with methylene chloride. The filtrate was concentrated in vacuo to provide the desired intermediate. 2. Preparation of 4-r(3-cvclopentyloxy-4-methoxy-phenyl)-pyridin-3-ylmethyl-am inol- phenol

The product from Step 1 (150 mg), TsOH (200 mg) and Pd-C (70 mg) were heated overnight in of 5:1 MeOHZH ₂ O (1 rnL). The cooled reaction mixture was then filtered through Celite® and the filtrate concentrated in vacuo. The residue was diluted with ethyl acetate and basified with NaHCO ₃ (aq). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ (anhyd) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 20% acetone/methylene chloride, to obtain 90 mg of product, confirmed by NMR spectroscopy.

The following analogs were made in a similar fashion:

3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethy l)amino]phenol 4-[[3,4-bis(difluoromethoxy)phenyl](3-pyridylmethyl)amino]ph enol, and 4-[3-cyclopentyloxy-4-methoxy)phenyl](l,3-thiazol-5-ylmethyl )amino]phenol

EXAMPLE 24

Synthesis of ethyl {4-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3- ylmethvDaminolphenoxvlacetate

To a solution of 4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]phenol: (270 mg, 0.69 mmol) in DMF was added NaH (60% oil dispersion; 80 mg, 2.0 mmol) and the mixture stirred for 15 minutes. Ethyl bromoacetate (117 mg, 0.69 mmol) was added and stirring continued for an additional 30 minutes. Saturated aq. NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The organic fraction was isolated and washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by flash chromatography using 20% acetone in hexanes to provide ethyl {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino] phenoxy} acetate. Elemental Analysis Calcd for C _2S H ₃₂ N ₂ O ₃ : Theory C, 70.56; H, 6.77; N, 5.88. Found C, 70.34; H, 6.55; N, 5.93.

EXAMPLE 25 Synthesis of 2-{4-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3- ylmethvDaminolphenoxylethanol

To an ice-cold solution of ethyl {4-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy} acetate (70 mg, 0.15 mmol) in THF was added a 0.5 M solution of LAH in THF and the solution stirred for 10 minutes. Saturated aq. NH ₄ Cl was added followed by EtOAc. The precipitates were removed by filtration and the combined filtrate was dried over Na ₂ SO ₄ and purified by flash chromatography to provide 2-{4-[[3- (cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)amino]p henoxy}ethanol. Elemental analysis calcd for C ₂₆ H ₃₀ N ₂ O ₄ + 0.5 H ₂ O: Theory C, 70.39; H, 6.99; N.6.31. Found C, 70.86; H, 6.81; N, 6.41.

EXAMPLE 26

Synthesis of 3,4-bis(difluoromethoxy)-N-r3-(methylsulfonyl)phenyl1-N-(pyr idin-3- ylmethvDaniline

To a solution of 3,4-bis(difluoromethoxy)-N-[3-(methylthio)phenyl]-N-(pyridin -3- ylmethyl)aniline (130 mg, 0.30 mmol) in CH ₂ Cl ₂ (4 rnL) with stirring at 0°C was added MCPBA (213 mg, 0.74 mmol) in two portions. The mixture was stirred at 0°C for 20 minutes and then quenched by the addition of 20% aq. Na ₂ SO ₃ and saturated aq NaHCO ₃ solution. The mixture was then extracted with EtOAc and the organic fraction was washed with H ₂ O, brine, dried (MgSO ₄ ) and concentrated to give a residue. Purification by chromatography over SiO ₂ using 50% EtOAc in hexanes as eluant provided 98 mg of 3,4- bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyridin -3-ylmethyl)aniline as a clear oil.

The following compounds were made in a similar fashion:

N-(3-fluorobenzyl)-4-methoxy-N-[4-(methylsulfonyl)phenyl] -3-[(3R)- tetrahydrofuran- 3 -yloxy] aniline

3,4-bis(difluoromethoxy)-N-[4-(methylsulfonyl)phenyl]-N-( l,3-thiazol-5- ylmethyl)aniline

3,4-bis(difluoromethoxy)-N-[4-(ethylsulfonyl)phenyl]-N-(l ,3-thiazol-5- ylmethyl)aniline

3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-( l,3-thiazol-5- ylmethyl)aniline, and 3,4-bis(difluoromethoxy)-N-[3-(methylsulfonyl)phenyl]-N-(pyr imidin-5- ylmethyl)aniline.

