Title of Invention	"A PHENYLAMINE COMPOUND HAVING PDE4 INBIBITOR ACTIVITY"
Abstract	A phenylamine compound of Formula I wherein: R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen; R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -OC-, R3 is alkyl having 1 to 8, carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof, R4 is aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxy aboxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-, or combinations thereof.

Title of Invention

"A PHENYLAMINE COMPOUND HAVING PDE4 INBIBITOR ACTIVITY"

Abstract

A phenylamine compound of Formula I wherein: R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen; R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -OC-, R3 is alkyl having 1 to 8, carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof, R4 is aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxy aboxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-, or combinations thereof.

Full Text	The present invention relates to a phenylamine compound of formula I. This application claims benefit of U.S. Provisional application Serial No. 60/262,651, filed January 22, 2001, U.S. provisional application Serial No. 60/267,196, filed February 8, 2001, and U.S. Provisional application Serial No. 60/306,140, filed July 14,2001. FIELD OF THE INVENTION The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically this invention relates to selective PDE4 inhibition by novel compounds, e.g., N-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof. 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 c AMP 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 Ca2-/calmoduim. 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 4 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 PD'E4D [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 anthnflanimator/ 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 roiipram, xanthine derivatives such as pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received considerable attention of late 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 ceils, such as those located in the nervous system and elsewhere in the body. Roiipram, 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 TV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et ai., Drugs of the Future 1992, 17(9):799-807 for a general review). Further clinical developments of roiipram 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 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 in trace 11 ular 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 pan to catabolism of intracellular cAMP 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 of Formula I: wherein R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH3, CHF2, CF3, etc.); R2 is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C=C- (e.g., CH3, CHF3, CF3, methoxyethyl, etc.), cycloaikyi having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano. alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkyjalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloaikyi portion and/or the alkyl portion.one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethyienedioxy,.cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.), aryl alkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CH2- groups are each optionally-replaced by -0- or -NH- and/or the alkyi portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenyiburyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyi-, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereo'f (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, 0 or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyi, alkoxy, cyano, tnfluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, 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, 0 or S atom, and the 'alkyi portion is branched or unbranched and has I to 5 carbon atoms, the heterocycle-alkyl group is • unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF3, hydroxy, aryJ, alkyl, alkoxy; cyano, trifluoromethyl, rutro, oxo, or combinations thereof, wherein in the aikyl portion one or more -CH2CH3- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CHj- groups are each optionally replaced by -0- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydndylpropyl, methylpiperazinylethyl, etc.); R . is H, 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, cyano, C1-4-alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), a partially unsaturated carbocycle-alkyi group wherein the carbocyclic portion has 5 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 carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C1-4-alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl. portion, wluch -is branched or unbranched, has 1 to 5 carbon atoms,-arylalkyl radical is unsubstituted or substituted., in the aryl portion, one or more times by halogen, trifluoromethyl, GF3O, nitro, ammo, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the aikyf portion by halogen, cyano, or methyl (e.g., benzyl, phenethyi. phenpropyl, methylbenzyl, methoxybenzyi, trfluoromethyi, benzyl, methyienedioxobenzyl, etc.), or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom, the alky! portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyi group is unsubstituted or substituted one or more times in the heteroaryi portion by halogen, alkyl, alkoxy, cyano, trifmoromethyl, C7^0, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portipn by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyi, chloropyridylmethyl, dichloropyridylmethyl, thienylrnethyl, thiazoiylmethyi, quinolinylmethyi, isoquinoiinylmethyl, piperidinylmethyi, fur any 1m ethyl, imidazolylmethyl, methyiimidazolyimethyl, pyrrolylmethyl, etc.); R4 is H, aryi having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyaikoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyi, OCF3, amino, aminoaikyl, aminoaikoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yi, 2(-heterocycie)tetrazole- 5-yl (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyi, ethoxycarbonyl), cyano, acyl, aJkyithio, alkylsulfinyl, alkylsuifonyl, phenoxy, trialkylsilyloxy (eg. tertbutyidimethylsilyioxy), R5-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyi, rnethylphenyl,,chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methyienedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyi, hydroxymethylpheny!, nitrophenyl, aminophenyl, etc.), or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is uns'ubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethyienedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkyiamino, hydroxyalkyi (eg., hydroxymethyl), hydroxamic acid, tetrazoie-5-yl, hydroxyalkoxy, carboxy, alkoxycarbony! (e.g., tert-butyloxycarfaonyl, ethoxycarbonyl), cyano, acyl, aikyithio, alkylsulfmyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tertbutyldimethylsilyloxy). R3-L-, or combinations thereof (e.g., pyridyl, thienyl,.pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazoiyl, thiazolyl, etc.); R5 isH, alkyl having I to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy,. oxo, or combinations thereof (e.g., methyl, ethyl, propyI, etc.), aikylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyciic 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 carbocyciic portion, one or more times by halogen, alkyl, alkoxy, nitro. cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, aikoxy, aJkyl having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, aikoxy or combinations thereof (e.g., cyciopentylmethyl, cyclopropyimethyl, etc,), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, aikoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, •dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyi, etc.), arylaiky! 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 10 5 carbon atoms, aryialkyi radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CFsO, nitro, amino, alkyl, aikoxy, amino, alkylamino, dialkyjamino and/or substituted in the aikyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl. trfluoromethyi, benzyl, methylenedioxobenzyi, 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, 0 or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, ailcoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyi, aminoalkyl, aminoaikoxydialkylarnino, hydroxyalkyi (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyioxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazoiyl, thiazolyl, etc.), or a heterocycie-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, 0 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 heterocyciic ; portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF^O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.); L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms ; wherein one or more-CH?-groups are each optionally replaced by-0-, ' -S-, -KR6-, -S02NH~, -NHSCV, -CO-, ~NR'6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-0-, , CHr, -CO-, -CO-O-, -0-CO, -CO-NH-, -NH-CO-, -CH2CH2CH2-NHu CO-, -CH2-CH2-O-, -SO2NH-CH2CHrO-, -0-CH2CH?-0-, -CH2-NHCO-, -CO-NH-CH2-, -SCVNH-, -CH2-NH-S02-, -CH2CH2CH2-SO2- NH-, etc.); and isH, 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, d-n-aJkyl, Ci-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.); wherein at least one of R3 and R4 is other than H; and phamvaceutically acceptable salts thereof. According to a further aspect of the invention there is provided a genus of novel compounds according to the formulas II and III: 111 wherein R1, R2, R3, and R4 are as defined above. The compounds of this subgenus of fonnula I not only have PDE4 inhibitory activity, but also are useful as intermediates for preparing compounds of Formula I in which R3 and R4 are both other than H. In addition, preferred compounds of formula I are those of the subformula IV (Figure Removed) wherein R1, R2, and R4 ars as defined in Formula I and one of A, B and D is N and the others are C. Preferably, B is N. Also, R4 is preferably pyridyl or phenyl which in each case is substituted or unsubstituted. The present invention also includes compounds of Formula I' (Figure Removed) wherein . R1' is methoxy, F, Cl, CHF2 or CF3; R2' is alkyl having I to 12 carbon atoms, alkyl having .1 to 12 carbon atoms which is substituted one or more 'times by halogen, oxo, cyano, or combinations thereof, alkeny] having 2 to 12 carbon atoms, .alkenyi having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having. 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, cycloalky! having 3 to 10 carbon atoms substituted one or more times by haiogen, oxo, aikyl, or combinations thereof, cycloalkylalkyl having 4 to 12 carbon atoms, cycloalkylalky] having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof, a partially unsaturated carbocyclie group having 5 to 14 carbon atoms, a partially unsaturated carbocyclie .group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof, arylalkyi having 7 to 26 carbon atoms arylaikyl having 7 to 26 carbon atoms which is "substituted one or more times by halogen, aikyl, alkoxy, nitro, cyano, oxo, trifluoromethyi, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryialkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, aikyl, alkoxy, cyano, trifluoromethyi, nitro, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; X isOorS; RJ is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, ammo, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,. cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyisulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof, heteroaryl having 5 to 10 nng atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, tnfluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations 'thereof;' • • L is -NH-, -KR4'-, -NHCH2-, -NR4'CHr, or -CH2NR4'-; and R4 is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyisulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is. a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amirio, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and pharmaceutically acceptable salts thereof. The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in animals, 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 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., US 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 with in this application. Thus, there are provided intermediate compounds which correspond to compounds of Formula I, wherein R2, R3, and R4 are as previously defined for Formula I, but R1 is H, ten'-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, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for.the synthesis of radio-labeled compounds, such as where R1 is 3HjC-, 14CH3- or ' 'CHj-, for example by removing the protecting group and reacting the resultant compound in which R1 is H with suitable radio-labelled 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!, RJ, and R4 are as previously defined for Formula I, but R2 is H, rerf-butyldimethylsilyioxy-, 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, 3rd Edition, John Wiley & Sons, 1999, pp. 246- 293. Compounds m which R2 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 H, C, or C. As previously described, compounds according to formula II, wherein R , R" and R4 are as previously described are useful intermediates for the production of compounds according to formula I where in R3 is other than H. Also, as previously described, compounds according to formula III, wherein R1, R2 and R3 are as previously, described are useful intermediates for the production of compounds according to formula I where in R4 is other than H. Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl. Alkyl, as a group or substituent per se or as part of a group or substituent (e.g., alkylaminc, trialkyisilyloxy, 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 alkyi groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alky! groups include 1-, 2- or 3- methylbutyl, 1,1-, 1,2- or2,2-dimethyipropyl, 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, ethyimethylbutyi, dimethyibutyl, and the like. Substituted alkyi groups are alky! groups as described above which are substituted in one or more positions by halogens, oxo, hydroxyl, Ci-4-alkoxy and/or cyano., Halogens are preferred substituents, especially F and CL Alkoxy means alkyl-O- groups and alkoxyalkoxy means alky 1-0-alkyl-0- groups' in which the alkyi portions are in accordance with the previous discussion. Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, buroxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxyrnethoxy, and methoxyetboxy. PTefened 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 methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butcxycarbonyl. Cycloalky! 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 cyclopropyl, cyclobucyl. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-i-yl, and adamant-2-yl. Other suitable cycloalky! groups include spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2,4]heptyl, spiro[2;5]octyi, bicyclo[5.1.0]octyi, spiro(2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]hepty!, bicyclo[4.2.0]ocryl, and spiro[3.5]nonyl. Preferred cycloalklyl groups are cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, substituted by halogens and/or alkyl groups. Cycioalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include cyclopropylmethyl and cyciopentylmethyl. 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 phenyl, naphrhyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by, for example, halogen, alkyl, hydroxy, alkoxy, mtro, methylenedioxy, ethylenedioxy, amino, alkylammo, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, aikylthio, alkyisuifinyi, alkylsulfonyl, and phenoxy. Arylalkyl refers to an aryi-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include benzyl, 1- phenethyl, 2-phenethyl, phenpropyi, phenbutyl, phenpentyi, and napthylmetfayl. Heteroaryl refers to an aromatic heterocyciic 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 heteroaryi group contains 1 to 3, especially 1 or 2, hetero-nng atoms which are selected from N, O and S. Suitable heteroaryi groups include furyl, thJenyl, pyrrolyl, p yrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl, oxazolyi, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazoiyi, dioxazolyl, oxathiazolyl, •Ihiadiazolyt, pyridyl, pyridazmyl, pyrimidinyl, pyrazinyl, tnazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, •isothionaphthenyl, indolyl, isoindolyl, indazoly'I, benzisoxazolyi, benzoxazolyl, benzthiazolyl, benzisolhiazolyl, purinyi, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyi, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-tnienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or Sisoquinolinyl. Substituted heteroaryi refers to the heteroaryi groups described above which are substirued in one or more places by, for example, halogen, aryi, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl. nitro, oxo, amino, alkylamino, and dialkylamino. Heterocycles include heteroaryi groups as described above as well as nonaromatic cyclic groups containing at least one hetero-ring atom, preferably selected from N, S and 0, for example, tetrahydrofuranyl, pipendinyl, and pyrrolidinyl. Heterocycle-alky! refers to a heterocycle-alkyl-group wherein the heterocyciic and alkyl portions are in accordance with the previous discussions. Suitable examples are pyndyimethyl, thienyimethyl, pyrimidinylmethyl. pyrazinylmethyi, and isoquinolmylmethyl. Partially unsafurated 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 or* C=C bond. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, terrahydronaphthenyl and indan-2-yl. Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures are each replaced by - CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2- butene, i-pentenyl, and 2-pentenyl. Alkynyi refers to straight-chain or branched-chain aliphatic radicals containing 2 - to 12 carbon atoms in which one or more -CHi-CHa- structures are each replaced by -OC-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl. Acyl refers to alkanoyi 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. Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents, In the compounds of Formula I, R1 is an alkyl group having preferably 1 to 4 carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine. In particular, R1 is preferably methyl or difluoromethyl. R'IS preferably cycioalkyi, particularly cyclopentyl. R2 is also preferably aryi or arylalkyl, particularly substituted or unsubstituted phenyl or phenylalkyl, such as phenyl, methyiphenyl, rnethoxyphenyl, chlorophenyi. phenethyi, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, pbenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyi, chiorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl, chiorophenbutyl, nitrophenbutyl, chlorophenylammoethyl, and the like, R2 is also preferably a partially unsaturated carbocyclic groups, which is unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl, indan-2-yl, R2 is also preferably an alkyl group having 1 to 8 carbon atoms, especially 1 to 4 carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl, trifiuoromethyl, and methoxyethyl. R2 is also preferably a heterocyclic or heterocycle—alkyl group, particularly radicals in which the heterocyclic group has 5 to 6 ring atoms and 1 to 2 hetero-ring atoms selected from N, 0 and S, e.g., tetrahydrofuranyi, pyrroiidinyi, pyrrolyl, pyridylmethyl, pyridylethyl, pyri-dylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like. Preferred R" include cyclopentyl, tetrahydrofuranyi, CHFi, methoxyethyl, cyclopropyimethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phecylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl. R3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, or n-batyi), arylalkyl (e.g., substituted or unsubstitituted benzyl, phenethyl, and phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted pyridylmethyi, furanyimethyi, thienyimethyl, pyrrolylmethyl, pyrimidinyirnethyi, thiazolylmethyl, isoquinolinyimethyl and.quinolinylrnethyl). Preferred substituents for aryl and heteroaryl portions of R3 are F, Cl, CH3, C2H5, OCH3, and CN. R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl, pyrazmyl, pynmidinyl. pyridyL, quinolinyl. and isoquinolinyl, which in each case is unsubstituted or is substituted one or more times. Preferred substiruents are OH, F, CI. CF;,, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH2OH, CONHOH, CONH2, methyienedioxy, COOH, and combinations thereof. In addition, when R is aryl, especially, phenyl, preferred substituents include RJL; e.g., R5-, R5-0-, R5-CO-, R5-NH-CO-, R5-S02-NH-, R5-S02-NH-alkylene-0-, NH2- alkyl-NH-CO-, R5-alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, Ci, F, CN, OCH3, CF3, amino, nitro, HOCH2 and COOH. When R4 is aryl substituted by R5-SO2-NH- it is preferably a substituted phenyl group and R5 is preferably methyl, ethyl, propyl or phenyl. When R4 is aryl substituted by R5-S02-NH-aIkylene-0- it is preferably a ited phenyl. In such cases, R5 is preferably methyl, e alkylene is preferably -CH2-, -CH2CH2- or-CH2CH2CH2-. substituted ethyl, propyl or phenyl and When R4 is aryl substituted by R3-L- it is preferably substituted phenyl. In such cases, preferred R5 groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadiny!, or methylpiperadinyl, and L is preferably a single bond, -O-, -CO-, -CH2-, -CH2CH2-, -CH2CH2CH2-3 -CH2-0- -CH2CHrO-, -CH2CH2CH2-O-, -CH2-NH-CH2CH2-O-, -CO-NH- or -NH-CO-. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas la-Ih which correspond to formula I but exhibit the following preferred groups: la R1 is methyl or CHF2; R2 is aikyl, alkenyl, alkynyl, cycloalkyl, aryialkyl, heterocycle-alkyl, cycloalkylalkyl, aryi, or heterocyclic, in each case substituced or unsubstituted; RJ is H, aikyl, aryialkyl or heteroaryialkyi, in each case substituted or unsubstituted; and R4 is aryi or heteroaryi, in each case substituted or unsubstituted. Ib RJ is heteroarylalky! which is substituted or unsubstituted. Ic R1 is methyl or CHF2; and R2 is cyclopentyl, CHFi, cyclopropylmethyl, pyridyiethyi (particularly-2-pyridylethyl), or tetrahydrofurany! (particularly (3R)-tetrahydrofuranyl). Id R1 is methyl or CHF2; R2 is cyclopentyi; R3 is heteroarylaiky!, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryi or heteroaryi. le R1 is methyl; R2 is cyclopentyi; and R3 is heteroarylaikyl which is substituted or unsubstituted. If R1 is methyl; R" is cyclopentyl; R3 is heteroarylaikyi which is substituted or unsubstituted; and R4 is phenyl which is substituted or unsubstituted. Ig . R1 is methyl; T JR." is cyclopentyl; RJ is pyridylmethyl, phenethy!, benzyl, thienylmethyi., pyndylpropyl, piperidinylmeihyL or pyrazinylmethyl, which in each case is substituted or unsustiruted, or methyl, ethyl, or propyl; and R4 is phenyi or phenyl substituted with 1 to 3 subsrituents. Ih R! is methyl; R2 is cyciopentyl; RJ is pyridylmethyl, phenethy!, benzyl, thienylmethyl, pyridylpropyl, pip_eridinyimethyl, pyrazinylmethyl, which in each case is substituted or unsustiruted, or methyl, ethyl, or propyl; and R4 is phenyl, naphthyi, biphenyl, pyridyi, pyrimidinyl, thiazoly], pyrazinyl, quinolinyi, or isoquinolinyl, in each case substituted or unsubstituted. . In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas Ila-Hd which correspond to formula II but exhibit the following preferred groups: Ha R1 is methyl or CHF?; R: is cyclopentyl, CHF^ cyclopropylmethyi, pyndylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and R4 is phenyl, naphthyi, pyridyi, quinolinyl, or isoqumolmyl, which in each case is substituted or unsubstituted. lib R1 is methyl or CHF2; R2 is cyclopentyl, CHF?, cyclopropyimethyi, p>Tidylethyi (particularly 2-pyridylethyl), or tetrahydrofurany! (particularly (3R)-tetrahydrofuranyl); and R4 is phenyl which is unsubstiruted or substituted by methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsuifonamido, or is 3-pyridyl. which is unsubstituted or substituted by carboxy or alkoxycarbonyl. He R1 is methyl; . R" is cyclopentyl; and R is phenyl, naphthyl, pyridyl, quinolinyi, or isoquinolinyl, which in each case is substituted or "unsubstituted. . lid R1 is methyl; R2 is cyclopentyl; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, arnzno, carboxy, hydroxymethyl, or ethyisulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyf. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by sub formulas UIa-!IId which correspond to formula m but exhibit the following preferred groups: Ilia R1 is methyl or CHF2; R2 is cyclopentyl, CHFj, cyclopropylmethyl, pyridylethyl (particularly 2-pyndylethyl), or tetrahydrofurany! (particularly (3R)-tetrahydrofuranyl); and R3 is benzyl, phenethyl, cyclohexenyknethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylrnethyl, which in each case is substituted or unsubsti tuted. IIIb R1 is methyl or CHF2; R2 is cyclopentyl, CHFa, cyclopropylmethyl, pyridylethyl (particularly 2- pyridyiethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and R3 is pyrazinylmethyl, pyrimidinylmethyl or pyndylmethyi, which in each is unsubstituted or substituted. ttlc R1 is merhyi; R2 is cyclopentyl; and RJ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyranidinylmethyl, pyridylmethyl quinolinymethyl, isoquinolinylmethyl, isoimidazolyl, thiazoiylmethyi, or pyrrolylmethyl, which in each case is substituted or unsubstifuted. Hid R1 is methyl; R2 is cyclopentyl; and RJ is pyrazinylmethyl or pyridylmethyl, which in each -is unsubstiruted or substituted. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas IVa-IVp which correspond to formula IV but exhibit the following preferred groups: IVa R1 is methyl or CHF2. IVb R! is methyl or CHF2, and BisN. IVc Rs is methyl or CHFz, and R2 is cyclopentyl, CHFa, cyciopropylmethyl, pyridyiethyi (panicuiarly 2- pyridyiethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydroruTanyl). IVd R1 is methyl or CHF2, B is N, and R2 is cyclopentyl, CHFz, cyclopropyimethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyi). IVe R1 is methyl or CHF2, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. IVf R1 is methyl or CHF2, B is N, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. IVg R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyciopropylmethyl, pyridylethy! (particularly-2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. TVh R! is methyl or CHF2; BisN, - R2 is cyclopenjyi. CHF:; cyclopropyimethyl. pyridylethyi (paniculariy 2- pyridylethyl), or tetrahydrofuranyi (panicularly (3R)-tetrahydTofuranyi). and Ra is 3-pyri'dyl or phenyl, which in each case is substituted or unsubstituted. IVi R! is methyl or CHF2, and R4"is pKenyl which is substituted in the 3- or 4- position. IVj R1 is methyl or CHF2) ' .BisN, and . R4 is phenyl which is substituted in the 3- or 4- position. TVk R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropyimethyl, pyndylethyl (panicularly 2- pyridylethyl), or tetrahydrofuranyi (panicularly (3R)-tetrahydrofuranyl), and R4 is phenyl which is substituted in the 3- or 4- position. IVI R1' is methyl or CHF2, B is N, R" is cyclopentyl. CHFa.. cyclopropylmethyl, pyridyleth-yl (pardcularly 2- pyridylethyl), or letrahydrofurany! (panicularly (3R)-ceirahydrofuranyl), and R4 is phenyl which is substituted in the 3- or 4- position. IVm R1 is methyl or CHF2, and Rd is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonarnido-phenyl, 3-tetra2ol-5-yl-phenyl, 3-hydroxymethylphenyl, 4-pyndyi, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-y!-phenyl, or 4-hydroxymethyl-phenyl. IVn' R1 is methyl or CHF2, . B is N, arid R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonamido-phenyl, 3-tetra2ol-5-yl-phenyl, 3-hydroxymethyiphenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamidophenyl, 4-tetra2ol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. TVo R1 is methyl or CHF2j R: is cyclopentyi, CHFs, cyclopropylmethyi, pyridylethyl (panicularly 2- pyridylethyl), or tetrahydrofurany! (particularly (3R)-tetrahydrofuranyl), and R" is 3-pyridyi, 3-COOK-phenyl. 3-Cl-phenyl. 3-cyano-phenyl. 3- athylsulionamido-phenyi, 3-tetrazol-5-yl-phenyl. 3-hydroxymethylphenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl. 4-ethylsulfonamidophenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. IVp RJ is methyl or CHF2) BisN, R2 is cyclopentyl, CHFi, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl); or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and . R4 is 3-pyndyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanb-phenyl, 3- ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 3-mtro-phenyl, 4-pyridyl. 4-COOH-phenyl, 4-cyano-phenyl, 4- ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxvmethylphenyl. Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an isoenzvme, 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. Toe 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. SCHEME I (Figure Removed) Starting nitrophenols of the type 1 are either commercially available (e.g., Rl = ]) or prepared by published procedures (e.g., Rl = CHF2 or both Rl and R2 = CHFa, . see Mueller, Klaus-Helmut. Eur. Pat. Appi. (1994), 8 pp. CODEN: EPXXDW EP 626361A1": Touma, ToshihiJco; Asai. Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN: JK.XXAF J? 11071319 A2; Platonov, Andrew; Seavakov, .Andrew; Maiyorova, Helen: Chistokletov. Victor. Int. Symp. Wood. Pulping Chem.. 1995. 8th, J, 295-299; Chnstensen, Siegfried Benjamin:.Dabbs. Steven; Karpinski, Joseph M. PCT int. Appl. (1996),, 12pp. CODEN: PIXXD2' WO 9623754 A l " 19960808). 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 alkylanon reactions. Compounds where R2 is aryl or heteroaryi can be prepared by copper catalyzed reactions with aryl or heteroaryi iodides under Ullman conditions or by coupling aryl-, vinyl-, or heteroaryi- boroaic 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, DLAD), and a suitable phosphine (e.g., PrnP, Bu3P) provides alkylated nitrophenols 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^CCh or NaH) in a polar aprotic solvent (e.g., DMF or CH3CN).-. Nitrocatechols 2 are subsequently reduced to the corre'sponding 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, mtrocatechols 3 can be reduced by using a hydnde source (e.g., NaBH4) and a transition metal catalyst (e.g., NiCl?, Pd on carbon) or by using metals (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g.-, HC1) to produce the corresponding anilines. Generally polar protic solvents such as ethanol or methanol are used in these reactions. /Y-Arylalkyl-anilines 4 are synthesized by standard methods in the an such as by reductive animation reaction, alkylation reaction, or by reduction of corresponding amides. For example, the reductive animation reaction of an aryl or arylalkyl aldehyde with appropriately substimted anilines in the presence of a borohydnde reducing agent such as NaBtL or NaBHsCN with an acid catalyst such as acetic acid or pTsOK provides desrrea .V-aryialkylaniiines. These reactions generally take place in polar protic solvents such as methanol. ethanol, isopropanol. n-propanol and the like. - jV-Aryialkyianilines 4 rsadiiy undergo A'-arylation by methods standard TO the art including Ullman coupling reaction, metal-catalyzed coupling, or aromatic nucieophilic substitution reaction. For example, the metal catalyzed reaction between an Nbenzylaniline and an aryl halide using a palladium catalyst, (e.g., Pd^dba-j), a bulky electron rich phosphineligand (e.g., tributylphosphme), and suitable base (e.g., NaOtBu) provides Tv'-Arylalkyldipaenylamines. Nickel and copper catalysts have been employed as well. Solvents useful in this reaction include non-polar aprotic solvems.such as toluene, benzene, xylenes, tetrahydTofuran, and ether. When synthesizing compounds of the type 5 wherein R4 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 (tBu)3P, 5.5 mol % of Pd2(dba);, and 1.3 equivalents of tBuONa are used. SCHEME 2 (Figure Removed) Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7. For example, an ethyl ester (R5 = Et) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOH) and a water miscible solvent (e.g., EtOH, THF). While r-Butyl esters (R5* = i-butyl) can be hydrolyzed using an aqueous acid (e.g., HCI. formic acid. TFA) in a water miscible orEanic solvent, if necessarv. SCHEME 3 (Figure Removed) Coupling of protected tetrazole bromO'Or iodobenzenes (e.g., 5-(3-iodophenyl)-2- - / (2-tetrahydropyran)tetrazole) with. JV- substituted aniline derivatives 4 produce THP- . protected tetrazoles 8. Hydrolysis of THP -protected tetrazoles 8 can be accomplished by using an aqueous acid, such as HC1 in water and a miscible solvent such-as THF or EtOH to provide tetrazoles 9. Further, THP terrazoles 8 can also be oxidatively cleaved using reagents such as CAN and DDQ in halognenated hydrocarbon solvents such as dichioromethane, chloroform., dichloroethane and the like to yield tetrazoles 9. Alternatively; tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with aside ion (e.g., KN}, NaN~3, etc.) and a proton source (e.g., NELiCl) 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:) 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., Me3SiN3, Bu3SaNT3) in an aprotic organic solvent such as benzene, toluene, dichioromethane, dichloroethane, ether, THF, and the like. SCHEME 4 (Figure Removed) Diphenylamines 10 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 tnethylamine 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 norrpolar aprotic solvents such as benzene, toluene, or xylene are utilized. Such diphenylamines (e.g., 10) can more preferably be synthesized by metal catalyzed animation reactions. For example, reaction of an appropriately substituted aniline 3 with an arylhalide in the presence of a base (e.g., K^POo, CsCCh, orNaOtBu) and a palladium or nickel catalyst, for example Pd(dppf)Cb, a ligand (e.g., dppf) and a base (e.g., NaOtBu) (JACS. 1996, J18, 7217) or with Pdidba}, a bulky electron nch phosphine such as P(tBu)3; and a base (e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired diphenylamines 10. Solvents most commonly utilized in this type of reaction include non-polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like. Diphenylamines 10 can then be alkylated with various alkyl haiides or arylalkyl halides such as. but not limited to iodomethane, ethylbromide, benzylchloride, 3- (chloromethyljpyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4-(bromomethyl)- benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium : hydnde, potassium hexamethyldisilazide or potassium diisopropylamide to provide Nsubstimted diphenylamines 5. Solvents useful in this reaction include aptotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like. SCHEME 5 (Figure Removed) Carboxylic acids 7 can be further manipulated to form carboxamides 11 using methods standard in the art. For example, 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^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 6 or acids 7 can be reduced using methods standard in the an to give the corresponding carboxaldehyde or hydroxymethyl analogs. For example, an aryl ethyl ester (e.g., structure 6, R5 = ethyl) can be treated with an appropriate reducing agent (e.g., LAH, DIBAL, etc.)'in an aprotic solvent sueh as ether or TKF, ro produce the corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and alcohols can be further derivatised by methods standard in the art. Similarly carboxamides (e.g., structure 11) and nitriles can be reduced-using methods standard in the art to provide the corresponding substituted amines or aminomethy] analogs. For example,.an aryl carboxamide 11 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 nitrite'yields the corresponding primary aminomethyl analog. SCHEME 6 (Figure Removed) Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 bymethods standard in the an such as hydrosenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12 can also be reduced using a hydnde source (e.g., NaBH Pd on carbon) in polar protic solvents such as EtOH, to produce the corresponding anilines 13. These anilines can then befurther substituted by methods standard in the an. For example, anilines of the type 13 can be alkylated, acylated, or sulfonylated to give the corresponding N-alkyl amines, carboxamides (e.g., structure 15) or sulfonamides (e.g., structure 14) respectively. For example, a sulfonamide can be prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (e.g./MeSO^CL EtSO^Cl, BnSO^Cl, PhSOiCl, etc.) in the presence of a base (e.g., Et/jN, pyndine, DIEA, etc.). Suitable solvents for .this reaction include non-polar aprotic solvents such as dichloromethane, chloroform, ether, and the like. SCHEME 7 (Figure Removed) Trialkylsilylethers of the type 16 are prepared as described in Scheme 1. The Jerr-butyldrmethylsilyl protected catechol intermediates 16 are readily deprotected by numerous literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 273-276.) such as by using a fluoride ion source (e.g., BmNF) in an aprotic solvent such as ether or THF; or under acidic conditions (e.g., KF, 48% HBr, DMF). The resultant phenol 17, 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. For example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by Ullman type ary! coupling or by reaction with vinyl-, aryl- or heteroarylbororuc acids in the precence of a copper catalyst. SCHEME 8 (Figure Removed) Haioalkoxy intermediates 18. prepared by aikylanon of the corresponding phenol can be aikylated by reactions with substituted amines, alcohols, or tbaois in the presence of a base to provide analogs such as 19. For example, an alkyl halide can be ammated with an appropriate primary or secondary amme and a base such as K^CCb, in a polar aprotic solvent such as THF, DMF, OT CH3CN. Many of these synthetic procedures are described more fully in the examples below. One of ordinary skill in the-art will recognize that some of the compounds of Formulae (I) and (T) 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 diastereorners and diastereomenc 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% wAv of the corresponding opposite enannomer, preferably no more than 2%, most preferably no more than 1%. The optical isomers can be obtained by resolution of the racerruc mixtures according to conventional processes, for example, by the formation of diastereoisomenc salts using an optically active acid or-base or formation of covalent diastereorners. Examples of appropriate acids are tananc, diacetyltartaric, dibenzoyltanaric, ditoluoyltartanc and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereorners on the basis of their physical and/or chemical differences by methods known to those skilled in the an, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomenc salts. A different process for separation of optical isomers involves the use of chir-al chromatography (e.g., chiral FEPLC columns), _n with or without conventional derivation, optimally chosen to maximize the separation of the enannomers. Suitable chirai HPLC columns are manufactured by Diacel. e.g.. Chiracel OD and Chiracei OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization. are also useful. Tne optically active compounds of Formulae I and F can likewise be obtained by crural syntheses utilizing optically active starting materials. 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 mam compound,, functioning as a base, with an inorganic or organic acid to farm, a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid^ camphor sulfonic acid, oxalic acid, maleic acid, succmic 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, mangnesium, ammonium, and choline salts. Those skilled in the an 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 reacting the compounds of the invention with the appropriate base via a vanety of known methods. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, buryrates, camphorates, digluconates. cyclopentanepropionates, dodecylsulfai.es, ethanesulfonates, glucoheptanoates, giveerophosphates, hemisulfaies, heptanoates, hexanoates. fiimarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates. lactates, maleates. methanesulfonates, nicotmaces. I-naphthalenesulfonates, oxaiates. paimoares, pectinates, persulfates, 3- phenylpropionates, picrates, pivalates, propionates. succinates, tanrates, thiocyanates,. tosylates, mesylates and undecanoates. Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. Kovvever, 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. The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical composftitms of compounds of Formulae I or I' containing, for example, one or more pharmaceutical!y acceptable earners. Numerous standard references are available that describe.procedures for prepanng 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, intraveneousiy, . intramuscularly, intrastemally and by infusion), by inhalation, rectally, vagmally. topically, locally, transaermally, 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, capiets, granules. - lozenges and bulk powders. The- compounds of the present invention can be administered alone or combined with various pharmaceuucally acceptable earners, diluents (such as sucrose, mannitol. lactose, starches) and excipients known in the an, including but not limited to suspending agents, solubilizers. buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubncanis 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 excrpients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or Suspending the compounds of die 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, geis, 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 rransdermal parches. 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 invenuon can be administered by inhalation in the form of a powder (e.g., micromzed) or in the form of atomized solutions or suspensions, ine aerosol formulation can be placed into a pressurized acceptable propellant. The compounds 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 block ers, chlomergic drugs, adenosine receptor modulators, amphakmes NMD AR modulators, mGluR modulators, and cholmesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamme). 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 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 compnse administering to an'1 animal 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, Huntmgton's disease. Pick's disease, Creutzfeld-Jakob disease, HIV', cardiovascular disease, and head trauma as well as age-related cognitive decline. Dementias are diseases thai 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: neurodegeneraave dementias (e.g., Alzheimer's. Parkinson's disease, Huntingtor/s disease. Pick's disease), vascular (e.g.. mfarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subcural / hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g.. vitamin B12 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 rreatment 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 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 ami-apoptotic and anti-inflammatory properties make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury" neurogenesis, Alzheimer's disease, multiple sclerosis, amyiolateroscierosis (ALS), and multiple systems atrophy (MSA). Thus, m accordance with a preferred embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntmgron's disease. Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, , csrebral senility, multiinfarct dementia and other neurological conditions including acute neuronai ciseases, as .well as HIV' and cardiovascular diseases, comprising adininisierinj an effective amount of a compound according to Formula (I) or (T) or pharmaceuhcally accepiabie sails thereof. The compounds of the present invention can also be used in a method of treating patients suffering from disease states characterized by decreased NMD A 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- , - 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, 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) or (I1) or a pharrhaceuticaily 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 anhntis, 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, atherosclerosis, • keratosis, rheumatoid spondylitis, osieoarthritis, pyresis. diabetes mellims, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, roxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruntis in the anogenital area, alopecia areata, hypertrophac scars, discoid lupus erythematosus. systemic iupus erythematosus, follicuiar and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease. anaphylacioid purpura nephritis, inflammatory bowei 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, J?l 1-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, and US 5,935,9778. 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. PDJ54 inhibitors maybe 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 unnary obstruction secondary to benign prostatic hyperpiasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (BCLL), for inhibition of uterine contractions, to attenuate pulmonary vascular ischemiareperfusion injury (IRI), for comeal hydration , for inhibition of IL-2R expression and thereby abolishing HTV-1 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 the present invention 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, chloinergic drugs, adenosine receptor modulators, amphakmes NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil. rivastigimine, and gianthanamrne). In such combinations, each active ingredient can be administered either m accordance with their usual dosage range or a dose below their usual dosase ranse. The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the seventy 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 mamma] 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, 0.01-100 mg/kg/day, preferably 0.1- 70 mg/kg/day, especially 0.5-10 mgAcg/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 ing/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 nonlimiting 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 se: forth uncorrectea in degrees Celsius; and, unless otherwise indicated, all pans and percentages are by weight. The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference. EXAMPLE 1A l-Cyclop'entyloxy-2-methoxy-5-mtrobenzene To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium carbonate (643.5g, 4.66 mol) 'in dimethylformamide (1 L), under NT protection, was added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100°C for 6h. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mo!) were added. The suspension was heated to 100°C for 4h. TLC indicated the reaction was complete (9:1 DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was re-extracted with ether (2L). The combined organic layers were washed with IN NaOH (2L), water (2L), and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2 x 300 mL) to obtain 736".7g (99.6% yield) as a yellow solid. Tne following compounds were prepared in a similar manner as described above: a) l-CyclopropyLmethoxy-2-methoxy-5-nitrobenzene b) 1 -C yclopentoxy-2-difluoromethoxy-5-nitrobenzene c) i-Cyciopropylmethoxy-2-difiuoromethoxy-5-nitrobenzene EXAMPLE IB 2-Methoxy-5-nitro-l-((37?)-tetrahydrofuryloxy)benzene To amixture of 2-Methoxy-5-nitrophenol (1.69 g, 10 mmol), tnphenyiphosphine (5.24 g, 20 mmol) and 3-(JR)-hydroxytetrahydrofuran (1.80 g. 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added drop-wise, with stirring, diisopropyiazodicarboxyiate (4.0 mL, 20 mmol) and the mixture was allowed to stir at room temperature for 16 h. The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL) and bnne (50 mL), (MgSCU) and concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product . • The following compounds were prepared iii a similar manner as described-above: a) 2-Methoxy-5-nitro-l-(3-tetrahydrofuryloxy)benzene b) 2-Methoxy-5.-n]tro-l-((35)-tetrahydrofuryloxy)benzene c) 2-DifJuoromethoxy-5-rutro-1 -(3-tetrahydrofurylox'y)benzene d) 2-Difluoromethoxy-5-nitro-l -((3J?)-tetrahydrofuryloxy)ben2ene e) 2-Difluoromethoxy-5-nitro-1 -((3,S)-terrahydrofuryloxy)benzene f) 2-Methoxy-5-nitro-1 -(3-phenpropyloxy)benzene g) 1 -(2-Indanyloxy)-4-rnethoxy-5-nitrobenzene EXAMPLE 1C l-{r£rt-Buryldimethylsilyl)axy-2-methoxy-5-nitrobenzene To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 : g,. 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, ten- , butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and. filtered through 10 g of silica-gel The silica gel was washed with an additionaF'200. mL of 50% ethyl acetate in hexanes and the nitrates were combined and concentrated in vacua to give 2.01 g of product as a tan crystalline solid. !H NMR(CDCh) 5 7.89 (dd, IE, J = 9.0 Hz, 2.8 Hz), 7.69 (d, IE, J = 2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H). EXAMPLE 2 3-Cydopentyloxy-4-methoxyaniline To a suspension of 10% Pd on activated carbon (25g) in ethanol (4L), under N2 protection, was added 1 -eyelopemyloxy-2-methoxy-5-nitrobenzene (250g, 1.054 mol). Tne reaction mixture was degassed under vacuum three times. The reaction mixture was 'stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol.- The solvent was removed in-vacuo to obtain 208.33g (95% yield) of 3-cyclopentyloxy-4- methoxyanilme as a red liquid, 'H.NMR (CDC13) 5 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (pf J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m,6H), 1.61-1.55 (m,2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopenty.loxy-4-difluoromethoxyaniline b) 3-Cyclopropyimethoxy-2-methoxyaniline c) 3-Cyclopropyrnieiihoxy-4-difluoromethoxyanilitse d) 4-Methoxy-3-((3J?)-tetrahydrofuryloxy)aniline e) 4-Methoxy-3-(.teirahydrofuryloxy)aniline f) 4-Methoxy-3-('(35)-retrahydrofuryioxy)aniline g) 4-Difiuoromethoxy-3-('3-tetrahydrofuryloxy)aniiine h) 4-Difiuoroniethoxy-3-((3Jl?)-tetrahydrofuryioxy)aniline i) 4-Difiuoromethoxy-3-((35)-tetrahydrofuryloxy)aniline ) 3-{/err-Butyldimerhylsiiyl)oxy-4-methoxyaniline k) 4-Methoxy-3-(3-phenpropyioxy)aniiine i) 3-{2-Incany!oxy)-4-merhoxyaruiine EXAMPLE 3 3-CyclopeDty!-4-metboxy-yV-(3-pyridylmethyi)aiii]ine To a mixture of 3-pyndinecarboxaldehyde (106.55g, 0.995 moi) in methanoi (5L) was added 3-cyclopen,tyloxy-4-methoxyaniline (208.38g, 1.005 mol) and p-toluenesuifonic acid monohydrate (200 mg). The reaction mixture was stirred for 4h. The flask was then cooled to 0°C and sodium horohydride (37.64g, 2.3 mol) was added porrionwise over 4h. The reaction mixture was allowed to warm to room temperature over I6h with stirring. TLC indicated the reaction was complete (1:3 bex:EA). The solvent was evaporated unti] approximately 0.5.L of slurry remained. Toe slurry was diluted with water (1L) and extracted with ethyl acetate (2 x 2L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to yield 300g (100% yield) of the desired product as a brown viscous liquid. 'H NMR (CDC13) 5 8.61-S.48 (m, 2H)S 7.69-7.67 (m. 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, IK), 6.13 (dd, J =» 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H>, 1.83-1,70 (m, 6H), 1.65-1.45(mr2H). . - The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-V-(3-thjenylmethyl)aniline b) 3-CyclopentyJoxy-4-methoxy-A'-(4-pyridylmethyI)analine c) 3-Cyc]openryloxy-/V-(2.6-dichloTO-4-pyridylmethyl)- 4-methoxyaniline d) 3-Cyclopentyloxy-4-rnethoxy-.'V-{2-quinolinylmethy!)aniline e) 3-Cyciopentyloxy-4-tnethoxy-iV-{3-quinolinylmethyl)aniIine f) 3-Cyclopenryloxy-4-methQxy-.iV'-(4-quinolinylmethyl)amline g) 3-CyciopenTyloxy-4-methoxy-A-(--pyi"22ir!yfene^yi)ariiIii!e h) 4-Meihoxy-//-.(3-pyricybnethyI)-3-(3-tetrahydro-furyloxy)aniiine i) 4-Mechoxy-/V-{3-pyridylmemy!)-3-((3^}-tecrahydrofuryloxy)aniline j) 4-Metfaoxy-//-{3-pyridylmethyl)-3-((3l5)-cetrahydrofuryloxy)am'line k) 3-CyciopropyImethoxy-4-Giiluororaethoxy-,V-(3-pv-ndyimerhyi)aniiine i) 3-CyciopenTyloxy---difjuoromethoxy-Ai'-{3-p}TidylmeLiyl)arilline m) 4-Dii1uoromerboxy-A^(3-pyridyb7iethyl)-3-(3-ten'ahydrofury!o7cy)aBiliT)e n) 4-DifJuoromechoxy-A"-{3-pYridylme±yl)-3-((3j;?)-tenrahydrofun'loxy)anHine o) 3.4-Bis(difjuoromethoxy)-Ar-(3-pyridylmethyl)aniline p) 3-tert-Butyidimethyisi]yloxy-4-methoxy-.¥-(3-p'yridylmethyI)arii]me q) 3-Cyclopentyloxy-4-methoxy-//-(2-pyridylmethyl)aniline r) 3-Cyclopenryioxy-4-methoxy-.'V-[ I -{2-phenethyl)Janiline s) A"-Benzyl-3-c.yclopentyloxy-4-methcxyaniline t) jV-[(Cyclohex-l -en-i -y])methylj-3-cyciopenty]oxy-4-methoxyaniline u) 3-Cyclopentyioxy-4-Tnethoxy-A'-(3;4,5-tnmethoxybenzyi)anilme v) yV-[(Cyclohex-3-en-l-yl)rnethyl]-3-cyclopentyloxy-4-methoxyaniline w) 3-Cyclopenryloxy-4-metboxy-/vr-(2,4J6-trimethylbenzyl)aniline x) 3-CycIopentyloxy-4-methoxy-A-(2-methyiben2yl)aniline y) 3-Cyciopenry]oxy-4-methoxy-A/-(2-trifjuorometbylben2yl)auiline z) 3-Cylclopentyloxy-4-methoxy-A-((3:4-methylenedioxy)ben2y!)aniliBe aa) 3-Cyclo.penryloxy-//-(2-hydroxy-3-methoxylbenzyl)-4-rnethoxyaTiiiine bb)3-CycIopenryloxy-.;V'-(3-i:urylmethyl)-4-methoxyani]ine cc) 3-Cyclopenty]oxy-4-rnethoxy-/V-(3-methylbenzyl)aniline dd)3-CyclopentyJoxy-4-methoxy-AL(2-me.tboxybenzyl)aniline ee) 3-Cyclopenfy}oxy-4-methoxy-.'V-{3-chlorobenzyl)aniline ff) 3-Cyciopentyloxy-4-methoxy-A/-(3-methoxyben2yl)amIine .gg)3-CyciopentyJoxy-4-methoxy-,Y-(2-chJorobenzyI)aniline hh)3-Cyc]opencyloxy-4-methoxy-.'V-{3-raethy3be7i2yl)aniline ii) 4-Methoxy-3-(3-phenpropyloxy)-A-(4-pyridyimethyl)aniline jj) A'-(2.6-Dichloro-4-pyridyimethyl}-3-(2-mdanyloxy)-4-methoxyaniline ick)4-Merhoxy-3-(3-phenpropylcxy)-/V-(2-pyndyimethyl)aniline 1!) yV-(2,6-Dichloro-4-pyridyiine:hyi)-4-methoxy-3-{3-phenpropy}oxy)aniIine mm) 4-Methoxy-3-(3-pbenpropyioxy)-A'-(3-pyridyirneihyl)aniline . im)3-Cyclopentyloxy-4-methoxy-.A/-(2-thienylmethyI)aniline oo) 3-(2-Iudanyloxy)-4-methoxy-?/-(3-thienykafithyl)aniliDe pp) 4-Meihoxy-3 -{3-phenpropyioxy}-.A'"-(3-chienyiniethyl)aniliiie qc) 3 -{2 -Ind an yloxy)-4-methoxy-/V-(2 -pyri d ylmethyl)ani line rr) 3-(2-Indanyloxy)-4-meihoxy-A'-(3-pyridyIineihy!)aiiiline ss) 3-(2-Indanyloxy)-4-rnethoxy-A'-(4-pyndyimethy!)anilme ft) 3-Cyclopentyloxy-4-methoxy-A-(3-pipendinernethyl)aniJine uu) 3-Cyclopentyloxy-4~rnethoxy-/Y-(3-(l -tenbutyloxycarbonyl) piperidinemethyl)aniline vv)3-Cyc]opentyloxy-4-methoxy-A/-(6-methy]-2-pyridy[inethy])aTii3ine ww) jV-(2-Chloro-3-pyridyimethyI)-3-cyclopentyloxy-4-raethoxyaniline xx)7V-(2-Chloro-5-pyridylTnethyl)-3-cyciopentyloxy-4-methoxyani'lme yy) 3-Cyclopenryloxy-4-methoxy-Ar-(2-thia2olyimerhyI)anilijie EXAMPLE 4 . 3-Cyclopentyloxy-4-metbo.ry-.Y-(3-pyridylmetfayI)diphenyiamiDe To a 100 mL oven dried, argon flushed flask was added in the following order 0.59 g (6.10 mmol) of NaOtBu, 360 mg ofPd2dba3, 20 mL of toluene, 0.14 mL ofPftBu)3, and a 20 mL solution of 1.3 g (436 mmol) of N-{3-pyridylmethyI}-3-cyclopentyloxy-4- methoxyaniline in toluene. With stirring, 3'. 1 g (15 mmol) of icdoberrzene was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted wirh EtOAc and washed twice with HiO and extracted with 3 x 1 5 mL of 3,V HCL The combined acid extracts were washed wirh 15 mL of EiOAc and then carefully neutralized with 6N NaOK to pH greater than 12. The b-asic solution was extracted with 2 x 15 mL of EtOAc and the combined organic fractions were subseauenilv washed with 15 mL of •C? i u H20 and brine, dried (MgSO), and concentrated. Tne residue was purified by chromacography over silica gel (Biotage Flash 40M) eiuting with 25% EtOAc in hexanes. The material was further punned by crystallization from hexanes to give 550 mg of a white solid. !H NMR (CDC13) 5 8.61 (s, IH), S.49 (d, IK, J = 42 Hz), 7.67 (d, 1R 7.9 ,' Hz), 7.30-7,10 (m, 3E), 6.90-6.80 (m, 4K), 6.80-6,60 (m. 2H), 4.94 (sr 2H)r 4.64 (p, IH, J : = 4.1 Hz),3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).' The following compounds were prepared in a.similar manner as described above: a'i 3-Cyclopenrvicxy---meihcxy-2'-methyl-yY-(3-pvndyimsthyl)diphenylam.ine b) 3-Cyclopenryloxy-4-methoxy-3'-meihyl-A'-(3-pyridylniethyl)diphenylamine c) 3-Cyc]opentyloxy-4-methoxy-4'-methyl-A-(3-pyridylmethyl)diphenylamine d) 3-Cyclopemyloxy-4'-ethyl-4-methoxy-A'-(3-pyndylmethyl)diphenyIa-mine e) 3'-Ch]oro-3-cyciopentyloxy-4-methoxy-.A/-(3-pyTidylrnethyl)dipheTiylarnme f) 4'-Chloro-3-cyclopentyloxy-4-methoxy-Ar-(3-pyridylinethyl)Qiphenylarnine g) 3-Cyclopentyioxy-2: ,4-dimethoxy-/V-(3-pyTidylTnethyi)diphenylamine h) 3-Cyclopentyioxy-3'.4-dimethoxy-A7-(3-pyndylmethyl)diphenylamine • i) 3-Cyclopentyloxy-4,4'-dirnethoxy-/Y-(3-pyridylmethyl)diphenylamine j) 3-Cyclopentyloxy-4-methoxy-A'-(3-pyndylmethyl)-3'-tnfliioromethyldiphenylaTnine k) 3-Cyclopentyloxy-4-methoxy-A-(3-pyndylmethyl)-4'-trifluoromethyldiphenylamme 1) 3-CYclopentYloxy-3'-fluoro-4-methoxy-A/-(3-pyridylmethyl)diphenylamine m) 3-Cyclopentyloxy-4'-f]uoro-4-methoxy-,V-(3-pyTidylmethyl)dipheTiyiamine. n) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-A/r-(3-pyTidylmethyl)diphenylamine o) 3-Cyclopentyloxy-4-methoxy-4'-phenyl--'V-(3-pyridylmethyl)diphenylamine p) 3'-Cyano-3-cyclopentyioxy-4-methoxy-A'-(3-pyndylinethyl)diphenYlamine. q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-.V-(3-pyridylrnethyl)diphenylamine r) Ethyl 7V-(3-cyclopentyloxy-4-methoxyphenyl)-A/r-(3-pyTidylmethyl)-3-aminobenzoate s] Ethyl A-(3-cyclopentyloxy-4-methoxYphenyl)-Ar-(3-pyTidylmethyl)-4-aminobenzoate t) 3-Cyclopentyloxy-4-tnethoxy-3I-nitro-A'-(3-pyridylrnethyl)dipheny!amine u) S-Cyclopentyloxy^-methoxy^'-mtro-A^^S-pyridylmethy^diphenylamme v) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-pyridylmethyl)-1 -naphthyiarnme w) 3-Cyclopentyloxy-2' ,3 '-dimethyl-4-methoxy-Ar-(3-pyridylmethyl)diphenylainme x) 3-Cyclopentyloxy-2> J4'-dimethyl-4-methoxy-/V-(3-pYndyimethyl)diphenYlainine y) 3-Cyclopencyloxy-2'.5'-dimediyl-4-methoxy-A-(3-pYridylmethyl)Qipheiiyiamme z) 3-Cyclopentyloxy-3\4'-dimethyl-4-me!:hoxy-A-(3-pyTidylmethyl)dipheiiylarnirie aa) 3-Cyciopentyioxy-2! ,3'-dichloTo-4-methoxy-.'V-(3-pYridyiineihyl)diphenylamme bb)3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-A'-(3-pyndyimethyl)Giphenylamine cc) 3-Cyclopenryloxy-3\5'-dicaloro-4-methoxy-.V-(3-pyndylrnethyl)diphenylamine dd) 3'-ChloTo-3-eyclopencyloxy-4'-fiuoro-4-methoxy-.'V'-(3-pyridylmethyl)dipheTiylaTnine ee) -:-Chioro-3-cyclopenrylpXY-3>fluoro-4-inerhoxy-jV'-(3-pvTidyimethyi)diphenylaniine ff) 4;-ChJorc-3-cycJopenryloxy-4-meiiioxy-.V-{3-pyridylmethyl)-3'- tniluoromethyldiphenylarnifle gg) 5-Cyclopenty]oxy-4-Tnechoxy-Ar-(3-tkienyimeihyl)diphenylainiTie hh)JV-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-chienyimethyl)-l-naphthylamine 11) 3-Cyc]openTyIoxy-2'.3'-d}chloro-4-methoxy-;V-(3-thienylrnethyi)diphenyianaine jj) 3-Cyclopencyloxy-4-methoxy-4'-methyl-yV-(4-pyridylmethy])Qipheiiylamme kk')3-Cyclopenryloxy-Ar-(2.6-dichloro-4-pyndyliTiethyl)-4-methoxy-3'- methyldiphenyiamine 11) 2!-Chioro-3-cyc}opentyloxy-A'-(2,6-dichloro-4-pyTidyknethyl)-4- methoxydiphenylamme _ mm) 3-Cyclopentyloxy-A-(2,6-dichloro-4-pyridylmethyl)-4-niethoxydiph€nylamine nn) 3-Cyclopentyloxy-4-methoxy-A-(6-methy!-2-pyridylmethyl)diphenyiamine oo)3-Cyclopeniyloxy-4-methoxy-A-(3-quinolinylmethyl)diphenylamine pp)3-Cyclopenty]oxy-4-methoxy-Ar-(4-quinoIinyimethyl)diphenylamine qq33-Cyc]openty]oxy-4-n]ethoxy-A/-{2-pyrazinyImethyl)diphenYlamine rr) 4-Mschoxy-3'-methy3rA7-(3-pyndyimethyl)-3-(3-tetrahydrofuryloxy)dipheTiylarnine ss) 4-Methoxy--'-methyl-A7-{3-pyridylTnetby!)-3-(3-tetrahydrofury!oxy)diphenylaTTiirie tt) 4,4^DLmethbxy-A?-(3-pyricylmethyi)-3-(3-Letrahydrofuryloxy)diphenylamirie uu) 3'-ChJoro-4-methoxy-A-(3-pyndyimeihyl)-3-(3-tetrahydrofurytoxy)diphenyiarnine w) 4-Methoxy-4 '-{4-methylpiperazin-1 -ylcarbonyl)-A-(3-pyridylmethy!)-3-(3- tetrah ydro furyloxy)diphenylamine ww) 3 '-Cyano-4-meihoxy-A-(3-pyridy}methyl)-3-((3j!?)- tecrahydrofury]oxy)diphenyiamine "" xx) 3 '-Cyano-4-methoxy-A-(3-pyTidylraethyl)-3-((3J?}-tetrahydrofuryJoxy)diphenylamme yy) 3-Cyciopropylmethoxy-4-dif3uoromelhoxy-A-(3-pyTidyimethyl)diphenylamme 22) 3-Cyciopen[y!oxy-4-dii3uoroinethoxy-A'-{3-pyridylrnethyl)diphenylaniine aaa.) 4-Diiiuoromethoxy-A'-(3-pyridyimerhyl)-3-(3-tetraJiydrofuryioxy)diphenylamine bbb) 3;4-Bis(difluoromethoxy)-A-(3-pyridyimethyi)diphenylanime ccc) 4-Difluoromethoxy-'V-{3-pyridyimetbyl)-3-((3j!?)- teirahydro fury 1 oxy) dip hen ylamine ddd) 3'-Cyano---di3uoromethoxy-A7-{3-pyTidyimethyl)-3-((3/?}- rsirah ydro fury j oxy)diphen yl amine eee) 3'-Chloro-4-difluororaethoxy-A"-(3-pyridylmethyl)-3-((3/?)- tetrahydrofuTyloxy)diphenylamine iff) Ethyl A'-(3-cyclopropylmethoxy-4-di3uorometiioxypbe-nyl)-A-(3-pyridylrnethyl}-3- aimnobenzoate ggg) 3-Cyciopentyloxy-4-methoxy-3 '-{^-methylpiperazin-l -yicarbonyI)-7V-(3- pyndylmethyl)diphenyiaraine hhh) 3-Cyclopentyloxy-4-metboxy-4'-(4-methyipipera2Tn-l -ylcarbony])-yV-(3- pyridylmethyl)diphenylamine 111) 3 '-?erf-ButyldiTnethyisi]yloxy-3-cyciopentyJoxy-4-methoxy-jV-(3- pyndylmeihyl)diphenylamine JJj) 4'-/er/-Butyldiiriethylsi]yloxy-3-cyc!opentyloxy-4-methoxy-A'-(3- pyndylitierhyl)dipbenylarnine kkk) rm-Butyl A'-(3-cyclopentyloxY-4-methoxyphenyI)-A-(3-pyridylmethyl)-3- amiriobenzoate 111) Ethyl A-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-7v-(3-pyridylinethy])-3- am:noben2oate mmrn) Ethyl ,V-(4-dif]uoromeihoxy-3-(3-Letrahydrofuryloxy)phenyl)-.A/'-(3- pyridylmethy!)-3-aminobenzoate Tinn) Ethyl /V-(334-Bis(difluoromethoxy)phenyl)-/V-(3-pyridyimethyl)-3-aminoben2oats ooo) Ethyl ^-(4-methoxy-3-((3^)-tecrahydrofuryloxy)phenYi)-A-(3-pyridylrnethyl)- -3- amiiiobenzoate ppp) Ethyl ,V-(3-cyclopropyiinethoxy~4-methoxyphenyl)-jV-(3-pyridyimethyi)-3- ammobenzoate qqq) 3-CyclopenTyloxy-4-methoxy-4'-(2-(teirahydropyran-2-yi)-2H-teira2ol-5-yl)-/V- (3-pyndyimethyI)diphenylamine rrr) 3-Cyciopentytoxy^-methoxy-3!-(2-{ieu'ahydropyTan-2-yl)-2H-tetra2ol-5-yl)-A'-{3- pvTidyimethyl)diphenylamine sss) 4-Methoxy^'-(2^tetrahydropvran-2-yl)-2H-tec-azol-5-y[}r^-(3-pyridylinethy]>3r- ((3^?)-tetraJiydroiuryloxy)diphenylaraine iu} 3-Cyciopropvlmethoxy-i-meLho>:y-^!-{2-{tetrahydropyTan-2-y])-2E-tc:ra2oi-5-y!)-V- (3-pyriGyirnerhy!)dipheriyiamine uuu) 4-Diiluoromethoxy-4: -(2-{tetrahydropyTan-2-vl)-2H-cetrazo i-5-yI)-/V-(3- pyndyknethyl)-3-{(3^)-tetrahydrofurylcxy)diphenylamine vvv) 3-Cyclopropylrnethoxy-4-difluorornethoxy-4'-{2-{tetrahyd.ropyran-2-yl)-2Hte: ra2o]-5-yJ)-jV.(3-pyridylmethyl)diphenylamine www) 3-Cyclopenty]oxy-4-dif]uoromethoxy-4'-(2-(tetrahydropyran-2-yI)-2H-tetrazol-5- yl)-A-(3-pyndylmethyl)diphenylanime xxx) 3-CycJopropyimethoxy-4-difjTiorornethoxy-3!-(2-(tetrahydropyran-2-yi)-2Htetrazol- 5-yl)-jV-(3-pyridylmethyl)diphenyla:mine yyy) . Bis-(3,4-difluorotnethoxy)-3'-{2-(tetrahydropyran-2-.yl)-2H-tetrazo]-5-y])-.;V-(3- pyndylmethyijaiphenylamine 222) 3-^rf-Butyldirnethylsilyloxy-4-mechoxy-AA-(3-pyridyirnethyl)diphenyJamin.e aaaa) 3-/err-Butyldimethylsilyloxy-3:-chloro-4-methoxy-A-(3- pyridylmethyl)diphenylaraine bbbb) Ethyl yV-(3-:erf-butyldimethylsilyIoxy-4-methoxyphenyI)-A/'-(3-pyndYlmethyl)-3- amtrioberizoate cccc) 37Cyciopenry!oxy-2'-chloro-4-methoxy-yV-(3-pyridyimethyl)dipheny]amine dddd) 3-(2-i-ndanyloxy)-4-methoxy-iV-(3-pyTidylmethyl)diphenylamine EXAMPLE 5 yY-(3-CYclopentyloxy^4-methoxyfphenyl)-A'-(3-pyridylmethyl)-3-aminobenzoic acid A solurion of 6.5 g of ethyl jV-(3-cyclopentyloxy-4-methoxyphenyl)-.'V-(3- ; pyndyimethy!}-3-aminoben2oate in 50 mL of EtOH was created with 10 ml of 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 ; mL of H:>0. The aqueous mixture was extracted with 2 x 50 mL of ether, acidified with Ac OH to pH 3, and extracted with 2 x 50 mL of EtOAc. The combined EiOAc fractions were washed with 25 mL of JLO and. 25 mL of brine, dried (MgSOa),. and concentrated. The residue was purified by chroniatography over SiCK (35 g ReaiSep® column) usirvg a linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20 - minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60°C.; "'H NMR (CDC13) 5 i 1,15 (bsr IE), 8.70-8.55 (m, 2K), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p., J = 3.8 Hz; iH); 3.34 (s. 3H), 1.86-1.70 (m, 6H)r 1.65-1.45 (m, 2K). The following compounds were prepared in a similar manner as described above: a) A'-{3-CycIopenLyloxy-4-methoxyphenyl}-.V-{3-pyTidylrnethyr)-4-arninoberi2oic acid b) /V-(3-Cyclopentyloxy-4-difluorornethoxypheny!)-/V-(3-pyridylmethyl)-3- aminobsnzoic acid c) M{4-Difluoromethoxyo-(3-tetrahyQrofuryloxY)phenyl]-A-(3-pyndyirnethyl)-3- .aminobeiizoic acid d). ./V-3,4-Bis(difluoromethoxy)p.henyl)-A'-{3-pyridylinethyl)-3-aminoben2oic acid • e) Af-[4-Methoxy-3-{(3j?)-'t-etrahydrofuryloxy)phenyl]-7V-(3-pyndy{rnethyl)-3- ammobenzoic acid f)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-iV-(3-pyridylmethyi)-4-aminobenzoic acid g) A'-(3-Cyclopropylrnethox}'-4-difmoromethoxyphenyl)-/v-(3-pyrjdyirnethyl)-3- ammobenzoic acid h) Ar-(3-Cyciopentyloxy-4-methoxyphenyl}-3-aminobenzoic acid i) -[3-(4-Chlorophenyl)prop-l-yloxy-4-m.ethoxyphenyl]-A'-(3-pyridylmethyl)-3- ammobenzoic acid j) A-(3-Cyc]opropylmethoxy^-methoxyphenyI)-/V-(3-pyridylmethyl)-3-arninobeii2oic acid k) A'-[3-(2-Indaiiyloxy)-4-methoxyphenyl]-A;-(3-pyridyiiriethyl)-3-aminoben2oic acid ]) A-{4-MethoxY-3-(3-tetrahydrofuryloxy)phenyl]-A'X3-pyridylrnethyl)-3-arninoberizoic acid m) 7V-[4-Meihoxy-3-((3R)-iet:rahYdroiuryloxy)phenyl]-A/-(3-pyridylmethyi)-3- aratnobenzoic acid n) A/-r5-(2-Msd3oxyethoxy)-4-meihoxyphenyij-/V-(3-pyridyirne[hyl)-3-aminobenzoic acid o) A-[4-Methoxy-3-(2-{2-pyridyl)ethyI)oxyphenyl]-/v-{3-pyTidylmethyl)-3- ammobenzoic acid EXAMPLE 6 A-{3-Cyclopentyioxy-4-methoxypbenyJ)-/Y-{3-pyridyimetfayl)-2-amiDoben2oic acid Ten-Butyl .'V-(3-cyciopentyloxY-4-methoxyphenyl)-A/'-(3-pyriGy}methyl)-2- arninobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL 98% formic acid and heated at 40 UC for 4 h. The formic acid was removed in vacua and the residue was loaded onto a column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 mm to yield 16 me of product as a brown solid. :H NMR (CDC13) 5 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H),. 8.10 (df 1H, J = 7.8.), 7.67 (d,.lH, J = 7.8 Hz), 7.56 (m, IH), 7.40-7.20 (m, 3H), 6.75 (d, IH, J = 8.7), 6.57 (d.. IH, J = 8,7), 5.47 (s, IH), 4.72 (s, 2H). 4.54 (p, IH, J - 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m,2H).- The following compounds were prepared in a similar manner as described above: a) A'-{3-Cyc!opentyloxy-4-methoxvphenyl)-A-{3-p-yridyimeLbyl)-3-aminoben2oic acid b) W-(3-Cyclopentyloxy-4-methoxypheny!)-.V-(3-pyridylrnethyi)-6-arnirion]cormic acid EXAMPLE'7 3-Cyclopropylmethyioxy-4-difiuorometboxy-jV-{3-pyridylmettiyl)-4;- (2H-tetrazol-5-yl)diphenylamine 3-Cyciopropy]rnethoxy-4-difluoromerhoxy-Ar-(3-pyridylmethyI)-4'-[2-(2- tetrahydropyrany!}-2H-ietrazol-5-yl]diphenylamine (1.5 g, 0.26 rnmol) was dissolved in THF (5 mL) and 3 mL of IN HC1 was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 50 mL). The EiOAc extracts were combined, washed with bnne (50 mL), dried (MgSOO, and concentrated in vacua. The crude residue was loaded onto a RediSep column (10 g, silica gel) and the product was eiuted using a linear gradient from 0% MeOK in EtOAc to 5% MeOH hi EtOAc over 20 mm to give 0.96 g of product as a white powder. 'H NMR (CD3OD) 5 8.55 (s, IH), 8.43 (d, IH, J = 4.9 Ez), 7.65 (d, IH, 8.0'Hz), 7.21 (dd: IH, J4.9 Hz, 8.0Hz), 7.18 (d, IH, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.S7 (dd, IK, J = 8.6Hz;2.5Hz);6.75 (i, 1H, J = 75.5 Hz), 5,I4(s:2H), 3.82 (d, 2K, J = 6.9 Hz), 1.23 (m: iH), 0.60-(m, 2H), 0.33 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-A/-(3-pyndylmethyl)-4'-{2H-tetra2oi-5- yOdiphenyiamine b) 3-Cyclopenryloxy-4-methoxy-./V-(3-p>ridylmethyl)-3'-(2H-tetrazol-5- yl)drpheny]armne c) 4-Methoxy-.V-{3-pyndyimethyl)-3-((3^)-tetrahydTofurYioxy)-4:-{2'H-tetra2o[-5- y3)diphenyiamine d) 3-Cyclopropylrnethyloxy-4-metho'xy-.Ar-(3-pyndylmethyl)-4>-(2H-tetra2ol-5- yl)diphenylarnine e) 4-Difluoromethoxy-A'-(3-pyn'dylmethyl)-3-((37?)-tetrahydroruryioxy)-4' -(2H-tetra20J- 5-y[)dipheny]amine f) 3-Cyclopentyioxy-4-diflurornethoxy-A'"-(3-pyridylmethyl)-4'-(2H-terrazol'5- yOdiphenylarnrne. g) 3-Cyclopropylrne£hyloxy-4-diiluoromethoxy-/V-(3-pyndylrnethYl)-3:-{2H-tetrazo3-5- yJ)diphenyiamine h) Bis-3,4-difluoromethoxy-vV-(3-pYndylrrjethyl)-4'-(2H-cetrazol-5-yI)diphenyiaTnme EXAMPLE 8 (Method A) 3-CyciopentyIoxy-4-methoxydipbenylamine Method A. (Rsf. Chan, D:M.T., Monaco, K.L.; Wang, R.P.; Wincers, M.P., Tetrahedron Lett., 1998, 39, 2933-2936.). A slurry of 207 mg of 4-methoxy-3- cyclopencyloxyanilme, 2SO mg of phenylboronic acid, 182 mg of Cu(OAc}i, 280 uL of Et3N and 4.0 ml of C&Cl? was stirred for 20 h at room lemp. The black mixture was filtered through silica eluting with CHjC1^, concenrrarsd. and purified by chromacoghraphy over SiOi using EtOAc/Eexanes (15/85) as.eluant ID provide 75 mg of the desired product. !H NMK (CDC13) 6 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s5 1H), 4.71 (m, 1H), 3.32 (s, 3E), 1.89-1.54 (m, 8H). The following compounds were prepared in a similar manner as described above: a) 3~CycIopemyloxy-3 \4-djroethoxydiphenyiamme . b) 3'-Chloro~3-cyclopentylcxy-4-methoxydiphenylarnine c) 3-Cyclopentyloxy-4-methoxy-3'mechyidiphenyiamine d) S-Cyciopentyloxy^'-fluoro^-methoxydiphenylamine e) 3-Cyc]opentyioxy-4-methoxy-4'-vinyidiphenylamine f) 3 '-Cyano-3-cyciopentyloxy-4-methoxydipherjylarrane g) 4'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine h) 3-Cyclopemyloxy-4,47-dimethoxydiphenylarrune i) 3-Cyclopentylcxy-4-methoxy-2'-methyidiphenylamine j). 3-Cyciopenty!oxy-4-methoxy-4'-rnethyldipheny]amine k) 2'-Chloro-3~cydopentyloxy-4-methoxydipheTiyIamine !) 3-Cyclopentyloxy-2 ',4-dimethoxydiphenylaraine m) 3-Cyclopentyloxy-4-methoxy-3'-infiuoromethyldiphenylamine n) 3-CyclopenryJoxV-4-methoxy-4' -trifluorolnethyldiphenylamme o) 3-Cyclopentyloxy-2'p'-dimethyl-4-methoxydiphenylamine EX4MPLE 8 (Method B) 3-CycJopentyloxy-4-metiioxydiphenylamine MethodB (Angerw Chem. Int. Ed., 1995, 34(11), 1348-1351.) A mixture of 207 rng of 3-cyclopentyloxy-4-methoxyanilme, 204 mg of iodobenzene, 115 mg ofNaOtBu, 9 mg of Pd2(dba)3, 12 mg of P(o-iol)3 and'7 ml of toluene was combined and warmed with stirring 10 100 °C for 4h. The mixture was cooled to room .temp, diluted with 25 ml of EtOAc and washed with 10 ml of H^O, 10 mL of brine, dned (MgSO^ and concentrated. The residue was purified by chromatography over SiO? using ErOAc/hexanes (5/95) as eluanr to provide 8^ mg of the desired product. The following compounds were prepared in a similar manner as described above: a) 3-Cyciopentyioxy-4-methoxy-2',4'-dimethyidiphenylamiiie b) 3-Cyclopenryioxy-2'.5?-dirDethYl---raefhoxydiphenylamine c) 3-Cyclcpenryioxy-2'.3 '-dimethyl-4-methoxydiphenylanrine d) 3-Cyciopentyloxy-3\4'-dimethyl-4-methoxydiphenylarnme e) 3-Cyclopenty3oxy-3'.4?-methyienedioxydiphenylamine f) 4/-ferf-3iiiyi-3-cyciopenryloxy-4-methoxydiphenylamine g) 3-Cyclopentyloxy-3',4'-dichJoro-4-methoxydipheny3amme h) 3-Cyciopentyloxy-2\3' EXAMPLE 8 (Method C) 3-Cyclopentyloxy-21,4,5'-trimethoxydiphenylamine Method C. To a mixture ofPd(dppf)Cl2 (0.025 ramol, 5mol%), dppf (0.075 mmol, 3dpp£Td) and NaOtBu (0.70 mmol, i ."4 equivalents) and 1.0 ml THF was added 1- bromo-2,5-d]methoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a 0.5/V/solution of 3-cyc!opentyioxy-4-methoxyaniIme in THF. The mixture was heated to 60 °C for 3 hours and diluted with ether and washed with H?Q and brine, dried (MgSCu), and concentrated. The crude residue was purified by chromatography over silica gel (Biorage Flash 12) eluting with 15% EtOAc in hexanes: The following compounds were prepared in a similar manner as described above: a) Ar-(3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamiTie b) 3-Cyclopentyloxy-2 ',4\4-!:rimethoxydiphenylarnine c) A-(3-Cyciopentyloxy-4-methox-ypheriyl)-2-pyridylamirie d) /V-(3-Cyclopeniyioxy-4-rnethoxvphenyI)-8-qu.inoIinylamine e) jV-(5-Cyclopenryloxv-4-inethoxyphenyl}-2-naphthylamine f) A-(j-Cyclopentyloxy-4-nierhoxyphenyi)-l-naphthylamine g) 3-Cyclopenryioxy-4'-ethyl-4-rcethoxydiphenyiamine h) 3-Cyclopenryloxy-2>-fluoro-4-niethoxy-5:'-niethyidiphenylarnine i) 3-Cyclopenryloxy-3'-fiuoro-4-methoxy-4'-methyldipher;ylainine j) 7/-(3-CycIopenryJoxy-4-methoxvphenyl}-2-pyriinidinylamine k) 3-Cyciopentyioxy-3:,5,"-dichloro-4-methoxydiphenylamme 1) 3-Cyclopentyloxy-2'-ethyi-4-methoxytiiphenyiamine m) 4:-Chioro-3-cyclopentyloxyo'-fluoro-4-methoxydiphenyiamine n) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquiTiolmylamme o) A-(3-Cyclopenryioxy-4-iTiethoxYphenyl)-2-pyrazinylarmne p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-5-pynmidmylarnine q) yY-(3-Cyclopentyloxy~4-methoxyphenyl)-l-isoquinolinyiamirie r) /v"-(3-Cyc!opeTiTy]oxy-4-methoxyphenyl)-3-quinolinylamine s) yV-(3-Cyclopentyloxy-4-methoxyphenYl)-4-pyndylamme t) yV-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-pyridylaini-ne u) 7V-(3-Cyclcrpropylmethyloxy-4-methoxyphenyl)-3-pyTidylamme v) A'f-(3-Cycl9propylTnethyIoxy-4-difJuorornethoxyphenyl)-3-pyridylamine ' w) /V-(4-Methoxy-3-(3^)-tetrahydTofuryloxyphenyl)-3-pyridylamine x) A'r-(4-Difluoromethoxy-3-(3J?)-tetrahydrofaryloxyphenyl)-3-pyndylainine y) Ethyl yV-(3-cyclopentyloxy-4-methoxyphenyl)-3-ammobenzoate z) 3-Cyclopentyloxy-4'-(Ar,A'-diinethylamino)-4-methoxydiphenylarame aa) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyndyI)ainme bb) Methyl A'-(3-cyclopeniyloxY-4-methoxyp1henyl)-21aminonicotinate cc) rerf-Butyl Ar-{3-cyclopentyloxy-4-methoxyphenyl)-6-arainonicotmate dd) 2 '-Amino-3-cyclopentyloxy-4-Tnethoxydiphenylamine ee) 3-Cyclopentyloxy-4~methoxy-3'-(l -phthalimido)diphenylarmne if) 3-Cyclopentyioxy-4-methoxy-3'-[2-(2-tetrahydropyranyl)-2H-tetra2ol-5- yl]diphenylamine EXAMPLE 9 (Method A) 3-Cyclopentyloxy-4-methoxy- A-methyldipbenylamine To a solution of 3-cyclopentyloxy-4-metboxydiphenylairune (70 mg. 0-25 mmol) m 3 mL of THF at 0 °C was added 0.55 mL of 0.5 M KN(TMS); in toluene. The soiution was stirred at 0 °C for 0.5 h and 2.0 eauivalents of iodomethane was added and the reaction mixture was warmed to room temperature. Upon reaction completion as indicated by TLC. 10 rnL of EtOAc was added and the mixture was washed with 3 mL of &0, 3 mL of brine, dned (MgSO) and concentrated. The crude residue was purified by column chromatography (Biotage flash 12) using 5% EtOAc in hexanes as eluant. The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxv-Ar-ethyl-4-methoxydiphenylamme b) 3-Cyclopentyioxy-4-meihoxy-A'-(l-propyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy~Ar-[l-(3-phenpropyl)]diphenylamme d) .V-Benzyl-3-cyclopentyloxy-4-methoxydiphenylarnine e) 3-Cyclopen:yloxy-4-methoxy-A'-(4-pyndyiTnethyl)diphenylamine f) S-Cyclopenryloxy^-methoxy-A'^i-pyTidylmethyOdiphenylamme g) 3-Cyciopentyloxy-4-methoxy-Ar-(3-pyridylrnet±iyl)diphenylamme h) 3-Cyclopentyloxy-4-methoxy-A-[3-(3-pyridyl}-l-propyljdipheriylaraine i) jV-(3-Cyclopentyioxy-4-methoxyphenYl)-Ar-ethyl-4-isoquinolinylamine j) Ar-(3-Cyclopentyloxy-4'-methoxyphenyl)-7v'-ben2yl-4-isoquinolinylarnine k) A-(3-Cyclopentyloxy-4-methoxyphenyi)-;V-methyl-4-isoquinolmylamine 1) A'-(3-Cyclopentyioxy-4-methoxyphenyl)-Ar-propyl-4-isoquinolinylamine rn) A7-(3-Cyc]opentyloxy-4-methoxyphenyl)--'V-(4-isoquinoUnyl)-Ar-(4- pyndylmethyijamine n) A-(3-Cyclopentyloxy-4-methoxypheny!)-A/-(4-isoqainolmyl)-A-(3- : pyridylmethyl)amine o) /V-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-pyridylrnethyl)-.Y-(5- : pyrimidinyl)amine p) A-(3-Cyclopentyloxy-4-methoxyphenyl}-;V-{2-pyTa2inyl)-.A/-(3-pyridyjrnethyl)arnirie q) A-{3-Cyciopentyioxy-4-methoxyphenyl)-A/-(2-pYridy!)-A-(3-pyncylmethyl)amine ; r) A-(3-Cyclopentyloxy-4-methoxypheny3}-jV-(3-pyridyl)-A-(3-pyndyirneihyl)ainine s) •A-(3-Cyclopentyioxy-4-methoxyphenyl)-A-(4-pyridy1)-A'-(3-pyridyliriethy!)amine t) /err-Butyl A-{3-cyclopentyloxy-^-methoxyphenyl)-A'-(3-pynGylmethy!)-6- aminoni connate u) A-(3-CyclopropykneEhoxy-4-rnethoxypheny])-A-(3-pvTidyi)-V-(3- pyndylmethyijarnine v) yV-(4-Methoxy-3-(3J?)-tetrahydrofuryioxyphenyl)-/V-(3-pyTjdyl)-7v-(3- pyndy]methyl)arnine w) yY-{3-Cyclopentyloxy-4-difluoromethoxyphenyl}-.Y-(3-pyndyl)-.'V-(3- pyndylmethyl)amine x) A/-(3-CyciopropylTnethoxy-4-dii]uoromethoxypheiiyl)-Ar-(3-pyndyl}-A-(3- pyridylmechyl)amine y) .V-{4-Difluoromethoxy-3-(3^)-tetrahydrofuryloxypheny]}-A'-(3-pyridyl)-.A'-(3- pyndylmethyijarmne 2} A-(4-ChJoro-3-pyridylrnethyl)-Ar-(3-cyciopentyloxy-4-rnethoxyphenyi)-/V-(2- "pyndy!)amme aa) /V-(3-cyclopeniyloxy-4-methoxyphenyl)-A'-(4-methy!-3-pyndylniethyl)-A-{2- pyndyljamine bb) 3-CyclopenTyloxy-4-rnethoxy-A'-{2-thiazolylmethy])diphenylamjne cc) A-{2-Ch]oro-3-pyridylrnerhyn-3-cycloper!tyloxy-4-methoxydiphenylamine dd)A-{6-Chloro-3-pyridyiinethyl)-3-cyclopentyioxy-4-methoxydipheny]amine EXAMPLE 9 (Method B) Ar-4-Chloro-3-pyridyimetfayiX'V-(3-cyclopeBtyl-4~ metioxypbeny!}-A-(2-pyridyi)amine To a solution of (3-cyciopentyloxy-4-memoxyphenyl)-2-pyridylamine (30 ing, 0.10 mmoi) and 4-chioropicolyl chJoride hydrochloride (50 mg, 0.25 mraol) was dissolved in DMF (] mL) and sodium hydride (50 mg of a 60% mineral oil dispersion. 1.3 mmoi) was added in small portions. After stirring for Ih at room temperature., the mixture was poured into 25' mL ice water. The mixture was extracted wirh EtOAc (2 x 15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSOd), and concentrated in vacua. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline solid. 1H NMR (CDC13) 5 8,61 (&, IH), 8.34'(d, IH, J * 5.3 Hz), S.17 (d, IH, 5.0 Hz), 7.33 (m, LE), 7.25 (m, IH), 6.S3 (d,, LH, J - 8.5), 6.75 (G, IK J = 3.5), 6~\ (s; 1H): 6.62 (m, 1H), 6.42 (d 1H, J = 8.6), 5.51 (s, 2K), 4.63 (p.'IK J = 4.i2 Hz)r 3.83 (s, 3H), 1.86-1.70 (m. 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3,4-Bis(difmoromei:hoxy)-/V-(4-chloro-3-pyndylmethyl)-3'-(2-(tetrahyQropyran-2- yl)-2H-tetrazol-5-yl)diphenylamme b) 3,4-Bis(difiuoromethoxy)-Af-(4-methyl-3-pyridylrnethyl)-3'-(2-(tetrahydropyT3n-2- yl)-2H-tetra2ol-5-y!)diphenylamine EXAMPLE 10 3-Cy.clopentyloxy-4-methoxyanilino-A-{3-pyridylm«thyl)-A'-3-(4-pyridyl)benzamide To a solution of M-(3-cyclopentyloxy-4-me'thoxyphenyl)-A'-(3-pyridylmethyl)-3- aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CH2C12 (2 mL) at room temperature was added diisopropylethylamine (20 L, 0.11 mmol). After stirring for 15 mm. 4-aminopyridme (15 mg, 0.15 mmol) was added and the mature was allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2x15 mL) and brine (15 mL), dried (MgSCUX'and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eiuted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 mm to give 22 mg of product. 'H NMR (CDCVj) 6 8.70-8.40 (m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, J = 8.5), 6.80- 6.65 (m, 3H)r 4.98 (s, 2H), 4.66 (p, 1H, 1 = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m,2H). The following compounds were prepared m a similar manner as described above: a) 3-(3-Cyclopentyloxy^methoxyanilino)-A'-{3-pyTiQylmethyI)-;V-3-[3-(JV,.'Vdimethylamino) prop-1-yl]ben2amide b) 3-Cyclopentyloxy-4-methoxy-3!-(4-merhylpiperazin-l-ylcarbonyl)-A-(3- - : pyridylmethyl)diphenylamine ; c) 3-Cyc]opentyloxy-4-difjuoromeihoxy-4'-(4-methylpipers2in-l-ylcarborJy!)-A'-(3- pyndylmechyijdiphenylamine d) 3-Cyciopentyloxy-4-rnethoxy-4:-(4-niethyipipera2iii-l-yicarbonyI)-A-(3- pyTidyimethyi)-3-{3-tetrahydrofaranyloxy)-dipheny]amine EXAMPLE 11 The following compounds were-prepared in- a similar fashion as described in Example oa) 4'-Amirio-3-cyclopentyloxy-4-methoxy-//-(3-pyridylinethyI)ciiphenylaniine bj 3?-Arnino-3-cyclopentyloxy-4-rnethoxy-Ar-(3-pyridylmethyl)dipheriylamine c) 3 '-Amino-3-cyclopropyimethoxy-4-rnethoxy-JY-(3-pyridylmethyl)diphenylamine d) 3'-Amino-4-rnethoxy-/yr-(3-pyndylmeLhyI)-3-[(3^)- tetrahydrofuryioxyjdiphenylamine EXAMPLE 12 3-Cyclopentyioxy-4'-metbanesulfonylamino-4-metboxy-A'- (3-pyridylmef.hyl)-diphenySamine To a solution of 4'-amino-3-cyc]opentyloxy-4-methoxy-A'-(3-pyridylinethyl)- diphenyiarnine (47 mg, 0.12 mmol) in CH^Cl? (2 mL) at room temperature was added pyndine (20 microlners, 0.24 mmol) followed by methanesuifonyl chloride (15 microliters, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was diluted with ether (50 mL) and washed with water (25 mL) and bnne (25 mL). dned (MgS04), and concentrated. The crude residue was purified by flash colurnn chromaiography (4.2 g RediSep column, silica gel) eiuting with a linear gradient from 45% EtOAc in hexanes to 60% EiOAc in hexanes over 20 mm to yield 41 mg of product. 