BG108003A - Phosphodiesterase 4 inhibitors - Google Patents

Abstract

PDE4 inhibition is achieved by novel compounds, e.g. N-substituted aniline and diphenylamine analogs. The compounds of the present invention are of formula wherein R1, R2, R3 and R4 are as defined in the description. 70 claims

Description

Technical field

The invention relates mainly to the field of phosphodiesterase 4 (PDE4) enzyme inhibitors. More specifically, the invention relates to selective PDE4 inhibition by novel compounds, for example, N-substituted aniline and diphenylamine analogs, to methods for their preparation and to compositions containing these compounds and methods for their use.

BACKGROUND OF THE INVENTION

Specific cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as secondary messengers in the cells and, as messengers, transmit impulses from cell surface receptors that bind different hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides in cells and maintain cyclic nucleotide homeostasis by breaking down such cyclic mononucleotides, leading to the end of their messenger role.

PDE enzymes can be grouped into eleven families in terms of their specificity for hydrolysis of cAMP and cGMP and their selective inhibition by different compounds. For example, PDE 1 is stimulated by Ca ²⁺ / calmodulin. PDE 2 is cGMP dependent and is located in the heart and adrenals. PDE 3 is cGMP dependent and inhibition of this enzyme produces positive inotropic activity. PDE 4 is cAMP specific and its inhibition causes airway relaxation, has anti-inflammatory and antidepressant activity. PDE 5 appears to play an essential role in regulating cGMP content in vascular smooth muscle and therefore PDE 5 inhibitors may have cardiovascular activity. Because PDEs have certain biochemical properties, they are likely to be subject to different forms of regulation.

PDE 4 has various kinetic properties including low Michaelis constant for cAMP and sensitivity to known drugs. The PDE4 enzyme family consists of four genes that produce 4 isoforms of the PDE4 enzyme, designated PDE4A, PDE4B, PDE4C and PDE4D [see Ref. Wang et al., Expression, Purification and Characterization of Human cAMPS Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Really. Comm. 234, 320 - 324 (1997)]. In addition, different attachment variants of each PDE4 isoform have been identified.

PDE4 isoenzymes are located in the cytosol of cells and are not related to any of the known membrane structures. PDE4 isoenzymes specifically deactivate cAMP by catalyzing its hydrolysis to adenosine 5′-monophosphate (AMP). Regulation of cAMP activity is essential in many biological processes, including inflammation and memory. PDE4 inhibitors of isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are potent anti-inflammatory agents and can therefore be used in the treatment of diseases in which inflammation is a problem such as asthma and arthritis. Moreover, rolipram enhances the cognitive performance of rats and mice in learning paradigms.

rolipram piklamilast

In addition to compounds such as rolipram, skantine derivatives such as pentoxifylline, denbufilin and theophylline inhibit PDE4 and have recently attracted attention with cognition-enhancing properties. cAMP and cGMP are second messengers that mediate the cellular responses of many different hormones and neurotransmitters. Thus, significant effects on PDE inhibition and the resulting increases in intracellular cAMP or cGMP in key cells, such as those localized in the nervous system and elsewhere in the body, may be obtained.

Rolipram, previously developed as an anti-depressant, selectively inhibits the PDE4 enzyme and has become a standard tool in classifying PDE enzyme subtypes. Earlier work on PDE4 focused on depression and inflammation, but later expanded to include indications of dementia (see The PDE IV Family of Calcium Phosphodiesterases Enzymes, ”John A. Lowe, III, et al., Drugs of the Future 1992, 17 (9): 799-807 for general review). Further clinical development of rolipram and other first generation PDE4 inhibitors has been discontinued because of the side-effect profile of these compounds. The first side effect in primates is emesis (vomiting), while the primary side effect in rodents is testicular degranulation, weakening of vascular smooth muscle, psychotropic effects, increased gastric acid secretion and erosion of the stomach.

SUMMARY OF THE INVENTION

The invention relates to novel compounds, for example new N-substituted aniline and diphenylamine compounds, which inhibit PDE 4 enzymes and in particular have improved side-effect profiles, for example, they do not relatively induce vomiting (i.e., compared to those described previously compounds of the prior art). Preferably the w compounds selectively inhibit PDE 4 enzymes. The compounds of the invention, at the same time, facilitate entry into cells, especially into cells of the nervous system.

The present invention further provides methods for synthesizing compounds of such activity and selectivity as well as methods (and corresponding pharmaceutical compositions) for treating a patient, e.g., a mammal, including humans in need of inhibition, in particular PDE 4 inhibition, in a disease state , which includes elevated intracellular PDE 4 levels or decreased cAMP levels, for example, including neurological syndromes, especially such conditions associated with memory impairment, in particular long-term memory impairment where impaired then memory is partly due to catabolism of intracellular cAMP levels by PDE4 enzymes, or where such memory impairment may be improved by effectively inhibiting the PDE 4 enzyme activity.

In a preferred embodiment, the compounds of the invention ameliorate such diseases by inhibiting PDE4 enzymes at doses that do not induce vomiting.

The invention includes compounds of formula I:

wherein:

R ¹ is alkyl having 1 to 4 carbon atoms which may be branched or unbranched and may be unsubstituted or substituted once or more than once by halogen (for example CH ₃ , CHF ₂ , CF ₃ , etc.);

R is alkyl of 1 to 12, preferably 1 to 8, carbon atoms which may be branched or unbranched and may be unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C1-4 alkoxy, oxo or a combination thereof and where optionally one or more -CH ₂ CH ₂ groups are substituted in each case by -CH = CH- or -C (e.g. CH ₃ , CHF ₂ , CF ₃ , methoxyethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8, carbon atoms which may be unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl of 1 to 4 carbon ether atoms, alkoxy having 1 to 4 carbon atoms or a combination thereof (eg cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms which is unsubstituted or substituted in the cycloalkyl moiety and / or the alkyl moiety one or more times with halogen, oxo, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy or a combination thereof (e.g. cyclopentylmethyl, cyclopropylmethyl, etc.).

aryl having 6 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or a combination thereof (eg methylphenyl, methoxyphenyl, chlorophenyl etc.), arylalkyl having in the aryl moiety 6 to 14 carbon atoms and in the alkyl moiety which may be branched or unbranched there are 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted in the aryl moiety by one or more times with halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alk oxy, nitro, cyano, methylenedioxy, ethylenedioxy or a combination thereof, and wherein in the alkyl moiety one or more -CH ₂ CH ₂ groups are replaced in each case by -CH = CH- or -C 4 C- and one or more - CH ₂ groups may each be optionally substituted by -O- or NH- and / or the alkyl moiety may be optionally substituted by halogen, oxo, hydroxy, cyano or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl) , ζ », chlorophenylethyl, chlorophenylpropyl, phenylethyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophene laminoethyl, etc.), 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 (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthalenyl, etc.), a heterocyclic group which is saturated, saturated or unsaturated having 5 to 10 ring atoms in which at least 1 ring atom is Ν, O or S which is substituted or substituted by one or more times halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof (e.g. 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.) or a heterocyclic-alkyl group in which the heterocyclic moiety is saturated, partially saturated or unsaturated and has 5 to 10 ring atoms of which at least 1 ring atom is Ν, O or S, and the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms, the heterocyclic-alkyl group is unsubstituted or substituted by one or more times in heterocyclic moiety with halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano , trifluoromethyl, nitro, oxo or combinations thereof, wherein in the alkyl moiety one or more -CH 2 CH 2 - groups are optionally substituted in each case by -CH = CH- or -C = C- and one or more CH ₂ groups each of which may be optionally substituted by -O- or -NH and / or the alkyl moiety may be optionally substituted by halogen, oxo, hydroxy, cyano or combinations thereof (e.g. pyridylethyl, pyridylpropyl, methylpiperazinylethyl, etc.);

R ³ is hydrogen, alkyl having 1 to 8, preferably 1 to 4, carbon atoms which is branched or unbranched and which may be unsubstituted or substituted one or more times by halogen, cyano, C 1-4 alkoxy or a combination thereof (e.g. methyl , ethyl, propyl, etc.), a partially unsaturated carbocyclic-alkyl group in which the carbocyclic moiety has 5 to 14 carbon atoms and an alkyl moiety that is branched or unbranched has 1 to 5 carbon atoms, which is unsubstituted or substituted in the carbocyclic moiety one or more times with halogen, alkyl, alk xy, nitro, cyano, oxo or combinations thereof and the alkyl moiety is optionally substituted by halogen, C1-6alkoxy, cyano or combinations thereof (e.g. cyclohexenylmethyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl moiety has 6 to 14 carbon and the alkyl moiety which may be branched or unbranched has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted on the aryl moiety one or more times by halogen, CF ₃ , OCF3, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in alkyl moiety with halogen, cyano or methyl (eg benzyl, phenethyl, phenylpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.) or heteroarylalkyl group, wherein the heteroaryl moiety may be partially or wholly 5 moieties ring atoms in which at least 1 ring atom is N, O or S, the alkyl moiety 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 moiety by halogen, alkyl , alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety by halogen, cyano or methyl or combinations thereof (e.g. pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylethylmethyl, pyridylmethylmethylpyridylmethyl) , quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);