EXAMPLE 27 Synthesis of l-{4-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)am ino1-2- hydroxyphenyllethanone

To a solution of l-{4-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]-2- te/t-butyldimethylsilyloxyphenyl}ethanone (1 mmol) in toluene was added 100 mg of pTsOH and the mixture was warmed to 80 °C for 30 minutes with stirring. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated aq. NaHCO ₃ , H ₂ O, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 10%acetone in CH ₂ Cl ₂ provided l-{4-[[3,4- bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] -2-hydroxyphenyl } ethanone . Elemental analysis calculated for C ₂₂ H ₁₈ F ₄ N ₂ O ₄ . Theory C, 58.67; H, 4.03; N, 6.22. Found C, 58.71; H, 3.97; N, 6.15.

The following compounds were prepared in a similar fashion: 2- [ [3 ,4-bis (difluoromethoxy)phenyl] (phenyl)amino] ethanol.

EXAMPLE 28

Synthesis of 5-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)amino 1-2,3- difluoro- 1 -hydroxyphenyl

5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]-2,3-difluoro-l-(fert- butyldimethylsilyl)oxyphenyl and 0.5M NaOMe in MeOH (5 niL) were combined and stirred for 30 minutes. The mixture was diluted with EtOAc and washed with dilute HCl, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 10% acetone in CH ₂ Cl ₂ provided 50 mg of 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino] -2,3-difluoro- 1 -hydroxyphenyl.

EXAMPLE 29

Synthesis of 5-{3-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)am ino1phenyl}- l,3-oxazolidin-2-one

Step 1. Synthesis of 3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]phenyl}- oxirane

To a solution of sodium hydride (60% in mineral oil, 225 mg, 5.63 mmol, washed with hexanes twice) in DMSO (1OmL) was added trimethylsulfoxonium iodide (1.19 g, 5.4 mmol). The suspension was stirred at room temperature for 45 minutes. A solution of 3-[[3,4- bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino]phenyl} carboxaldehyde (2.03 g, 4.8 mmol) in DMSO (5 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with ethyl acetate 3 times. The organic extracts were dried with magnesium sulfate, concentrated, and chromatographed (20% ethyl acetate/hexane gradient to 50% ethyl acetate/hexane) to give 409 mg of a tan oil (20%).

Step 2. Synthesis of l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-azidoethan-l-ol and 2-{3-[[3,4- bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2-azidoethan- 1 -ol

Sodium azide (75 mg, 1.154 mmol) was added to a solution of 3-[[3,4- bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino]phenyl} -oxirane (248 mg, 0.571 mmol) and lithium perchlorate (141 mg, 1.325 mmol) in acetonitrile- acetone- water (7:1:1, 9 mL). The reaction was stirred overnight at 40°C, concentrated, and chromatographed (20% ethyl acetate/hexane, gradient to 35%, then 45%) to give 24 mg (9%) of secondary alcohol 1- {3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amin o]phenyl}-2-azidoethan-l-ol and 163 mg (60%) of primary alcohol 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-azidoethan-l-ol. Rf (1:1 hexane/ethyl acetate 0.2 secondary alcohol, 0.1 primary alcohol).

Step 3. l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2- aminoethan-1-ol

A solution of azide-alcohol l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-azidoethan-l-ol (105 mg, 0.220 mmol) and tin chloride dihydrate (104 mg, 0.461 mmol) in methanol (4 mL) was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and IN NaOH was added and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate 3 times and the organic extracts were dried with sodium sulfate. The crude residue was concentrated and chromatographed (10% MeOH (w/ 5% NH ₄ OHVCH ₂ Cl ₂ ) to give 42 mg of a white solid (42%).