'H NMR (CDC13) 5 8.51 (s, IK), S.41 (d, 1H, J = 4.8 Hz), 7.56 (d, IE. 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.SO-6.60 (m, 6H), ^.82 (s, 2H), 4.56 (p, IE, J = 4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45'(m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopeniyloxy-3'-eThanesulfonyiannno-4-methoxy-/v-(3- pyridylmethy1)diphenylarnine b) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-A/-(3- pyndylmethyl)diphenylarnine c) 3'-(l -Butanesulfonyiamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenyiarriine d) 3>-Ben2ylsulfonylarruno-3-cyclopentyloxy-4-methoxy-yV-(3- • pyndylmethyljdiphenyiamine e) 3'-AcstaTnido-3-cyclopentyloxy-4-methoxy-A/r-(3-pyridylmethyl)dipheriYlamme f) S-Cyclopehtyloxy^'-ethanesulfonyiamino^-methoxy-^Spyndyimetbyl) diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4'-(1 -propanesulfonylamino)-?V-(3- pyndylrnethyl)diphenylarnine h) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-A'-(3- pyndylmethyl)diphenylamine i) 4-Difluoromethoxy-3'-ethanesulfonyiammo-,V-(3-pyndylmethyl)-3-[(3R)- letrahydrofuryloxyjdiphenylarnine EXAMPLE 13 3-Cyclopentyloxy-4-metboxy-3'-bydroxymethyl-Ar-(3-pyrid-ylmethyl)diphenylamine To a solution of Ethyl ./V-{3-cyclopenTyloxy-4-methoxyphenyl)-./V-{3- pyridyImethyl)-3-aminoben2oate (50 mg, 0.11 rnmol) in THF (5 mL) at 0 °C was added drop-wise, with stirring, 2.5M diisobutylaluminum hydride in toluene (0.4 mL. 1.00 mmol). The mixture was stirred at 0 °C for 1 h and the excess diisobutylaluminum hydride was quenched by adding 5 drops of EtOAc 10 the mixmre. The mixture w'as concentrated and the residue was partitioned between CILd-; (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CEjClt (2x10 mL). The organic extracts were combined and washed with brine (50 mL), dried ; (MgSCV). and concentrated. The crude residue was purified by -flash column chromaiography (4.2 g ReoiSep column, silica gel) eluting with 300 mL 50% EtOAc in hexanes then 100% EiOAc to give 15 mg of product. 'H NMR (CDCb>5 8.51 (s. IE). 8.40 (br: 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5E), 4.85 (s, 2H), 4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopenryioxy-4-methoxy-4'-hydTOxymethyl-N-(3-pyTidyteDethyl)d\phenylairiine EXAMPLE 14 3-Cyclopentyloxy-4-methoxy-A'-(3-pyridylmetfayl)-4'-{2H-tetrazol-5- yl)diphenylamine To a solution of Af-(3-cyciopentyloxy-4-meLhoxyphenyl)-/vT-(3-pyridylmethyl)-3- aminobenzonitrile (100 mg, 0.25 rranol) in DMF (3 mL) was added NaN3 (163 mg, 2.5 mmol) and NiUCl (135 mg, 2.5 mmol) and the mixture was stirred at 120 °C for 6 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgSCU), and concentrated in vacua. The residue was loaded onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes to yield 12 mg of product. 'H NMR (CDC13) 6 12.50 for, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz), 7.36 (m, 1H), 6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H). EXAMPLE 15 3-Cyclopentyloxy-4-methoxy-4'-(4-metfayl-l-pipera2inylmethy!)- A-(3-pyndylmetiiyi)diphenylamine To a solution of 3-cyclopenryloxy-4-methoxy-4!-(4rmethyipiperazin-1 - ylcarbonyl)dipheylamine (100 mg. 0.20 mmol) in THF .(5 mL) was carefully added, with stirring, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stirred for 15 mm and a few drops of h-tOAc was carefully added to quench the excess hydride. Water (50 mL) and CILQ- (50 mL) were added and the mixtures were filtered through Ceiite. The CHoCh layer was separated, washed with brine (25 mL), dned (MgSCU), and concentrated in vacua. The crude residue was purified on an 1SCO RediSep column (4.2 g, silica) eluting with a gradient from 5% MeOH m EtOAc to 15% MeOH in EtOAc to yield 60 mg of product as'a light yellow oil. 'HNMR (CDC13) 5 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 -Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.31 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz), 3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m,2H). . The following compounds were prepared in a similar manner-as'described above: a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-l-pipera2inylmethyi)7vr-(3- pyndylmethyl)diphenylamine EXAMPLE 16 3;-Aminomethyl-3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmetfayi)diphenylamine To a solution of A/-(3-cyclopentyloxy-4-metnoxypheny!)-./V-(3-pyndyLmethyl)-3- armnobenzomtrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydnde (20 mg, 0.52 mmol). The mixture was stirred for 4 h and a few drops of water were carefully added to quench the excess hydride. Water (50 mL) and CHiCb (50 mL) were added and the mixtures were filtered through Celite. The CH^Cb layer was separated, washed with brine (25 mL), dried (MgS04), and concentrated in vacua. The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with 10% MeOH in EtOAc to yield 20 mg of product. 'H NMR (CDCb) 5 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, IE, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4,63 (p, IE, J = 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H). 2.29 (br, 2H), 1.86-1.70 (m,6E), 1-65-1.45 (m, 2H), EXAMPLE 17 3-Hydroxy-4-methoxy-/V-{3-pyridylmethyi)diphenylamine To a solution of 3-(ierr-baty]diraethyisiloxy)-./V-(3-pyridyimethyl)-4- methoxydiphenylamine (1.20 g, 2.85 mmol) in TKF (40 mL) at 0 °C; was added I.OM tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred at 0 C for 30 min. Water (50 mL) was added and the mixture was extracted with ether (3 x 25 mL), The ether extracts were combined and washed with water (3 x 25 mL) and bnne (25 mL), dried (MgSCU), and concentrated in vacua. The residue was triturated with hexanes and collected by vacuum filtration to give. 0.85 g of product. 'H NMR (CDC13) 6 8.58 (s, 1H), 8.46 6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, IH), 4.92 (s, 2H), 3.86 (s, 3H). The following compounds were prepared in a similar manner as described above: a) 3'-Chloro-3-hydroxy-4-methoxy-A'-(3-pyridylmethyl)diphenylamine b) Ethyl /^-(3-hydroxy-4-metho.xvphenyl)--V-(.3-pyridyknethyl)-3-aminobenzoate EXAMPLE 18 (Method B) . The following compounds were.prepared in a similar manner as described in Example IB: a) 3~[3~(4-Chlorophenyl)prop-1 -yloxy]-4-methoxy-A/f(3-pyTidylmethyl)diphenylamine . b) 3-[2-(4-CMorophenyI)ethoxy]-4-mei:hoxy-.V-(3-pyridylrnethyl)diphenylamine c) 4-Methoxy-3-(4-phenoxybut-1 -yl)oxy-N'-(3-pyridyimethyl)diphenyianiine d) 4-Methoxy-A'-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-N-(3- pyndylmechyl)diphenylamine f) 4-Memoxy-3-[3-(4-pyridyI)prop-l-yl]oxy-A'-(3-pyridyrrnethyl)diphenyiamine g) 4-Memoxy-3-r2-(4-merhoxyphenyl)ethoxyj-A/-{3-pyndyhnerhyl)diphenylarnine h) 4-Methoxy-3-(4-phenylbut-l-yl)oxy-A/'-{3-pyridylme!:hyl)dipheny]aniine i) 4-Memoxy-3-[4-{4-methoxyphenyl)but-l-yl]oxy-A^-(3-pyndylmethyl)diphenylamihe j) 4-Methoxy-3-[4-(4-nitrophenyl)but-1 -yl]oxy-A'-(3-pyridyknethyl)diphenylamine k) 4-Methoxy-3-[2-(2-pyTidyI)ethoxyj-N-(3-pyridylmethyl)diphenyiarnine i) 4-Methoxy-3-[2-(4'-pyridyl)ethcxy]-N-(3-pyridyimethyl)diphenyiamine m) 4-Methoxy-3-(3-(2-pynayl)prop-l-yl]oxy-N-(3-pyTidyimethyl)Qiphenyiamine n) 4-Methoxy-3-(2-Tnethoxyethoxy)-N-(3-pyridylmethyl)diphenylamine o) 3-Cyclopropylmeihoxy-4-methoxy-N-(3-pyTidylmethyl)diphenylainme p) 4-Methoxy-3-(l-methylpyTTohdin-3-yl)oxy-N-{3-pYridylmethyl)diphenylarnine q) 4-Methoxy-3-(l-methylpipenditi-4-yl)oxy-N'-(3-pyTidylmethyl)diphenylairLine r) 4-Methoxy-A-{3-pyridylmethyl)-3-[(35)-tetrahydrofuryloxy]diphenylamine s) 4-Methoxv-A'-(3-pyridylniethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamme t) 3"-Chloro-4-meihoxy-3-[2-(2-pyridYl)ethoxy]-N-(3-pyndylmethyl)diphenylamine u) 3'-Cbloro-4-meLhoxy-3-[2-(4-pyndyl)ethoxy]-N-(3-pyridyLmethy])diphenylanune v) 3'-Chloro-4-methoxy-3-(2-methQxyeihoxy)-N-(3-pyTidylmethyl)dipheiiyiamine w) 31-Ch}oro-4-methoxy-/v-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy]diphenylamine x) 3-Cyclohexyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine y) 3-Cyclohepryloxy-4-methoxy-N'-(3-pyTidylmethyl)diphenylainine z) 3-(2-Cyclopropylethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine aa) 3-Cyclopentylmet±ioxy-4-methoxy-N-{3-pyndylmethyl)diphenylamine bb) Ethyl A'-[3-(4-chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-Ar-(3-pyndylrnet±iyi)-3- aminobenzoate cc) Ethyl A'-(3-cyclopropylmeth.oxy-4-methoxyphenyl)-/v-(3-pyndyknethyl)-3- ammobenzoate dd) Ethyl N(3-cyclopropylmethoxy-4-difluorornethoxyphenyl)-N(3-pyridylrnethyl)-3- aminobenzoate ee) Ethyl ^-[3-{2-indanyloxy)-4-methoxyphenyl]-A-(3-pyridylmei:hyi)-3-arnin.oben2oate ff) Ethyl Ar-{4-methoxy-3-(3-tetrahydrofQryloxy)phenyl]-.V-(3-pyndylmeihyl)-3- aminobenzoate gg)Ethyi A-f^-7nethoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-A'-{3-pyridylmethyl)-3- ammobenzoate hh) Ethyl A-[3-(2-methoxyethoxy)-^-methoxypheriyl]-A'-{3-pYridylmediYl)-3- arninobenzoate ii)Ethyl N-[4-meihoxy-3-(2-(2-pyridyi)eihyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoate EXAMPLE 18 (Method C) The following compounds were prepared in a similar manner as described in Example 8A by coupling a phenol with a boronic acid rather than coupling an aniline with a boronic acid: a) 4-Methoxy-3-{4-methoxyphenoxy)-.V-(3-pyridytaiethyl)diphenYlamine b) 4-Methoxy-3-phenoxy-N-(3-pyridylmethyl)diphenylamine . • c) .'4-Methoxy-3-(4-methylphenoxy)-N-{3-pyridylmethyl)diphenylamiDe d) 3-(4-Chlorophenoxy)-4-methoxy-N-(3-pyndyknethyl)diphenylamine e) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylajnine . EXAMPLE 19 The following compounds were prepared in a similar manner as described in Example 17 a) 3-Cyclopentyloxy-3'-hydTOxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyndylmethyl)diphenylamine c) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyndybtnethyl)diphenylamine EXAMPLE 20 (Method A) The following compounds were prepared in a similar manner as described in Example 1A: a) 3'-(2-Bromoethoxy)-3-cyclopemyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine EXAMPLE 20 (Method B) The following compounds were prepared in a similar manner as described in Example IB: a) 3-Cyclopentyioxy-4X2-nieihoxyethoxy)-4-meihoxy-A-(3- pyridylrnethyl)diphenylamine b) 3-Cyclopentyloxy-4'-(3-methyl-l-butoxy)-4-methoxy-A-{3- pyri dy imethy l)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-AX^-p)^dy^e^yO-4'-[(36)-te diphenylamine d) 3-Cyclopentyloxy-4-methoxy-yV-(3-pyridylinethyl)-4>-[(3jR)-tetrahydrofuranyloxy] diphenylamine e) 3-Cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-Ar-(3- pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpiperidin-4-yloxy)-N-(3- pyridylmethyl)diphenylamme i) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpyrrolidin-3-yloxy)-N-(3- pyridylmethyl)diphenylainine j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-.N-(3- pyridylmethyl)diphenylamine k) 3-Cyclopentyloxy-4-metho-xy-4'-[2-(l-pyn-olidinylethoxy)-N-(3- pyTidylmethyl)diphenyiamine I) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyi)methoxy)-N-(3- pyTidylmethyl)diphenylamine m) 3-Cyclopenr/loxy-4-methoxy-4>-[3-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylaraine n) 3-Cyciopenryloxy-4-methoxy-4'-[2-(l-methyipiperidinyI)methoxy]-N-(3- pyridylmeihyl)diphenyiamine o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyTToiidinyl)meihoxy]-N-(3-- pyndyimethy3)diphenylamine p) 4'-[ I -(3-3romopropyOoxyj-3-cyc]opentyloxy-4~methoxy-A-(3~ pyndylmethyl)dipheny!amme q) 3-CycIopentyloxy-4-methoxy-4'-[2-(7v'-phthalimido)ethoxyJ-A-(3- pyridylrnethyl)diphenylamine EXAMPLE 21 3-Cyclopentyioxy-4-rnetboxy-3'-{2-(l-piperidinyl)etiioxy]-;V-{3- pyndylraethy{)diphenylamine To a solution of 3'-{2-bromoethoxy)-3-cyclopentyloxy-4-methoxy-jV-{3- pyridvime'chyl)diphenylamme (17 mg, 0,03 mmol) in acetonitrile (1 mL) was added .potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 uL, 0.05 mmol) and the mixture was stirred at 60 °C for 4 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO residue was loaded on an ISCO RediSep column (4.2g, silica) and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg of product. 'K NMR (CDC13) 5 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7.20 (m, 1H), 7.06 (t, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.75-6.6& (m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p.. 1H, J = 4.1 Hz), 4.00 (t, 2H, J - 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1..70 (m, 6H), 1.86-1.70 (m, 6H)3 1.65- 1.45(m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-3 '-[2-(l-imidazolyI)ethoxy]-4-methoxy-N-(3- pyridyimethyl)Qiphenylamine b) 3-Cyciopencyloxy-4-methoxy-3 3-[2-( 1 -methylpiperaziii-4-yI)euioxy]-/v-{3- pyridylmet±iyl)diphenylamine c) 3-Cydopenryioxy-4-methoxy-4)-[3-(2-methyipipera2in-4-yi)propoxy]-N-(3- pyridyimethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4;-[3-(l-methyipipera2iri---yl)pTOpoxy]-N-(3- pyndylmeihyl)diphenylamine e) 3-CyclopenTyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxyj-A-(3- pyridylmethyl)diphenylamine f) 4-Methoxy-3-(2-phenoxyethoxy)-/V-(3-pyridylmethyl)diphenylamme g) 3-[2-(4-Chiorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylaTnine h) 4-Methoxy-3-(2-pyrrolidin-1 -yl)etiioxy-N-(3-pyridylrnethyl)diphenYlaniine i) 4.-Methoxy-3-(2-(4-methylpiperazin-1 -yl)ethoxy)-Ar-(3-pyridylmethyl)diphenyiamine j) 3:[2-{4-Chlorophenylamin©)ethoxy]-4-methoxy-A'"-(3-pyTidylmethyl)diphenYlamme EXAMPLE 22 4'-A'minoethoxy-3-cyclopentyloxy-4-methoxy-A'*-(3-pyridylrnethyl)diphenylamine .To a solution of N-(3-pyridylmethyl)-3'-[2-(2-phthalimido)ethoxY]-3- cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 rrrrnol) in MeOH (5 mL) was added hydrazine hydrate (1.0 -mL, 20 ramol). After 6 h at room temperature, EtOAc was added (50 mL) and the precipitate was filtered off. The filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSC^), and concentrated in vacuo. The residue was loaded on an ISCO RediSep column (10 g, silica). The column was washed with 10% MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH m EtOAc to yield 0.2.1 g. !H NMR (CDC13) 5 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10 (m, 1H), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9..0 Hz), 6.70 (d, IK, J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3,74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H). EXAMPLE 23 The following compounds were prepared in a similar manner as described in Example 12: a) 3-Cyclopentyloxy-4'-{2-methanesulfonylamino)et±ioxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine bl 3-Cyclopenryloxy-4'-(2-eth2nesulfonyiainmo)ethoxy-4-niethoxy-,A/-{3- pynd ylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4:-[2-{2-propaT]esulfonYiamino)ethoxyj-/v-(3- pyridylmethyl)diphenylamine d). 3-Cyciopentyloxy-4-methoxy-41-[2-{l-propanesulfonylanuno)ethoxyj-/V-(3- p yri dylmeth yl)cliphenylamine e) 4'-[2-(i-3utanesulfonylaraino)ethoxy]-3-cyclopentyloxy-4-met±ioxy-A/'-(3- pyridyimethyl)dipheny]amme EXAMPLE 24 In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity Human PD-E4 was obtained from baculovirus-infected Sf9 celis that expressed the 'recombinant enzyme. The c'DNA encoding hPDE-4D6 was subcloned into, a baculoviras 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 iysate was used as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAJE 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'-AM?). 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 ui of assay mix and 10 ul of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0. 4 ug enzyme, lOrruVl Tris-HCl (pH 7.5), lOmM MgCk 3 uM cAMP, 0.002 U 5r-nucieoridase, and 3 x 1C4 cpm of [3H]cAMP. . The reaction was stopped by adding 100 ul of boiling 5mN KC1. An aliquot of 75 ul of reaction mixture was iransferred from each well to alumina columns (Muitiplate; Millipore). Labeled adenosine was eluted into an OpdPlate by spinning at 2000 rprn for 2 mm; 150 ul per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [JH]adenosine was determined-using a WalJac Influx®. 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.. pICso 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 3H-adenosine concentration. Nonlinear regression software (Assay Explorer®) was used to estimate pICso values, EXAMPLE 25 (Method A) . Passive Avoidance in Rats, an in vivo Test for Learning and Memory The test was performed as previously described (Zhang, H.-T., Cnssman, A.M., Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology., 2000, 23, 198-204.). The apparatus (Model E10-16SC, Coulboum Instruments, Alien town, 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 rnA electric shock was administered for 3 seconds. Twenty-four hours later, the rat was administered O.I 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, i.p.), 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. Naive rats required less than 30 •secondsj on average, to cross from the illuminated compartment co 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 markedly reduced this latency when compared to the vehicle (p effect of MK-801 is reversed in a statistically significant manner by actual test compounds in'a dose-dependent fashion (e.g., 3-cyclopentyioxy-4-methoxy-/V-(3- pyridylmethyl) diphenylamine, Effective dose range = 0.5 to 2.5 mg/kg, i.p.; and ^-{3- cyclopentyloxy-4-methoxyphenyl)-/Y-(3-pyridybuethyl)-3-aminobenzoic acid, effective • dose range = 0.1 to 2.5 ma/kg, ip). EXAMPLE 25 (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., Cnssman, A.M., Dorairaj. N.R., Chandler,. L.J., and O'Donnell, J.M., Neuropsychopharmacoiogy, 2000, 23, 198-204.). Five days after initial housing, rats (rnaJe Spraque-Dawley (Earlan) weighing 250 to 350 §) were placed in the eight-arm radial maze (each arm was 60x10x12 cm high; me maze was elevated 70 cm above the floor) for acclimation for TWO days. Rats were then placed individually m 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 corriparisons 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 statistically significant manner by the administration of actual test compounds in a dosedependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-.V-(3- pyndyimethy])diphenylamtne, Effective dose = 2.5 ma/kg, i.p.; p The preceding examples can be repeated with similar success by substituting the genetically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. White 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. We Claim: 1. A phenylamine compound of Formula I (Formula Removed) wherein: R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen; R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C=C-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms alkoxy having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C-C-, and one or more -CH2- 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, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof, 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, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or a heterocyclicalkyl 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-. , and one or more -CH2- 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; R3 is alkyl having 1 to 8, carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C1-4-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 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 carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C1-4-alkoxy, cyano or combinations thereof, 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, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R4 is aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-), or combinations thereof, or 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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, or combinations thereof; R5 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof, alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, a partially unsaturated carbocycle-alkyl group wherein the carbocycle portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, 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, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, 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, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, methyl, or combinations thereof, 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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or a heterocyclicalkyl 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, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and R6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof; and pharmaceutically acceptable salts thereof of the kind such as herein described. 2. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; R3 is alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is aryl or heteroaryl, in each case substituted or unsubstituted. 3. A compound as claimed in claim 1, wherein R3 is heteroarylalkyl which is substituted or unsubstituted. 4. A compound as claimed in claim 1, wherein R1 is methyl or CHF2, and R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or (3R)-tetrahydrofuranyl. 5. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl; R3 is heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl or heteroaryl. 6. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl. 7. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is heteroarylalkyl which is substituted or unsubstituted. 8. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is heteroarylalkyl which is substituted or unsubstituted; and R4 is phenyl which is substituted or unsubstituted. 9. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; and R4 is phenyl or phenyl substituted with 1 to 3 substituents. 10. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; and R4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted. 11. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted. 12. A compound as claimed in claim 1, R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, OF ethylsulfonamido, or combinations thereof, or is 3-pyridyl which is unsubstituted or substituted by carboxy, alkoxycarbonyl or combinations thereof. 13. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted. 14. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. 15. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted. 16. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R3 is pyrazinylmethyl, pyrimidinylmethyl, or pyridylmethyl, which in each case is unsubstituted or substituted. 17. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrirnidinylrnethyl, pyridylmethyl, quinolinylmethyl, isoqumolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted. 18. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted. 19. A compound as claimed in claim 1, wherein said compound is of formula IV (Formula Removed) wherein at least one of A, B, and D is N and the others are CH, and R4 is pyridyl or phenyl which in each case is substituted or unsubstituted, or a pharmaceutically acceptable salt thereof of the kind such as herein described. 20. A compound as claimed in claim 19, wherein R1 is methyl or CHF2. 21. A compound as claimed in claim 20, wherein B is N. 22. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetr ahydrofuranyl. 23. A compound as claimed in claim 22, wherein B is N. 24. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. 25. A compound as claimed in claim 24, wherein B is N. 26. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. 27. A compound as claimed in claim 26, wherein B is N. 28. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is phenyl which is substituted in the 3- or 4- position. 29. A compound as claimed in claim 28, wherein B is N. 30. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is phenyl which is substituted in the 3- or 4- position. 31. A compound as claimed in claim 30, wherein B is N. 32. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. 33. A compound as claimed in claim 32, wherein B is N. 34. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. 35. A compound as claimed in claim 34, wherein B is N. 36. A compound as claimed in claim 1, wherein said compound is selected from: 3-Cyclopentyloxy-4'-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-3,4-dimethoxy-N-(3-pyridymlethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl)diphenylamine 4'-Cyano-3-cyclopentyloxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-nitro-iN-(3-pyridylmethyl)diphenylamine 4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine 4-Methoxy-3'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine 3-Cyclopen1yloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl) amine 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-[3-(4-Chlorophenyl)prop-1 -yloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3-[3-(4-methoxyphenyl)prop-1-yl]oxy-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3-[3-(2-pyridyl)prop-1-yl]oxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4-[(3R)-tetrahydrofuranyloxy]-diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-( 1 -methylpiperidin-4-yloxy)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-( 1 -methylpyrrolidin-3-yloxy)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-pyrrolidinylethoxy)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N-(3-pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4 -methoxy-4'- [2 - (1 -methylpiperidinyljmethoxy] - N- (3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-[2-(l-piperidmyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-3'-[2-(l-imidazolyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4 -methoxy-4'- [3 - (2 -methylpiperazin-4-yl)propoxy] - N- (3 -pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxy]-JV-(3-pyridylmethyl)diphenylamine 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4'- [2 - (1 -Butanesulfonylamino) ethoxy] -3 -cyclopentyloxy-4-methoxy- JV- (3-pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4 -me thoxy- N- (3 -pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine 4-^tethoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-v^tetrahydrofuryloxy)diphenylamine 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3 -Indanyloxy-4-methoxy- N- (3-pyridylmethyl)diphenylamine N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid N- (3 - Cy clopentyloxy- 4-methoxyphenyl) -N- (4-isoquinolinyl) - N- (3 -pyridylmethyl) amine N- (3 -Cyclopentyloxy-4-methoxyphenyl) - N-(3-pyridylmethyl) -N-(5-pyrimidinyl) amine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-iV-(3-pyridylmethyl) amine N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine 4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3-tetr ahydr ofuryloxy) diphenylamine 3'-( 1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4 -Methoxy- N- (3 -pyridylmethyl) - 3 - (3 - tetrahydrofuryloxy) diphenylamine 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine 3 - Cyclopropylmethoxy-4 - methoxy- N- (3 -pyridylmethyl) diphenylamine 4 - Methoxy- N- (3 -pyridylmethyl) -3 - [ (3S) -tetrahydrofuryloxy] diphenylamine 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperidinyl)methoxy]-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yl)propoxy]-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3- (2 -phenoxyethoxy) - N- (3 -pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'- Cyano-3 - cyclopentyloxy-4 -methoxy- N- (3 -pyridylmethyl) diphenylamine 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3- pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-iV-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) -diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4 -methoxy-4 '-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3-[3-(4-pyridyl)prop-1 -yl]oxy-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3 - Cyclopentyloxy-4'- (2 - ethane sulf onylamino) ethoxy-4-methoxy- JV- (3 -pyridylmethyl) diphenylamine 3 - Cyclopentyloxy-4 -methoxy-4'- [2 -(1 -propanesulfonylamino) ethoxy] - JV- (3 -pyridylmethyl) diphenylamine 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3,4 -Bis(difluoromethoxy) -N- (3 -pyridylmethyl)diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 3 '-Cyano-4-difluoromethoxy- N- (3 -pyridylmethyl) -3- {(3R)-tetrahy drofuryloxy) diphenylamine 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetr ahydr ofuryloxy) diphenylamine 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N- (3 - Cy clopentyloxy- 4 -methoxyphenyl) - N-(3 -pyridylmethyl) -4-aminobenzoic acid N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol- 5 -yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3,-(2H-tetrazol-5-yl) diphenylamine 4-Methoxy-iV-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) diphenylamine 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-yl)diphenylamine 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5 -yl) diphenylamine Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridy lmethy 1) amine N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl)amine 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3-pyridy lmethy 1) diphenylamine 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine 4 -Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 R) - tetrahydrofuryloxy] diphenylamine 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 3 -Cyclopentyloxy-4-methoxy-4'- [2 - (5-oxopyrrolidinyl)methoxy] - N- (3 -pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof of the kind such as herein described. A compound as claimed in claim 1, wherein said compound is selected from: 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine 3 - Cyclopentyloxy-4 -methoxy-4'- methyl- N- (3 -pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4 -methoxy-4 '-nitro- N- (3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine 4-Methoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine 3 -Indanyloxy-4-methoxy-N- (3 -pyridylmethyl) diphenylamine N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidinyl) amine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl) amine N-(4-Methoxy-3-(3R)-tetrahydrofaryloxyphenyl)-N-(3-pyTidyl)-N-(3-pyridylmethyl) amine 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide 3 - Cy clopentyloxy-4 -methoxy- 3'- (4 - methylpiperazin-1 -ylcarbonyl) - N- (3 - pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N- (3 -pyridylmethyl) diphenylamine 4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3-tetrahydrofuryloxy) diphenylamine 3'-( 1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4 -Methoxy- N- (3 -pyridylmethyl) - 3 - (3 -tetrahydrofuryloxy) diphenylamine 4 - Methoxy- 3 - [2 - (4-pyridyl) ethoxy] - N- (3 -pyridylmethyl) diphenylamine 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)dipheriylamine 4 -Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 S) -tetrahydrofuryloxy] diphenylamine 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3 - [2 - (4-Chlorophenyl) ethenyloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4-methoxy-4'- [3 - (1 -methylpiperidinyl)methoxy] - N- (3-pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4-methoxy-4'- [3 - (1 -methylpiperazin-4-yl)propoxy] - N- (3 -pyridylmethyl) diphenylamine 4- Methoxy-3 - (2 -phenoxyethoxy) - N- (3 -pyridylmethyl) diphenylamine 3 -Cyclopentyloxy-4 -methoxy-4'- [2 - (2 -propanesulfonylamino)ethoxy] - N- (3-pyridylmethyl) diphenylamine 3'- Cyano- 3 - cyclopentyloxy-4 -methoxy- N- (3-pyridylmethyl) diphenylamine 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl) - N- (3 -pyridylmethyl) diphenylamine 3 - Cyclopentyloxy-4 '-methane sulfonylamino-4-methoxy- N- (3 -pyridylmethyl) -diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3-[3-(4-pyridyl)prop-1 -yl]oxy-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethooxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4 -methoxy-4'- [2 -(1 -propanesulfonylamino)ethoxy] - N- (3-pyridylmethyl) diphenylamine 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3,4 -Bis(diflu oromethoxy) - N- (3 -pyridylmethyl) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine 3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine N- (3 - Cy clopentyloxy- 4-methoxyphenyl) - N- (3-pyridylmethyl) - 3 -aminobenzoic acid N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N-(3-Cyclopentylo^-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylniethyl)-3-aminobenzoic acid N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N- (3 -Cy clopropylmethoxy-4 - methoxyphenyl) - N- (3 -pyridylmethyl) - 3 -aminobenzoic acid N-[3-(2-Indanyloxy)-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol- 5 -yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) dipheny lamine 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylniethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 4-Difluoromethoxy- N- (3 -pyridylmethyl) -3-((3R)-te1xahydrofuryloxy) -4 '-(2 H-tetrazol- 5 -yl) diphenylamine 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5 -yl) diphenylamine Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3 -pyridylmethyl) amine 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-ethanesulfonylammo-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3 - Cy clopropylmethoxy- 3 '-ethane sulfonylamino-4-methoxy-N- (3 - pyridylmethyl) diphenylamine 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylrnethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylinethyl)diphenylamine 4 - Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 R) -tetrahydrofuryloxy] diphenylamine 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetr ahydrofuryloxy] diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof of the kind such as herein described. A compound as claimed in claim 1, wherein said compound is selected from: 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-4-difluoromethoxy-N:-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine 3 - Cyclopentyloxy-4 '-methane sulfonylamino-4-methoxy- N- (3 -pyridylmethyl) -diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylme thy1) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine 4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine 3 - Cyclopropylmethoxy-4 '-hydroxy- 4 -methoxy- N- (3-pyridylmethyl) diphenylamine 3 - Cyclopentyloxy-4'- (2 - ethane sulfonylamino) ethoxy-4-methoxy- N- (3 -pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3,4 -Bis(difluoromethoxy) - N- (3 -pyridylmethyl)diphenylamine 4-Difluoromethoxy- N- (3 -pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine 3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N- (3 - Cy clopentyloxy- 4 - difluoromethoxyphenyl) - N- (3 -pyridylmethyl) - 3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylraethyl)-3-aminobenzoic acid N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylinethyl)-4-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid 3 - Cy clopropylmethyloxy- 4 -diflu or omethoxy- N- (3-pyridylmethyl) -4'- (2 H -tetrazol-5-yl)diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3,-(2H-tetrazol-5-yl) diphenylamine 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) diphenylamine 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2 H-tetrazol-5-yl) diphenylamine 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5-yl) diphenylamine Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3 '-(1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3 - Cy clopropylmethoxy- 3 '-ethane sulfonylamino-4-methoxy- N- (3- pyridylmethyl) diphenylamine 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 4 - Methoxy-3 - [2 -'(2 -pyridyl) ethoxy] - N- (3 -pyridylmethyl) diphenylamine 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof of the kind such as herein described. A compound as claimed in claim 1, wherein said compound is selected from: 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 4-Difiuoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydr ofuryloxy) diphenylamine 3'-Cyano-4-dinuoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine N-(3-Cyclopentyloxy-4-inethoxphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N- (3 - Cy clopentyloxy- 4 - difluoromethoxyphenyl) -N- (3 -pyridylmethyl) - 3 -aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid N- [3- (2 -Indanyloxy) -4-methoxyphenyl] -N-(3-pyridylmethyl) -3-aminobenzoic acid N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid 3-Cyclopropylmethyloxy-4-difluoromethoxy-(3-pyridylmethyl)-4'-(2H-tetrazol- 5-yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl) diphenylamine 4-Methoxy-N-(3-pyridylmethyl)-3-((3,R)-tetrahydrofuryloxy)-4,-(2H-tetrazol- 5 -yl) diphenylamine 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine 4-Difluoromethoxy-N- (3-pyridylmethyl) -3-((3R)-tetrahydrofuryloxy) -4 '-(2 H - tetrazol- 5 -yl) diphenylamine 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine N- (4-Difluoromethoxy-3 - (3R) -tetrahydrofuryloxyphenyl) - N-(3-pyridyl) - N-(3-pyridylmethyl) amine 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine 4-Difluoromethoxy-3 '-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R) -tetrahydrofuryloxy] diphenylamine 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine 4-Methoxy -N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof of the kind such as herein described. A compound as claimed in claim 1, wherein said compound is of formula I': (Formula Removed) wherein R1' is methoxy; R2' is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, alkenyl having 2 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof, cycloalkylalkyl having 4 to 12 carbon atoms, cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof, arylalkyl having 7 to 19 carbon atoms arylalkyl having 7 to 19 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or" combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; X isO; R3' is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, car boxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof; L is -NR4'-, or -NR4'CH2-; and R4' is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and pharmaceutically acceptable salts thereof of the kind such as herein described. 41. A compound of the Formula (Formula Removed) wherein: R1 is 3H3C-, 14CH3-, or UCH3-; R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -OC-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CH2- 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, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof, 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, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CH2- 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; is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C1-4-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 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 carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci-4-alkoxy, cyano or combinations thereof, 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, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; is aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5- yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-, or combinations thereof, or 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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R5-L-, dialkylamino-L-, or combinations thereof; R5 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof, alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, 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, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, 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, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, 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, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, 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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, 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, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and R6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof; and pharmaceutically acceptable salts thereof of the kind such as herein described. 42. A compound as claimed in claim 1, wherein said compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 43. A compound as claimed in claim 1, wherein said compound is N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 44. A compound as claimed in claim 42, wherein said compound is N-3,4-bis(dinuoromethoxy)phenyl-N-(3-pyridylmethyl)-3-ammobenzoic acid. 45. A compound as claimed in claim 43, wherein said compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid.