R ⁴ is hydrogen, 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, OCF ₃ , amino, OCF ₃ , amino aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg hydroxymethyl), hydroxamic acid, tetrazol-5-yl, 2- (heterocyclic) tetrazol-5-yl (eg 2-2,2tetrahydropyranyl) tetrazol-5-yl) carboxycarboxylicoxycarboxy for example tert-butyloxycarbonyl, ethoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg tert-butyldimethylsilyloxy), R ⁵ -L- or combinations thereof (e.g. substituted or unsubstituted phenyl, naphthyl and biphenyl, phenyl, methylphenyl, fluorophenyl, fluorophenyl, fluorophenyl) , dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.) or heteroaryl having from 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom or a heteroatom, or once again with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (eg hydroxymethyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl) alkoxycarbonyl (for example tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg tert-butyldimethylsilyloxy), R ⁵ L- or pyrrolylines, hydrochloride, isochas Olin, pyrimidinyl, imidazolyl, thiazolyl, etc.);

R ⁵ is hydrogen, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C 1-4 alkyl, C 1-4 alkoxy, oxo or a combination thereof (e.g. methyl, ethyl, propyl and the like. N.), allylamino or dialkylamino, wherein each alkyl moiety has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g. dimethylamino, etc.), a partially unsaturated carbocyclic alkyl group, wherein the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms which is unsubstituted or h amestene, preferably in the carbocyclic moiety, one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof (eg 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, alkoxy, alkyl having 1 to 4 carbon atoms or combinations thereof (eg cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon an atom which is unsubstituted or substituted on the cycloalkyl moiety and / and and in the alkyl moiety one or more times with halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (eg cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms and which is an unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoapyl, aminoalkoxy dialkylamino, hydroxyalkyl (for example hydroxymethyl, hydroxyalkyl, hydroxyalkyl, oxyxoxymethyl) alkoxycarbonyl (e.g. Ymer tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl (e.g., substituted or nezamasten phenyl and naphthyl, methylnaphthyl, chlorophenyl, fluorophenyl, vinifenil, cyanophenyl, metilendioksofenil, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl , nitrophenyl, aminophenyl, etc.) arylalkyl having 7 to 19 carbon atoms in which the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms, the arylalkyl radical al is unsubstituted or substituted in the aryl moiety, one or more times by halogen, trifluoromethyl, OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl (eg benzyl, phenethyl , fenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), a heterocyclic group which is saturated, partially saturated or unsaturated having 5 to 10 ring atoms, of which at least 1 ring atom is N, 0 ring atom or S, which is unsubstituted or substituted one or more times by halogen en, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl group, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g. hydroxymethyl) hydroxyboxycarboxycarboxycarboxycarboxycarboxyl for example tert, butyloxycarbonyl, ethoxycarbonyl) cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof (e.g. pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolidinyl) imidazolinyl a silt group wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and has 5 to 10 ring atoms in which at least 1 ring atom is N, O or S, and an alkyl moiety that is branched or unbranched and has 1 to 5 carbon atoms, the heterocyclic alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in alkyl part with halogen, cyano or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, metilpiridilmetil, etc.);

L means a single bond or a bivalent aliphatic radical having 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups, each of which may be optionally substituted by -O-, -S-, -NR ⁶ -, -SO2NH -, -NHSO2- CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH, -NHCOO-, SCONH-, SCSNHor -NHCSNH- (e.g. -Ο-, CH2-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NHCO-, -CH ₂ CH ₂ CH ₂ -NH-CO-, -ch ₂ ch ₂ -co-, -so ₂ -nh- ch ₂ ch ₂ -o-, -O-CH ₂ CH ₂ 0-, -ch ₂ -nh-co-, -co-nh-ch ₂ -, -so ₂ -nh-, -ch ₂ -nh-so ₂ -, -CH ₂ CH ₂ CH ₂ -SO ₂ NH etc.) and

R ⁶ is hydrogen, 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, C 1-4 alkyl, with low xy, oxo or a combination thereof (e.g. methyl, ethyl, propyl, etc.), and wherein at least one of R ³ and R ⁴ is other than hydrogen and their pharmaceutically acceptable salts.

According to another aspect of the invention, a group of novel compounds of formulas II and III have been developed:

R2

NH

R2

III in which R ¹ , R ² and R ⁴ have the meanings indicated above. The compounds of this subgroup of formula I not only possess PDE4 inhibitory activity, but are also useful as intermediates for the preparation of compounds of formula I wherein R ³ and R ⁴ are both other than hydrogen.

In addition, preferred compounds of formula I are those of formula IV:

IV wherein R ¹ , R ² and R ⁴ have the meanings given in formula I and one of A, B or D is N and the others are C. It is preferred that B represents N. Also R ⁴ is preferably pyridyl or phenyl, which in each case may be substituted or unsubstituted.

The invention also includes compounds of formula D

R ¹ '

R2 '

K j,

R ¹ is methoxy, F, Cl, CHF ₂ or CF ₃ ;

R ² is alkyl having 1 to 12 carbon atoms;

alkyl having 1 to 12 carbon atoms which is substituted one or more times with 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 with 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 with halogen, oxo, cyano or combinations thereof;

cycloalkyl having 3 to 10 carbon atoms;

cycloalkyl having 3 to 10 carbon atoms which is substituted one or more times with 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 with 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 with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof;

arylalkyl having 7 to 26 carbon atoms; .

arylalkyl having 7 to 26 carbon atoms which is substituted one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof;

heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom or a 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 moiety aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and / or is substituted in the alkyl moiety by halogen, oxo, cyano or combinations thereof;

X is O or S;

R ³ is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, , carboxy, 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 having at least one ring atom is a heteroatom or a substituent a tan heteroaryl having from 5 to 10 ring atoms in which at least one ring atom is a heteroatom which is substituted one or more times with halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations from them;

L is -NH-, -NR ⁴ '-, -NHCH 2 -, -NR ⁴ CH 2 - or -CH ₂ NR ⁴ -, and

R ⁴ is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times with halogen, oxo, cyano or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinylthinyl, ethylsulfinyl, phenylthiol having 5 to 10 rings your 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 with 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, nitro, cyano , oxo, trifluoromethyl or combinations thereof, heteroarylalkyl having from 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom or substituted heteroarylalkyl having from 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 moiety by halogen, aryl , alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety 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, for example mammals, especially humans. These compounds exhibit neurological activity, especially when this activity affects cognition, including distant memory. These compounds are also effective in the treatment of diseases involving reduced cAMP levels. These compounds may also act as antidepressants or be useful in the treatment of cognitive and negative symptoms in schizophrenia.

Tests for determining PDE inhibitory activity as well as selectivity for PDE4 inhibitory activity and selectivity for inhibiting PDE4 isoenzymes are known to those skilled in the art. See, e.g., U.S. 6 136 821, incorporated herein by reference.

According to another aspect of the invention, compounds are useful as intermediates for the preparation of PDE4 inhibitors described herein (e.g. PDE4 inhibitors of Formula I) and / or useful in the synthesis of radiolabeled analogues of PDE4 inhibitors of the present description.

Thus, intermediates are provided which correspond to compounds of formula I in which R ² , R ³ and R ⁴ have the meanings given above in formula I, but R ¹ is hydrogen, tert-butyldimethylsilyl or a suitable phenolic protecting group . Suitable phenolic protecting groups are described for example, by Green, T. W. And Wuts, P. G. M., Protective Groups in Organic Synthesis, 3 ^rd Edition. John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radiolabeled compounds such that R ¹ is ³ H ³ C-, ¹⁴ CH ₃ - or ^I CH ₃ -, for example, by removing the protecting group and the resulting compound wherein R ¹ is hydrogen, reacts with suitable radiolabelled reagents. Such radiolabeled compounds are useful for determining the distribution of the compound in animal tissues, in imaging studies and for in vivo, ex vivo and in vitro assay.

Intermediates have also been developed which correspond to the compounds of formula I in which R ¹ , R ³ and R ⁴ have the meanings given above in formula I, but R is hydrogen, tert-butyldimethylsilyloxy or a suitable phenolic protecting group. Suitable phenolic protecting groups are described in Green, T. W. And Wuts, P. G. M., Protective Groups in Organic Synthesis, 3 ^rd Edition. John Wiley & Sons, 1999, pp. 246 - 293. Compounds in which R ² is hydrogen are useful as intermediates, for example as skeletons for parallel or combination chemical applications. In addition, these compounds are useful for introducing radiolabeling such as ³ H, ¹⁴ C or

As previously described, the compounds of formula II in which R ¹ , R ² and R ⁴ have the meanings indicated above are useful intermediates for the preparation of compounds of formula I wherein R ³ is other than hydrogen.

As previously described, the compounds of formula III in which R ¹ , R ² and R ³ have the meanings indicated above are useful intermediates for the preparation of compounds of formula I wherein R ⁴ is other than hydrogen.

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

Alkyl as a group or substituted per se or as part of a group or substituent (e.g. alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl) means a straight or branched chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon, preferably 1 to 8 carbon, in particular 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. Other examples of suitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl and similar.

Substituted alkyl groups are alkyl groups as described above, which are substituted in one or more positions by halogen, oxo, hydroxyl, C 1-4 alkoxy and / or cyano. Halogens are the preferred substituents, in particular F and CI.