Step 4. l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2-(fert- butyloxycarbonylamino)ethan- 1 -ol

A solution of amino alcohol l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-aminoethan-l-ol (42 mg, 0.093 mmol), di-tert-butyl dicarbonate (23 mg, 0.105 mmol), potassium carbonate (32 mg, 0.232 mmol) in water-THF (1:1, 4 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and chromatographed (50% Ethyl acetate/hexane) to give l-{3-[[3,4- bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2-(tert- butyloxycarbonylamino)ethan-l-ol as a colorless oil (29 mg, 56%). Step 5. 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-l,3- oxazolidin-2-one

To a solution of l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}- 2-(te/t-butyloxycarbonylamino)ethan-l-ol (29 mg, 0.053 mmol) in THF (3 niL), was added sodium hydride (60% in mineral oil, 3 mg, 0.075 mmol). The slurry was stirred overnight at 65°. The crude reaction was concentrated and chromato graphed (3% MeOH (w/5%NH ₄ OH)/CH ₂ Cl ₂ ) to give oxazolidinone 101 as a colorless oil (11 mg, 44%).

EXAMPLE 30

Synthesis of 4-{3-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)am ino1phenyl}- l,3-oxazolidin-2-one

Step 1. 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2- aminoethan-1-ol

A solution of 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2- azidoethan-1-ol (267 mg, 0.560 mmol) and tin chloride dihydrate (263 mg, 1.166 mmol) in methanol (8 mL) was stirred overnight at room temperature. The reaction was concentrated, diluted with ethyl acetate and IN NaOH was added and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate 3 times and the organic extracts were dried with sodium sulfate. The crude residue was concentrated and chromatographed (10% MeOH (w/ 5% NH ₄ OHVCH ₂ Cl ₂ ) to give 60 mg of 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-aminoethan-l-ol as a colorless oil (24%)

Step 2. 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2-(?er?- butyloxycarbonylamino)ethan- 1 -ol

A solution of 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-2- aminoethan-1-ol (60 mg, 0.133 mmol), di-te/t-butyl dicarbonate (34 mg, 0.156 mmol), potassium carbonate (37 mg, 0.268 mmol) in water-THF (1:1, 4 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and chromatographed (50% Ethyl acetate/hexane) to give 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-2-(?ert-butyloxycarbonylamino)ethan-l -ol as a colorless oil (54 mg, 74%).

Step 3. 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}-l,3- oxazolidin-2-one

To a solution of 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)am ino]phenyl}- 2-(ter^butyloxycarbonylamino)ethan-l-ol (54 mg, 0.098 mmol) in THF (5 mL), was added sodium hydride (60% in mineral oil, 5 mg 0.125 mmol). The slurry was stirred for 3 hours at 65°. The crude reaction was concentrated and chromatographed (3% MeOH (w/5%NH ₄ OH)/CH ₂ Cl ₂ ) to give 4-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}-l,3-oxazolidin-2-one as a colorless oil (12 mg, 26%).

EXAMPLE 31

Synthesis of 3,4-bis(difluoromethoxy)-N-r3-(lH)-pyrazol-3-yl)phenyl1-N-(p yridin-3- ylmethvDaniline

A solution of 3,4-bis(difluoromethoxy)-N-[3-(lH)-l-triphenylmethyl-pyrazol -3-yl)phenyl]- N-(PF ^idin -3-ylmethyl)aniline (0.3g, 0.42 mmol), CF ₃ CO ₂ H (1 niL) and CH ₂ Cl ₂ (3 niL) was stirred for 30 minutes and then diluted with H2O and EtOAc. The solution was basified with NaHCO ₃ and the organic fraction was separated and washed with H ₂ O, brine, dried (Na ₂ SO ₄ ), and concentrated. Purification by chromatography over SiO ₂ using 3% MeOH in CH ₂ Cl ₂ gave 100 mg of 3,4-bis(difluoromethoxy)-N-[3-(lH)-pyrazol-3-yl)phenyl]-N-(p yridin-3- ylmethyl)aniline as a glassy solid.

EXAMPLE 32

Synthesis of 3,4-bis(difluoromethoxy)-N-(pyridin-3-ylmethyl)-N-r3-(lH-l,2 ,4-triazol-5- vDphenyllaniline

A solution of 3,4-bis(difluoromethoxy)- N-(3-cyanophenyl)-N-(pyridin-3-ylmethyl)aniline (75 mg, ) in MeOH was treated with 60% NaH (20 mg) and formic hydrazide (50 mg). The mixture was stirred for 30 minutes at room temperature and then heated to reflux for 16 hours. The mixture was cooled, concentrated and purified by chromatography over SiO2 using 3.5% MeOH in CH2C12 as eluant to provide 15 mg of 3,4-bis(difluoromethoxy)-N- (pyridin-3-ylmethyl)-N-[3-(lH-l,2,4-triazol-5-yl)phenyl]anil ine.