Full Text

The present invention relates to a phenylamine compound of formula I.
This application claims benefit of U.S. Provisional application Serial No. 60/262,651, filed January 22, 2001, U.S. provisional application Serial No. 60/267,196, filed February 8, 2001, and U.S. Provisional application Serial No. 60/306,140, filed July 14,2001.
FIELD OF THE INVENTION
The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically this invention relates to selective PDE4 inhibition by novel compounds, e.g., N-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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 c AMP 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 Ca2-/calmoduim. 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 4 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 PD'E4D [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 anthnflanimator/ 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 roiipram, xanthine derivatives such as
pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received
considerable attention of late 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 ceils, such as
those located in the nervous system and elsewhere in the body.
Roiipram, 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 TV
Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et ai., Drugs of the
Future 1992, 17(9):799-807 for a general review). Further clinical developments of
roiipram 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 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 in trace 11 ular 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 pan to catabolism of intracellular cAMP 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 of Formula I:
wherein
R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and
which is unsubstituted or substituted one or more times by halogen (e.g.,
CH3, CHF2, CF3, etc.);
R2 is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched
or unbranched and which is unsubstituted or substituted one or more times
by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof,
and wherein optionally one or more -CH2CH2- groups is replaced in each
case by -CH=CH- or -C=C- (e.g., CH3, CHF3, CF3, methoxyethyl, etc.),
cycloaikyi having 3 to 10, preferably 3 to 8 carbon atoms, which is
unsubstituted or substituted one or more times by halogen, hydroxy, oxo,
cyano. alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon
atoms, or combinations thereof (e.g., cyclopentyl),
cycloalkyjalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is
unsubstituted or substituted in the cycloaikyi portion and/or the alkyl
portion.one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl,
C1-4-alkoxy or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.),
aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one
or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro,
methylenedioxy, ethyienedioxy,.cyano, or combinations thereof (e.g.,
methylphenyl, methoxyphenyl, chlorophenyl, etc.),
aryl alkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl
portion, which is branched or unbranched, has 1 to 5 carbon atoms, which
the arylalkyl radical is unsubstituted or is substituted in the aryl portion
one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro,
cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and
wherein in the alkyl portion one or more -CH2CH2- groups are each
optionally replaced by -CH=CH- or -OC-, and one or more -CH2- groups
are each optionally-replaced by -0- or -NH- and/or the alkyi portion is
optionally substituted by halogen, oxo, hydroxy, cyano, or combinations
thereof (e.g., phenylethyl, phenylpropyl, phenyiburyl,
methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl,
chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl,
chlorophenoxyethyl, chlorophenylaminoethyl, etc.),
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
which is unsubstituted or substituted one or more times by halogen, alkyi-,
alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereo'f (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, 0 or S
atom, which is unsubstituted or substituted one or more times by halogen,
hydroxy, aryl, alkyi, alkoxy, cyano, tnfluoromethyl, nitro, oxo, or
combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, 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, 0 or S atom, and the 'alkyi portion is branched or
unbranched and has I to 5 carbon atoms, the heterocycle-alkyl group is •
unsubstituted or substituted one or more times in the heterocyclic portion
by halogen, OCF3, hydroxy, aryJ, alkyl, alkoxy; cyano, trifluoromethyl,
rutro, oxo, or combinations thereof, wherein in the aikyl portion one or
more -CH2CH3- groups are each optionally replaced by -CH=CH- or
-OC-, and one or more -CHj- groups are each optionally replaced by -0-
or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo,
hydroxy, cyano, or combinations thereof (e.g., pyridylethyl,
pydndylpropyl, methylpiperazinylethyl, etc.);
R . is H,
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, cyano, C1-4-alkoxy, or combinations thereof (e.g., methyl,
ethyl, propyl, etc.),
a partially unsaturated carbocycle-alkyi group wherein the carbocyclic
portion has 5 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 carbocyclic portion one or more times by halogen, alkyl,
alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is
optionally substituted by halogen, C1-4-alkoxy, cyano or combinations
thereof (e.g., cyclohexenylmethyl, etc.),
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14
carbon atoms and the alkyl. portion, wluch -is branched or unbranched, has
1 to 5 carbon atoms,-arylalkyl radical is unsubstituted or substituted., in the
aryl portion, one or more times by halogen, trifluoromethyl, GF3O, nitro,
ammo, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the
aikyf portion by halogen, cyano, or methyl (e.g., benzyl, phenethyi.
phenpropyl, methylbenzyl, methoxybenzyi, trfluoromethyi, benzyl,
methyienedioxobenzyl, etc.), or
heteroarylalkyl group, wherein the heteroaryl portion may be partially or
fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a
N, 0 or S atom, the alky! portion, which is branched or unbranched, has 1
to 5 carbon atoms, the heteroarylalkyi group is unsubstituted or substituted
one or more times in the heteroaryi portion by halogen, alkyl, alkoxy,
cyano, trifmoromethyl, C7^0, nitro, oxo, amino, alkylamino,
dialkylamino, or combinations thereof and/or substituted in the alkyl
portipn by halogen, cyano, or methyl or combinations thereof (e.g.,
pyridylmethyl, pyridylpropyl, methylpyridylmethyi, chloropyridylmethyl,
dichloropyridylmethyl, thienylrnethyl, thiazoiylmethyi, quinolinylmethyi,
isoquinoiinylmethyl, piperidinylmethyi, fur any 1m ethyl, imidazolylmethyl,
methyiimidazolyimethyl, pyrrolylmethyl, etc.);
R4 is H,
aryi having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,
alkoxyaikoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyi,
OCF3, amino, aminoaikyl, aminoaikoxy dialkylamino, hydroxyalkyl (eg.,
hydroxymethyl), hydroxamic acid, tetrazole-5-yi, 2(-heterocycie)tetrazole-
5-yl (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy,
alkoxycarbonyl (e.g., tert-butyloxycarbonyi, ethoxycarbonyl), cyano, acyl,
aJkyithio, alkylsulfinyl, alkylsuifonyl, phenoxy, trialkylsilyloxy (eg. tertbutyidimethylsilyioxy),
R5-L-, or combinations thereof (e.g., substituted
or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyi,
rnethylphenyl,,chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl,
methyienedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl,
ethoxycarbonylphenyl, dimethylphenyi, hydroxymethylpheny!,
nitrophenyl, aminophenyl, etc.), or
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, which is uns'ubstituted or substituted one or more times by
halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,
ethyienedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl,
aminoalkoxy dialkyiamino, hydroxyalkyi (eg., hydroxymethyl),
hydroxamic acid, tetrazoie-5-yl, hydroxyalkoxy, carboxy, alkoxycarbony!
(e.g., tert-butyloxycarfaonyl, ethoxycarbonyl), cyano, acyl, aikyithio,
alkylsulfmyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tertbutyldimethylsilyloxy).
R3-L-, or combinations thereof (e.g., pyridyl,
thienyl,.pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazoiyl,
thiazolyl, etc.);
R5 isH,
alkyl having I to 8, preferably 1 to 4 carbon atoms, which is unsubstituted
or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy,.
oxo, or combinations thereof (e.g., methyl, ethyl, propyI, etc.),
aikylamino or dialkylamino wherein each alkyl portion has independently
1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.),
a partially unsaturated carbocycle-alkyl group wherein the carbocyciic
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 carbocyciic
portion, one or more times by halogen, alkyl, alkoxy, nitro. cyano, oxo, or
combinations thereof (e.g., cyclohexenylmethyl, etc.),
cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is
unsubstituted or substituted one or more times by halogen, hydroxy, oxo,
cyano, aikoxy, aJkyl having 1 to 4 carbon atoms, or combinations thereof
(e.g., cyclopentyl),
cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is
unsubstituted or substituted in the cycloalkyl portion and/or the alkyl
portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, aikoxy
or combinations thereof (e.g., cyciopentylmethyl, cyclopropyimethyl,
etc,),
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, hydroxy, aikoxy, alkoxyalkoxy,
nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino,
aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg.,
hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy,
carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl),
cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or
unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl,
fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl,
ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl,
•dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyi, etc.),
arylaiky! 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 10 5 carbon atoms, aryialkyi radical is unsubstituted or substituted, in the
aryl portion, one or more times by halogen, trifluoromethyl, CFsO, nitro,
amino, alkyl, aikoxy, amino, alkylamino, dialkyjamino and/or substituted
in the aikyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl,
phenpropyl, methylbenzyl, methoxybenzyl. trfluoromethyi, benzyl,
methylenedioxobenzyi, 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, 0 or S
atom, which is unsubstituted or substituted one or more times by halogen,
alkyl, hydroxy, alkoxy, ailcoxyalkoxy, nitro, methylenedioxy,
ethylenedioxy, trifluoromethyl, amino, aminomethyi, aminoalkyl,
aminoaikoxydialkylarnino, hydroxyalkyi (eg., hydroxymethyl),
hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl
(e.g., tert-butyioxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g.,
pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl,
imidazoiyl, thiazolyl, etc.), or
a heterocycie-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, 0 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 heterocyciic ;
portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF^O, nitro,
oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or
substituted in the alkyl portion by halogen, cyano, or methyl or
combinations thereof (e.g., pyridylmethyl, pyridylpropyl,
methylpridylmethyl, etc.);
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms ;
wherein one or more-CH?-groups are each optionally replaced by-0-, '
-S-, -KR6-, -S02NH~, -NHSCV, -CO-, ~NR'6CO-, -CONR6-, -NHCONH-,
-OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-0-, ,
CHr, -CO-, -CO-O-, -0-CO, -CO-NH-, -NH-CO-, -CH2CH2CH2-NHu
CO-, -CH2-CH2-O-, -SO2NH-CH2CHrO-, -0-CH2CH?-0-, -CH2-NHCO-,
-CO-NH-CH2-, -SCVNH-, -CH2-NH-S02-, -CH2CH2CH2-SO2-
NH-, etc.); and
isH,
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, d-n-aJkyl, Ci-4-alkoxy, oxo, or combinations thereof (e.g.,
methyl, ethyl, propyl, etc.);
wherein at least one of R3 and R4 is other than H; and
phamvaceutically acceptable salts thereof.
According to a further aspect of the invention there is provided a genus of novel
compounds according to the formulas II and III:
111
wherein R1, R2, R3, and R4 are as defined above. The compounds of this subgenus of
fonnula I not only have PDE4 inhibitory activity, but also are useful as intermediates for
preparing compounds of Formula I in which R3 and R4 are both other than H.
In addition, preferred compounds of formula I are those of the subformula IV
(Figure Removed)
wherein R1, R2, and R4 ars as defined in Formula I and one of A, B and D is N
and the others are C. Preferably, B is N. Also, R4 is preferably pyridyl or phenyl which
in each case is substituted or unsubstituted.
The present invention also includes compounds of Formula I'
(Figure Removed)