Alkoxy means alkyl-O groups and alkoxyalkoxy means alkyl-O-alkyl-O- groups in which the alkyl moiety is in accordance with the previous description. Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxy, ethoxymethoxy, propoxymethoxy and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl-O-CO in which the alkyl moiety is in accordance with the above description. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl,

Cycloalkyl means a monocyclic, bicyclic or tricyclic non-aromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, in particular 3 to 6 carbon atoms. Suitable cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl and adamant-2-yl. Other suitable cycloalkyl groups of bicyclo [3.1.0] hexyl, bicyclo [5.1.0] octyl are spiropentyl, spiro [2.4] heptyl, spiro [2.6] nonyl, bicyclo [2.1,0] pentyl, spiro [2.5] octyl, bicyclo [2.2.0] hexyl, spiro [3.3] heptyl, bicyclo [4.2.0] octyl and spiro [3.5] nonyl. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be substituted, for example, by halogens and / or alkyl groups.

Cycloalkylalkyl refers to cycloalkyl - alkyl radicals in which the cycloalkyl and alkyl moieties are in accordance with the above. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

Aryl, as a group or substituent per se or as part of a substituent group, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, in particular 6 to 10 carbon atoms. Suitable aryl groups are phenyl, naphthyl and biphenyl. Substituted aryl groups include the above aryl groups which are substituted one or more times with, for example, halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyanoxy, cyanoxy , alkylsulfinyl, alkylsulfonyl and N-phenoxy.

An arylalkyl radical refers to an aryl-alkyl radical in which the aryl and alkyl moieties are in accordance with the above description. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl and naphthylmethyl.

Heteroaryl refers to an aromatic heterocyclic group having one or two rings and a total number of from 5 to 10 ring atoms in which at least one of the ring atoms is a heteroatom. Preferably the heteroaryl group contains 1 to 3, in particular 1 or 2, heteroaryl atoms selected from N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, dithialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, izobenzoferanil, thionaphthenyl, izotionaftenil, indole l, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cininolinyl, quinazolinyl, naphthyridinyl and benzoxazinyl, for example 3-thienyl, 2-thienyl, 2-thienyl, 2- , 3-, 4-, 5-, 6-, 7- or 8-quinolinyl and 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl.

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

Heterocycles include heteroaryl groups as described above, as well as non-aromatic cyclic groups containing at least one atom in the heterocycle, preferably selected from Ν, O and S, for example tetrahydrofuranyl, piperidinyl and pyrrolidinyl.

Heterocycle-alkyl refers to a heterocycle-alkyl group in which the heterocyclic and alkyl moieties are in accordance with the above. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl and isoquinolinylmethyl.

Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring structures contain at least one C = C bond. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexanedienyl, tetrahydronaphenyl and indan-2-yl.

Alkenyl refers to straight or branched chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH ₂ CH ₂ groups are each replaced by -CH = CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl and 2-pentenyl.

Alkynyl refers to straight or branched chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH ₂ CH ₂ groups are each replaced by -OC-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl and 2-butynyl.

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

The substituted radicals preferably have 1 to 3 substituents, preferably 1 to 2 substituents.

In the compounds of formula I, R ¹ is an alkyl group having preferably 1 to 4 carbon atoms, which is optionally substituted by halogen, preferably fluorine or chlorine. In particular, R ¹ is preferably methyl or difluoromethyl.

Rec preferably cycloalkyl, in particular cyclopentyl.

Is also preferably aryl or arylalkyl, in particular substituted or unsubstituted phenyl, phenyl, methoxyphenyl, phenopropyl, phenbutyl, phenylethenyl, phenoxyphenyl, phenoxyphenol, phenoxypropionenyl , nitrophenbutyl, chlorophenylaminoethyl and the like.

R is also preferably partially unsaturated carbocyclic chlorophenylethyl, chlorophenoxyethyl, methoxyphenbutyl, groups which are unsubstituted or substituted, in particular cyclohexyl, cyclohexadienyl, indan-2-yl.

R is also preferably an alkyl group having 1 to 8 carbon atoms, in particular 1 to 4 carbon atoms, which is substituted or unsubstituted, for example methyl, difluoromethyl, trifluoromethyl and methoxyethyl.

R ² is also preferably a heterocyclic or heterocyclic alkyl group, in particular radicals in which the heterocyclic group has up to 6 ring atoms and 1 to 2 ring heteroatoms selected from N, O and S, for example tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl pyridylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like.

Preferred R are cyclopentyl, tetrahydrofuranyl, CHF ₂ , methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridyl-ethyl and pyridylpropyl.

R ³ is preferably hydrogen, alkyl of 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl or n-butyl), arylalkyl (e.g. substituted or unsubstituted benzyl, phenethyl and phenpropyl) or heteroarylalkyl (e.g. substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for aryl and heteroaryl in R ³ are F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ and CN.

R ⁴ is preferably aryl or heteroaryl, in particular phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl and isoquinolinyl, which may in each case be unsubstituted or substituted one or more times. Preferred substituents are OH, F, Cl, CF ₃ , alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH ₂ OH, CONHOH, CONH ₂ , methylenedioxy, COOH and combinations thereof.

In addition, when R ⁴ is aryl, in particular phenyl, preferred substituents include R ⁵ - L, for example R ⁵ -, R ⁵ -O-, R ⁵ -CO-, R ⁵ -NH-CO-, R ⁵ SO 2 -NH-, R ⁵ -SO2-NH-anKHnen-O-, NH ₂ -anKHn-NH-CO, and ⁵ -alkylene-NH-CO-, alkyl-CO-PF-alkyl- as well as methyl, ethyl, F , Cl, CN, OCH ₃ , CF ₃ , amino, nitro, HOCH ₂ and COOH.

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

When R ⁴ is aryl substituted with R ⁵ -SO 2 -NH-alkylH-O-, it is preferably substituted phenyl. In this case, R ⁵ is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH ₂ -, CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -.

When R ⁴ is aryl substituted with R ⁵ - L, it is preferably substituted phenyl. In these cases, preferred R ⁵ groups are tetrazole, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl or methylpiperadinyl and L is preferably a single bond, -O-, -CO-, -CH ₂ -, - CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ -O-, CH2CH2-O-, -CH2CH2CH2-O-, -, -CH2-NH-CH2CH2-O-, -CONH- -NH -CO-.

In addition, preferred PDE4 inhibitors according to the invention are compounds described by sub-formulas 1a-1h, which correspond to formula I but have the following preferred groups:

la R ¹ is methyl or CHF ₂ ;

R is an alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl or heterocyclic group which may be substituted or unsubstituted,

R ³ is hydrogen, arylalkyl or heteroarylalkyl which may be substituted or unsubstituted and

R ⁴ is aryl or heteroaryl which may be substituted or unsubstituted.

Ib R ³ is heteroarylalkyl which is substituted or unsubstituted.

Ic R ¹ is methyl or CHF ₂ and

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl, (especially (3R) tetrahydrofuranyl).

Id R ¹ is methyl or CHF ₂ ,

R ² is cyclopentyl,

R ³ is heteroarylalkyl, in each case substituted or unsubstituted and

R ⁴ is substituted or unsubstituted aryl or heteroaryl.

Ie R ¹ is methyl;

R ² is cyclopentyl,

R ³ is heteroarylalkyl which is substituted or unsubstituted.

If R ¹ is methyl;

r is cyclopentyl, w

R ³ is heteroarylalkyl which is substituted or unsubstituted and

R ⁴ is phenyl which is substituted or unsubstituted.

Ig R ¹ is methyl;

R ² is cyclopentyl,

R ³ is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl or pyrazinylmethyl, which may be substituted or unsubstituted, or methyl, ethyl or propyl, and

R ⁴ is phenyl or phenyl which is substituted by 1 to 3 substituents.

¹ R ¹ is methyl;

'W • y

R is cyclopentyl;

R is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which may be substituted or unsubstituted, or methyl, ethyl or propyl, and

R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyrimidyl, thiazolyl, pyrazinyl, quinolinyl or isoquinolinyl, which may be substituted or unsubstituted.

In addition, preferred PDE4 inhibitors according to the invention are the compounds described by Pallid formulas that correspond to formula II but have the following preferred substituents:

Ila R ¹ is methyl or CHF 2;

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is phenyl, naphthyl, quinolinyl or isoquinolinyl which may be substituted or unsubstituted.

lib R ¹ is methyl or CHF 2;

R is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido, or is 2-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.

Ps ¹ is methyl;

R ² is cyclopentyl and

R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl which may be substituted or unsubstituted.

lid R ¹ is methyl,

R ² is cyclopentyl and

R ⁴ is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.

In addition, preferred PDE4 inhibitors according to the invention are the compounds described by formulas IIIa-Hid, which correspond to formula III but have the following preferred substituents:

Sha R ¹ is methyl or CHF ₂ ;

R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl or pyrrolylmethyl, which may be substituted or unsubstituted.

III b R ¹ is methyl or CHF ₂ ;

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ³ is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, which may be unsubstituted or substituted.

R ¹ is methyl;

R ² is cyclopentyl and

R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, isoimidazolyl, thiazolylmethyl or pyrrolylmethyl, which may be optionally substituted.

Hid R ¹ is methyl,

R ² is cyclopentyl and

R is pyrazinylmethyl or pyridylmethyl which may be substituted or unsubstituted.