EXAMPLE 33

Synthesis of 4-rr3,4-bis(difluoromethoxy)phenyl1(l,3-thiazol-5-ylmethyl)a mino1- benzenesulphonic acid

A mixture of isobutyl 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]- benzenesulphonate (100 mg), acetone (2 mL) and NaI (100 mg) was heated to reflux for 16 hours. The mixture was cooled, concentrated and used as such in the next step. EXAMPLE 34

Synthesis of 4-rr3,4-bis(difluoromethoxy)phenyl1(l,3-thiazol-5-ylmethyl)a mino1-N,N- dimethylbenzenesulfonamide

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-benzenesulphonic acid (from above) was taken up in 3 rnL of CH2C12, and 2 drops of DMF and 100 μL of oxalyl chloride were added and the mixture stirred for 30 minutes. All volatiles were removed under reduced pressure and the residue was taken up in THF (2 mL) and 40% aq. Me2NH was added. The reaction mixture stirred for 30 minutes, was diluted with EtOAc and washed with H2O, brine, dried (Na2SO4) and concentrated. Purification by chromatography over SiO2 using 8% acetone in hexanes as eluant to give 20 mg of 4-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]-N, N- dimethylbenzenesulfonamide.

The following compounds were prepared in a similar fashion: 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]benzenesulfonamide

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-N- methylbenzenesulfonamide.

EXAMPLE 35

Synthesis of 4-rr3,4-bis(difluoromethoxy)phenyl1(l,3-thiazol-5-ylmethyl)a mino1-N- methvlbenzamide

Oxalyl chloride (43μL, 0.5 mmol) was added to a solution of 4-[[3,4- bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)amino]-be nzoic acid (109 mg, 0.25 mmol), DMF (1 drop) and CH2C12 (2 mL). The mixture stirred at 38°C for 1.5 hours and was concentrated under reduced pressure. The residue was diluted with THF (2 mL) followed by the addition of 2.0 M methylamine in THF (600 μL, 1.2 mmol). The mixture stirred for 1 hour at room temperature and then filtered through celite and concentrated. Purification by chromatography over SiO2 using 5% MeOH, 1%TEA, 94% CH2C12 as eluant provided 64 mg of 4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethyl)a mino]-N- methylbenzamide.

The following compounds were prepared in a similar fashion:

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]benzamide

4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]-N,N- dimethylbenzamide.

EXAMPLE 36

Synthesis of N-{5-rr3,4-bis(difluoromethoxy)phenyl1(l,3-thiazol-5-ylmethy l)amino1-2- methylphenyllmethanesulfonamide

To a mixture of N-(3-amino-4-methylphenyl)-N-[[3,4-bis(difluoromethoxy)pheny l](l,3- thiazol-5-ylmethyl)amine (65 mg, 0.15 mmol) and Amberlite IRA67 (54 mg, 0.30 mmol) in CH ₂ Cl ₂ in a vial was added methanesulfonylchloride (17.8μL, 0.23 mmol). The vial was sealed and stirred for several hours and then DMAP was added. This mixture stirred for 3 days and then diluted with CH ₂ Cl ₂ and PS-trisamine and (macroporous polystyrene-2,4,6- trimercaptotriazine) TMT were added. This mixture stirred for 16 hours and was then filtered and concentrated. Purification by preparative TLC using 2.5% MeOH in CH ₂ Cl ₂ gave 18 mg of N- { 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-miazol-5-ylmethyl)amino]-2- methylphenyljmethanesulfonamide.

The follow compounds were prepared in a similar manner: N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylmethy l)amino]phenyl}- methanesulfonamide

N-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylme thyl)amino]phenyl}- ethanesulfonamide. EXAMPLE 37

Synthesis of l-rr3,4-bis(difluoromethoxy)phenyl1(3-chlorophenyl)amino1-2- methylpropan-2-ol

l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amine (100 mg, 0.33 mmol), 2,2- dimethyloxirane (200 μL), CaCO ₃ (40 mg, 0.4 mmol) and DMF were combined and warmed to 90°C for 3 days. The mixture was diluted with H ₂ O and extracted with EtOAc. The organic fractions were combined and washed with H ₂ O, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 20% CH ₂ Cl ₂ in hexanes to elute unreacted starting material and 10% acetone in hexanes to elute the product provided 24 mg of l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]-2- methylpropan-2-ol as an oil.