wherein .
R1' is methoxy, F, Cl, CHF2 or CF3;
R2' is
alkyl having I to 12 carbon atoms,
alkyl having .1 to 12 carbon atoms which is substituted one or more 'times
by halogen, oxo, cyano, or combinations thereof,
alkeny] having 2 to 12 carbon atoms,
.alkenyi having 2 to 12 carbon atoms which is substituted one or more
times by halogen, oxo, cyano or combinations thereof,
alkynyl having 2 to 12 carbon atoms,
alkynyl having. 2 to 12 carbon atoms which is substituted one or more
times by halogen, oxo, cyano or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms,
cycloalky! having 3 to 10 carbon atoms substituted one or more times by
haiogen, oxo, aikyl, or combinations thereof,
cycloalkylalkyl having 4 to 12 carbon atoms,
cycloalkylalky] having 4 to 12 carbon atoms which is substituted one or
more times by halogen, oxo, alkyl or combinations thereof,
a partially unsaturated carbocyclie group having 5 to 14 carbon atoms,
a partially unsaturated carbocyclie .group having 5 to 14 carbon atoms
which is substituted one or more times by halogen, alkyl, alkyloxy, nitro,
cyano, oxo, or combinations thereof,
arylalkyi having 7 to 26 carbon atoms
arylaikyl having 7 to 26 carbon atoms which is "substituted one or more
times by halogen, aikyl, alkoxy, nitro, cyano, oxo, trifluoromethyi, or
combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, or
substituted heteroaryialkyl having 5 to 10 ring atoms in which at least 1
ring atom is a heteroatom and which is substituted one or more times in
the heteroaryl portion by halogen, aryl, aikyl, alkoxy, cyano,
trifluoromethyi, nitro, amino, alkylamino, dialkylamino or combinations
thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or
combinations thereof;
X isOorS;
RJ is aryl having 6 to 14 carbon atoms,
aryl having 6 to 14 carbon atoms which is substituted one or more times
by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,
ammo, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,.
cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyisulfonyl,
phenoxy, heteroaryl which is unsubstituted or substituted by halogen,
alkyl or alkoxy, or combinations thereof,
heteroaryl having 5 to 10 nng atoms in which at least 1 ring atom is a
heteroatom, or
substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring
atom is a heteroatom which is substituted one or more times by halogen,
aryl, alkyl, alkoxy, cyano, tnfluoromethyl, nitro, oxo, amino, alkylamino,
dialkylamino or combinations 'thereof;' • •
L is -NH-, -KR4'-, -NHCH2-, -NR4'CHr, or -CH2NR4'-; and
R4 is alkyl having 1 to 12 carbon atoms,
alkyl having 1 to 12 carbon atoms which is substituted one or more times
by halogen, oxo, cyano, or combinations thereof,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, hydroxy, alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,
hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,
alkylthio, alkylsulfinyl, alkyisulfonyl, phenoxy or combinations thereof,
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom,
substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring
atom is a heteroatom and which is substituted one or more times by
halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
alkylamino, dialkylamino or combinations thereof,
arylalkyl having 7 to 16 carbon atoms,
arylalkyl having 7 to 16 carbon atoms which is substituted one or more
times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or
combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is. a
heteroatom, or
substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1
ring atom is a heteroatom and which is substituted one or more times in
the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano,
trifluoromethyl, nitro, oxo, amirio, alkylamino, dialkylamino or
combinations thereof and/or substituted in the alkyl portion by halogen,
oxo, cyano, or combinations thereof; and
pharmaceutically acceptable salts thereof.
The compounds of the present invention are effective in inhibiting, or modulating
the activity of PDE4 in animals, 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 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., US 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 with in this application.
Thus, there are provided intermediate compounds which correspond to
compounds of Formula I, wherein R2, R3, and R4 are as previously defined for Formula I,
but R1 is H, ten'-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, 3rd Edition, John Wiley & Sons, 1999,
pp. 246-293. These intermediates are also useful for.the synthesis of radio-labeled
compounds, such as where R1 is 3HjC-, 14CH3- or ' 'CHj-, for example by removing the
protecting group and reacting the resultant compound in which R1 is H with suitable
radio-labelled 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!, RJ, and R4 are as previously defined for Formula I, but R2 is H,
rerf-butyldimethylsilyioxy-, 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, 3rd Edition, John Wiley & Sons, 1999, pp. 246-
293. Compounds m which R2 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 H, C, or C.
As previously described, compounds according to formula II, wherein R , R" and
R4 are as previously described are useful intermediates for the production of compounds
according to formula I where in R3 is other than H.
Also, as previously described, compounds according to formula III, wherein R1,
R2 and R3 are as previously, described are useful intermediates for the production of
compounds according to formula I where in R4 is other than H.
Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.
Alkyl, as a group or substituent per se or as part of a group or substituent (e.g.,
alkylaminc, trialkyisilyloxy, 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 alkyi groups include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, undecyl, and dodecyl. Other examples of suitable alky! groups include 1-, 2- or 3-
methylbutyl, 1,1-, 1,2- or2,2-dimethyipropyl, 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, ethyimethylbutyi,
dimethyibutyl, and the like.
Substituted alkyi groups are alky! groups as described above which are substituted
in one or more positions by halogens, oxo, hydroxyl, Ci-4-alkoxy and/or cyano., Halogens
are preferred substituents, especially F and CL
Alkoxy means alkyl-O- groups and alkoxyalkoxy means alky 1-0-alkyl-0- groups'
in which the alkyi portions are in accordance with the previous discussion. Suitable
alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, buroxy, pentoxy,
hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxyrnethoxy, and
methoxyetboxy. PTefened 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 methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, and tert-butcxycarbonyl.
Cycloalky! 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 cyclopropyl,
cyclobucyl. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin,
adamant-i-yl, and adamant-2-yl. Other suitable cycloalky! groups include spiropentyl,
bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2,4]heptyl, spiro[2;5]octyi,
bicyclo[5.1.0]octyi, spiro(2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]hepty!,
bicyclo[4.2.0]ocryl, and spiro[3.5]nonyl. Preferred cycloalklyl groups are cyclopropyl,
cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example,
substituted by halogens and/or alkyl groups.
Cycioalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and
alkyl portions are in accordance with previous discussions. Suitable examples include
cyclopropylmethyl and cyciopentylmethyl.
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 phenyl,
naphrhyl and biphenyl. Substituted aryl groups include the above-described aryl groups
which are substituted one or more times by, for example, halogen, alkyl, hydroxy,
alkoxy, mtro, methylenedioxy, ethylenedioxy, amino, alkylammo, dialkylamino,
hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, aikylthio,
alkyisuifinyi, alkylsulfonyl, and phenoxy.
Arylalkyl refers to an aryi-alkyl-radical in which the aryl and alkyl portions are in
accordance with the previous descriptions. Suitable examples include benzyl, 1-
phenethyl, 2-phenethyl, phenpropyi, phenbutyl, phenpentyi, and napthylmetfayl.
Heteroaryl refers to an aromatic heterocyciic 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 heteroaryi group contains 1 to 3, especially 1 or 2, hetero-nng atoms
which are selected from N, O and S. Suitable heteroaryi groups include furyl, thJenyl,
pyrrolyl, p yrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl,
oxazolyi, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazoiyi, dioxazolyl, oxathiazolyl,
•Ihiadiazolyt, pyridyl, pyridazmyl, pyrimidinyl, pyrazinyl, tnazinyl, oxazinyl, isoxazinyl,
oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl,
•isothionaphthenyl, indolyl, isoindolyl, indazoly'I, benzisoxazolyi, benzoxazolyl,
benzthiazolyl, benzisolhiazolyl, purinyi, benzopyranyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinazolinyi, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-tnienyl, 2-,
3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or Sisoquinolinyl.
Substituted heteroaryi refers to the heteroaryi groups described above which are
substirued in one or more places by, for example, halogen, aryi, alkyl, alkoxy, carboxy,
methylene, cyano, trifluoromethyl. nitro, oxo, amino, alkylamino, and dialkylamino.
Heterocycles include heteroaryi groups as described above as well as nonaromatic
cyclic groups containing at least one hetero-ring atom, preferably selected from
N, S and 0, for example, tetrahydrofuranyl, pipendinyl, and pyrrolidinyl.
Heterocycle-alky! refers to a heterocycle-alkyl-group wherein the heterocyciic
and alkyl portions are in accordance with the previous discussions. Suitable examples are
pyndyimethyl, thienyimethyl, pyrimidinylmethyl. pyrazinylmethyi, and
isoquinolmylmethyl.
Partially unsafurated 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 or* C=C bond. Suitable examples are
cyclopentenyl, cyclohexenyl, cyclohexadienyl, terrahydronaphthenyl and indan-2-yl.
Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2
to 12 carbon atoms in which one or more -CH2-CH2- structures are each replaced by -
CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-
butene, i-pentenyl, and 2-pentenyl.
Alkynyi refers to straight-chain or branched-chain aliphatic radicals containing 2
- to 12 carbon atoms in which one or more -CHi-CHa- structures are each replaced by
-OC-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl.
Acyl refers to alkanoyi 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.
Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2
substituents,
In the compounds of Formula I, R1 is an alkyl group having preferably 1 to 4
carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine.
In particular, R1 is preferably methyl or difluoromethyl.
R'IS preferably cycioalkyi, particularly cyclopentyl.
R2 is also preferably aryi or arylalkyl, particularly substituted or unsubstituted
phenyl or phenylalkyl, such as phenyl, methyiphenyl, rnethoxyphenyl, chlorophenyi.
phenethyi, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, pbenoxypropyl,
phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyi,
chiorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl,
chiorophenbutyl, nitrophenbutyl, chlorophenylammoethyl, and the like,
R2 is also preferably a partially unsaturated carbocyclic groups, which is
unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl, indan-2-yl,
R2 is also preferably an alkyl group having 1 to 8 carbon atoms, especially 1 to 4
carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl,
trifiuoromethyl, and methoxyethyl.
R2 is also preferably a heterocyclic or heterocycle—alkyl group, particularly
radicals in which the heterocyclic group has 5 to 6 ring atoms and 1 to 2 hetero-ring
atoms selected from N, 0 and S, e.g., tetrahydrofuranyi, pyrroiidinyi, pyrrolyl,
pyridylmethyl, pyridylethyl, pyri-dylpropyl, piperazinylmethyl, piperazinylethyl,
methylpiperazinylethyl and the like.
Preferred R" include cyclopentyl, tetrahydrofuranyi, CHFi, methoxyethyl,
cyclopropyimethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl,
phecylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl.
R3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl,
n-propyl, or n-batyi), arylalkyl (e.g., substituted or unsubstitituted benzyl, phenethyl, and
phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted pyridylmethyi,
furanyimethyi, thienyimethyl, pyrrolylmethyl, pyrimidinyirnethyi, thiazolylmethyl,
isoquinolinyimethyl and.quinolinylrnethyl). Preferred substituents for aryl and heteroaryl
portions of R3 are F, Cl, CH3, C2H5, OCH3, and CN.
R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl,
pyrazmyl, pynmidinyl. pyridyL, quinolinyl. and isoquinolinyl, which in each case is
unsubstituted or is substituted one or more times. Preferred substiruents are OH, F, CI.
CF;,, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl,
CH2OH, CONHOH, CONH2, methyienedioxy, COOH, and combinations thereof.
In addition, when R is aryl, especially, phenyl, preferred substituents include RJL;
e.g., R5-, R5-0-, R5-CO-, R5-NH-CO-, R5-S02-NH-, R5-S02-NH-alkylene-0-, NH2-
alkyl-NH-CO-, R5-alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, Ci, F,
CN, OCH3, CF3, amino, nitro, HOCH2 and COOH.
When R4 is aryl substituted by R5-SO2-NH- it is preferably a substituted phenyl
group and R5 is preferably methyl, ethyl, propyl or phenyl.
When R4 is aryl substituted by R5-S02-NH-aIkylene-0- it is preferably a
ited phenyl. In such cases, R5 is preferably methyl, e
alkylene is preferably -CH2-, -CH2CH2- or-CH2CH2CH2-.
substituted ethyl, propyl or phenyl and
When R4 is aryl substituted by R3-L- it is preferably substituted phenyl. In such
cases, preferred R5 groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl,
pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadiny!, or methylpiperadinyl,
and L is preferably a single bond, -O-, -CO-, -CH2-, -CH2CH2-, -CH2CH2CH2-3 -CH2-0-
-CH2CHrO-, -CH2CH2CH2-O-, -CH2-NH-CH2CH2-O-, -CO-NH- or -NH-CO-.
In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by subformulas la-Ih which correspond to formula I but exhibit the
following preferred groups:
la R1 is methyl or CHF2;
R2 is aikyl, alkenyl, alkynyl, cycloalkyl, aryialkyl, heterocycle-alkyl,
cycloalkylalkyl, aryi, or heterocyclic, in each case substituced or
unsubstituted;
RJ is H, aikyl, aryialkyl or heteroaryialkyi, in each case substituted or
unsubstituted; and
R4 is aryi or heteroaryi, in each case
substituted or unsubstituted.
Ib RJ is heteroarylalky! which is substituted or unsubstituted.
Ic R1 is methyl or CHF2; and
R2 is cyclopentyl, CHFi, cyclopropylmethyl, pyridyiethyi
(particularly-2-pyridylethyl), or tetrahydrofurany!
(particularly (3R)-tetrahydrofuranyl).
Id R1 is methyl or CHF2;
R2 is cyclopentyi;
R3 is heteroarylaiky!, in each case substituted or
unsubstituted; and
R4 is substituted or unsubstituted aryi or heteroaryi.
le R1 is methyl;
R2 is cyclopentyi; and
R3 is heteroarylaikyl which is substituted or unsubstituted.
If R1 is methyl;
R" is cyclopentyl;
R3 is heteroarylaikyi which is substituted or unsubstituted;
and
R4 is phenyl which is substituted or unsubstituted.
Ig . R1 is methyl;
T JR." is cyclopentyl;
RJ is pyridylmethyl, phenethy!, benzyl, thienylmethyi.,
pyndylpropyl, piperidinylmeihyL or pyrazinylmethyl,
which in each case is substituted or unsustiruted, or methyl,
ethyl, or propyl; and
R4 is phenyi or phenyl substituted with 1 to 3 subsrituents.
Ih R! is methyl;
R2 is cyciopentyl;
RJ is pyridylmethyl, phenethy!, benzyl, thienylmethyl,
pyridylpropyl, pip_eridinyimethyl, pyrazinylmethyl, which
in each case is substituted or unsustiruted, or methyl, ethyl,
or propyl; and
R4 is phenyl, naphthyi, biphenyl, pyridyi, pyrimidinyl, thiazoly],
pyrazinyl, quinolinyi, or isoquinolinyl, in each case substituted or
unsubstituted. .
In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by subformulas Ila-Hd which correspond to formula II but exhibit
the following preferred groups:
Ha R1 is methyl or CHF?;
R: is cyclopentyl, CHF^ cyclopropylmethyi, pyndylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R4 is phenyl, naphthyi, pyridyi, quinolinyl, or isoqumolmyl, which in each
case is substituted or unsubstituted.
lib R1 is methyl or CHF2;
R2 is cyclopentyl, CHF?, cyclopropyimethyi, p>Tidylethyi
(particularly 2-pyridylethyl), or tetrahydrofurany!
(particularly (3R)-tetrahydrofuranyl); and
R4 is phenyl which is unsubstiruted or substituted by methyl, ethyl,
methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or
ethylsuifonamido, or is 3-pyridyl. which is unsubstituted or substituted by
carboxy or alkoxycarbonyl.
He R1 is methyl; .
R" is cyclopentyl; and
R is phenyl, naphthyl, pyridyl, quinolinyi, or isoquinolinyl, which in each
case is substituted or "unsubstituted. .
lid R1 is methyl;
R2 is cyclopentyl; and
R4 is phenyl which is unsubstituted or substituted by methyl, ethyl,
methoxy, Cl, F, CF3, vinyl, cyano, arnzno, carboxy, hydroxymethyl, or
ethyisulfonamido, or is 3-pyridyl which is unsubstituted or substituted by
carboxy or alkoxycarbonyf.
In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by sub formulas UIa-!IId which correspond to formula m but
exhibit the following preferred groups:
Ilia R1 is methyl or CHF2;
R2 is cyclopentyl, CHFj, cyclopropylmethyl, pyridylethyl
(particularly 2-pyndylethyl), or tetrahydrofurany!
(particularly (3R)-tetrahydrofuranyl); and
R3 is benzyl, phenethyl, cyclohexenyknethyl, furanylmethyl,
thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl,
thiazolylmethyl, or pyrrolylrnethyl, which in each case is substituted or
unsubsti tuted.
IIIb R1 is methyl or CHF2;
R2 is cyclopentyl, CHFa, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridyiethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl);
and
R3 is pyrazinylmethyl, pyrimidinylmethyl or pyndylmethyi, which in each
is unsubstituted or substituted.
ttlc R1 is merhyi;
R2 is cyclopentyl; and
RJ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl,
thienylmethyl, pyrazinylmethyl, pyranidinylmethyl, pyridylmethyl
quinolinymethyl, isoquinolinylmethyl, isoimidazolyl, thiazoiylmethyi, or
pyrrolylmethyl, which in each case is substituted or unsubstifuted.
Hid R1 is methyl;
R2 is cyclopentyl; and
RJ is pyrazinylmethyl or pyridylmethyl, which in each -is unsubstiruted or
substituted.
In addition, preferred PDE4 inhibitors in accordance with the invention
are compounds described by subformulas IVa-IVp which correspond to formula IV but
exhibit the following preferred groups:
IVa R1 is methyl or CHF2.
IVb R! is methyl or CHF2, and
BisN.
IVc Rs is methyl or CHFz, and
R2 is cyclopentyl, CHFa, cyciopropylmethyl, pyridyiethyi (panicuiarly 2-
pyridyiethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydroruTanyl).
IVd R1 is methyl or CHF2,
B is N, and
R2 is cyclopentyl, CHFz, cyclopropyimethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyi).
IVe R1 is methyl or CHF2, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
IVf R1 is methyl or CHF2,
B is N, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
IVg R1 is methyl or CHF2,
R2 is cyclopentyl, CHF2, cyciopropylmethyl, pyridylethy! (particularly-2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
TVh R! is methyl or CHF2;
BisN, -
R2 is cyclopenjyi. CHF:; cyclopropyimethyl. pyridylethyi (paniculariy 2-
pyridylethyl), or tetrahydrofuranyi (panicularly (3R)-tetrahydTofuranyi).
and
Ra is 3-pyri'dyl or phenyl, which in each case is substituted or
unsubstituted.
IVi R! is methyl or CHF2, and
R4"is pKenyl which is substituted in the 3- or 4- position.
IVj R1 is methyl or CHF2) '
.BisN, and .
R4 is phenyl which is substituted in the 3- or 4- position.
TVk R1 is methyl or CHF2,
R2 is cyclopentyl, CHF2, cyclopropyimethyl, pyndylethyl (panicularly 2-
pyridylethyl), or tetrahydrofuranyi (panicularly (3R)-tetrahydrofuranyl),
and
R4 is phenyl which is substituted in the 3- or 4- position.
IVI R1' is methyl or CHF2,
B is N,
R" is cyclopentyl. CHFa.. cyclopropylmethyl, pyridyleth-yl (pardcularly 2-
pyridylethyl), or letrahydrofurany! (panicularly (3R)-ceirahydrofuranyl),
and
R4 is phenyl which is substituted in the 3- or 4- position.
IVm R1 is methyl or CHF2, and
Rd is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-
ethylsulfonarnido-phenyl, 3-tetra2ol-5-yl-phenyl, 3-hydroxymethylphenyl,
4-pyndyi, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamidophenyl,
4-tetrazol-5-y!-phenyl, or 4-hydroxymethyl-phenyl.
IVn' R1 is methyl or CHF2, .
B is N, arid
R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetra2ol-5-yl-phenyl, 3-hydroxymethyiphenyl,
4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamidophenyl,
4-tetra2ol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
TVo R1 is methyl or CHF2j
R: is cyclopentyi, CHFs, cyclopropylmethyi, pyridylethyl (panicularly 2-
pyridylethyl), or tetrahydrofurany! (particularly (3R)-tetrahydrofuranyl),
and
R" is 3-pyridyi, 3-COOK-phenyl. 3-Cl-phenyl. 3-cyano-phenyl. 3-
athylsulionamido-phenyi, 3-tetrazol-5-yl-phenyl. 3-hydroxymethylphenyl,
4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl. 4-ethylsulfonamidophenyl,
4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVp RJ is methyl or CHF2)
BisN,
R2 is cyclopentyl, CHFi, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl); or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and .
R4 is 3-pyndyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanb-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl,
3-mtro-phenyl, 4-pyridyl. 4-COOH-phenyl, 4-cyano-phenyl, 4-
ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxvmethylphenyl.
Preferred aspects include pharmaceutical compositions comprising a compound of
this invention and a pharmaceutically acceptable carrier and, optionally, another active
agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an
isoenzvme, 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.
Toe 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.
SCHEME I
(Figure Removed)
Starting nitrophenols of the type 1 are either commercially available (e.g., Rl =
]) or prepared by published procedures (e.g., Rl = CHF2 or both Rl and R2 = CHFa, .
see Mueller, Klaus-Helmut. Eur. Pat. Appi. (1994), 8 pp. CODEN: EPXXDW EP
626361A1": Touma, ToshihiJco; Asai. Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp.
CODEN: JK.XXAF J? 11071319 A2; Platonov, Andrew; Seavakov, .Andrew;
Maiyorova, Helen: Chistokletov. Victor. Int. Symp. Wood. Pulping Chem.. 1995. 8th, J,
295-299; Chnstensen, Siegfried Benjamin:.Dabbs. Steven; Karpinski, Joseph M. PCT int.
Appl. (1996),, 12pp. CODEN: PIXXD2' WO 9623754 A l " 19960808). 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 alkylanon reactions. Compounds where R2 is aryl or heteroaryi can be prepared
by copper catalyzed reactions with aryl or heteroaryi iodides under Ullman conditions or
by coupling aryl-, vinyl-, or heteroaryi- boroaic 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, DLAD), and a suitable phosphine (e.g., PrnP, Bu3P)
provides alkylated nitrophenols 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^CCh or NaH) in a polar aprotic solvent (e.g., DMF or
CH3CN).-.
Nitrocatechols 2 are subsequently reduced to the corre'sponding 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, mtrocatechols 3 can be reduced by using a hydnde source (e.g.,
NaBH4) and a transition metal catalyst (e.g., NiCl?, Pd on carbon) or by using metals
(e.g., Zn, Sn, Fe) in mineral acid solutions (e.g.-, HC1) to produce the corresponding
anilines. Generally polar protic solvents such as ethanol or methanol are used in these
reactions.
/Y-Arylalkyl-anilines 4 are synthesized by standard methods in the an such as by
reductive animation reaction, alkylation reaction, or by reduction of corresponding
amides. For example, the reductive animation reaction of an aryl or arylalkyl aldehyde
with appropriately substimted anilines in the presence of a borohydnde reducing agent
such as NaBtL or NaBHsCN with an acid catalyst such as acetic acid or pTsOK provides
desrrea .V-aryialkylaniiines. These reactions generally take place in polar protic solvents
such as methanol. ethanol, isopropanol. n-propanol and the like. -
jV-Aryialkyianilines 4 rsadiiy undergo A'-arylation by methods standard TO the art
including Ullman coupling reaction, metal-catalyzed coupling, or aromatic nucieophilic
substitution reaction. For example, the metal catalyzed reaction between an Nbenzylaniline
and an aryl halide using a palladium catalyst, (e.g., Pd^dba-j), a bulky
electron rich phosphineligand (e.g., tributylphosphme), and suitable base (e.g., NaOtBu)
provides Tv'-Arylalkyldipaenylamines. Nickel and copper catalysts have been employed
as well. Solvents useful in this reaction include non-polar aprotic solvems.such as
toluene, benzene, xylenes, tetrahydTofuran, and ether. When synthesizing compounds of
the type 5 wherein R4 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 (tBu)3P,
5.5 mol % of Pd2(dba);, and 1.3 equivalents of tBuONa are used.
SCHEME 2
(Figure Removed)
Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic
conditions to give the corresponding carboxylic acids 7. For example, an ethyl ester (R5
= Et) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOH) and a water
miscible solvent (e.g., EtOH, THF). While r-Butyl esters (R5* = i-butyl) can be
hydrolyzed using an aqueous acid (e.g., HCI. formic acid. TFA) in a water miscible
orEanic solvent, if necessarv.
SCHEME 3
(Figure Removed)
Coupling of protected tetrazole bromO'Or iodobenzenes (e.g., 5-(3-iodophenyl)-2-
- /
(2-tetrahydropyran)tetrazole) with. JV- substituted aniline derivatives 4 produce THP- .
protected tetrazoles 8. Hydrolysis of THP -protected tetrazoles 8 can be accomplished by
using an aqueous acid, such as HC1 in water and a miscible solvent such-as THF or EtOH
to provide tetrazoles 9. Further, THP terrazoles 8 can also be oxidatively cleaved using
reagents such as CAN and DDQ in halognenated hydrocarbon solvents such as
dichioromethane, chloroform., dichloroethane and the like to yield tetrazoles 9.
Alternatively; tetrazole analogs 9 can be prepared from the corresponding nitriles
by treatment with aside ion (e.g., KN}, NaN~3, etc.) and a proton source (e.g., NELiCl) 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:) 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., Me3SiN3, Bu3SaNT3) in an aprotic organic solvent such as
benzene, toluene, dichioromethane, dichloroethane, ether, THF, and the like.
SCHEME 4
(Figure Removed)
Diphenylamines 10 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 tnethylamine 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 norrpolar
aprotic solvents such as benzene, toluene, or xylene are utilized. Such diphenylamines
(e.g., 10) can more preferably be synthesized by metal catalyzed animation reactions.
For example, reaction of an appropriately substituted aniline 3 with an arylhalide in the
presence of a base (e.g., K^POo, CsCCh, orNaOtBu) and a palladium or nickel catalyst,
for example Pd(dppf)Cb, a ligand (e.g., dppf) and a base (e.g., NaOtBu) (JACS. 1996,
J18, 7217) or with Pdidba}, a bulky electron nch phosphine such as P(tBu)3; and a base
(e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired diphenylamines 10.
Solvents most commonly utilized in this type of reaction include non-polar aprotic
solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.
Diphenylamines 10 can then be alkylated with various alkyl haiides or arylalkyl
halides such as. but not limited to iodomethane, ethylbromide, benzylchloride, 3-
(chloromethyljpyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4-(bromomethyl)-
benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium :
hydnde, potassium hexamethyldisilazide or potassium diisopropylamide to provide Nsubstimted
diphenylamines 5. Solvents useful in this reaction include aptotic solvents
such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like.
SCHEME 5
(Figure Removed)
Carboxylic acids 7 can be further manipulated to form carboxamides 11 using
methods standard in the art. For example, 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^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 6 or acids 7 can be reduced using methods standard in the an to
give the corresponding carboxaldehyde or hydroxymethyl analogs. For example, an aryl
ethyl ester (e.g., structure 6, R5 = ethyl) can be treated with an appropriate reducing agent
(e.g., LAH, DIBAL, etc.)'in an aprotic solvent sueh as ether or TKF, ro produce the
corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and alcohols
can be further derivatised by methods standard in the art.
Similarly carboxamides (e.g., structure 11) and nitriles can be reduced-using
methods standard in the art to provide the corresponding substituted amines or
aminomethy] analogs. For example,.an aryl carboxamide 11 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 nitrite'yields the corresponding primary aminomethyl analog.
SCHEME 6
(Figure Removed)
Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 bymethods
standard in the an such as hydrosenation using a suitable catalyst (e.g., Pd on
carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12 can also be
reduced using a hydnde source (e.g., NaBH Pd on carbon) in polar protic solvents such as EtOH, to produce the corresponding
anilines 13. These anilines can then befurther substituted by methods standard in the an.
For example, anilines of the type 13 can be alkylated, acylated, or sulfonylated to give the
corresponding N-alkyl amines, carboxamides (e.g., structure 15) or sulfonamides (e.g.,
structure 14) respectively. For example, a sulfonamide can be prepared from an aniline
and an appropriate sulfonyl halide or sulfonic anhydride (e.g./MeSO^CL EtSO^Cl,
BnSO^Cl, PhSOiCl, etc.) in the presence of a base (e.g., Et/jN, pyndine, DIEA, etc.).
Suitable solvents for .this reaction include non-polar aprotic solvents such as
dichloromethane, chloroform, ether, and the like.
SCHEME 7
(Figure Removed)
Trialkylsilylethers of the type 16 are prepared as described in Scheme 1. The
Jerr-butyldrmethylsilyl protected catechol intermediates 16 are readily deprotected by
numerous literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in
Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 273-276.) such as by using
a fluoride ion source (e.g., BmNF) in an aprotic solvent such as ether or THF; or under
acidic conditions (e.g., KF, 48% HBr, DMF). The resultant phenol 17, 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. For
example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a
base, or by Ullman type ary! coupling or by reaction with vinyl-, aryl- or heteroarylbororuc
acids in the precence of a copper catalyst.
SCHEME 8
(Figure Removed)
Haioalkoxy intermediates 18. prepared by aikylanon of the corresponding phenol
can be aikylated by reactions with substituted amines, alcohols, or tbaois in the presence
of a base to provide analogs such as 19. For example, an alkyl halide can be ammated
with an appropriate primary or secondary amme and a base such as K^CCb, in a polar
aprotic solvent such as THF, DMF, OT CH3CN.
Many of these synthetic procedures are described more fully in the examples
below.
One of ordinary skill in the-art will recognize that some of the compounds of
Formulae (I) and (T) 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 diastereorners and
diastereomenc 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% wAv of the corresponding
opposite enannomer, preferably no more than 2%, most preferably no more than 1%.