In addition, preferred PDE4 inhibitors according to the invention are the compounds described by formulas IVa - IVd, which correspond to formula IV but have the following preferred substituents:

IVa R ¹ is methyl or CHF ₂ ;

IVb R ¹ is methyl or CHF ₂ and

BeN.

IVc R ¹ is methyl or CHF ₂ and

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl).

IVd R ¹ is methyl or CHF ₂ ,

B is N and

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl).

D IVe R ¹ is methyl or CHF ₂ and

R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted.

IVf R ¹ is methyl or CHF ₂ ,

B is N and

R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted.

IVg R ¹ is methyl or CHF ₂ ,

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted.

IVh R ¹ is methyl or CHF ₂ ,

BeN,

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted.

I Vi R ¹ is methyl or CHF ₂ ,

R ⁴ is phenyl which is substituted at the 3 or 4 position.

IVj R ¹ is methyl or CHF ₂ ,

B is N and

R ⁴ is phenyl which is substituted at the 3 or 4 position.

IVk R ¹ is methyl or CHF ₂ ,

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is phenyl which is substituted at the 3 or 4 position.

IV1 R ¹ is methyl or CHF ₂ ,

BeN, 'In

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is phenyl which is substituted at the 3 or 4 position.

IVm R ¹ is methyl or CHF ₂ and

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-C 1 -phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH -phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethyl-phenyl.

IVn R ¹ is methyl or CHF ₂ ,

B is N and

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-C 1 -phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH -phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethyl-phenyl.

IVo R ¹ is methyl or CHF ₂ ,

Λ

R is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-C 1 -phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH -phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethyl-phenyl.

IVp R ¹ is methyl or CHF ₂ ,

BeN,

Λ

R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (in particular (3R) tetrahydrofuranyl) and

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-C1-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4 -pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethyl-phenyl.

Preferred aspects comprise pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier and optionally other active substances as described below; a method of inhibiting the PDE4 enzyme, in particular an isoenzyme, for example as defined by conventional assays or described herein, either in vitro or in vivo (in an animal, for example an animal model, or in a mammal or human); a method of treating neurological symptoms, such as memory loss, in particular long-term memory, impairment or loss of cognition, memory impairment, etc. and a method of treating a disease condition modulated by PDE4 activity in a mammal, e.g., a human.

The compounds of the invention may be prepared by conventional means. Some of the methods that can be used are described here.

All starting materials are known or can be synthesized from known starting materials.

Scheme 1

la) R ² Br, K ₂ CO ₃ , DMF 1b) R2OH, PPh ₃ DIAD, THF 1c) TBDMSCI, hyd., DMF 1d) R2B (OH) ₂ , Cu (OAc) ₂

Et ₃ N

2) FL.10% Pd / C, EtOH __2__________R ²

3) R3CHO, NaBH ₄ pTsOH, MeOH

4) Pd ₂ dba ₃ , NaOtBu

P (tBu) ₃ , R4 |

R2

The starting nitrophenols of type 1 are either commercially available (e.g. R ^{1 =} CH 3) or prepared by known methods (for example R ¹ is CHF 2 or both R ¹ and R ² are CHF _2> see Mueller, Klaus - Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN: EPXXDW EP 626361A1; Touma, Toshihiko; Asai,

Tomoyuki, Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN: JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor., Int. Symp. Wood. Pulping Chem., 1995, 8 ^th , 3, 295 - 299; Christensen, Siegfried Benjamin, Dabbs, Steven; Karpinski, Joseph M., PCT Int. Appl. (1996), 12 pp. CODEN: PLXXD2 WO 9623754 Al 19960808). Aniline derivatives 3 are obtained in two steps: first a coupling reaction provides intermediate 2, followed by reduction of the nitro group. The intermediate nitro compound 2 can be prepared by many methods, such as Mitsunobu reactions or standard reactions of

A alkylation. Compounds in which R is aryl or heteroaryl may be prepared by copper-catalyzed reactions with aryl or heteroaryl iodides under Ullman conditions or by coupling aryl, vinyl or heteroaryl boronic acids with phenol 2 in the presence of a copper catalyst (e.g. Cu (OAc) ₂ ) and base as TEA. The reaction of Mitsunobu between appropriately substituted nitrophenol and primary or secondary alcohol using azodicarboxylate (eg DEAD, DIAD) and suitable phosphine (eg Ph ₃ P, Bu ₃ P) yields alkinated nitrophenols 2. Mitsunobu reactions are usually carried out in suitable solutions such as dichloromethane or tetrahydrofuran. Alternatively, alkylation may be achieved by reaction between a suitably substituted nitrophenol and an alkyl halide in the presence of a base (e.g. potassium carbonate or sodium hydride) in a suitable polar solvent (e.g. dimethylformamide or CH ₃ CN).

Nitrocatechols 2 are then reduced to the corresponding anilines 3 by standard methods in the art such as hydrogenation using a suitable catalyst (e.g. palladium on carbon) in a polar protic solvent (e.g. methanol or ethanol) in a hydrogen atmosphere. Alternatively, nitrocatechol 3 can be reduced by using a hydride source (eg NaBELi) and a transit metal catalyst (eg NiCl ₂ , Pd on carbon) or using metals (eg zinc, tin and iron) in mineral acid solutions (eg HCI ) to obtain the corresponding anilines. Generally, these reactions use polar protic solvents such as ethanol or methanol.

N-arylalkylanilides 4 are synthesized by standard methods such as a reductive amination reaction, an alkylation reaction, or by reduction of the corresponding amides. For example, the reaction for the reductive amination of aryl or arylalkyl aldehyde with suitably substituted anilides in the presence of borohydride reducing agents such as NaBH ₄ or NaBH ₃ CN with an acid catalyst such as acetic acid or pTsOH provides the desired N-arylalkyl anilides. These reactions generally occur in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.

The N-arylalkylanilides 4 readily undergo N-arylation by standard methods including a Ullman coupling reaction, a metal catalyzed coupling or an aromatic nucleophilic substitution reaction. For example, the metal-catalyzed reaction between N-benzylanilide and aryl halide using a palladium catalyst (e.g. Pd ₂ dda ₃ ), and a bulk electron-rich phosphine ligand (e.g. tributylphosphine) and a suitable base (e.g. NaOtBu) provides N-arylalkyldiphenylamino. Nickel and copper catalysts are also used. Suitable solvents for this reaction are non-polar aprotic solvents such as toluene, benzene, xylene, tetrahydrofuran and ether. When synthesizing compounds of type 5 in which R ⁴ is alkoxycarbonylphenyl, it is preferred that the amine 4 be coupled to 1.1 equivalents of tert-butyl 3-iodobenzene and use 22 mol% (tBu) ₃ P, 5.5 mol% Pd ₂ dda ₃ and 1.3 equivalents of NaOtBu.

Scheme 2 zinc, tin and iron) in mineral acid solutions (eg HCl) to give the corresponding anilines. Generally, these reactions use polar protic solvents such as ethanol or methanol.

N-arylalkylanilides 4 are synthesized by standard methods such as a reductive amination reaction, an alkylation reaction, or by reduction of the corresponding amides. For example, the reaction for the reductive amination of aryl or arylalkyl aldehyde with suitably substituted anilides in the presence of borohydride reducing agents such as NaBH ₄ or NaBH ₃ CN with an acid catalyst such as acetic acid or pTsOH provides the desired C, N-arylalkyl anilides. These reactions generally occur in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.

The N-arylalkylanilides 4 readily undergo N-arylation by standard methods including a Ullman coupling reaction, a metal catalyzed coupling or an aromatic nucleophilic substitution reaction. For example, the metal-catalyzed reaction between N-benzylanilide and aryl halide using a palladium catalyst (e.g. Pd2dda ₃ ), and a bulk electron-rich phosphine ligand (e.g. tributylphosphine) and a suitable base (e.g. NaOtBu) provides N-arylalkyldiphenylamino. Nickel and copper catalysts are also used. Suitable solvents for this reaction are non-polar aprotic solvents such as toluene, benzene, xylene, tetrahydrofuran and ether. When synthesizing compounds of type 5 in which R ⁴ is alkoxycarbonylphenyl, it is preferred that the amine 4 be coupled to 1.1 equivalents of tert-butyl 3-iodobenzene and use 22 mol% (tBu) ₃ P, 5.5 mol% Pd ₂ dda ₃ and 1.3 equivalents of NaOtBu.

Scheme 2

Carboxylic esters, intermediate

5) NaOH, EtOH

6) H ⁺

compounds can be hydrolyzed under acidic or alkaline conditions to give the corresponding carboxylic acids 7. For example, ethyl ester (R ⁵ = Et) can be hydrolyzed using a mixture of water base (e.g. sodium hydroxide or potassium hydroxide) and miscible with water solvent eg ethanol, tetrahydrofuran). While tert -butyl ethers (R ⁵ = tert -butyl) can be hydrolyzed using aqueous acid (eg HCl, formic, trifluoroacetic) and a water miscible organic solvent, if necessary.