The following compounds were prepared in a similar fashion, but with different starting materials: l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]-pr opan-2,3-oxirane 3-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-l-ol.

EXAMPLE 38 Synthesis of l-rr3,4-bis(difluoromethoxy)phenyl1(3-chlorophenyl)amino1pro pan-2-ol

A solution of l-[[3,4-bis(difluoromethoxy)phenyl](3-chlorophenyl)amino]pro pan-2,3-oxirane (40 mg, 0.1 mmol) in THF (3 niL) was treated with a IM solution Of LiAlH ₄ in THF (0.5 rnL, 0.5 mmol). The mixture was stirred at room temperature for 10 minutes and quenched by the addition of NH ₄ Cl. EtOAc was added and the mixture was filtered through a pad of celite, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 25% EtOAc in hexanes as eluant provided 25 mg of l-[[3,4-bis(difluoromethoxy)phenyl](3- chlorophenyl)amino]propan-2-ol as an oil.

EXAMPLE 39

Preparation of 4-r(3-cvclopentyloxy-4-methoxy-phenyl)-pyridin-3-ylmethyl-am ino1-

1. Preparation of (3-cyclopentyloxy-4-methoxy-phenyl)-{4-r((E and Z)-propenyl)oxyl- phenyl I -pyridin-3-ylmethyl-amine

To a mixture of 400 mg (1.53 mmol) of 4-allyloxy-iodobenzene and 371 mg (1.0 mmol) 3- cyclopentyloxy-4-methoxy-phenyl)-pyridin-3-ylmethyl-amine in toluene ( rnL) were added 70 mg of Pd ₂ (dba) ₃ , tri-£-butylphosphine (40μL) and sodium ^-butoxide (500 mg). The reaction mixture was heated for 18 h at 90 °C, after which time the disappearance of the starting amine was observed by TLC. The reaction mixture was cooled and passed through a 1O g column of silica gel, eluting with methylene chloride, then 5% acetone/methylene chloride. The crude material (300 mg), whose MS was consistent with product, was isolated and repurified by flash chromatography, using 20% acetone/hexane as eluent to give 250 mg of material. An analytical sample was obtained by dissolving 100 mg of the material in methylene chloride and stirring with MP-TMT overnight. The resin was removed by filtration and washed with methylene chloride. The filtrate was concentrated in vacuo to provide the desired intermediate.

2. Preparation of 4-r(3-cvclopentyloxy-4-methoxy-phenyl)-pwidin-3-ylmethyl-ami nol- phenol

The product from Step 1 (150 mg), TsOH (200 mg) and Pd-C (70 mg) were heated overnight in of 5:1 MeOH/H ₂ O (1 mL). The cooled reaction mixture was then filtered through Celite® and the filtrate concentrated in vacuo. The residue was diluted with ethyl acetate and basified with NaHCO ₃ (aq). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ (anhyd) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 20% acetone/methylene chloride, to obtain 90 mg of product, confirmed by NMR spectroscopy.

EXAMPLE 40

Synthesis of 3-(cvclopentyloxy)-N-(4-{r(4S)-2,2-dimethyl-l,3-dioxolan-4- yl1methoxy}phenyl)-4-methoxy-N-(pyridin-3-ylmethvl)aniline

To a solution of 4- [(3-cyclopentyloxy-4-methoxy-phenyl)-pyridin-3-ylmethyl-amin o] -phenol (50 mg, 0.13 mmol) in DMF (2 mL) was added NaH (60% dispersion; 10 mg, 0.25 mmol) and the mixture stirred at room temperature for 15 minutes. (R)-2,2-Dimethyl-l,3-dioxolane- 4-ylmethyl p-toluenesulfonate (100 mg, 0.35 mmol) was added and the mixture was stirred at 60°C for 15 minutes. The mixture was cooled to room temperature and diluted with H2O and extracted with EtOAc. The organic fraction was collected and washed with H2O, brine, dried (Na2SO4) and concentrated. Purification by chromatography over SiO2 using 20% acetone in hexanes as eluant provided about 40 mg of 3-(cyclopentyloxy)-N-(4-{ [(4S)-2,2-dimethyl- 1 ,3-dioxolan-4-yl]methoxy }phenyl)-4-methoxy-N-(pyridin-3-ylmethyl)aniline, which was used as such in the next step. EXAMPLE 41