The optical isomers can be obtained by resolution of the racerruc mixtures
according to conventional processes, for example, by the formation of diastereoisomenc
salts using an optically active acid or-base or formation of covalent diastereorners.
Examples of appropriate acids are tananc, diacetyltartaric, dibenzoyltanaric,
ditoluoyltartanc and camphorsulfonic acid. Mixtures of diastereoisomers can be
separated into their individual diastereorners on the basis of their physical and/or
chemical differences by methods known to those skilled in the an, for example, by
chromatography or fractional crystallization. The optically active bases or acids are then
liberated from the separated diastereomenc salts. A different process for separation of
optical isomers involves the use of chir-al chromatography (e.g., chiral FEPLC columns),
_n
with or without conventional derivation, optimally chosen to maximize the separation of
the enannomers. Suitable chirai HPLC columns are manufactured by Diacel. e.g..
Chiracel OD and Chiracei OJ among many others, all routinely selectable. Enzymatic
separations, with or without derivitization. are also useful. Tne optically active
compounds of Formulae I and F can likewise be obtained by crural syntheses utilizing
optically active starting materials.
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 mam compound,, functioning as a base, with an inorganic or organic acid to
farm, a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid,
methane sulfonic acid^ camphor sulfonic acid, oxalic acid, maleic acid, succmic 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, mangnesium, ammonium, and choline salts. Those skilled
in the an 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 reacting the compounds of the invention with the appropriate base via a
vanety of known methods.
The following are further examples of acid salts that can be obtained by reaction
with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates,
benzoates, benzenesulfonates, bisulfates, buryrates, camphorates, digluconates.
cyclopentanepropionates, dodecylsulfai.es, ethanesulfonates, glucoheptanoates,
giveerophosphates, hemisulfaies, heptanoates, hexanoates. fiimarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates. lactates, maleates. methanesulfonates,
nicotmaces. I-naphthalenesulfonates, oxaiates. paimoares, pectinates, persulfates, 3-
phenylpropionates, picrates, pivalates, propionates. succinates, tanrates, thiocyanates,.
tosylates, mesylates and undecanoates.
Preferably, the salts formed are pharmaceutically acceptable for administration to
mammals. Kovvever, 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.
The compounds of the invention can be administered alone or as an active
ingredient of a formulation. Thus, the present invention also includes pharmaceutical
composftitms of compounds of Formulae I or I' containing, for example, one or more
pharmaceutical!y acceptable earners.
Numerous standard references are available that describe.procedures for prepanng
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, intraveneousiy, .
intramuscularly, intrastemally and by infusion), by inhalation, rectally, vagmally.
topically, locally, transaermally, 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, capiets, granules. -
lozenges and bulk powders. The- compounds of the present invention can be administered
alone or combined with various pharmaceuucally acceptable earners, diluents (such as
sucrose, mannitol. lactose, starches) and excipients known in the an, including but not
limited to suspending agents, solubilizers. buffering agents, binders, disintegrants,
preservatives, colorants, flavorants, lubncanis 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 excrpients known in the art such as preservatives,
wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or
Suspending the compounds of die 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, geis, 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
rransdermal parches.
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 invenuon can be administered by inhalation in the form of a powder (e.g.,
micromzed) or in the form of atomized solutions or suspensions, ine aerosol formulation
can be placed into a pressurized acceptable propellant.
The compounds 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 block ers, chlomergic drugs, adenosine receptor modulators, amphakmes NMD AR
modulators, mGluR modulators, and cholmesterase inhibitors (e.g., donepezil,
rivastigimine, and glanthanamme). 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 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 compnse administering to an'1 animal 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,
Huntmgton's disease. Pick's disease, Creutzfeld-Jakob disease, HIV', cardiovascular
disease, and head trauma as well as age-related cognitive decline.
Dementias are diseases thai 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: neurodegeneraave dementias (e.g.,
Alzheimer's. Parkinson's disease, Huntingtor/s disease. Pick's disease), vascular (e.g..
mfarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial
meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subcural
/
hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome),
toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g.. vitamin B12 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 rreatment 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 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 ami-apoptotic
and anti-inflammatory properties make these compounds useful to treat
neurodegeneration resulting from any disease or injury, including stroke, spinal cord
injury" neurogenesis, Alzheimer's disease, multiple sclerosis, amyiolateroscierosis (ALS),
and multiple systems atrophy (MSA).
Thus, m accordance with a preferred embodiment, the present invention includes
methods of treating patients suffering from memory impairment due to, for example,
Alzheimer's disease, schizophrenia, Parkinson's disease, Huntmgron's disease. Pick's
disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, ,
csrebral senility, multiinfarct dementia and other neurological conditions including acute
neuronai ciseases, as .well as HIV' and cardiovascular diseases, comprising adininisierinj
an effective amount of a compound according to Formula (I) or (T) or pharmaceuhcally
accepiabie sails thereof. The compounds of the present invention can also be used in a method of treating
patients suffering from disease states characterized by decreased NMD A 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- , -
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, 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) or (I1) or a pharrhaceuticaily 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 anhntis,
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, atherosclerosis, •
keratosis, rheumatoid spondylitis, osieoarthritis, pyresis. diabetes mellims,
pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary
disease, roxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen
simplex, sunburn, pruntis in the anogenital area, alopecia areata, hypertrophac scars,
discoid lupus erythematosus. systemic iupus erythematosus, follicuiar and wide-area
pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease.
anaphylacioid purpura nephritis, inflammatory bowei 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, J?l 1-18957, JP 10-072415, WO 93/25517, WO
94/14742, US 5,814,651, and US 5,935,9778. 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.
PDJ54 inhibitors maybe 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 unnary obstruction
secondary to benign prostatic hyperpiasia, for suppression of chemotaxis and reduction of
invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (BCLL),
for inhibition of uterine contractions, to attenuate pulmonary vascular ischemiareperfusion
injury (IRI), for comeal hydration , for inhibition of IL-2R expression and
thereby abolishing HTV-1 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 the present invention 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, chloinergic drugs, adenosine receptor modulators,
amphakmes NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors
(e.g., donepezil. rivastigimine, and gianthanamrne). In such combinations, each active
ingredient can be administered either m accordance with their usual dosage range or a
dose below their usual dosase ranse.
The dosages of the compounds of the present invention depend upon a variety of
factors including the particular syndrome to be treated, the seventy 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 mamma] 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, 0.01-100 mg/kg/day, preferably 0.1-
70 mg/kg/day, especially 0.5-10 mgAcg/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 ing/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 nonlimiting
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 se: forth
uncorrectea in degrees Celsius; and, unless otherwise indicated, all pans and percentages
are by weight.
The entire disclosures of all applications, patents and publications, cited above
and below, are hereby incorporated by reference.
EXAMPLE 1A
l-Cyclop'entyloxy-2-methoxy-5-mtrobenzene
To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium
carbonate (643.5g, 4.66 mol) 'in dimethylformamide (1 L), under NT protection, was
added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100°C
for 6h. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46
mo!) were added. The suspension was heated to 100°C for 4h. TLC indicated the
reaction was complete (9:1 DCM:MeOH). The reaction mixture was cooled to room
temperature and diluted with water (3L) and ether (3L). The layers were separated and
the aqueous layer was re-extracted with ether (2L). The combined organic layers were
washed with IN NaOH (2L), water (2L), and brine (2L). The organic layer was dried
over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with
toluene (2 x 300 mL) to obtain 736".7g (99.6% yield) as a yellow solid.
Tne following compounds were prepared in a similar manner as described above:
a) l-CyclopropyLmethoxy-2-methoxy-5-nitrobenzene
b) 1 -C yclopentoxy-2-difluoromethoxy-5-nitrobenzene
c) i-Cyciopropylmethoxy-2-difiuoromethoxy-5-nitrobenzene
EXAMPLE IB
2-Methoxy-5-nitro-l-((37?)-tetrahydrofuryloxy)benzene
To amixture of 2-Methoxy-5-nitrophenol (1.69 g, 10 mmol), tnphenyiphosphine
(5.24 g, 20 mmol) and 3-(JR)-hydroxytetrahydrofuran (1.80 g. 20 mmol) in anhydrous
tetrahydrofuran (40 mL) was added drop-wise, with stirring, diisopropyiazodicarboxyiate
(4.0 mL, 20 mmol) and the mixture was allowed to stir at room temperature for 16 h.
The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL)
and bnne (50 mL), (MgSCU) and concentrated in vacuo. The crude residue was purified
by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20%
ethyl acetate in hexanes to give 1.05 g of product . •
The following compounds were prepared iii a similar manner as described-above:
a) 2-Methoxy-5-nitro-l-(3-tetrahydrofuryloxy)benzene
b*) 2-Methoxy-5.-n]tro-l-((35)-tetrahydrofuryloxy)benzene
c) 2-DifJuoromethoxy-5-rutro-1 -(3-tetrahydrofurylox'y)benzene
d) 2-Difluoromethoxy-5-nitro-l -((3J?)-tetrahydrofuryloxy)ben2ene
e) 2-Difluoromethoxy-5-nitro-1 -((3,S)-terrahydrofuryloxy)benzene
f) 2-Methoxy-5-nitro-1 -(3-phenpropyloxy)benzene
g) 1 -(2-Indanyloxy)-4-rnethoxy-5-nitrobenzene
EXAMPLE 1C
l-{r£rt-Buryldimethylsilyl)axy-2-methoxy-5-nitrobenzene
To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 :
g,. 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, ten- ,
butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at
room temperature for 16 h. The solvent was removed in vacuo and the residue was
dissolved in 40 mL of 50% ethyl acetate in hexanes and. filtered through 10 g of silica-gel
The silica gel was washed with an additionaF'200. mL of 50% ethyl acetate in hexanes and
the nitrates were combined and concentrated in vacua to give 2.01 g of product as a tan
crystalline solid. !H NMR(CDCh) 5 7.89 (dd, IE, J = 9.0 Hz, 2.8 Hz), 7.69 (d, IE, J =
2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).
EXAMPLE 2
3-Cydopentyloxy-4-methoxyaniline
To a suspension of 10% Pd on activated carbon (25g) in ethanol (4L), under N2
protection, was added 1 -eyelopemyloxy-2-methoxy-5-nitrobenzene (250g, 1.054 mol).
Tne reaction mixture was degassed under vacuum three times. The reaction mixture was
'stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture.
After 4h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was
filtered through a pad of celite and the celite was rinsed with additional ethanol.- The
solvent was removed in-vacuo to obtain 208.33g (95% yield) of 3-cyclopentyloxy-4-
methoxyanilme as a red liquid, 'H.NMR (CDC13) 5 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H),
6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (pf J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81
(m,6H), 1.61-1.55 (m,2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopenty.loxy-4-difluoromethoxyaniline
b) 3-Cyclopropyimethoxy-2-methoxyaniline
c) 3-Cyclopropyrnieiihoxy-4-difluoromethoxyanilitse
d) 4-Methoxy-3-((3J?)-tetrahydrofuryloxy)aniline
e) 4-Methoxy-3-(.teirahydrofuryloxy)aniline
f) 4-Methoxy-3-('(35)-retrahydrofuryioxy)aniline
g) 4-Difiuoromethoxy-3-('3-tetrahydrofuryloxy)aniiine
h) 4-Difiuoroniethoxy-3-((3Jl?)-tetrahydrofuryioxy)aniline
i) 4-Difiuoromethoxy-3-((35)-tetrahydrofuryloxy)aniline
) 3-{/err-Butyldimerhylsiiyl)oxy-4-methoxyaniline
k) 4-Methoxy-3-(3-phenpropyioxy)aniiine
i) 3-{2-Incany!oxy)-4-merhoxyaruiine
EXAMPLE 3
3-CyclopeDty!-4-metboxy-yV-(3-pyridylmethyi)aiii]ine
To a mixture of 3-pyndinecarboxaldehyde (106.55g, 0.995 moi) in methanoi (5L) was
added 3-cyclopen,tyloxy-4-methoxyaniline (208.38g, 1.005 mol) and p-toluenesuifonic
acid monohydrate (200 mg). The reaction mixture was stirred for 4h. The flask was then
cooled to 0°C and sodium horohydride (37.64g, 2.3 mol) was added porrionwise over 4h.
The reaction mixture was allowed to warm to room temperature over I6h with stirring.
TLC indicated the reaction was complete (1:3 bex:EA). The solvent was evaporated unti]
approximately 0.5.L of slurry remained. Toe slurry was diluted with water (1L) and
extracted with ethyl acetate (2 x 2L). The combined organic layers were washed with
brine (500 mL), dried over sodium sulfate, and concentrated to yield 300g (100% yield)
of the desired product as a brown viscous liquid. 'H NMR (CDC13) 5 8.61-S.48 (m, 2H)S
7.69-7.67 (m. 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, IK), 6.13 (dd, J =»
2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H>, 1.83-1,70 (m, 6H),
1.65-1.45(mr2H). . -
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-V-(3-thjenylmethyl)aniline
b) 3-CyclopentyJoxy-4-methoxy-A'-(4-pyridylmethyI)analine
c) 3-Cyc]openryloxy-/V-(2.6-dichloTO-4-pyridylmethyl)- 4-methoxyaniline
d) 3-Cyclopentyloxy-4-rnethoxy-.'V-{2-quinolinylmethy!)aniline
e) 3-Cyciopentyloxy-4-tnethoxy-iV-{3-quinolinylmethyl)aniIine
f) 3-Cyclopenryloxy-4-methQxy-.iV'-(4-quinolinylmethyl)amline
g) 3-CyciopenTyloxy-4-methoxy-A-(--pyi"22ir!yfene^yi)ariiIii!e
h) 4-Meihoxy-//-.(3-pyricybnethyI)-3-(3-tetrahydro-furyloxy)aniiine
i) 4-Mechoxy-/V-{3-pyridylmemy!)-3-((3^}-tecrahydrofuryloxy)aniline
j) 4-Metfaoxy-//-{3-pyridylmethyl)-3-((3l5)-cetrahydrofuryloxy)am'line
k) 3-CyciopropyImethoxy-4-Giiluororaethoxy-,V-(3-pv-ndyimerhyi)aniiine
i) 3-CyciopenTyloxy---difjuoromethoxy-Ai'-{3-p}TidylmeLiyl)arilline
m) 4-Dii1uoromerboxy-A^(3-pyridyb7iethyl)-3-(3-ten'ahydrofury!o7cy)aBiliT)e
n) 4-DifJuoromechoxy-A"-{3-pYridylme±yl)-3-((3j;?)-tenrahydrofun'loxy)anHine
o) 3.4-Bis(difjuoromethoxy)-Ar-(3-pyridylmethyl)aniline
p) 3-tert-Butyidimethyisi]yloxy-4-methoxy-.¥-(3-p'yridylmethyI)arii]me
q) 3-Cyclopentyloxy-4-methoxy-//-(2-pyridylmethyl)aniline
r) 3-Cyclopenryioxy-4-methoxy-.'V-[ I -{2-phenethyl)Janiline
s) A"-Benzyl-3-c.yclopentyloxy-4-methcxyaniline
t) jV-[(Cyclohex-l -en-i -y])methylj-3-cyciopenty]oxy-4-methoxyaniline
u) 3-Cyclopentyioxy-4-Tnethoxy-A'-(3;4,5-tnmethoxybenzyi)anilme
v) yV-[(Cyclohex-3-en-l-yl)rnethyl]-3-cyclopentyloxy-4-methoxyaniline
w) 3-Cyclopenryloxy-4-metboxy-/vr-(2,4J6-trimethylbenzyl)aniline
x) 3-CycIopentyloxy-4-methoxy-A-(2-methyiben2yl)aniline
y) 3-Cyciopenry]oxy-4-methoxy-A/-(2-trifjuorometbylben2yl)auiline
z) 3-Cylclopentyloxy-4-methoxy-A-((3:4-methylenedioxy)ben2y!)aniliBe
aa) 3-Cyclo.penryloxy-//-(2-hydroxy-3-methoxylbenzyl)-4-rnethoxyaTiiiine
bb)3-CycIopenryloxy-.;V'-(3-i:urylmethyl)-4-methoxyani]ine
cc) 3-Cyclopenty]oxy-4-rnethoxy-/V-(3-methylbenzyl)aniline
dd)3-CyclopentyJoxy-4-methoxy-AL(2-me.tboxybenzyl)aniline
ee) 3-Cyclopenfy}oxy-4-methoxy-.'V-{3-chlorobenzyl)aniline
ff) 3-Cyciopentyloxy-4-methoxy-A/-(3-methoxyben2yl)amIine
.gg)3-CyciopentyJoxy-4-methoxy-,Y-(2-chJorobenzyI)aniline
hh)3-Cyc]opencyloxy-4-methoxy-.'V-{3-raethy3be7i2yl)aniline
ii) 4-Methoxy-3-(3-phenpropyloxy)-A-(4-pyridyimethyl)aniline
jj) A'-(2.6-Dichloro-4-pyridyimethyl}-3-(2-mdanyloxy)-4-methoxyaniline
ick)4-Merhoxy-3-(3-phenpropylcxy)-/V-(2-pyndyimethyl)aniline
1!) yV-(2,6-Dichloro-4-pyridyiine:hyi)-4-methoxy-3-{3-phenpropy}oxy)aniIine
mm) 4-Methoxy-3-(3-pbenpropyioxy)-A'-(3-pyridyirneihyl)aniline
. im)3-Cyclopentyloxy-4-methoxy-.A/-(2-thienylmethyI)aniline
oo) 3-(2-Iudanyloxy)-4-methoxy-?/-(3-thienykafithyl)aniliDe
pp) 4-Meihoxy-3 -{3-phenpropyioxy}-.A'"-(3-chienyiniethyl)aniliiie
qc) 3 -{2 -Ind an yloxy)-4-methoxy-/V-(2 -pyri d ylmethyl)ani line
rr) 3-(2-Indanyloxy)-4-meihoxy-A'-(3-pyridyIineihy!)aiiiline
ss) 3-(2-Indanyloxy)-4-rnethoxy-A'-(4-pyndyimethy!)anilme
ft) 3-Cyclopentyloxy-4-methoxy-A-(3-pipendinernethyl)aniJine
uu) 3-Cyclopentyloxy-4~rnethoxy-/Y-(3-(l -tenbutyloxycarbonyl)
piperidinemethyl)aniline
vv)3-Cyc]opentyloxy-4-methoxy-A/-(6-methy]-2-pyridy[inethy])aTii3ine
ww) jV-(2-Chloro-3-pyridyimethyI)-3-cyclopentyloxy-4-raethoxyaniline
xx)7V-(2-Chloro-5-pyridylTnethyl)-3-cyciopentyloxy-4-methoxyani'lme
yy) 3-Cyclopenryloxy-4-methoxy-Ar-(2-thia2olyimerhyI)anilijie
EXAMPLE 4 .
3-Cyclopentyloxy-4-metbo.ry-.Y-(3-pyridylmetfayI)diphenyiamiDe
To a 100 mL oven dried, argon flushed flask was added in the following order 0.59 g
(6.10 mmol) of NaOtBu, 360 mg ofPd2dba3, 20 mL of toluene, 0.14 mL ofPftBu)3, and a
20 mL solution of 1.3 g (436 mmol) of N-{3-pyridylmethyI}-3-cyclopentyloxy-4-
methoxyaniline in toluene. With stirring, 3'. 1 g (15 mmol) of icdoberrzene was added
dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted wirh
EtOAc and washed twice with HiO and extracted with 3 x 1 5 mL of 3,V HCL The
combined acid extracts were washed wirh 15 mL of EiOAc and then carefully neutralized
with 6N NaOK to pH greater than 12. The b-asic solution was extracted with 2 x 15 mL
of EtOAc and the combined organic fractions were subseauenilv washed with 15 mL of •C? i u
H20 and brine, dried (MgSO*), and concentrated. Tne residue was purified by
chromacography over silica gel (Biotage Flash 40M) eiuting with 25% EtOAc in hexanes.
The material was further punned by crystallization from hexanes to give 550 mg of a
white solid. !H NMR (CDC13) 5 8.61 (s, IH), S.49 (d, IK, J = 42 Hz), 7.67 (d, 1R 7.9 ,'
Hz), 7.30-7,10 (m, 3E), 6.90-6.80 (m, 4K), 6.80-6,60 (m. 2H), 4.94 (sr 2H)r 4.64 (p, IH, J :
= 4.1 Hz),3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).'
The following compounds were prepared in a.similar manner as described above:
a'i 3-Cyclopenrvicxy---meihcxy-2'-methyl-yY-(3-pvndyimsthyl)diphenylam.ine
b) 3-Cyclopenryloxy-4-methoxy-3'-meihyl-A'-(3-pyridylniethyl)diphenylamine
c) 3-Cyc]opentyloxy-4-methoxy-4'-methyl-A-(3-pyridylmethyl)diphenylamine
d) 3-Cyclopemyloxy-4'-ethyl-4-methoxy-A'-(3-pyndylmethyl)diphenyIa-mine
e) 3'-Ch]oro-3-cyciopentyloxy-4-methoxy-.A/-(3-pyTidylrnethyl)dipheTiylarnme
f) 4'-Chloro-3-cyclopentyloxy-4-methoxy-Ar-(3-pyridylinethyl)Qiphenylarnine
g) 3-Cyclopentyioxy-2: ,4-dimethoxy-/V-(3-pyTidylTnethyi)diphenylamine
h) 3-Cyclopentyioxy-3'.4-dimethoxy-A7-(3-pyndylmethyl)diphenylamine
• i) 3-Cyclopentyloxy-4,4'-dirnethoxy-/Y-(3-pyridylmethyl)diphenylamine
j) 3-Cyclopentyloxy-4-methoxy-A'-(3-pyndylmethyl)-3'-tnfliioromethyldiphenylaTnine
k) 3-Cyclopentyloxy-4-methoxy-A-(3-pyndylmethyl)-4'-trifluoromethyldiphenylamme
1) 3-CYclopentYloxy-3'-fluoro-4-methoxy-A/-(3-pyridylmethyl)diphenylamine
m) 3-Cyclopentyloxy-4'-f]uoro-4-methoxy-,V-(3-pyTidylmethyl)dipheTiyiamine.
n) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-A/r-(3-pyTidylmethyl)diphenylamine
o) 3-Cyclopentyloxy-4-methoxy-4'-phenyl--'V-(3-pyridylmethyl)diphenylamine
p) 3'-Cyano-3-cyclopentyioxy-4-methoxy-A'-(3-pyndylinethyl)diphenYlamine.
q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-.V-(3-pyridylrnethyl)diphenylamine
r) Ethyl 7V-(3-cyclopentyloxy-4-methoxyphenyl)-A/r-(3-pyTidylmethyl)-3-aminobenzoate
s] Ethyl A-(3-cyclopentyloxy-4-methoxYphenyl)-Ar-(3-pyTidylmethyl)-4-aminobenzoate
t) 3-Cyclopentyloxy-4-tnethoxy-3I-nitro-A'-(3-pyridylrnethyl)dipheny!amine
u) S-Cyclopentyloxy^-methoxy^'-mtro-A^^S-pyridylmethy^diphenylamme
v) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-pyridylmethyl)-1 -naphthyiarnme
w) 3-Cyclopentyloxy-2' ,3 '-dimethyl-4-methoxy-Ar-(3-pyridylmethyl)diphenylainme
x) 3-Cyclopentyloxy-2>
J4'-dimethyl-4-methoxy-/V-(3-pYndyimethyl)diphenYlainine
y) 3-Cyclopencyloxy-2'.5'-dimediyl-4-methoxy-A-(3-pYridylmethyl)Qipheiiyiamme
z) 3-Cyclopentyloxy-3\4'-dimethyl-4-me!:hoxy-A-(3-pyTidylmethyl)dipheiiylarnirie
aa) 3-Cyciopentyioxy-2! ,3'-dichloTo-4-methoxy-.'V-(3-pYridyiineihyl)diphenylamme
bb)3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-A'-(3-pyndyimethyl)Giphenylamine
cc) 3-Cyclopenryloxy-3\5'-dicaloro-4-methoxy-.V-(3-pyndylrnethyl)diphenylamine
dd) 3'-ChloTo-3-eyclopencyloxy-4'-fiuoro-4-methoxy-.'V'-(3-pyridylmethyl)dipheTiylaTnine
ee) -:-Chioro-3-cyclopenrylpXY-3>fluoro-4-inerhoxy-jV'-(3-pvTidyimethyi)diphenylaniine
ff) 4;-ChJorc-3-cycJopenryloxy-4-meiiioxy-.V-{3-pyridylmethyl)-3'-
tniluoromethyldiphenylarnifle
gg) 5-Cyclopenty]oxy-4-Tnechoxy-Ar-(3-tkienyimeihyl)diphenylainiTie
hh)JV-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-chienyimethyl)-l-naphthylamine
11) 3-Cyc]openTyIoxy-2'.3'-d}chloro-4-methoxy-;V-(3-thienylrnethyi)diphenyianaine
jj) 3-Cyclopencyloxy-4-methoxy-4'-methyl-yV-(4-pyridylmethy])Qipheiiylamme
kk')3-Cyclopenryloxy-Ar-(2.6-dichloro-4-pyndyliTiethyl)-4-methoxy-3'-
methyldiphenyiamine
11) 2!-Chioro-3-cyc}opentyloxy-A'-(2,6-dichloro-4-pyTidyknethyl)-4-
methoxydiphenylamme _
mm) 3-Cyclopentyloxy-A-(2,6-dichloro-4-pyridylmethyl)-4-niethoxydiph€nylamine
nn) 3-Cyclopentyloxy-4-methoxy-A-(6-methy!-2-pyridylmethyl)diphenyiamine
oo)3-Cyclopeniyloxy-4-methoxy-A-(3-quinolinylmethyl)diphenylamine
pp)3-Cyclopenty]oxy-4-methoxy-Ar-(4-quinoIinyimethyl)diphenylamine
qq33-Cyc]openty]oxy-4-n]ethoxy-A/-{2-pyrazinyImethyl)diphenYlamine
rr) 4-Mschoxy-3'-methy3rA7-(3-pyndyimethyl)-3-(3-tetrahydrofuryloxy)dipheTiylarnine
ss) 4-Methoxy--'-methyl-A7-{3-pyridylTnetby!)-3-(3-tetrahydrofury!oxy)diphenylaTTiirie
tt) 4,4^DLmethbxy-A?-(3-pyricylmethyi)-3-(3-Letrahydrofuryloxy)diphenylamirie
uu) 3'-ChJoro-4-methoxy-A-(3-pyndyimeihyl)-3-(3-tetrahydrofurytoxy)diphenyiarnine
w) 4-Methoxy-4 '-{4-methylpiperazin-1 -ylcarbonyl)-A-(3-pyridylmethy!)-3-(3-
tetrah ydro furyloxy)diphenylamine
ww) 3 '-Cyano-4-meihoxy-A-(3-pyridy}methyl)-3-((3j!?)-
tecrahydrofury]oxy)diphenyiamine ""
xx) 3 '-Cyano-4-methoxy-A-(3-pyTidylraethyl)-3-((3J?}-tetrahydrofuryJoxy)diphenylamme
yy) 3-Cyciopropylmethoxy-4-dif3uoromelhoxy-A-(3-pyTidyimethyl)diphenylamme
22) 3-Cyciopen[y!oxy-4-dii3uoroinethoxy-A'-{3-pyridylrnethyl)diphenylaniine
aaa.) 4-Diiiuoromethoxy-A'-(3-pyridyimerhyl)-3-(3-tetraJiydrofuryioxy)diphenylamine
bbb) 3;4-Bis(difluoromethoxy)-A-(3-pyridyimethyi)diphenylanime
ccc) 4-Difluoromethoxy-'V-{3-pyridyimetbyl)-3-((3j!?)-
teirahydro fury 1 oxy) dip hen ylamine
ddd) 3'-Cyano---di3uoromethoxy-A7-{3-pyTidyimethyl)-3-((3/?}-
rsirah ydro fury j oxy)diphen yl amine
eee) 3'-Chloro-4-difluororaethoxy-A"-(3-pyridylmethyl)-3-((3/?)-
tetrahydrofuTyloxy)diphenylamine
iff) Ethyl A'-(3-cyclopropylmethoxy-4-di3uorometiioxypbe-nyl)-A-(3-pyridylrnethyl}-3-
aimnobenzoate
ggg) 3-Cyciopentyloxy-4-methoxy-3 '-{^-methylpiperazin-l -yicarbonyI)-7V-(3-
pyndylmethyl)diphenyiaraine
hhh) 3-Cyclopentyloxy-4-metboxy-4'-(4-methyipipera2Tn-l -ylcarbony])-yV-(3-
pyridylmethyl)diphenylamine
111) 3 '-?erf-ButyldiTnethyisi]yloxy-3-cyciopentyJoxy-4-methoxy-jV-(3-
pyndylmeihyl)diphenylamine
JJj) 4'-/er/-Butyldiiriethylsi]yloxy-3-cyc!opentyloxy-4-methoxy-A'-(3-
pyndylitierhyl)dipbenylarnine
kkk) rm-Butyl A'-(3-cyclopentyloxY-4-methoxyphenyI)-A-(3-pyridylmethyl)-3-
amiriobenzoate
111) Ethyl A-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-7v-(3-pyridylinethy])-3-
am:noben2oate
mmrn) Ethyl ,V-(4-dif]uoromeihoxy-3-(3-Letrahydrofuryloxy)phenyl)-.A/'-(3-
pyridylmethy!)-3-aminobenzoate
Tinn) Ethyl /V-(334-Bis(difluoromethoxy)phenyl)-/V-(3-pyridyimethyl)-3-aminoben2oats
ooo) Ethyl ^-(4-methoxy-3-((3^)-tecrahydrofuryloxy)phenYi)-A-(3-pyridylrnethyl)- -3-
amiiiobenzoate
ppp) Ethyl ,V-(3-cyclopropyiinethoxy~4-methoxyphenyl)-jV-(3-pyridyimethyi)-3-
ammobenzoate
qqq) 3-CyclopenTyloxy-4-methoxy-4'-(2-(teirahydropyran-2-yi)-2H-teira2ol-5-yl)-/V-
(3-pyndyimethyI)diphenylamine
rrr) 3-Cyciopentytoxy^-methoxy-3!-(2-{ieu'ahydropyTan-2-yl)-2H-tetra2ol-5-yl)-A'-{3-
pvTidyimethyl)diphenylamine
sss) 4-Methoxy^'-(2^tetrahydropvran-2-yl)-2H-tec-azol-5-y[}r^-(3-pyridylinethy]>3r-
((3^?)-tetraJiydroiuryloxy)diphenylaraine
iu} 3-Cyciopropvlmethoxy-i-meLho>:y-^!-{2-{tetrahydropyTan-2-y])-2E-tc:ra2oi-5-y!)-V-
(3-pyriGyirnerhy!)dipheriyiamine
uuu) 4-Diiluoromethoxy-4: -(2-{tetrahydropyTan-2-vl)-2H-cetrazo i-5-yI)-/V-(3-
pyndyknethyl)-3-{(3^)-tetrahydrofurylcxy)diphenylamine
vvv) 3-Cyclopropylrnethoxy-4-difluorornethoxy-4'-{2-{tetrahyd.ropyran-2-yl)-2Hte:
ra2o]-5-yJ)-jV.(3-pyridylmethyl)diphenylamine
www) 3-Cyclopenty]oxy-4-dif]uoromethoxy-4'-(2-(tetrahydropyran-2-yI)-2H-tetrazol-5-
yl)-A-(3-pyndylmethyl)diphenylanime
xxx) 3-CycJopropyimethoxy-4-difjTiorornethoxy-3!-(2-(tetrahydropyran-2-yi)-2Htetrazol-
5-yl)-jV-(3-pyridylmethyl)diphenyla:mine
yyy) . Bis-(3,4-difluorotnethoxy)-3'-{2-(tetrahydropyran-2-.yl)-2H-tetrazo]-5-y])-.;V-(3-
pyndylmethyijaiphenylamine
222) 3-^rf-Butyldirnethylsilyloxy-4-mechoxy-AA-(3-pyridyirnethyl)diphenyJamin.e
aaaa) 3-/err-Butyldimethylsilyloxy-3:-chloro-4-methoxy-A-(3-
pyridylmethyl)diphenylaraine
bbbb) Ethyl yV-(3-:erf-butyldimethylsilyIoxy-4-methoxyphenyI)-A/'-(3-pyndYlmethyl)-3-
amtrioberizoate
cccc) 37Cyciopenry!oxy-2'-chloro-4-methoxy-yV-(3-pyridyimethyl)dipheny]amine
dddd) 3-(2-i-ndanyloxy)-4-methoxy-iV-(3-pyTidylmethyl)diphenylamine
EXAMPLE 5
yY-(3-CYclopentyloxy^4-methoxyfphenyl)-A'-(3-pyridylmethyl)-3-aminobenzoic acid
A solurion of 6.5 g of ethyl jV-(3-cyclopentyloxy-4-methoxyphenyl)-.'V-(3- ;
pyndyimethy!}-3-aminoben2oate in 50 mL of EtOH was created with 10 ml of 6N
NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 ;
mL of H:>0. The aqueous mixture was extracted with 2 x 50 mL of ether, acidified with
Ac OH to pH 3, and extracted with 2 x 50 mL of EtOAc. The combined EiOAc fractions
were washed with 25 mL of JLO and. 25 mL of brine, dried (MgSOa),. and concentrated.
The residue was purified by chroniatography over SiCK (35 g ReaiSep® column) usirvg a
linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20 -
minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60°C.;
"'H NMR (CDC13) 5 i 1,15 (bsr IE), 8.70-8.55 (m, 2K), 7.77-6.71 (m, 9H), 4.99 (s, 2H),
4.65 (p., J = 3.8 Hz; iH); 3.34 (s. 3H), 1.86-1.70 (m, 6H)r 1.65-1.45 (m, 2K).
The following compounds were prepared in a similar manner as described above:
a) A'-{3-CycIopenLyloxy-4-methoxyphenyl}-.V-{3-pyTidylrnethyr)-4-arninoberi2oic acid
b) /V-(3-Cyclopentyloxy-4-difluorornethoxypheny!)-/V-(3-pyridylmethyl)-3-
aminobsnzoic acid
c) M{4-Difluoromethoxyo-(3-tetrahyQrofuryloxY)phenyl]-A-(3-pyndyirnethyl)-3-
.aminobeiizoic acid
d). ./V-3,4-Bis(difluoromethoxy)p.henyl)-A'-{3-pyridylinethyl)-3-aminoben2oic acid •
e) Af-[4-Methoxy-3-{(3j?)-'t-etrahydrofuryloxy)phenyl]-7V-(3-pyndy{rnethyl)-3-
ammobenzoic acid
f)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-iV-(3-pyridylmethyi)-4-aminobenzoic
acid
g) A'-(3-Cyclopropylrnethox}'-4-difmoromethoxyphenyl)-/v-(3-pyrjdyirnethyl)-3-
ammobenzoic acid
h) Ar-(3-Cyciopentyloxy-4-methoxyphenyl}-3-aminobenzoic acid
i) -[3-(4-Chlorophenyl)prop-l-yloxy-4-m.ethoxyphenyl]-A'-(3-pyridylmethyl)-3-
ammobenzoic acid
j) A-(3-Cyc]opropylmethoxy^-methoxyphenyI)-/V-(3-pyridylmethyl)-3-arninobeii2oic
acid
k) A'-[3-(2-Indaiiyloxy)-4-methoxyphenyl]-A;-(3-pyridyiiriethyl)-3-aminoben2oic acid
]) A-{4-MethoxY-3-(3-tetrahydrofuryloxy)phenyl]-A'X3-pyridylrnethyl)-3-arninoberizoic
acid
m) 7V-[4-Meihoxy-3-((3R)-iet:rahYdroiuryloxy)phenyl]-A/-(3-pyridylmethyi)-3-
aratnobenzoic acid
n) A/-r5-(2-Msd3oxyethoxy)-4-meihoxyphenyij-/V-(3-pyridyirne[hyl)-3-aminobenzoic
acid
o) A-[4-Methoxy-3-(2-{2-pyridyl)ethyI)oxyphenyl]-/v-{3-pyTidylmethyl)-3-
ammobenzoic acid
EXAMPLE 6
A-{3-Cyclopentyioxy-4-methoxypbenyJ)-/Y-{3-pyridyimetfayl)-2-amiDoben2oic acid
Ten-Butyl .'V-(3-cyciopentyloxY-4-methoxyphenyl)-A/'-(3-pyriGy}methyl)-2-
arninobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL 98% formic acid and heated at
40 UC for 4 h. The formic acid was removed in vacua and the residue was loaded onto a
column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from
40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 mm to yield 16 me of product
as a brown solid. :H NMR (CDC13) 5 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H),. 8.10 (df 1H, J =
7.8.), 7.67 (d,.lH, J = 7.8 Hz), 7.56 (m, IH), 7.40-7.20 (m, 3H), 6.75 (d, IH, J = 8.7), 6.57
(d.. IH, J = 8,7), 5.47 (s, IH), 4.72 (s, 2H). 4.54 (p, IH, J - 4.3), 3.77 (s, 3H), 1.80-1.60
(m, 6H), 1.60-1.40 (m,2H).-
The following compounds were prepared in a similar manner as described above:
a) A'-{3-Cyc!opentyloxy-4-methoxvphenyl)-A-{3-p-yridyimeLbyl)-3-aminoben2oic acid
b) W-(3-Cyclopentyloxy-4-methoxypheny!)-.V-(3-pyridylrnethyi)-6-arnirion]cormic acid
EXAMPLE'7
3-Cyclopropylmethyioxy-4-difiuorometboxy-jV-{3-pyridylmettiyl)-4;-
(2H-tetrazol-5-yl)diphenylamine
3-Cyciopropy]rnethoxy-4-difluoromerhoxy-Ar-(3-pyridylmethyI)-4'-[2-(2-
tetrahydropyrany!}-2H-ietrazol-5-yl]diphenylamine (1.5 g, 0.26 rnmol) was dissolved in
THF (5 mL) and 3 mL of IN HC1 was added. After 6 h at room temperature, the mixture
was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with
EtOAc (3 x 50 mL). The EiOAc extracts were combined, washed with bnne (50 mL),
dried (MgSOO, and concentrated in vacua. The crude residue was loaded onto a RediSep
column (10 g, silica gel) and the product was eiuted using a linear gradient from 0%
MeOK in EtOAc to 5% MeOH hi EtOAc over 20 mm to give 0.96 g of product as a white
powder. 'H NMR (CD3OD) 5 8.55 (s, IH), 8.43 (d, IH, J = 4.9 Ez), 7.65 (d, IH, 8.0'Hz),
7.21 (dd: IH, J*4.9 Hz, 8.0Hz), 7.18 (d, IH, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.S7 (dd,
IK, J = 8.6Hz;2.5Hz);6.75 (i, 1H, J = 75.5 Hz), 5,I4(s:2H), 3.82 (d, 2K, J = 6.9 Hz),
1.23 (m: iH), 0.60-(m, 2H), 0.33 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-A/-(3-pyndylmethyl)-4'-{2H-tetra2oi-5-
yOdiphenyiamine
b) 3-Cyclopenryloxy-4-methoxy-./V-(3-p>ridylmethyl)-3'-(2H-tetrazol-5-
yl)drpheny]armne
c) 4-Methoxy-.V-{3-pyndyimethyl)-3-((3^)-tetrahydTofurYioxy)-4:-{2'H-tetra2o[-5-
y3)diphenyiamine
d) 3-Cyclopropylrnethyloxy-4-metho'xy-.Ar-(3-pyndylmethyl)-4>-(2H-tetra2ol-5-
yl)diphenylarnine
e) 4-Difluoromethoxy-A'-(3-pyn'dylmethyl)-3-((37?)-tetrahydroruryioxy)-4' -(2H-tetra20J-