Scheme 3

R2

R ³

5) NaOH, EtOH

6) H ⁺

R2

CO ₂ H

Carboxyl esters, intermediates

6, can be given corresponding = Et) can be hydrolyzed under acidic or basic conditions to carboxylic acids 7. For example, the ethyl ester (R ⁵ hydrolysed using a mixture of aqueous base (e.g. sodium hydroxide or potassium hydroxide) and mixing with water (eg ethanol, tetrahydrofuran). While tert -butyl ethers (R ⁵ = tert -butyl) can be hydrolyzed using aqueous acid (eg HCl, formic, trifluoroacetic) and a water miscible organic solvent, if necessary.

Scheme 3

7) H ⁺ , THF

----- ► solvents in this type of reaction are non-polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether and the like.

In addition, diphenylamines 10 may be alkylated with various alkyl halides or arylalkyl halides such as, but not limited to, iodomethane, ethyl bromide, benzyl chloride, 3 (chloromethyl) pyridine, 4- (chloromethyl) -2,6-dichloropyridine and 4 ( bromomethyl) -benzoic acid or their salts in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide, or potassium diisopropylamide to give N-substituted diphenylamines 5. w The solvents used in this reaction are aprotic solvents such as benzene, benzene, tetrachloride, benzene n, ether, dimethylformamide and the like.

Figure 5

10) RuBOP, DIPEA, NHR5R6

CH ₂ CH ₂

--- R ³

Carboxylic acids 7 may further yield carboxamides 11 using standard methods. For example, a carboxylic acid may be reacted with a suitable primary or secondary amine in the presence of a suitable coupling reagent such as BOP, pBOP or DCC and on a base such as triethylamine or DIE A to give carboxamide. These reactions usually take place in non-polar aprotic solvents such as dichloromethane, chloroform or dichloroethane.

Carboxylic esters 6 or acids 7 can be reduced using standard methods to obtain the corresponding carboxaldehydes or hydroxymethyl analogs. For example, an aryl ethyl ester (e.g. of structure 6, R ⁵ = ethyl) may be treated with a suitable reducing agent (eg LAH, DIBAL, etc.) in an aprotic solvent such as ether or tetrahydrofuran to obtain the corresponding carboxyaldehydes or hydroxymethyl analogues. Such aldehydes and alcohols can then be derivatized by standard methods used in the art.

Similarly, carboxamides (e.g. of structure 11) and nitriles can be reduced using standard methods in the art to give the corresponding substituted amines or aminomethyl analogs. For example, aryl carboxamide 11 may be reduced with a suitable reducing agent (e.g. LAH) in an aprotic solvent (e.g. benzene, ^x toluene, ether, tetrahydrofuran, etc.) to give the corresponding substituted aminomethyl analogue. However, reduction of arylnitrile yields the corresponding primary aminomethyl analogue.

Figure 6

--- R ^{3 R2}

11) 10% Pd / C, H ₂

EtOH

12) R ⁵ SO ₂ CI or R ⁶ COCI

---------------->

Pyr., CH ₂ CH ₂

Cr ^^ NR ³

Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by standard methods such as hydrogenation using a suitable catalyst (e.g. palladium on carbon) in a polar protic solvent (eg ethanol, methanol, etc.). The nitrobenzenes 12 can also be reduced using a hydride source (eg NaHFd) and a transit metal catalyst (e.g. NiCh, palladium on carbon) in polar protic solvents such as ethanol to obtain the corresponding anilides 13. These anilides can then be replaced by well-known standard methods. For example, anilines of type 13 may be alkylated, acylated or sulfonylated to give the corresponding N-alkyl amines, carboxamides (e.g. with structure 15) or respectively sulfonamides (e.g. with structure 14). For example, sulfonamide may be prepared from aniline and a suitable sulfonyl halide or sulfonic acid anhydride (e.g. MeSO ₂ Cl, EtSO ₂ Cl, BnSChCl, PhSO ₂ Cl, etc.) in the presence of a base (e.g. triethylamine, pyridine, DIEA and m .n.). Suitable solvents for this reaction are non-polar aprotic solvents such as dichloromethane, chloroform, ether and the like.

Scheme 7

17) TBAF, THF, 0 ° C

--- R ³

R ⁴

18A) R2-Br, K ₂ CO ₃ , DMF

18B) DIAD, PPh ₃ , Imd., R2-OH, THF

--- R ³

R ² _r4

Trialkyl silyl ethers of type 16 are prepared as described in Scheme 1. The tert-butyldimethylsilyl protected catechol intermediates 16 are easily released from protection by various literature methods (see Green, T. W. and Wuts, R. G. M. ., Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 273 - 276.) such as using a fluoride ion source (e.g. BU4NF) in an aprotic solvent such as ether or tetrahydrofuran or under acidic conditions (e.g. KF, 48% HBr, DMF). The resulting phenol 17, which is a very valuable synthetic intermediate, can then be alkylated by standard methods in a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1. For example, in the reaction of Mitsunobu, in the reaction of alkyl halide in the presence of base or in Ullman type aryl coupling or by reaction with vinyl, aryl or heteroaryl-boric acids in the presence of a copper catalyst.

Scheme 8

21) NHR5R6, K ₂ CO ₃

CH ₃ CN

R2

ΓΐΙ

Μ

R5

R ⁶

Haloalkoxy intermediates 18 obtained by alkylation of the corresponding phenol may be alkylated by reaction with substituted amines, alcohols or thiols in the presence of a base to obtain analogs such as 19. For example, an alkyl halide may be aminated with a suitable primary or secondary amine and a base such as potassium carbonate in a polar aprotic solvent such as tetrahydrofuran, dimethylformamide or CH ₃ CN.

Many of these synthesis methods are described in more detail in the examples below.

It will be apparent to one of ordinary skill in the art that some of the compounds of formula (I) and (D) may exist in different geometric isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric carbon atoms and are therefore able to exist in the form of optical isomers, and inter alia in the form of racemic or non-racemic mixtures thereof. All these compounds, including the cis and trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, and practically pure and pure enantiomers within the scope of the present invention. Virtually pure enantiomers contain not more than 5% w / w of the corresponding inverse enantiomer, preferably not more than 2%, most preferably more than 1%.

Optical isomers can be obtained by separating the racemic mixtures by conventional methods, for example by forming diastereomeric salts using an optically active acid or base to form covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluyltartaric and camphorsulfonic acid. Mixtures of distoisomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods well known in the art, for example by chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. A different method for separating optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, optimally selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, for example Chiracel OD and ChiracelOJ among many others, all of which are routinely selected. Enzymatic separation with or without derivatization may also be used. The optically active ingredients of formulas (I) and (D) can also be prepared by chiral synthesis using optically active starting materials.

The present invention also relates to useful forms of the compounds described herein, such as pharmaceutically acceptable salts and prodrugs of all compounds of the invention. Pharmaceutically acceptable salts include those obtained by reacting the base compound as a base with an inorganic or organic acid to form a salt, for example hydrochloric acid, sulfuric, phosphoric, methanesulfonic, camphorsulfonic, oxalic, maleic, succinic and citric acid . Pharmaceutically acceptable salts also include those in which the parent compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. It will be appreciated by those skilled in the art that the acid addition salt of the compounds claimed can be obtained by reacting the compounds with a suitable organic or inorganic acid by any of the known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with a suitable base according to known methods.

The following are other examples of acid salts that may be obtained by reacting with inorganic and organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconate, cyclopentanopropionate, cyclopentane , glucoheptanates, glycerophosphates, hemisulfates, heptanates, hexanates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactate, maleates, methanesulfonates, nicotinates, 2naphthalenesulfonate, 2naphthalenesulfonate, 2naphthalenesulfonate propionate, picrates, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoates.

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

The compounds of the invention may be administered alone or as an active ingredient in a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of formulas I and D containing for example one or more pharmaceutically acceptable carriers.

Numerous sources are available that describe methods for preparing various formulations suitable for administration of the compounds of the invention. Examples of such formulations and formulations are exemplified, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwarz, editors) current edition published by Marcel Dekker, Inc. As in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553 - 1593 (current edition).

In view of the high degree of PDE4 inhibition, the compounds of the present invention may be administered to anyone in need of PDE4 inhibition and / or improvement in cognition. Administration may be performed according to the patient's need, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastenally, and by infusion), by inhalation, rectal, vaginal, external, topical, transdermal, and ocular.

Various solid oral dosage forms may be used to administer the compounds of the invention including such solid forms as tablets, gelatin capsules, hard capsules, granules, lozenges and bulk powder. The compounds of the invention may be administered alone or in combination with a variety of pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients, including, but not limited to, suspending agents, solubilizers, buffering agents , binders, disintegrants, preservatives, colorants, flavors, lubricants and the like. Sustained release capsules, tablets and gels may be advantageous in the administration of the compounds of the invention.

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

Suppositories for rectal administration of the compounds of the invention may be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of a pessary, swab, cream, gel, paste, foam or spray containing, in addition to the active ingredient, suitable carriers known in the art.

For external use, the pharmaceutical compositions may take the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for application to the skin, eyes, ears or nose. External administration may also include transdermal administration by means such as transdermal patches.

Aerosol formulations for administration by inhalation may also be obtained. For example, for the treatment of respiratory disorders, the compounds of the invention may be administered by inhalation in the form of powder (eg, micronized) or in the form of atomized solutions or suspensions. The aerosol formulations may be pressurized into a propellant.