Synthesis of (2R)-3-{4-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3- ylmethyl)aminolphenoxv}propane-l,2-diol

3-(Cyclopentyloxy)-N-(4-{ [(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy}phenyl)-4- methoxy-N-(pyridin- 3 -ylmethyl) aniline (50 mg, 0.1 mmol) was dissolved in 1 niL of 20% aqueous acetone and 200 μL of 6N HCl was added. The mixture stirred for 20 minutes, was basified by addition of saturated aq. NaHCO ₃ and then extracted with EtOAc. The organic fraction was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 3% MeOH in CH ₂ Cl ₂ provided 17 mg of (2R)-3-{4-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol as a gum.

The following compounds were prepared in a similar fashion:

2R)-3-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenoxy Jpropane- 1,2-diol

(2R)-3-{4-[[3-(cyclopentyloxy)-4-methoxyphenyl](l,3-thiaz ol-5- ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

(2R)-3-{4-[(3,4-dimethoxyphenyl)(pyridin-3-ylmethyl)amino ]phenoxyJpropane- 1,2- diol 5-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3-ylmethyl)amino ]-2-{ [(2R)-2,3- dihydroxypropyl]oxy J benzoic acid

(2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5 - ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

(2R)-3-{4-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5 - ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol

(2R)-3-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5 - ylmethyl)amino]phenoxy Jpropane- 1 ,2-diol. EXAMPLE 42 Synthesis of 5-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3-ylmethyl)a mino1-l,2-

Step 1. Methyl 5-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-2-(?er?- butyldimethylsilyloxybenzoate (140 mg, 0.25 mmol), 50% hydroxylamine (2.5 niL) and MeOH (5 niL) were combined and stirred for 1 hour followed by the addition of 0.5M NaOMe (1.0 rnL). The mixture was concentrated and the remaining aqueous fraction was washed with hexanes (3 times) and acidified with IN HCl carefully to adjust the pH to 6.5 and a precipitate formed. The aqueous phase was decanted and the remaining precipitate was washed with water and dried in a vacuum oven to give 103 mg of 5-[[3- (cyclopentyloxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino] -N,2-dihydroxybenzamide as an off white solid that turned dark upon storage.

Step 2. 5-[[3-(Cyclopentyloxy)-4-methoxyphenyl](pyridin-3-ylmethyl)a mino]-N,2- dihydroxybenzamide (53 mg, 0.12 mmol), triphenylphosphine (37 mg, 0.14 mmol) and THF were combined and then DEAD (22 μl, 0.14 mmol) was added drop-wise with stirring. The mixture stirred for 24 hours and was diluted with CH ₂ Cl ₂ and washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using EtOAc as eluant gave crude material in need of further purification. Additional chromatography over SiO ₂ using a gradient elution going from 2% to 5% MeOH in CH ₂ Cl ₂ gave 15 mg of 5-[[3- (cyclopentyloxy)-4-methoxyphenyl](pyridine-3-ylmethyl)amino] -l,2-benzisoxazol-3(2H)- one as a purple foam.

The following compounds were prepared in a similar fashion: 5-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one 6-[[3,4-bis(difluoromethoxy)phenyl] ( 1 ,3-thiazol-5-ylmethyl)amino]- 1 ,2- benzisoxazol-3(2H)-one.

EXAMPLE 43

Synthesis of 5-{4-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3- ylmethvDaminolphenyl}- imidazolidine-2,4-dione

4-[[3-(cyclopentyloxy)-4-methoxyphenyl] (pyridin-3-ylmethyl)amino]benzaldehyde (380 mg, 0.94 mmol), ammonium carbonate (907 mg, 9.44 mmol), KCN (86 mg, 1.32 mmol), MeOH (15 mL) and H ₂ O (15 mL) were combined and heated to 55°C for 3 hours. The volatiles were removed in vacuo and the residue was taken up in EtOAc. The organic layer was washed with H ₂ O, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 5% MeOH in CH ₂ Cl ₂ provided 140 mg of 5-{4-[[3-(cyclopentyloxy)-4- methoxyphenyl](pyridin-3-ylmethyl)amino]phenyl}imidazolidine -2,4-dione.