5-y[)dipheny]amine
f) 3-Cyclopentyioxy-4-diflurornethoxy-A'"-(3-pyridylmethyl)-4'-(2H-terrazol'5-
yOdiphenylarnrne.
g) 3-Cyclopropylrne£hyloxy-4-diiluoromethoxy-/V-(3-pyndylrnethYl)-3:-{2H-tetrazo3-5-
yJ)diphenyiamine
h) Bis-3,4-difluoromethoxy-vV-(3-pYndylrrjethyl)-4'-(2H-cetrazol-5-yI)diphenyiaTnme
EXAMPLE 8 (Method A)
3-CyciopentyIoxy-4-methoxydipbenylamine
Method A. (Rsf. Chan, D:M.T., Monaco, K.L.; Wang, R.P.; Wincers, M.P.,
Tetrahedron Lett., 1998, 39, 2933-2936.). A slurry of 207 mg of 4-methoxy-3-
cyclopencyloxyanilme, 2SO mg of phenylboronic acid, 182 mg of Cu(OAc}i, 280 uL of
Et3N and 4.0 ml of C&Cl? was stirred for 20 h at room lemp. The black mixture was
filtered through silica eluting with CHjC1^, concenrrarsd. and purified by
chromacoghraphy over SiOi using EtOAc/Eexanes (15/85) as.eluant ID provide 75 mg of
the desired product. !H NMK (CDC13) 6 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s5
1H), 4.71 (m, 1H), 3.32 (s, 3E), 1.89-1.54 (m, 8H).
The following compounds were prepared in a similar manner as described above:
a) 3~CycIopemyloxy-3 \4-djroethoxydiphenyiamme .
b) 3'-Chloro~3-cyclopentylcxy-4-methoxydiphenylarnine
c) 3-Cyclopentyloxy-4-methoxy-3'mechyidiphenyiamine
d) S-Cyciopentyloxy^'-fluoro^-methoxydiphenylamine
e) 3-Cyc]opentyioxy-4-methoxy-4'-vinyidiphenylamine
f) 3 '-Cyano-3-cyciopentyloxy-4-methoxydipherjylarrane
g) 4'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
h) 3-Cyclopemyloxy-4,47-dimethoxydiphenylarrune
i) 3-Cyclopentylcxy-4-methoxy-2'-methyidiphenylamine
j). 3-Cyciopenty!oxy-4-methoxy-4'-rnethyldipheny]amine
k) 2'-Chloro-3~cydopentyloxy-4-methoxydipheTiyIamine
!) 3-Cyclopentyloxy-2 ',4-dimethoxydiphenylaraine
m) 3-Cyclopentyloxy-4-methoxy-3'-infiuoromethyldiphenylamine
n) 3-CyclopenryJoxV-4-methoxy-4' -trifluorolnethyldiphenylamme
o) 3-Cyclopentyloxy-2'p'-dimethyl-4-methoxydiphenylamine
EX4MPLE 8 (Method B)
3-CycJopentyloxy-4-metiioxydiphenylamine
MethodB (Angerw Chem. Int. Ed., 1995, 34(11), 1348-1351.) A mixture of 207
rng of 3-cyclopentyloxy-4-methoxyanilme, 204 mg of iodobenzene, 115 mg ofNaOtBu,
9 mg of Pd2(dba)3, 12 mg of P(o-iol)3 and'7 ml of toluene was combined and warmed
with stirring 10 100 °C for 4h. The mixture was cooled to room .temp, diluted with 25 ml
of EtOAc and washed with 10 ml of H^O, 10 mL of brine, dned (MgSO^ and
concentrated. The residue was purified by chromatography over SiO? using
ErOAc/hexanes (5/95) as eluanr to provide 8^ mg of the desired product.
The following compounds were prepared in a similar manner as described above:
a) 3-Cyciopentyioxy-4-methoxy-2',4'-dimethyidiphenylamiiie
b) 3-Cyclopenryioxy-2'.5?-dirDethYl---raefhoxydiphenylamine
c) 3-Cyclcpenryioxy-2'.3 '-dimethyl-4-methoxydiphenylanrine
d) 3-Cyciopentyloxy-3\4'-dimethyl-4-methoxydiphenylarnme
e) 3-Cyclopenty3oxy-3'.4?-methyienedioxydiphenylamine
f) 4/-ferf-3iiiyi-3-cyciopenryloxy-4-methoxydiphenylamine
g) 3-Cyclopentyloxy-3',4'-dichJoro-4-methoxydipheny3amme
h) 3-Cyciopentyloxy-2\3' EXAMPLE 8 (Method C)
3-Cyclopentyloxy-21,4,5'-trimethoxydiphenylamine
Method C. To a mixture ofPd(dppf)Cl2 (0.025 ramol, 5mol%), dppf (0.075 mmol,
3dpp£Td) and NaOtBu (0.70 mmol, i ."4 equivalents) and 1.0 ml THF was added 1-
bromo-2,5-d]methoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a
0.5/V/solution of 3-cyc!opentyioxy-4-methoxyaniIme in THF. The mixture was heated to
60 °C for 3 hours and diluted with ether and washed with H?Q and brine, dried (MgSCu),
and concentrated. The crude residue was purified by chromatography over silica gel
(Biorage Flash 12) eluting with 15% EtOAc in hexanes:
The following compounds were prepared in a similar manner as described above:
a) Ar-(3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamiTie
b) 3-Cyclopentyloxy-2 ',4\4-!:rimethoxydiphenylarnine
c) A-(3-Cyciopentyloxy-4-methox-ypheriyl)-2-pyridylamirie
d) /V-(3-Cyclopeniyioxy-4-rnethoxvphenyI)-8-qu.inoIinylamine
e) jV-(5-Cyclopenryloxv-4-inethoxyphenyl}-2-naphthylamine
f) A-(j-Cyclopentyloxy-4-nierhoxyphenyi)-l-naphthylamine
g) 3-Cyclopenryioxy-4'-ethyl-4-rcethoxydiphenyiamine
h) 3-Cyclopenryloxy-2>-fluoro-4-niethoxy-5:'-niethyidiphenylarnine
i) 3-Cyclopenryloxy-3'-fiuoro-4-methoxy-4'-methyldipher;ylainine
j) 7/-(3-CycIopenryJoxy-4-methoxvphenyl}-2-pyriinidinylamine
k) 3-Cyciopentyioxy-3:,5,"-dichloro-4-methoxydiphenylamme
1) 3-Cyclopentyloxy-2'-ethyi-4-methoxytiiphenyiamine
m) 4:-Chioro-3-cyclopentyloxyo'-fluoro-4-methoxydiphenyiamine
n) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquiTiolmylamme
o) A-(3-Cyclopenryioxy-4-iTiethoxYphenyl)-2-pyrazinylarmne
p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-5-pynmidmylarnine
q) yY-(3-Cyclopentyloxy~4-methoxyphenyl)-l-isoquinolinyiamirie
r) /v"-(3-Cyc!opeTiTy]oxy-4-methoxyphenyl)-3-quinolinylamine
s) yV-(3-Cyclopentyloxy-4-methoxyphenYl)-4-pyndylamme
t) yV-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-pyridylaini-ne
u) 7V-(3-Cyclcrpropylmethyloxy-4-methoxyphenyl)-3-pyTidylamme
v) A'f-(3-Cycl9propylTnethyIoxy-4-difJuorornethoxyphenyl)-3-pyridylamine
' w) /V-(4-Methoxy-3-(3^)-tetrahydTofuryloxyphenyl)-3-pyridylamine
x) A'r-(4-Difluoromethoxy-3-(3J?)-tetrahydrofaryloxyphenyl)-3-pyndylainine
y) Ethyl yV-(3-cyclopentyloxy-4-methoxyphenyl)-3-ammobenzoate
z) 3-Cyclopentyloxy-4'-(Ar,A'-diinethylamino)-4-methoxydiphenylarame
aa) A'-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyndyI)ainme
bb) Methyl A'-(3-cyclopeniyloxY-4-methoxyp1henyl)-21aminonicotinate
cc) rerf-Butyl Ar-{3-cyclopentyloxy-4-methoxyphenyl)-6-arainonicotmate
dd) 2 '-Amino-3-cyclopentyloxy-4-Tnethoxydiphenylamine
ee) 3-Cyclopentyloxy-4~methoxy-3'-(l -phthalimido)diphenylarmne
if) 3-Cyclopentyioxy-4-methoxy-3'-[2-(2-tetrahydropyranyl)-2H-tetra2ol-5-
yl]diphenylamine
EXAMPLE 9 (Method A)
3-Cyclopentyloxy-4-methoxy- A-methyldipbenylamine
To a solution of 3-cyclopentyloxy-4-metboxydiphenylairune (70 mg. 0-25 mmol)
m 3 mL of THF at 0 °C was added 0.55 mL of 0.5 M KN(TMS); in toluene. The soiution
was stirred at 0 °C for 0.5 h and 2.0 eauivalents of iodomethane was added and the
reaction mixture was warmed to room temperature. Upon reaction completion as
indicated by TLC. 10 rnL of EtOAc was added and the mixture was washed with 3 mL of
&0, 3 mL of brine, dned (MgSO*) and concentrated. The crude residue was purified by
column chromatography (Biotage flash 12) using 5% EtOAc in hexanes as eluant.
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxv-Ar-ethyl-4-methoxydiphenylamme
b) 3-Cyclopentyioxy-4-meihoxy-A'-(l-propyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy~Ar-[l-(3-phenpropyl)]diphenylamme
d) .V-Benzyl-3-cyclopentyloxy-4-methoxydiphenylarnine
e) 3-Cyclopen:yloxy-4-methoxy-A'-(4-pyndyiTnethyl)diphenylamine
f) S-Cyclopenryloxy^-methoxy-A'^i-pyTidylmethyOdiphenylamme
g) 3-Cyciopentyloxy-4-methoxy-Ar-(3-pyridylrnet±iyl)diphenylamme
h) 3-Cyclopentyloxy-4-methoxy-A-[3-(3-pyridyl}-l-propyljdipheriylaraine
i) jV-(3-Cyclopentyioxy-4-methoxyphenYl)-Ar-ethyl-4-isoquinolinylamine
j) Ar-(3-Cyclopentyloxy-4'-methoxyphenyl)-7v'-ben2yl-4-isoquinolinylarnine
k) A-(3-Cyclopentyloxy-4-methoxyphenyi)-;V-methyl-4-isoquinolmylamine
1) A'-(3-Cyclopentyioxy-4-methoxyphenyl)-Ar-propyl-4-isoquinolinylamine
rn) A7-(3-Cyc]opentyloxy-4-methoxyphenyl)--'V-(4-isoquinoUnyl)-Ar-(4-
pyndylmethyijamine
n) A-(3-Cyclopentyloxy-4-methoxypheny!)-A/-(4-isoqainolmyl)-A-(3- :
pyridylmethyl)amine
o) /V-(3-Cyclopentyloxy-4-methoxyphenyl)-A-(3-pyridylrnethyl)-.Y-(5- :
pyrimidinyl)amine
p) A-(3-Cyclopentyloxy-4-methoxyphenyl}-;V-{2-pyTa2inyl)-.A/-(3-pyridyjrnethyl)arnirie
q) A-{3-Cyciopentyioxy-4-methoxyphenyl)-A/-(2-pYridy!)-A-(3-pyncylmethyl)amine ;
r) A-(3-Cyclopentyloxy-4-methoxypheny3}-jV-(3-pyridyl)-A-(3-pyndyirneihyl)ainine
s) •A-(3-Cyclopentyioxy-4-methoxyphenyl)-A-(4-pyridy1)-A'-(3-pyridyliriethy!)amine
t) /err-Butyl A-{3-cyclopentyloxy-^-methoxyphenyl)-A'-(3-pynGylmethy!)-6-
aminoni connate
u) A-(3-CyclopropykneEhoxy-4-rnethoxypheny])-A-(3-pvTidyi)-V-(3-
pyndylmethyijarnine
v) yV-(4-Methoxy-3-(3J?)-tetrahydrofuryioxyphenyl)-/V-(3-pyTjdyl)-7v-(3-
pyndy]methyl)arnine
w) yY-{3-Cyclopentyloxy-4-difluoromethoxyphenyl}-.Y-(3-pyndyl)-.'V-(3-
pyndylmethyl)amine
x) A/-(3-CyciopropylTnethoxy-4-dii]uoromethoxypheiiyl)-Ar-(3-pyndyl}-A-(3-
pyridylmechyl)amine
y) .V-{4-Difluoromethoxy-3-(3^)-tetrahydrofuryloxypheny]}-A'-(3-pyridyl)-.A'-(3-
pyndylmethyijarmne
2} A-(4-ChJoro-3-pyridylrnethyl)-Ar-(3-cyciopentyloxy-4-rnethoxyphenyi)-/V-(2-
"pyndy!)amme
aa) /V-(3-cyclopeniyloxy-4-methoxyphenyl)-A'-(4-methy!-3-pyndylniethyl)-A-{2-
pyndyljamine
bb) 3-CyclopenTyloxy-4-rnethoxy-A'-{2-thiazolylmethy])diphenylamjne
cc) A-{2-Ch]oro-3-pyridylrnerhyn-3-cycloper!tyloxy-4-methoxydiphenylamine
dd)A-{6-Chloro-3-pyridyiinethyl)-3-cyclopentyioxy-4-methoxydipheny]amine
EXAMPLE 9 (Method B)
Ar-4-Chloro-3-pyridyimetfayiX'V-(3-cyclopeBtyl-4~
metioxypbeny!}-A-(2-pyridyi)amine
To a solution of (3-cyciopentyloxy-4-memoxyphenyl)-2-pyridylamine (30 ing,
0.10 mmoi) and 4-chioropicolyl chJoride hydrochloride (50 mg, 0.25 mraol) was
dissolved in DMF (] mL) and sodium hydride (50 mg of a 60% mineral oil dispersion.
1.3 mmoi) was added in small portions. After stirring for Ih at room temperature., the
mixture was poured into 25' mL ice water. The mixture was extracted wirh EtOAc (2 x
15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried
(MgSOd), and concentrated in vacua. The crude residue was loaded onto a RediSep
column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give
20 mg of product as a yellow crystalline solid. 1H NMR (CDC13) 5 8,61 (&, IH), 8.34'(d,
IH, J * 5.3 Hz), S.17 (d, IH, 5.0 Hz), 7.33 (m, LE), 7.25 (m, IH), 6.S3 (d,, LH, J - 8.5),
6.75 (G, IK J = 3.5), 6~\ (s; 1H): 6.62 (m, 1H), 6.42 (d 1H, J = 8.6), 5.51 (s, 2K), 4.63
(p.'IK J = 4.i2 Hz)r 3.83 (s, 3H), 1.86-1.70 (m. 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3,4-Bis(difmoromei:hoxy)-/V-(4-chloro-3-pyndylmethyl)-3'-(2-(tetrahyQropyran-2-
yl)-2H-tetrazol-5-yl)diphenylamme
b) 3,4-Bis(difiuoromethoxy)-Af-(4-methyl-3-pyridylrnethyl)-3'-(2-(tetrahydropyT3n-2-
yl)-2H-tetra2ol-5-y!)diphenylamine
EXAMPLE 10
3-Cy.clopentyloxy-4-methoxyanilino-A-{3-pyridylm«thyl)-A'-3-(4-pyridyl)benzamide
To a solution of M-(3-cyclopentyloxy-4-me'thoxyphenyl)-A'-(3-pyridylmethyl)-3-
aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CH2C12 (2
mL) at room temperature was added diisopropylethylamine (20 L, 0.11 mmol). After
stirring for 15 mm. 4-aminopyridme (15 mg, 0.15 mmol) was added and the mature was
allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed with
water (2x15 mL) and brine (15 mL), dried (MgSCUX'and concentrated in vacuo. The
crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was
eiuted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over
15 mm to give 22 mg of product. 'H NMR (CDCVj) 6 8.70-8.40 (m, 3H), 8.24 (s, 1H),
7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, J = 8.5), 6.80-
6.65 (m, 3H)r 4.98 (s, 2H), 4.66 (p, 1H, 1 = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H),
1.65-1.45 (m,2H).
The following compounds were prepared m a similar manner as described above:
a) 3-(3-Cyclopentyloxy^methoxyanilino)-A'-{3-pyTiQylmethyI)-;V-3-[3-(JV,.'Vdimethylamino)
prop-1-yl]ben2amide
b) 3-Cyclopentyloxy-4-methoxy-3!-(4-merhylpiperazin-l-ylcarbonyl)-A-(3- - :
pyridylmethyl)diphenylamine ;
c) 3-Cyc]opentyloxy-4-difjuoromeihoxy-4'-(4-methylpipers2in-l-ylcarborJy!)-A'-(3-
pyndylmechyijdiphenylamine
d) 3-Cyciopentyloxy-4-rnethoxy-4:-(4-niethyipipera2iii-l-yicarbonyI)-A-(3-
pyTidyimethyi)-3-{3-tetrahydrofaranyloxy)-dipheny]amine
EXAMPLE 11
The following compounds were-prepared in- a similar fashion as described in Example
oa)
4'-Amirio-3-cyclopentyloxy-4-methoxy-//-(3-pyridylinethyI)ciiphenylaniine
bj 3?-Arnino-3-cyclopentyloxy-4-rnethoxy-Ar-(3-pyridylmethyl)dipheriylamine
c) 3 '-Amino-3-cyclopropyimethoxy-4-rnethoxy-JY-(3-pyridylmethyl)diphenylamine
d) 3'-Amino-4-rnethoxy-/yr-(3-pyndylmeLhyI)-3-[(3^)-
tetrahydrofuryioxyjdiphenylamine
EXAMPLE 12
3-Cyclopentyioxy-4'-metbanesulfonylamino-4-metboxy-A'-
(3-pyridylmef.hyl)-diphenySamine
To a solution of 4'-amino-3-cyc]opentyloxy-4-methoxy-A'-(3-pyridylinethyl)-
diphenyiarnine (47 mg, 0.12 mmol) in CH^Cl? (2 mL) at room temperature was added
pyndine (20 microlners, 0.24 mmol) followed by methanesuifonyl chloride (15
microliters, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16
h. The mixture was diluted with ether (50 mL) and washed with water (25 mL) and bnne
(25 mL). dned (MgS04), and concentrated. The crude residue was purified by flash
colurnn chromaiography (4.2 g RediSep column, silica gel) eiuting with a linear gradient
from 45% EtOAc in hexanes to 60% EiOAc in hexanes over 20 mm to yield 41 mg of
product. 'H NMR (CDC13) 5 8.51 (s, IK), S.41 (d, 1H, J = 4.8 Hz), 7.56 (d, IE. 7.9 Hz),
7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.SO-6.60 (m, 6H), ^.82 (s, 2H), 4.56 (p, IE, J =
4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45'(m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopeniyloxy-3'-eThanesulfonyiannno-4-methoxy-/v-(3-
pyridylmethy1)diphenylarnine
b) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-A/-(3-
pyndylmethyl)diphenylarnine
c) 3'-(l -Butanesulfonyiamino)-3-cyclopentyloxy-4-methoxy-N-(3-
pyridylmethyl)diphenyiarriine
d) 3>-Ben2ylsulfonylarruno-3-cyclopentyloxy-4-methoxy-yV-(3-
• pyndylmethyljdiphenyiamine
e) 3'-AcstaTnido-3-cyclopentyloxy-4-methoxy-A/r-(3-pyridylmethyl)dipheriYlamme
f) S-Cyclopehtyloxy^'-ethanesulfonyiamino^-methoxy-^Spyndyimetbyl)
diphenylamine
g) 3-Cyclopentyloxy-4-methoxy-4'-(1 -propanesulfonylamino)-?V-(3-
pyndylrnethyl)diphenylarnine
h) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-A'-(3-
pyndylmethyl)diphenylamine
i) 4-Difluoromethoxy-3'-ethanesulfonyiammo-,V-(3-pyndylmethyl)-3-[(3R)-
letrahydrofuryloxyjdiphenylarnine
EXAMPLE 13
3-Cyclopentyloxy-4-metboxy-3'-bydroxymethyl-Ar-(3-pyrid-ylmethyl)diphenylamine
To a solution of Ethyl ./V-{3-cyclopenTyloxy-4-methoxyphenyl)-./V-{3-
pyridyImethyl)-3-aminoben2oate (50 mg, 0.11 rnmol) in THF (5 mL) at 0 °C was added
drop-wise, with stirring, 2.5M diisobutylaluminum hydride in toluene (0.4 mL. 1.00
mmol). The mixture was stirred at 0 °C for 1 h and the excess diisobutylaluminum
hydride was quenched by adding 5 drops of EtOAc 10 the mixmre. The mixture w'as
concentrated and the residue was partitioned between CILd-; (50 mL) and water (50
mL). The layers were separated and the aqueous layer was extracted with CEjClt (2x10
mL). The organic extracts were combined and washed with brine (50 mL), dried ;
(MgSCV). and concentrated. The crude residue was purified by -flash column
chromaiography (4.2 g ReoiSep column, silica gel) eluting with 300 mL 50% EtOAc in
hexanes then 100% EiOAc to give 15 mg of product. 'H NMR (CDCb>5 8.51 (s. IE).
8.40 (br: 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5E), 4.85 (s, 2H),
4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopenryioxy-4-methoxy-4'-hydTOxymethyl-N-(3-pyTidyteDethyl)d\phenylairiine
EXAMPLE 14
3-Cyclopentyloxy-4-methoxy-A'-(3-pyridylmetfayl)-4'-{2H-tetrazol-5-
yl)diphenylamine
To a solution of Af-(3-cyciopentyloxy-4-meLhoxyphenyl)-/vT-(3-pyridylmethyl)-3-
aminobenzonitrile (100 mg, 0.25 rranol) in DMF (3 mL) was added NaN3 (163 mg, 2.5
mmol) and NiUCl (135 mg, 2.5 mmol) and the mixture was stirred at 120 °C for 6 h. The
mixture was cooled to room temperature, diluted with water (50 mL) and extracted with
EtOAc (2 x 25 mL). The EtOAc extracts were combined, washed with water (25 mL)
and brine (25 mL), dried (MgSCU), and concentrated in vacua. The residue was loaded
onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient from 50% to
75% EtOAc in hexanes to yield 12 mg of product. 'H NMR (CDC13) 6 12.50 for, 1H),
8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz), 7.36 (m, 1H),
6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H),
1.65-1.45 (m, 2H).
EXAMPLE 15
3-Cyclopentyloxy-4-methoxy-4'-(4-metfayl-l-pipera2inylmethy!)-
A-(3-pyndylmetiiyi)diphenylamine
To a solution of 3-cyclopenryloxy-4-methoxy-4!-(4rmethyipiperazin-1 -
ylcarbonyl)dipheylamine (100 mg. 0.20 mmol) in THF .(5 mL) was carefully added, with
stirring, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stirred for 15
mm and a few drops of h-tOAc was carefully added to quench the excess hydride. Water
(50 mL) and CILQ- (50 mL) were added and the mixtures were filtered through Ceiite.
The CHoCh layer was separated, washed with brine (25 mL), dned (MgSCU), and
concentrated in vacua. The crude residue was purified on an 1SCO RediSep column (4.2
g, silica) eluting with a gradient from 5% MeOH m EtOAc to 15% MeOH in EtOAc to
yield 60 mg of product as'a light yellow oil. 'HNMR (CDC13) 5 8.59 (s, 1H), 8.47 (d,
1H, J = 4.8 -Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.31 (d, 2H, J =
8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz),
3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45
(m,2H). .
The following compounds were prepared in a similar manner-as'described above:
a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-l-pipera2inylmethyi)7vr-(3-
pyndylmethyl)diphenylamine
EXAMPLE 16
3;-Aminomethyl-3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmetfayi)diphenylamine
To a solution of A/-(3-cyclopentyloxy-4-metnoxypheny!)-./V-(3-pyndyLmethyl)-3-
armnobenzomtrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with stirring,
lithium aluminum hydnde (20 mg, 0.52 mmol). The mixture was stirred for 4 h and a
few drops of water were carefully added to quench the excess hydride. Water (50 mL)
and CHiCb (50 mL) were added and the mixtures were filtered through Celite. The
CH^Cb layer was separated, washed with brine (25 mL), dried (MgS04), and
concentrated in vacua. The crude residue was purified on an ISCO RediSep column (4.2
g, silica) eluting with 10% MeOH in EtOAc to yield 20 mg of product. 'H NMR (CDCb)
5 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, IE, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H),
4.94 (s, 2H), 4,63 (p, IE, J = 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H). 2.29 (br, 2H), 1.86-1.70
(m,6E), 1-65-1.45 (m, 2H),
EXAMPLE 17
3-Hydroxy-4-methoxy-/V-{3-pyridylmethyi)diphenylamine
To a solution of 3-(ierr-baty]diraethyisiloxy)-./V-(3-pyridyimethyl)-4-
methoxydiphenylamine (1.20 g, 2.85 mmol) in TKF (40 mL) at 0 °C; was added I.OM
tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred at 0 C
for 30 min. Water (50 mL) was added and the mixture was extracted with ether (3 x 25
mL), The ether extracts were combined and washed with water (3 x 25 mL) and bnne
(25 mL), dried (MgSCU), and concentrated in vacua. The residue was triturated with
hexanes and collected by vacuum filtration to give. 0.85 g of product. 'H NMR (CDC13) 6
8.58 (s, 1H), 8.46
6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, IH), 4.92 (s, 2H), 3.86 (s, 3H).
The following compounds were prepared in a similar manner as described above:
a) 3'-Chloro-3-hydroxy-4-methoxy-A'-(3-pyridylmethyl)diphenylamine
b) Ethyl /^-(3-hydroxy-4-metho.xvphenyl)--V-(.3-pyridyknethyl)-3-aminobenzoate
EXAMPLE 18 (Method B)
. The following compounds were.prepared in a similar manner as described in Example
IB:
a) 3~[3~(4-Chlorophenyl)prop-1 -yloxy]-4-methoxy-A/f*(3-pyTidylmethyl)diphenylamine .
b) 3-[2-(4-CMorophenyI)ethoxy]-4-mei:hoxy-.V-(3-pyridylrnethyl)diphenylamine
c) 4-Methoxy-3-(4-phenoxybut-1 -yl)oxy-N'-(3-pyridyimethyl)diphenyianiine
d) 4-Methoxy-A'-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-N-(3-
pyndylmechyl)diphenylamine
f) 4-Memoxy-3-[3-(4-pyridyI)prop-l-yl]oxy-A'-(3-pyridyrrnethyl)diphenyiamine
g) 4-Memoxy-3-r2-(4-merhoxyphenyl)ethoxyj-A/-{3-pyndyhnerhyl)diphenylarnine
h) 4-Methoxy-3-(4-phenylbut-l-yl)oxy-A/'-{3-pyridylme!:hyl)dipheny]aniine
i) 4-Memoxy-3-[4-{4-methoxyphenyl)but-l-yl]oxy-A^-(3-pyndylmethyl)diphenylamihe
j) 4-Methoxy-3-[4-(4-nitrophenyl)but-1 -yl]oxy-A'-(3-pyridyknethyl)diphenylamine
k) 4-Methoxy-3-[2-(2-pyTidyI)ethoxyj-N-(3-pyridylmethyl)diphenyiarnine
i) 4-Methoxy-3-[2-(4'-pyridyl)ethcxy]-N-(3-pyridyimethyl)diphenyiamine
m) 4-Methoxy-3-(3-(2-pynayl)prop-l-yl]oxy-N-(3-pyTidyimethyl)Qiphenyiamine
n) 4-Methoxy-3-(2-Tnethoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
o) 3-Cyclopropylmeihoxy-4-methoxy-N-(3-pyTidylmethyl)diphenylainme
p) 4-Methoxy-3-(l-methylpyTTohdin-3-yl)oxy-N-{3-pYridylmethyl)diphenylarnine
q) 4-Methoxy-3-(l-methylpipenditi-4-yl)oxy-N'-(3-pyTidylmethyl)diphenylairLine
r) 4-Methoxy-A-{3-pyridylmethyl)-3-[(35)-tetrahydrofuryloxy]diphenylamine
s) 4-Methoxv-A'-(3-pyridylniethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamme
t) 3"-Chloro-4-meihoxy-3-[2-(2-pyridYl)ethoxy]-N-(3-pyndylmethyl)diphenylamine
u) 3'-Cbloro-4-meLhoxy-3-[2-(4-pyndyl)ethoxy]-N-(3-pyridyLmethy])diphenylanune
v) 3'-Chloro-4-methoxy-3-(2-methQxyeihoxy)-N-(3-pyTidylmethyl)dipheiiyiamine
w) 31-Ch}oro-4-methoxy-/v-(3-pyridylmethyl)-3-[(3R)-
tetrahydrofuryloxy]diphenylamine
x) 3-Cyclohexyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
y) 3-Cyclohepryloxy-4-methoxy-N'-(3-pyTidylmethyl)diphenylainine
z) 3-(2-Cyclopropylethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
aa) 3-Cyclopentylmet±ioxy-4-methoxy-N-{3-pyndylmethyl)diphenylamine
bb) Ethyl A'*-[3-(4-chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-Ar-(3-pyndylrnet±iyi)-3-
aminobenzoate
cc) Ethyl A'-(3-cyclopropylmeth.oxy-4-methoxyphenyl)-/v-(3-pyndyknethyl)-3-
ammobenzoate
dd) Ethyl N(3-cyclopropylmethoxy-4-difluorornethoxyphenyl)-N(3-pyridylrnethyl)-3-
aminobenzoate
ee) Ethyl ^-[3-{2-indanyloxy)-4-methoxyphenyl]-A-(3-pyridylmei:hyi)-3-arnin.oben2oate
ff) Ethyl Ar-{4-methoxy-3-(3-tetrahydrofQryloxy)phenyl]-.V-(3-pyndylmeihyl)-3-
aminobenzoate
gg)Ethyi A-f^-7nethoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-A'-{3-pyridylmethyl)-3-
ammobenzoate
hh) Ethyl A-[3-(2-methoxyethoxy)-^-methoxypheriyl]-A'-{3-pYridylmediYl)-3-
arninobenzoate
ii)Ethyl N-[4-meihoxy-3-(2-(2-pyridyi)eihyl)oxyphenyl]-N-(3-pyridylmethyl)-3-
aminobenzoate
EXAMPLE 18 (Method C)
The following compounds were prepared in a similar manner as described in Example
8A by coupling a phenol with a boronic acid rather than coupling an aniline with a
boronic acid:
a) 4-Methoxy-3-{4-methoxyphenoxy)-.V-(3-pyridytaiethyl)diphenYlamine
b) 4-Methoxy-3-phenoxy-N-(3-pyridylmethyl)diphenylamine .
• c) .'4-Methoxy-3-(4-methylphenoxy)-N-{3-pyridylmethyl)diphenylamiDe
d) 3-(4-Chlorophenoxy)-4-methoxy-N-(3-pyndyknethyl)diphenylamine
e) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylajnine .
EXAMPLE 19
The following compounds were prepared in a similar manner as described in Example
17
a) 3-Cyclopentyloxy-3'-hydTOxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyndylmethyl)diphenylamine
c) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyndybtnethyl)diphenylamine
EXAMPLE 20 (Method A)
The following compounds were prepared in a similar manner as described in Example
1A:
a) 3'-(2-Bromoethoxy)-3-cyclopemyloxy-4-methoxy-N-(3-
pyridylmethyl)diphenylamine
EXAMPLE 20 (Method B)
The following compounds were prepared in a similar manner as described in Example
IB:
a) 3-Cyclopentyioxy-4X2-nieihoxyethoxy)-4-meihoxy-A-(3-
pyridylrnethyl)diphenylamine
b) 3-Cyclopentyloxy-4'-(3-methyl-l-butoxy)-4-methoxy-A-{3-
pyri dy imethy l)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-AX^-p)^dy^e^yO-4'-[(36)-te
diphenylamine
d) 3-Cyclopentyloxy-4-methoxy-yV-(3-pyridylinethyl)-4>-[(3jR)-tetrahydrofuranyloxy]
diphenylamine
e) 3-Cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-Ar-(3-
pyridylmethyl)diphenylamine
h) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpiperidin-4-yloxy)-N-(3-
pyridylmethyl)diphenylamme
i) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpyrrolidin-3-yloxy)-N-(3-
pyridylmethyl)diphenylainine
j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-.N-(3-
pyridylmethyl)diphenylamine
k) 3-Cyclopentyloxy-4-metho-xy-4'-[2-(l-pyn-olidinylethoxy)-N-(3-
pyTidylmethyl)diphenyiamine
I) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyi)methoxy)-N-(3-
pyTidylmethyl)diphenylamine
m) 3-Cyclopenr/loxy-4-methoxy-4>-[3-(l-methylpiperidinyl)methoxy]-N-(3-
pyridylmethyl)diphenylaraine
n) 3-Cyciopenryloxy-4-methoxy-4'-[2-(l-methyipiperidinyI)methoxy]-N-(3-
pyridylmeihyl)diphenyiamine
o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyTToiidinyl)meihoxy]-N-(3--
pyndyimethy3)diphenylamine
p) 4'-[ I -(3-3romopropyOoxyj-3-cyc]opentyloxy-4~methoxy-A-(3~
pyndylmethyl)dipheny!amme
q) 3-CycIopentyloxy-4-methoxy-4'-[2-(7v'-phthalimido)ethoxyJ-A-(3-
pyridylrnethyl)diphenylamine
EXAMPLE 21
3-Cyclopentyioxy-4-rnetboxy-3'-{2-(l-piperidinyl)etiioxy]-;V-{3-
pyndylraethy{)diphenylamine
To a solution of 3'-{2-bromoethoxy)-3-cyclopentyloxy-4-methoxy-jV-{3-
pyridvime'chyl)diphenylamme (17 mg, 0,03 mmol) in acetonitrile (1 mL) was added
.potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 uL, 0.05 mmol) and the
mixture was stirred at 60 °C for 4 h. The mixture was partitioned between water (50 mL)
and EtOAc (50 mL). The layers were separated and the organic layer was washed with
water (25 mL) and brine (25 mL), dried (MgSO residue was loaded on an ISCO RediSep column (4.2g, silica) and the column was eluted
with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg
of product. 'K NMR (CDC13) 5 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz),
7.26-7.20 (m, 1H), 7.06 (t, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.75-6.6& (m, 2H),
6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p.. 1H, J = 4.1 Hz), 4.00 (t, 2H, J - 6.2 Hz), 3.84 (s,
3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1..70 (m, 6H), 1.86-1.70 (m, 6H)3 1.65-
1.45(m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3 '-[2-(l-imidazolyI)ethoxy]-4-methoxy-N-(3-
pyridyimethyl)Qiphenylamine
b) 3-Cyciopencyloxy-4-methoxy-3 3-[2-( 1 -methylpiperaziii-4-yI)euioxy]-/v-{3-
pyridylmet±iyl)diphenylamine
c) 3-Cydopenryioxy-4-methoxy-4)-[3-(2-methyipipera2in-4-yi)propoxy]-N-(3-
pyridyimethyl)diphenylamine
d) 3-Cyclopentyloxy-4-methoxy-4;-[3-(l-methyipipera2iri---yl)pTOpoxy]-N-(3-
pyndylmeihyl)diphenylamine
e) 3-CyclopenTyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxyj-A-(3-
pyridylmethyl)diphenylamine
f) 4-Methoxy-3-(2-phenoxyethoxy)-/V-(3-pyridylmethyl)diphenylamme
g) 3-[2-(4-Chiorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylaTnine
h) 4-Methoxy-3-(2-pyrrolidin-1 -yl)etiioxy-N-(3-pyridylrnethyl)diphenYlaniine
i) 4.-Methoxy-3-(2-(4-methylpiperazin-1 -yl)ethoxy)-Ar-(3-pyridylmethyl)diphenyiamine
j) 3:[2-{4-Chlorophenylamin©)ethoxy]-4-methoxy-A'"-(3-pyTidylmethyl)diphenYlamme
EXAMPLE 22
4'-A'minoethoxy-3-cyclopentyloxy-4-methoxy-A'*-(3-pyridylrnethyl)diphenylamine
.To a solution of N-(3-pyridylmethyl)-3'-[2-(2-phthalimido)ethoxY]-3-
cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 rrrrnol) in MeOH (5 mL) was
added hydrazine hydrate (1.0 -mL, 20 ramol). After 6 h at room temperature, EtOAc was
added (50 mL) and the precipitate was filtered off. The filtrate was washed with water
(25 mL) and brine (25 mL), dried (MgSC^), and concentrated in vacuo. The residue was
loaded on an ISCO RediSep column (10 g, silica). The column was washed with 10%
MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH m EtOAc to
yield 0.2.1 g. !H NMR (CDC13) 5 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7
Hz), 7.20-7.10 (m, 1H), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9..0 Hz), 6.70 (d, IK, J
= 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1
Hz), 3,74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H).
EXAMPLE 23
The following compounds were prepared in a similar manner as described in Example
12:
a) 3-Cyclopentyloxy-4'-{2-methanesulfonylamino)et±ioxy-4-methoxy-N-(3-
pyridylmethyl)diphenylamine
bl 3-Cyclopenryloxy-4'-(2-eth2nesulfonyiainmo)ethoxy-4-niethoxy-,A/-{3-
pynd ylmethyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-4:-[2-{2-propaT]esulfonYiamino)ethoxyj-/v-(3-
pyridylmethyl)diphenylamine
d). 3-Cyciopentyloxy-4-methoxy-41-[2-{l-propanesulfonylanuno)ethoxyj-/V-(3-
p yri dylmeth yl)cliphenylamine
e) 4'-[2-(i-3utanesulfonylaraino)ethoxy]-3-cyclopentyloxy-4-met±ioxy-A/'-(3-
pyridyimethyl)dipheny]amme
EXAMPLE 24
In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity
Human PD-E4 was obtained from baculovirus-infected Sf9 celis that expressed the
'recombinant enzyme. The c'DNA encoding hPDE-4D6 was subcloned into, a baculoviras
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 iysate was used
as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAJE 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'-AM?). 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 ui of assay mix
and 10 ul of inhibitors and incubated for 12 min at room temperature. Final
concentrations of assay components were: 0. 4 ug enzyme, lOrruVl Tris-HCl (pH 7.5),
lOmM MgCk 3 uM cAMP, 0.002 U 5r-nucieoridase, and 3 x 1C4 cpm of [3H]cAMP.
. The reaction was stopped by adding 100 ul of boiling 5mN KC1. An aliquot of 75 ul of
reaction mixture was iransferred from each well to alumina columns (Muitiplate;
Millipore). Labeled adenosine was eluted into an OpdPlate by spinning at 2000 rprn for
2 mm; 150 ul per well of scintillation fluid was added to the OptiPlate. The plate was
sealed, shaken for about 30 min, and cpm of [JH]adenosine was determined-using a
WalJac Influx®.
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..
pICso 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 3H-adenosine
concentration. Nonlinear regression software (Assay Explorer®) was used to estimate
pICso values,
EXAMPLE 25 (Method A)
. Passive Avoidance in Rats, an in vivo Test for Learning and Memory
The test was performed as previously described (Zhang, H.-T., Cnssman, A.M.,
Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology., 2000,
23, 198-204.). The apparatus (Model E10-16SC, Coulboum Instruments, Alien town, 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 rnA electric shock
was administered for 3 seconds. Twenty-four hours later, the rat was administered O.I
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, i.p.), 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. Naive rats required less than 30
•secondsj on average, to cross from the illuminated compartment co 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 markedly reduced this latency when compared to the vehicle (p effect of MK-801 is reversed in a statistically significant manner by actual test
compounds in'a dose-dependent fashion (e.g., 3-cyclopentyioxy-4-methoxy-/V-(3-
pyridylmethyl) diphenylamine, Effective dose range = 0.5 to 2.5 mg/kg, i.p.; and ^-{3-
cyclopentyloxy-4-methoxyphenyl)-/Y-(3-pyridybuethyl)-3-aminobenzoic acid, effective
• dose range = 0.1 to 2.5 ma/kg, ip).
EXAMPLE 25 (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., Cnssman, A.M.,
Dorairaj. N.R., Chandler,. L.J., and O'Donnell, J.M., Neuropsychopharmacoiogy, 2000,
23, 198-204.). Five days after initial housing, rats (rnaJe Spraque-Dawley (Earlan)
weighing 250 to 350 §) were placed in the eight-arm radial maze (each arm was
60x10x12 cm high; me maze was elevated 70 cm above the floor) for acclimation for TWO
days. Rats were then placed individually m 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
corriparisons 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 statistically significant manner by the administration of actual test compounds in a dosedependent
fashion (e.g., 3-cyclopentyloxy-4-methoxy-.V-(3-
pyndyimethy])diphenylamtne, Effective dose = 2.5 ma/kg, i.p.; p The preceding examples can be repeated with similar success by substituting the
genetically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.
White 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.