The compounds may be administered as a single 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 psychoses, for example other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators, NMDA amphakins -R modulators, mGluR modulators and cholinesterase inhibitors (eg donepezil, rivastigimine and glanthanamine). In such combinations, any active ingredient may be administered either at or below the usual dosage range.

The invention further includes methods of treatment which include inhibition of PDE4 enzymes in animals, e.g., mammals, in particular humans, wherein such inhibition has a curative effect in which such inhibition may alleviate conditions involving neurological syndromes such as memory loss, -specially long-term memory. Such methods include administering to an animal in need thereof, particularly to a mammal, and in particular to a human, an inhibitory amount of a compound, alone or as part of a formulation as described herein.

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

Dementia is a disease that involves memory loss and additional intellectual disabilities other than memory. The invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include neurodegenerative dementia (eg Alzheimer's disease, Parkinson's, Huntington's, Pick's), vascular disease (eg heart attacks, hemorrhage, heart disorders), mixed vascular and Alzheimer's disease, bacterial meningitis, bacterial meningitis disease -Jakob, multiple sclerosis, traumatic (eg subdural hemorrhage or traumatic brain injury), infections eg HIV), genetic (Down syndrome), toxic (eg heavy metals, alcohol, some drugs), metabolic (eg vitae) yn B12 or folate deficiency), hypoxia of the central nervous system disease, Cushing, psychiatric (e.g., depression and schizophrenia) and hydrocephalus.

The invention includes methods for treating memory loss other than dementia, including mild cognitive impairment (MCI) and age-related cognitive impairment. The invention includes methods for treating a memory disorder as a result of a disease. In another embodiment, the invention includes methods of treating memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention.

The compounds can be used to treat psychiatric conditions including schizophrenia, bipolar or manic depression, major depression and drug addiction and morphine dependence. These compounds can enhance vigor. PDE4 inhibitors can be used to increase cAMP levels and protect neurons from apoptosis. PDE4 inhibitors are also known to be anti-inflammatory agents. The combination of anti-apoptotic and anti-inflammatory properties makes these compounds useful in the treatment of neurodegeneration resulting from disease or injury, including stroke, spinal cord injury, neurogenesis, multiple sclerosis, amylolaterosclerosis (ALS), and multiple MS atrophy.

Thus, in accordance with a preferred embodiment, the invention includes methods for treating patients suffering from memory impairment due, for example, to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob's disease , depression, aging, head trauma, stroke, central nervous system hypoxia, multi-infectious dementia and other neurological conditions including acute neurological diseases, as well as HIV and cardiovascular disease, including the administration of an effective amount from a compound of formula (I) or (I) or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may also be used in a method of treating patients suffering from disease conditions characterized by diminished NMDA function such as schizophrenia. The compounds can also be used to treat psychosis characterized by elevated levels of PDE4, 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, they are useful in the treatment of various allergic and inflammatory diseases, in particular disease states characterized by decreased cyclic AMP levels and / or increased phosphodiesterase 4 levels. Thus, in accordance with other embodiments of the invention, there is provided a method of treating allergic and inflammatory disease states comprising administering an effective amount of a compound of formula (I) or (I) or a pharmaceutically acceptable salt thereof. Such disease states include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, esoniophilic granulomatitis, psoriasis, psoriasis, psoriasis, psoriasis, psoriasis Crohn, reperfusion myocardial and brain damage, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, arteriosclerosis, keratosis, rheumatoid spondyl it, osteoarthritis, pyrexia, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple erysipelas, erysipelas, cicatris, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide area pyodermiasis, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease , leukemia, multiple sclerosis, gastrointestinal disease, autoimmune disease and the like.

The treatment of asthma, chronic bronchitis, psoriasis, allergic rhinitis and other inflammatory diseases with PDE4 inhibitors is known, as well as for the inhibition of tumor necrosis factor. See, for example, WO 98/58901, JP 11-18957, JP 10-072415, WO 93/25517, WO 94/14742, U.S. Pat. U.S. Patent No. 5,814,651 and U.S. Pat. 5 935 9778. These sources also describe test methods for determining PDE4 inhibitory activity and methods for synthesizing such compounds. These documents are included here for reference.

PDE4 inhibitors can be used to prevent or alleviate osteoporosis, such as an antibiotic for the treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, for the treatment of rheumatoid arthritis (RA), for long-term inhibition of mesenchymal transplantation, urinary obstruction secondary to benign prostatic hyperplasia to suppress chemotaxis and reduce invasion of colon cancer cells to treat B cell chronic lymphocyte leukemia (B-CLL), for the inhibition of uterine contractions, for the reduction of pulmonary vascular ischemic-reperfusion injury (IRI), for the corneal damping, for the inhibition of IL-2R expression and thus the elimination of HIV-1 DNA nuclear import in memory T cells, to enhance glucose-induced insulin secretion, to prevent and treat colitis, and to inhibit mast cell degranulation.

The compounds of the invention may be administered as a single 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, for example other PDE4 inhibitors, calcium channel blockers, haloinergic drugs, adenosine receptor modulators, amphakins NMDA-R modulators, mGluR modulators and cholinesterase inhibitors (eg donepezil, rivastigimine and glanthanamine). In such combinations, any active ingredient may be administered either at or below the usual dosage range.

The dosage of the compounds of the invention depends on various factors including, among others, the particular syndrome to be treated, the severity of the symptom, the route of administration, the frequency of dosing intervals, the particular compound used, its efficacy, its toxicological profile, the pharmacokinetic profile of the compound and the presence of harmful side effects.

The compounds of the invention are administered to a mammal at dosages as are customary for PDE4 inhibitors, such as those for the aforementioned known compounds. For example, the compounds may be administered in a single or multiple dose, by oral administration in an amount of about 0.01 to 100 mg / kg / day, preferably 0.1 - 70 mg / kg / day, in particular 0.5 - 10 mg / kg / daily. The unit dosage forms may contain, for example, 0.1-50 mg of an actin compound. For intravenous administration, the compounds may be administered in single or multiple doses, for example 0.001 - 50 mg / kg / day, preferably 0.001 10 mg / kg / day, in particular 0.01 - 1 mg / kg / day. The unit dosage forms may contain, for example, 0.1 - 10 mg of active compound.

In carrying out the methods of the present invention, it should be understood that the reference to specific buffers, media, reagents, cells, culture conditions and the like is not intended to limit, but to cover, related materials that one skilled in the art will deem to be of interest or value in a particular context. For example, it is often possible to replace one buffer system or culture medium with another and still achieve similar if not identical results. Those of skill in the art will have sufficient knowledge of these systems and methodologies to be able, without undue experimentation, to make such substitutions that optimally serve their purpose when using the methods and procedures described herein.

The present invention will be further described by the following non-limiting examples.

In the preceding and following examples, all temperatures are uncorrected and are in Celsius degrees and unless otherwise stated, all parts and percentages are by weight.

All patent applications, patents and publications cited throughout the specification of the present invention are incorporated herein by reference.

Examples of carrying out the invention

Example 1A

1-cyclopentyloxy-2-methoxy-5-nitrobenzene

Cyclopentyl bromide (4.99.2 ml, 4.66) was added to a suspension of 2-methoxy-5-nitrophenol (525 g, 3.104 mol) and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 l) under a nitrogen atmosphere. mole). The suspension was heated to 100 ° C for 6 hours. Potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 ml, 0.46 mol) were added. The suspension was heated to 100 ° C for 4 hours. TLC indicated that the reaction was complete (9: 1 OCM.methanol). The reaction mixture was cooled to room temperature and diluted with water (3 l) and ether (3 l). The layers were separated and the aqueous layer was re-extracted with ether (2 L). The combined organic extracts were washed with 1 N NaOH (2 l), water (2 l) and brine (2 l). The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting solid was azeotropically distilled with toluene (2 x 300 ml) to give 736.7 g (99.6% yield) of the product as a yellow solid.

The following compounds are prepared in a similar manner to those described above:

a) 1-Cyclopropylmethoxy-2-methoxy-5-nitrobenzene

b) 1-cyclopentoxy-2-difluoromethoxy-5-nitrobenzene

c) 1-cyclopropylmethoxy-2-difluoromethoxy-5-nitrobenzene

Example IB

2-methoxy-5-nitro-1 - ((3R) -tetrahydrofuranyloxy) benzene

To a mixture of 2-methoxy-5-nitrophenol (1.69 g, 10 mmol), triphenylphosphine (5.24 g, 20 mmol) and 3- (N) -hydroxytetrahydrofuran (1.80 g, 20 mmol) in anhydrous tetrahydrofuran (40 ml) was added. diisopropylazodicarboxylate (4.0 ml, 20 mmol) was added dropwise with stirring and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ether (150 ml) and washed with 2 N NaOH (3 x 50 ml) and brine, dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product.