The following compounds were prepared in a similar fashion:

5 - { 3 - [ [3 ,4-bis (difluoromethoxy)phenyl] (pyridine- 3 - ylmethyl)amino]phenyl}imidazolidine-2,4-dione

5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5-ylme thyl)amino]phenyl}- 1,3,5- trimethylimidazolidine-2,4-dione 5-{3-[[3,4-bis(difluoromethoxy)phenyl](l,3-thiazol-5- ylmethyl)amino]phenyl}imidazolidine-2,4-dione. EXAMPLE 44

Synthesis of 4-{3-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3-ylmethyl)am ino1phenyl}- imidazolidin-2-one

To a solution of 5-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridine-3- ylmethyl)amino]phenyl}imidazolidine-2,4-dione (80 mg, 0.16 mmol) in THF (10 niL) at 0°C with stirring was added a 1.0 M solution of LAH in THF (490 μL, 0.49 mmol) drop-wise. The mixture was then warmed to reflux for 5h and then maintained at 50°C for 16 h. The mixture was cooled to 0°C and quenched by the addition of MeOH and water. The precipitates were removed by filtration and the crude product was filtered through SiO ₂ using 5% MeOH in CH ₂ Cl ₂ as eluant. Further purification by SiO ₂ chromatography using a gradient elution going form 0 to 10% MeOH in EtOAc provided 4-{3-[[3,4- bis (difluoromethoxy)phenyl] (pyridin- 3 -ylmethyl) amino] phenyl } imidazolidin-2- one as an amorphous solid.

EXAMPLE 45

Synthesis of 2-{3-rr3,4-bis(difluoromethoxy)phenyl1(pyridin-3- ylmethyl)aminolphenyl}propan-2-ol

To a solution of l-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}ethanone (80 mg, 0.18 mmol) in THF was added 3M MeMgCl (100 μL, 0.30 mmol) and the mixture stirred for 10 minutes. Saturated NH ₄ Cl and EtOAc were added and the mixture was filtered through celite, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography over SiO ₂ using 10% acetone in CH ₂ Cl ₂ as eluant to provide 50 mg of 2-{3-[[3,4-bis(difluoromethoxy)phenyl](pyridin-3- ylmethyl)amino]phenyl}propan-2-ol as an oil.

EXAMPLE 46

Synthesis of 4-{3-rr3-(cvclopentyloxy)-4-methoxyphenyl1(pyridin-3- ylmethyl)aminolphenyl}-l-methvl-lH-pvrazol-5-ol

A solution of 3-{ [3-(cyclopentyloxy-4-methoxy)phenyl(pyridin-3- ylmethyl)amino]phenyl} acetic acid (100 mg, 0.23 mmol) and 200 μL of bis(dimethylamino)- te/t-butoxymethane (Bredereck's reagent) in THF was heated to reflux for 30 minutes. The mixture was cooled, concentrated and the residue was dissolved in MeOH and 100 μL of methyl hydrazine was added and the mixture was again warmed to reflux for 30 minutes.

The mixture was cooled to room temperature, diluted with EtOAc and washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by chromatography over SiO ₂ using 8%

MeOH in CH ₂ Cl ₂ gave 20 mg of 4-{3-[[3-(cyclopentyloxy)-4-methoxyphenyl](pyridin-3- ylmethyl)amino]phenyl } - 1 -methyl- lH-pyrazol-5-ol.

The following compound was made in a similar fashion:4-{3-[[3,4- bis(difluoromethoxy)phenyl] (pyridin-3-ylmethyl)amino]phenyl } -2-methyl- 1 ,2-dihydro-3H- pyrazol-3-one. C .

C H C

H C

.8-

C

H C

H C

C

N

1 N H: =

=

.7

of N = .7 =

1

of N

N

H C

H C

-

EXAMPLE 47

In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity

Human PDE4 was obtained from baculovirus-infected Sf9 cells that expressed the recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector.

Insect cells (Sf9) were infected with the baculovirus and cells were cultured until protein was expressed. The baculovirus-infected cells were lysed and the lysate was used as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAE ion exchange chromatography. This procedure can be repeated using cDNA encoding other PDE-4 enzymes.