We Claim:
1. A phenylamine compound of Formula I
(Formula Removed)

wherein:
R1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen;
R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C=C-,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof,
aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof,
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is

substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C-C-, and one or more -CH2- 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,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof,
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, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
a heterocyclicalkyl 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-. , and one or more -CH2- 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;
R3 is alkyl having 1 to 8, carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or

more times with halogen, cyano, C1-4-alkoxy, or combinations thereof,
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 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 carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C1-4-alkoxy, cyano or combinations thereof,
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, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or
heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
R4 is aryl having 6 to 14 carbon atoms and which is unsubstituted or
substituted one or more times by halogen, alkyl, alkenyl, alkynyl,
hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,
ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl,
aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid,
tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy,

carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-), or combinations thereof, or
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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, or combinations thereof;
R5 is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
a partially unsaturated carbocycle-alkyl group wherein the carbocycle portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, 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,

aryl having 6 to 14 carbon atoms and which is unsubstituted or
substituted one or more times by halogen, alkyl, hydroxy, alkoxy,
alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,
trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
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, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, methyl, or combinations thereof,
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, alkyl, hydroxy, alkoxy,
alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,
trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or
a heterocyclicalkyl 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, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or

substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and
R6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof; and
pharmaceutically acceptable salts thereof of the kind such as herein described.
2. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; R3 is alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is aryl or heteroaryl, in each case substituted or unsubstituted.
3. A compound as claimed in claim 1, wherein R3 is heteroarylalkyl which is substituted or unsubstituted.
4. A compound as claimed in claim 1, wherein R1 is methyl or CHF2, and R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or (3R)-tetrahydrofuranyl.
5. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl; R3 is heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl or heteroaryl.

6. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl.
7. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is heteroarylalkyl which is substituted or unsubstituted.
8. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is heteroarylalkyl which is substituted or unsubstituted; and R4 is phenyl which is substituted or unsubstituted.
9. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; and R4 is phenyl or phenyl substituted with 1 to 3 substituents.
10. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; and R4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
11. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
12. A compound as claimed in claim 1, R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl,

methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, OF ethylsulfonamido, or combinations thereof, or is 3-pyridyl which is unsubstituted or substituted by carboxy, alkoxycarbonyl or combinations thereof.
13. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
14. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
15. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted.
16. A compound as claimed in claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R3 is pyrazinylmethyl, pyrimidinylmethyl, or pyridylmethyl, which in each case is unsubstituted or substituted.
17. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrirnidinylrnethyl, pyridylmethyl, quinolinylmethyl, isoqumolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted.

18. A compound as claimed in claim 1, wherein R1 is methyl; R2 is cyclopentyl; and R3 is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted.
19. A compound as claimed in claim 1, wherein said compound is of formula IV
(Formula Removed)
wherein at least one of A, B, and D is N and the others are CH, and R4 is pyridyl or phenyl which in each case is substituted or unsubstituted, or a pharmaceutically acceptable salt thereof of the kind such as herein described.
20. A compound as claimed in claim 19, wherein R1 is methyl or CHF2.
21. A compound as claimed in claim 20, wherein B is N.
22. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetr ahydrofuranyl.
23. A compound as claimed in claim 22, wherein B is N.
24. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
25. A compound as claimed in claim 24, wherein B is N.

26. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
27. A compound as claimed in claim 26, wherein B is N.
28. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is phenyl which is substituted in the 3- or 4- position.
29. A compound as claimed in claim 28, wherein B is N.
30. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is phenyl which is substituted in the 3- or 4- position.
31. A compound as claimed in claim 30, wherein B is N.
32. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
33. A compound as claimed in claim 32, wherein B is N.
34. A compound as claimed in claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.

35. A compound as claimed in claim 34, wherein B is N.
36. A compound as claimed in claim 1, wherein said compound is selected from:
3-Cyclopentyloxy-4'-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-3,4-dimethoxy-N-(3-pyridymlethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine
3-Cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl)diphenylamine
4'-Cyano-3-cyclopentyloxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-nitro-iN-(3-pyridylmethyl)diphenylamine
4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine
4-Methoxy-3'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
3-Cyclopen1yloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl) amine
3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-[3-(4-Chlorophenyl)prop-1 -yloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3-[3-(4-methoxyphenyl)prop-1-yl]oxy-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3-[3-(2-pyridyl)prop-1-yl]oxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4-[(3R)-tetrahydrofuranyloxy]-diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-( 1 -methylpiperidin-4-yloxy)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-( 1 -methylpyrrolidin-3-yloxy)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(l-pyrrolidinylethoxy)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N-(3-pyridylmethyl) diphenylamine

3 -Cyclopentyloxy-4 -methoxy-4'- [2 - (1 -methylpiperidinyljmethoxy] - N- (3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-[2-(l-piperidmyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-3'-[2-(l-imidazolyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4 -methoxy-4'- [3 - (2 -methylpiperazin-4-yl)propoxy] - N- (3 -pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxy]-JV-(3-pyridylmethyl)diphenylamine
3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4'- [2 - (1 -Butanesulfonylamino) ethoxy] -3 -cyclopentyloxy-4-methoxy- JV- (3-pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4 -me thoxy- N- (3 -pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine

3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine
4-^tethoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-v^tetrahydrofuryloxy)diphenylamine
4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3 -Indanyloxy-4-methoxy- N- (3-pyridylmethyl)diphenylamine
N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid
N- (3 - Cy clopentyloxy- 4-methoxyphenyl) -N- (4-isoquinolinyl) - N- (3 -pyridylmethyl) amine
N- (3 -Cyclopentyloxy-4-methoxyphenyl) - N-(3-pyridylmethyl) -N-(5-pyrimidinyl) amine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-iV-(3-pyridylmethyl) amine
N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine

3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide
3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine
4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3-tetr ahydr ofuryloxy) diphenylamine
3'-( 1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4 -Methoxy- N- (3 -pyridylmethyl) - 3 - (3 - tetrahydrofuryloxy) diphenylamine
4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
3 - Cyclopropylmethoxy-4 - methoxy- N- (3 -pyridylmethyl) diphenylamine
4 - Methoxy- N- (3 -pyridylmethyl) -3 - [ (3S) -tetrahydrofuryloxy] diphenylamine
3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine

3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperidinyl)methoxy]-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yl)propoxy]-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3- (2 -phenoxyethoxy) - N- (3 -pyridylmethyl)diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3'- Cyano-3 - cyclopentyloxy-4 -methoxy- N- (3 -pyridylmethyl) diphenylamine
4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3- pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-iV-(3-pyridylmethyl)diphenylamine

3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) -diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4 -methoxy-4 '-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3-[3-(4-pyridyl)prop-1 -yl]oxy-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3 - Cyclopentyloxy-4'- (2 - ethane sulf onylamino) ethoxy-4-methoxy- JV- (3 -pyridylmethyl) diphenylamine
3 - Cyclopentyloxy-4 -methoxy-4'- [2 -(1 -propanesulfonylamino) ethoxy] - JV- (3 -pyridylmethyl) diphenylamine
3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine

3,4 -Bis(difluoromethoxy) -N- (3 -pyridylmethyl)diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
3 '-Cyano-4-difluoromethoxy- N- (3 -pyridylmethyl) -3- {(3R)-tetrahy drofuryloxy) diphenylamine
3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetr ahydr ofuryloxy) diphenylamine
4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N- (3 - Cy clopentyloxy- 4 -methoxyphenyl) - N-(3 -pyridylmethyl) -4-aminobenzoic acid
N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid

N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol- 5 -yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3,-(2H-tetrazol-5-yl) diphenylamine
4-Methoxy-iV-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) diphenylamine

3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-yl)diphenylamine
3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5 -yl) diphenylamine
Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridy lmethy 1) amine
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine
N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl)amine
3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3-pyridy lmethy 1) diphenylamine

3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
4 -Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 R) - tetrahydrofuryloxy] diphenylamine
3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
3 -Cyclopentyloxy-4-methoxy-4'- [2 - (5-oxopyrrolidinyl)methoxy] - N- (3 -pyridylmethyl)diphenylamine; and
pharmaceutically acceptable salts thereof of the kind such as herein described.
A compound as claimed in claim 1, wherein said compound is selected from:
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine

3 - Cyclopentyloxy-4 -methoxy-4'- methyl- N- (3 -pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4 -methoxy-4 '-nitro- N- (3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine
4-Methoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine
4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine
3 -Indanyloxy-4-methoxy-N- (3 -pyridylmethyl) diphenylamine
N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidinyl) amine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl) amine

N-(4-Methoxy-3-(3R)-tetrahydrofaryloxyphenyl)-N-(3-pyTidyl)-N-(3-pyridylmethyl) amine
3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide
3 - Cy clopentyloxy-4 -methoxy- 3'- (4 - methylpiperazin-1 -ylcarbonyl) - N- (3 -
pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N- (3 -pyridylmethyl) diphenylamine
4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3-tetrahydrofuryloxy) diphenylamine
3'-( 1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4 -Methoxy- N- (3 -pyridylmethyl) - 3 - (3 -tetrahydrofuryloxy) diphenylamine
4 - Methoxy- 3 - [2 - (4-pyridyl) ethoxy] - N- (3 -pyridylmethyl) diphenylamine
4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)dipheriylamine
4 -Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 S) -tetrahydrofuryloxy] diphenylamine
3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine

3 - [2 - (4-Chlorophenyl) ethenyloxy]-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4-methoxy-4'- [3 - (1 -methylpiperidinyl)methoxy] - N- (3-pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4-methoxy-4'- [3 - (1 -methylpiperazin-4-yl)propoxy] - N- (3 -pyridylmethyl) diphenylamine
4- Methoxy-3 - (2 -phenoxyethoxy) - N- (3 -pyridylmethyl) diphenylamine
3 -Cyclopentyloxy-4 -methoxy-4'- [2 - (2 -propanesulfonylamino)ethoxy] - N- (3-pyridylmethyl) diphenylamine
3'- Cyano- 3 - cyclopentyloxy-4 -methoxy- N- (3-pyridylmethyl) diphenylamine
4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl) diphenylamine

3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl) - N- (3 -pyridylmethyl) diphenylamine
3 - Cyclopentyloxy-4 '-methane sulfonylamino-4-methoxy- N- (3 -pyridylmethyl) -diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3-[3-(4-pyridyl)prop-1 -yl]oxy-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethooxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4 -methoxy-4'- [2 -(1 -propanesulfonylamino)ethoxy] - N- (3-pyridylmethyl) diphenylamine
3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine

4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3,4 -Bis(diflu oromethoxy) - N- (3 -pyridylmethyl) diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
N- (3 - Cy clopentyloxy- 4-methoxyphenyl) - N- (3-pyridylmethyl) - 3 -aminobenzoic acid
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
N-(3-Cyclopentylo^-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylniethyl)-3-aminobenzoic acid

N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N- (3 -Cy clopropylmethoxy-4 - methoxyphenyl) - N- (3 -pyridylmethyl) - 3 -aminobenzoic acid
N-[3-(2-Indanyloxy)-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol- 5 -yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine

3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine
4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) dipheny lamine
3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylniethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
4-Difluoromethoxy- N- (3 -pyridylmethyl) -3-((3R)-te1xahydrofuryloxy) -4 '-(2 H-tetrazol- 5 -yl) diphenylamine
3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5 -yl) diphenylamine
Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3 -pyridylmethyl) amine

3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-ethanesulfonylammo-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3 - Cy clopropylmethoxy- 3 '-ethane sulfonylamino-4-methoxy-N- (3 -
pyridylmethyl) diphenylamine
4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylrnethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylinethyl)diphenylamine
4 - Methoxy- N- (3 -pyridylmethyl) - 3 - [ (3 R) -tetrahydrofuryloxy] diphenylamine
3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetr ahydrofuryloxy] diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and
pharmaceutically acceptable salts thereof of the kind such as herein described.

A compound as claimed in claim 1, wherein said compound is selected
from:
3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-4-difluoromethoxy-N:-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
3 - Cyclopentyloxy-4 '-methane sulfonylamino-4-methoxy- N- (3 -pyridylmethyl) -diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylme thy1) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl) diphenylamine
4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) diphenylamine
3 - Cyclopropylmethoxy-4 '-hydroxy- 4 -methoxy- N- (3-pyridylmethyl) diphenylamine
3 - Cyclopentyloxy-4'- (2 - ethane sulfonylamino) ethoxy-4-methoxy- N- (3 -pyridylmethyl) diphenylamine

3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3,4 -Bis(difluoromethoxy) - N- (3 -pyridylmethyl)diphenylamine
4-Difluoromethoxy- N- (3 -pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine
3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid

N- (3 - Cy clopentyloxy- 4 - difluoromethoxyphenyl) - N- (3 -pyridylmethyl) - 3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylraethyl)-3-aminobenzoic acid
N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylinethyl)-4-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid

N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
3 - Cy clopropylmethyloxy- 4 -diflu or omethoxy- N- (3-pyridylmethyl) -4'- (2 H -tetrazol-5-yl)diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3,-(2H-tetrazol-5-yl) diphenylamine
4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5 -yl) diphenylamine
3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2 H-tetrazol-5-yl) diphenylamine
3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol- 5-yl) diphenylamine
Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine

N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-iV-(3-pyridylmethyl) amine
N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3 '-(1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3 - Cy clopropylmethoxy- 3 '-ethane sulfonylamino-4-methoxy- N- (3-
pyridylmethyl) diphenylamine
4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
4 - Methoxy-3 - [2 -'(2 -pyridyl) ethoxy] - N- (3 -pyridylmethyl) diphenylamine
4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine
3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine

3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and
pharmaceutically acceptable salts thereof of the kind such as herein described.
A compound as claimed in claim 1, wherein said compound is selected
from:
3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy) diphenylamine
3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
4-Difiuoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydr ofuryloxy) diphenylamine
3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine
4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydr ofuryloxy) diphenylamine
3'-Cyano-4-dinuoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy) diphenylamine
3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine

N-(3-Cyclopentyloxy-4-inethoxphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
N- (3 - Cy clopentyloxy- 4 - difluoromethoxyphenyl) -N- (3 -pyridylmethyl) - 3 -aminobenzoic acid
N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(4-Chlorophenyl)prop-1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
N- [3- (2 -Indanyloxy) -4-methoxyphenyl] -N-(3-pyridylmethyl) -3-aminobenzoic acid

N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
3-Cyclopropylmethyloxy-4-difluoromethoxy-(3-pyridylmethyl)-4'-(2H-tetrazol- 5-yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl) diphenylamine
4-Methoxy-N-(3-pyridylmethyl)-3-((3,R)-tetrahydrofuryloxy)-4,-(2H-tetrazol- 5 -yl) diphenylamine
3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
4-Difluoromethoxy-N- (3-pyridylmethyl) -3-((3R)-tetrahydrofuryloxy) -4 '-(2 H - tetrazol- 5 -yl) diphenylamine
3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine

Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4,-(2H-tetrazol-5-yl) diphenylamine
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
N- (4-Difluoromethoxy-3 - (3R) -tetrahydrofuryloxyphenyl) - N-(3-pyridyl) - N-(3-pyridylmethyl) amine
3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-3'-( 1 -propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3-pyridylmethyl) diphenylamine
3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl) diphenylamine
4-Difluoromethoxy-3 '-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R) -tetrahydrofuryloxy] diphenylamine
4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine

4-Methoxy -N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine

3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl) diphenylamine
3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine; and
pharmaceutically acceptable salts thereof of the kind such as herein described.
A compound as claimed in claim 1, wherein said compound is of formula I':
(Formula Removed)

wherein
R1' is methoxy;
R2' is alkyl having 1 to 12 carbon atoms,
alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof,
alkenyl having 2 to 12 carbon atoms,
alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof,
alkynyl having 2 to 12 carbon atoms,

alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms,
cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof,
cycloalkylalkyl having 4 to 12 carbon atoms,
cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof,
arylalkyl having 7 to 19 carbon atoms
arylalkyl having 7 to 19 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or" combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof;
X isO;
R3' is aryl having 6 to 14 carbon atoms,

aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, car boxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof,
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof;
L is -NR4'-, or -NR4'CH2-; and
R4' is alkyl having 1 to 12 carbon atoms,
alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof,
arylalkyl having 7 to 16 carbon atoms,
arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and

pharmaceutically acceptable salts thereof of the kind such as herein described.
41. A compound of the Formula
(Formula Removed)

wherein:
R1 is 3H3C-, 14CH3-, or UCH3-;
R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -OC-,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof,
aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof,
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy,

alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CH2- 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,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof,
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, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -OC-, and one or more -CH2- 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;
is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C1-4-alkoxy, or combinations thereof,
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 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 carbocyclic portion one or more

times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci-4-alkoxy, cyano or combinations thereof,
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, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or
heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
is aryl having 6 to 14 carbon atoms and which is unsubstituted or
substituted one or more times by halogen, alkyl, alkenyl, alkynyl,
hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,
trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino,
hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-
yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R5-L-, or
combinations thereof, or
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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,

alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R5-L-,
dialkylamino-L-, or combinations thereof;
R5 is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
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, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, 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,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
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, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen,

trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl,
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, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, 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, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and
R6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof; and
pharmaceutically acceptable salts thereof of the kind such as herein described.

42. A compound as claimed in claim 1, wherein said compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.
43. A compound as claimed in claim 1, wherein said compound is N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.
44. A compound as claimed in claim 42, wherein said compound is N-3,4-bis(dinuoromethoxy)phenyl-N-(3-pyridylmethyl)-3-ammobenzoic acid.
45. A compound as claimed in claim 43, wherein said compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid.

Documents:

01131-delnp-2003-abstract.pdf

01131-delnp-2003-claims.pdf

01131-delnp-2003-correspondence-others.pdf

01131-delnp-2003-description (complete).pdf

01131-delnp-2003-form-1.pdf

01131-delnp-2003-form-13.pdf

01131-delnp-2003-form-18.pdf

01131-delnp-2003-form-2.pdf

01131-delnp-2003-form-3.pdf

01131-delnp-2003-form-5.pdf

01131-delnp-2003-gpa.pdf

01131-delnp-2003-pct-101.pdf

01131-delnp-2003-pct-210.pdf

01131-delnp-2003-pct-301.pdf

01131-delnp-2003-pct-304.pdf

01131-delnp-2003-pct-308.pdf

01131-delnp-2003-pct-318.pdf

01131-delnp-2003-pct-332.pdf

01131-delnp-2003-pct-402.pdf

01131-delnp-2003-pct-409.pdf

01131-delnp-2003-pct-416.pdf

1131-DEL-2003-Abstract-(08-10-2008).pdf

1131-DEL-2003-Claims-(08-10-2008).pdf

1131-DEL-2003-Correspondence-Others(08-10-2008).pdf

1131-DEL-2003-Description (Complete)-(08-10-2008).pdf

1131-DEL-2003-Form-1(08-10-2008).pdf

1131-DEL-2003-Form-2(08-10-2008).pdf

1131-DEL-2003-GPA(08-10-2008).pdf

1131-DELNP-2003-Correspondence-Others-(13-10-2008).pdf

1131-DELNP-2003-Form-3-(13-10-2008).pdf

1131-DELNP-2003-Others-Document-(13-10-2008).pdf

1131-DELNP-2003-Petition-137-(13-10-2008).pdf

1131-DELNP-2003-Petition-138-(13-10-2008).pdf

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Patent Number

233340

Indian Patent Application Number

01131/DELNP/2003

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

28-Mar-2009

Date of Filing

18-Jul-2003

Name of Patentee

MEMORY PHARMACEUTICALS CORPORATION

Applicant Address

100 PHILIPS PARKWAY, MONTVALE, NEW JERSEY 07645, U.S.A.

Inventors:

#	Inventor's Name	Inventor's Address
1	ALLEN HOPPER	29 DEAN STREET, GLEN ROCK, NJ 07452, U.S.A.
2	RICHARD A. SCHUMACHER	16 DOROTHY DRIVE, MONROE, NY 10950, U.S.A.
3	ASHOK TEHIM	246 N. WALNUT STREET, RIDGEWOOD, NJ 07450, U.S.A.
4	MICHAEL DE VIVO	386 COLUMBUS AVE, APT.,1B NEW YORK, NY 10024, U.S.A.
5	WILLIAM FREDERICK BRUBAKER JR.	116 NOB HILL ROAD, CHESHIRE, CT 06410, U.S.A.
6	RUIPING LIU	95 HIGH STREET, APT. 1, HUNTINGTON, NY 11743, U.S.A.
7	HANS-JURGEN ERNST HESS	26 JERICHO DRIVE, OLD LYME, CT 06371, U.S.A.
8	AXEL UNTERBECK	205 WILDWOOD AVENUE, MADISON, CT 06433-0662, U.S.A.

PCT International Classification Number

C07C 217/00

PCT International Application Number

PCT/US02/01508

PCT International Filing date

2002-01-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/267,196	2001-02-08	U.S.A.
2	60/262,651	2001-01-22	U.S.A.
3	60/306,140	2001-07-19	U.S.A.