The following compounds are prepared in a similar manner to those described above:

a) 2-methoxy-5-nitro-1- (3-tetrahydrofuranyloxy) benzene

b) 2-metho xy-5-nitro-1 - ((3S) -tetrahydrofuryloxy) benzene

c) 2-difluoromethoxy-5-nitro-1- (3-tetrahydrofuryloxy) benzene

d) 2-difluoromethoxy-5-nitro-1 - ((31 <) - tetrahydrofuryloxy) benzene

e) 2-Difluoromethoxy-5-nitro-1 - ((3S) -tetrahydrofuryloxy) benzene

f) 2-methoxy-5-nitro-1- (3-phenpropyloxy) benzene

g) 1- (2-indanyloxy) -4-methoxy-5-nitrobenzene

Example 1C

1- (tert-butyldimethylsilyl) oxy-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 dimethylformamide (40 ml) was added stirring tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture. allowed to stir at room temperature for 16 hours. The solvent was removed in vacuo and the residue was dissolved in 40 ml of 50% ethyl acetate in hexanes and filtered through silica gel. The silica gel was washed with an additional 200 ml of 50% ethyl acetate in hexanes and the filtrates were combined and concentrated in vacuo to give 2.01 g of the product as a light brown crystalline solid.

^! H NMR (CDCl ₃ ) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, 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-cyclopentyloxy-4-methoxyaniline

To a suspension of 10% Pd on activated carbon (25 g) in ethanol (4 l) under a nitrogen atmosphere, 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250 g, 1.054 mol) was added. The reaction mixture was degassed in vacuo three times. The mixture was stirred vigorously by passing hydrogen gas over it. After 4 hours the reaction was complete, which was determined by TLC (5: 1 hexane: ethyl acetate). The reaction mixture was filtered through a pad of celite and the celite was washed with additional ethanol. The solvent was removed in vacuo to give 208.38 g (95% yield) of 3cyclopentyloxy-4-methoxyaniline as a red liquid.

1 H NMR (CDCl 3) δ 6.85 (d, 1H, .1 = 8.4 Hz), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p. 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 are prepared in a similar manner to those described above:

a) 3-cyclopentyloxy-4-difluoromethoxyaniline

b) 3-cyclopropylmethoxy-2-methoxyaniline

c) 3-cyclopropylmethoxy-4-difluoromethoxyaniline

d) 4-methoxy-3 - ((3R) -tetrahydrofuryloxy) aniline

e) 4-methoxy-3- (tetrahydrofuryloxy) aniline

f) 4-methoxy-3 - ((3S) -tetrahydrofuryloxy) aniline

g) 4-difluoromethoxy-3- (3-tetrahydrofuranyloxy) aniline

h) 4-difluoromethoxy-3 - ((3I) - tetrahydrofuryloxy) aniline

i) 4-Difluoromethoxy-3 - ((3 S) -tetrahydrofuryloxy) aniline

j) 3- (tert-butyldimethylsilyl) oxy-4-methoxyaniline

k) 4-methoxy-3- (3-phenpropyloxy) aniline

l) 3- (2-indanyloxy) -4-methoxyaniline

Example 3

3-cyclopentyl-4-methoxy-N- (3-pyridylmethyl) aniline

To a mixture of 3-pyridinecarboxaldehyde (106.55 g, 0.995 mol) in methanol (5 l) was added 3-cyclopentyloxy-4-methoxyaniline (208.38 g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg). The reaction mixture was stirred for 4 hours. The flask was cooled to 0 ° C and sodium borohydride (37.64 g, 2.3 mol) was added in portions over 4 hours. The reaction mixture was allowed to warm to room temperature for 16 hours with stirring. TLC indicated that the reaction was complete (1: 3 hexanes: ethyl acetate). The solvent was evaporated until approximately 0.5 l of suspension remained. The suspension was diluted with water (1 l) 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 give 300 g (100% yield) of the desired product as a brown viscous liquid.

1 H NMR (CDCl ₃ ) δ 8.61 - 8.48 (m, 2H), 7.69 - 7.67 (m, 1H), 7.24 - 7.21 (m, 1H), 6.72 (d,> 8.4 Hz, 1H), 6.23 (s. 1H), 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), 1.88 - 1.70 (m. 6H), 1.65-1.45 (m, 2H).

The following compounds are prepared in a similar manner to those described above:

a) 3-cyclopentyloxy-4-methoxy-b1- (3-thienylmethyl) aniline

b) 3-cyclopentyloxy-4-methoxy-N- (4-pyridylmethyl) aniline

c) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -455 methoxyaniline

d) 3-cyclopentyloxy-4-methoxy-N- (2-quinolinylmethyl) aniline

e) 3-cyclopentyloxy-4-methoxy-N- (3-quinolinylmethyl) aniline

f) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) aniline

g) 3-cyclopentyloxy-4-methoxy-N- (2-pyrazinylmethyl) aniline

11) 4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) aniline

i) 4-methoxy-N- (3-pyridylmethyl) -3 - ((31 < 3 &gt; - 3 tetrahydrofuranyloxy) aniline

j) 4-methoxy-N- (3-pyridylmethyl) -3 - ((38) tetrahydrofuryloxy) aniline

k) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) aniline

l) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) aniline

m) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) aniline

n) 4-difluoromethoxy-L- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) aniline

o) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) aniline

p) 3-1-tert-butyldimethylsilyloxy-4-methoxy-N- (2-pyridylmethyl) aniline

q) 3-Cyclopentyloxy-4-methoxy-N- (2-pyridylmethyl) aniline

d) 3-cyclopentyloxy-4-methoxy-T4- [1- (2-phenethyl)] aniline

s) N-benzyl-3-cyclopentyloxy-4-methoxyaniline

t) N - [(cyclohex-1-en-1-yl) methyl] -3-cyclopentyloxy-4-methoxyaniline

i) 3-cyclopentyloxy-4-methoxy-N- (3,4,5-1-dimethoxybenzyl) aniline

v) N - [(cyclohex-3-en-1-yl) methyl] -3-cyclopentyloxy-4-methoxyaniline

w) 3-cyclopentyloxy-4-methoxy-N- (2,4,6-trimethylbenzyl) aniline

x) 3-cyclopentyloxy-4-methoxy-T4- (2-methylbenzyl) aniline

y) 3-Cyclopentyloxy-4-methoxy-N- (2trifluoromethylbenzyl) aniline

z) 3-cyclopentyloxy-4-methoxy-N - ((3,4-methylenedioxy) benzyl) aniline aa) 3-cyclopentyloxy-L- (2-hydroxy-3-methoxybenzyl) -4-methoxyaniline bb) 3-cyclopentyloxy-N- (3 -furylmethyl) -4-methoxyaniline cc) 3-cyclopentyloxy-4-methoxy-N (3-methylbenzyl) aniline dd) 3-cyclopentyloxy-4-methoxy-N- (2-methoxybenzyl) aniline e) 3-cyclopentyloxy-4- methoxy-N- (3-chlorobenzyl) aniline ff) 3-cyclopentyloxy-4-methoxy-N (3-methoxybenzyl) aniline gg) 3-cyclopentyloxy-4-methoxy-N- (2-chlorobenzyl) aniline hh) 3-cyclopentyloxy -4-methoxy-N- (3-methylbenzyl) aniline ii) 4-methoxy-3- (3-phenpropyloxy) - N (4-pyridyl) ethyl) aniline jj) N- (2,6-dichloro-4-pyridylmethyl) -3- (2-indanyloxy) -4-methoxyaniline (kk) 4-methoxy-3- (3-phenpropyloxy) -N- (2-pyridylmethyl) aniline

11) N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3- (3-phenyloxy) aniline mm) 4-methoxy-3- (3-phenyloxy) -L- (3-pyridylmethyl) aniline PP) 3-Cyclopentyloxy-4-methoxy-N- (2-thienylmethyl) aniline oo) 3- (2-indanyloxy) -4-methoxy-L- (3-thienylmethyl) aniline pp) 4-methoxy-3- (3-phenpropyloxy) ) -N- (3-thienylmethyl) aniline qq) 3- (2-indanyloxy) -4-methoxy-N- (2-pyridylmethyl) aniline (II) 3- (2-indanyloxy) -4-methoxy-N - ( 3-pyridylmethyl) aniline ss) 3- (2-indanyloxy) -4-methoxy-N- (4-pyridylmethyl) aniline tert) 3-cyclopentyloxy-4-methoxy-N- (3-piperidinylmethyl) aniline uu) 3-cyclopentyloxy- 4-methoxy-L1- (3- (1-tert, butyloxycarbo) nyl) piperidinimethyl) aniline

w) 3-cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) aniline ww) N- (2-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline xx) N- (2-chloro-5- pyridylmethyl) -3-cyclopentyloxy-4methoxyaniline yu) 3-cyclopentyloxy-4-methoxy-b1- (2-thiazolylmethyl) aniline Example 4

3-cyclopentyloxy-4-methoxy-T4- (3-pyridylmethyl) diphenylamine

To the argon-purged 100-ml dry flask was added in the following sequence 0.59 g (6.10 mmol) of NaOtBu, 360 mg of Pd2dba ₃ '20 ml of toluene, 0.14 ml of P (tBu) ₃ and 20 ml of a solution of 1.3 g (4.36 mmol) ) No. (3-Pyridylmethyl) -3cyclopentyloxy-4-methoxyaniline in toluene. 3.1 g (15 mmol) of iodobenzene was added dropwise with stirring and the mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and extracted with 3 x 15 ml of 3 N HCl. The combined aqueous extracts were washed with 15 ml of ethyl acetate and then carefully neutralized with 6N NaOH to a pH higher than 12. The alkaline solution was extracted with 2 x 15 ml of ethyl acetate and the combined organic extracts were then washed with 15 ml of water and brine. solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (Biotage Flash 40M) eluting with 25% ethyl acetate in hexanes. The product was further purified by recrystallization from hexanes to give 550 mg of a white solid.