Assay:

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. Therefore the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. Adenosine is readily separated from cAMP by neutral alumina columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine. Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 μl of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0. 4 ug enzyme, 1OmM Tris-HCl (pH 7.5), 1OmM MgCl ₂ , 3 uM cAMP, 0.002 U 5 '-nucleotidase, and 3 x 10 ⁴ cpm of [3H]cAMP. The reaction was stopped by adding 100 μl of boiling 5mN HCl. An aliquot of 75 μl of reaction mixture was transferred from each well to alumina columns (Multiplate; Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000 rpm for 2 min; 150 μl per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [ ³ H] adenosine was determined using a Wallac Triflux ^® .

All test compounds are dissolved in 100% DMSO and diluted into the assay such that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration.

A decrease in adenosine concentration is indicative of inhibition of PDE activity. IC ₅₀ values were determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then plotting drug concentration versus ³ H-adenosine concentration. Nonlinear regression software (Assay Explorer ^® ) was used to estimate pICso values.

IC ₅₀ values for the preferred compounds of the invention are typically less than 300 nM, or even more preferred, less than 10.0 nM. A representative list of compounds with bioassay results appears in the table below.

EXAMPLE 48 (Method A)

Passive Avoidance in Rats, an in vivo Test for Learning and Memory

The test was performed as previously described (Zhang, H. -T., Crissman, A.M., Dorairaj, N.R., Chandler, LJ. , and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.). The apparatus (Model ElO- 16SC, Coulbourn Instruments, Allentown, PA) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by a guillotine door. The floor of the darkened compartment consisted of stainless steel rods through which an electric foot-shock could be delivered from a constant current source. All experimental groups were first habituated to the apparatus the day before the start of the experiment. During the training, the rat (Male Spraque-Dawley (Harlan) weighing 250 to 350 g) was placed in the illuminated compartment facing away from the closed guillotine door for 1 minute before the door was raised. The latency for entering the darkened compartment was recorded. After the rat entered the darkened compartment, the door was closed and a 0.5 mA electric shock was administered for 3 seconds. Twenty-four hours later, the rat was administered 0.1 mg/kg MK-801 or saline, 30 minutes prior to the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, Lp.), which was 30 minutes before the retention test started. The rat was again placed in the illuminated compartment with the guillotine door open. The latency for entering the darkened compartment was recorded for up to 180 seconds, at which time the trial was terminated.

All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Naϊve rats required less than 30 seconds, on average, to cross from the illuminated compartment to the darkened compartment. However, 24 hours after the electric shock exposure, most rats pretreated with vehicle did not re-enter the darkened compartment; the average latency was increased up to 175 seconds (p < 0.001).

Pretreatment with MK-801 (0.1 mg/kg) markedly reduced this latency when compared to the vehicle (p<0.001). EXAMPLE 49 (Method B)

Radial arm maze task in Rats, an in vivo Test for Learning and Memory

The test was performed as previously described (Zhang, H. -T., Crissman, A.M., Dorairaj, N.R., Chandler, LJ. , and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.). Five days after initial housing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) were placed in the eight-arm radial maze (each arm was 60x10x12 cm high; the maze was elevated 70 cm above the floor) for acclimation for two days. Rats were then placed individually in the center of the maze for 5 minutes with food pellets placed close to the food wells, and then, the next day, in the wells at the end of the arms; 2 sessions a day were conducted. Next, four randomly selected arms were then baited with one pellet of food each. The rat was restricted to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely throughout the maze until it collected all pellets of food or 10 minutes passed, whichever came first. Four parameters were recorded: 1) working memory errors, i.e., entries into baited arms that had already been visited during the same trial; 2) reference memory errors, i.e., entries into unbaited arms; 3) total arm entries; and 4) the test duration (seconds), i.e., the time spent in the collection of all the pellets in the maze. If the working memory error was zero and the average reference memory error was less than one in five successive trials, the rats began the drug tests. MK-801 or saline was injected 15 minutes prior to vehicle or test agent, which was given 45 minutes before the test.

Experiments were performed in a lighted room, which contained several extra-maze visual cues.

All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Compared to control, MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working and reference memory errors (p<0.01). This amnesic effect of MK-801 on working memory is reversed in a statistically significant manner by the administration of actual test compounds in a dose-dependent fashion.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

91 9 While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.