1 H NMR (CDCl ₃ ) δ 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30 - 7.10 (m, 3H), 6.90 - 6.80 ( m, 4H), 6.80 - 6.60 (m, 2H), 4.94 (s, 2H), 4.64 (p, 1H,> 4.1 Hz), 3.84 (s, 3H), 1.86 - 1.70 (m, 6H), 1.65 - 1.45 (m, 2H).

above:

The following compounds were prepared in a similar manner to those described above.

a) 3-cyclopentyloxy-4-methoxy-2'-methyl-L1- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4-methoxy-3'-methyl-L1- (3-pyridylmethyl) diphenylamine

c) 3-cyclopentyloxy-4-methoxy-4'-methyl-1 '- [- (3-pyridylmethyl) diphenylamine

d) 3-cyclopentyloxy-4'-ethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine

e) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

f) 4'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

g) 3-cyclopentyloxy-2 ', 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine

11) 3-cyclopentyloxy-3 ', 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine

i) 3-cyclopentyloxy-4,4'-dimethoxy-N- (3-pyridylmethyl) diphenylamine

j) 3-Cyclopentyloxy-4-methoxy-L [- (3-pyridylmethyl) - 3'-trifluoromethyldiphenylamine

k) 3-Cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) - 4'-trifluoromethyldiphenylamine

l) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine

t) 3-cyclopentyloxy-4'-fluoro-4-methoxy-L1- (3-pyridylmethyl) diphenylamine

n) 3-cyclopentyloxy-4-methoxy-3'-phenyl-N- (359 pyridylmethyl) diphenylamine

o) 3-cyclopentyloxy-4-methoxy-4'-phenyl-N- (3-pyridylmethyl) diphenylamine

p) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

q) 4′-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

d) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) - L3C-pyridylmethyl) -

3- Aminobenzoate

s) ethyl N- (3-cyclopentloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -

4- Aminobenzoate

t) 3-Cyclopentyloxy-4-methoxy-3'-nitro-LH- (3-pyridylmethyl) diphenylamine

i) 3-cyclopentyloxy-4-methoxy-4'-nitro-N- (3-pyridylmethyl) diphenylamine

v) No. (3-Cyclopentyloxy-4-methoxyphenyl) -1H- (3-pyridylmethyl) -1 naphthylamine

w) 3-cyclopentyloxy-2 ', 3'-dimethyl-4-methoxy-L1- (3-pyridylmethyl) diphenylamine

x) 3-cyclopentyloxy-2 ', 4'-dimethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine

y) 3-Cyclopentyloxy-2 ', 5' -dimethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine

z) 3-cyclopentyloxy-3 ', 4'-dimethyl-4-m ethoxy-L- (3-pyridylmethyl) diphenylamine aa) 3-cyclopentyloxy-2', 3'-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine bb) 3-cyclopentyloxy-3 ', 4' -dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine cc) 3-cyclopentyloxy-3 ', 5' -dichloro-4-methoxy-b1- (3-pyridylmethyl) diphenylamine dd ) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine) 4'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine ff) 4 '-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3' trifluoromethyldiphenylamine g g) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) diphenylamine hh) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-thienylmethyl) -1 naphthylamine

(j) 3-cyclopentyloxy-2 ', 3'-dichloro-4-methoxy-N- (3-thienylmethyl) diphenylamine jj) 3-cyclopentyloxy-4-methoxy-4'-methyl-N, N-pyridylmethyl) diphenylamine (kk) 3-cyclopentyloxy-L- (2,6-dichloro-4-pyridylmethyl) -4-methoxy3'-methyldiphenylamine

11) 2'-chloro-3-cyclopentyloxy-14- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine mm) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine PP) 3 -cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) diphenylamino) 3-cyclopentyloxy-4-methoxy-L- (3-quinolinylmethyl) diphenylamine pp) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) diphenylamine qq) 3-cyclopentyloxy-4-methoxy-N- (2-pyrazinylmethyl) diphenylamine 2) 4-methoxy-3'-methyl-1 N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine ss) 4-methoxy-4 ' -methyl- N- (3-pyridylmethyl) -3- (3tetrahydrofuryloxy) diphenyl min tt) 4,4'-dimethoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine uu) 3'-chloro-4-methoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine

w) 4-methoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine ww) 3'-cyano-4-methoxy-T4- (3-pyridylmethyl) ) -3 - ((3R) tetrahydrofuryloxy) diphenylamine xx) 3'-cyano-4-methoxy- and - (3-pyridylmethyl) -3 - ((31 ') tetrahydrofuryloxy) diphenylamine yy) 3-cyclopropylmethoxy-4-difluoromethoxy- N- (3-pyridylmethyl) diphenyl-amine zz) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine aaa) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) -3,4-dihydro-furanyloxy) 3,4-dihydro-furanyloxy) bis (difluoromethoxy) - 14- (3-pyridylmethyl) diphenylamine ccc) 4-difluorometho xy-T4- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine ddd) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((31 <) tetrahydrofuryloxy) diphenylamine eee) 3'-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3- (tetrahydrofuranyloxy) diphenylamine) fff) ethyl L [- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3- (3-Cyclopentyloxy-4-methoxy-3 '- (4-methylpiperazin-1-ylcarbonyl) -14- (3-pyridylmethyl) diphenylamine lily) 3-cyclopentyloxy-4-methoxy-4' - (4-methylpiperazine-1 ylcarbonyl) -1H- (3-pyridylmethyl) diphenylamine iii) 3 '- (tert-butyldimethylsilyloxy-3- cyclopentyloxy-methoxy-N (3-pyridylmethyl) diphenyl amine jjj) 4 '- (tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxyN- (3-pyridylmethyl) diphenylamine kkk) tert-butyl b1- (3-cyclohepenyl) 4-methoxyphenyl) ~ N- (3W pyridyl ethyl) -3-aminobenzoate

111) ethyl T4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -14- (3-pyridylmethyl) -3-aminobenzoate mmin) ethyl L1- (4-difluoromethoxy-3- (3-tetrahydrofuryloxy) phenyl-N- (3-pyridylmethyl) ) -3-Aminobenzoate PPP) ethyl N- (3, bis (difluoromethoxy) phenyl) -N [- (3-pyridylmethyl) -3-aminobenzoate ooo) ethyl N- (4-methoxy-3 - ((31 &apos;) - tetrahydrofuryloxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoate ppr) ethyl N- (3-cyclopropylmethoxy-4-methoxyphenyl) -L- (3-pyridylmethyl) -3-aminobenzoate qqq) 3-cyclopentyloxy-4-methoxy-4 '- ( 2- (tetrahydropyran-2-yl) -2Htetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine pt) 3-cyclopentyloxy-4-methoxy -3 '- (2- (tetrahydropyran-2-yl) -2Htetrazol-5-yl) -N- (3-pyridyl ethyl) diphenylamine sss) 4-methoxy-4' - (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) -3- ((3S) -tetrahydrofuranyloxy) diphenylamine tt) 3-cyclopropylmethoxy-4-methoxy-4 '- (2- (tetrahydropyran-2-yl) 2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine uu) 4-difluoromethoxy-4 '- (2- (tetrahydropyran-2-yl) -2H-tetrazole63

5-yl) -14- (3-pyridylmethyl) diphenylamine vw) 3-cyclopropylmethoxy-4-difluoromethoxy-4 '- (2 (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3- pyridylmethyl) diphenylamine [beta] 3-cyclopentyloxy-4-difluoromethoxy-4 '- (2 (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -14- (3yridylmethyl) diphenylamine xxx) 3-cyclopropylmethoxy-4-methyl-ethyloxy-4-methoxy-ethoxy-4-methoxy-ethoxy-4-methoxy-4-methoxy -3 '- (2 (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -1H- (3-pyridylmethyl) diphenylamine uyu) bis- (3,4-difluoromethoxy) -3' - (2- (tetrahydropyran-2-yl) -2Htetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine zzz) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine aaa ) 3-tert-butyldimethylsilyloxy-3'-chloro-4-methoxy-T4- (3-pyridylmethyl) -phenylamine bbbb) ethyl N- (3-t-butyldimethylsilyloxy-4-methoxyphenyl) - N (3-pyridylmethyl) -Z N-axis-3-cyclopentyloxy-2'-chloro-4-methoxy-L- (3-pyridylmethyl) diphenylamine dddd) 3- (2-indanoyloxy) -4-methoxy-T4- (3-pyridylmethyl) diphenylamine-aminobenzoate

Example 5

N- (3-cyclopentyl oxy-4-methoxyphenyl) -1 N - [(3-pyridylmethyl) -3-aminobenzoic acid

A solution of 6.5 g of N- (3-cyclopentyloxy-4-methoxyphenyl) -L- (3-pyridylmethyl) -3-aminobenzoate in 50 ml of ethanol was treated with 10 ml of 6 N NaOH. The mixture was allowed to stand for 6 hours, concentrated and diluted with 50 ml of water. The aqueous mixture was extracted with 2 x 50 ml of ether, acidified with acetic acid to pH 3 and extracted with 2 x 50 ml of ethyl acetate. The combined ethyl acetate fractions were washed with 25 ml of water and 25 ml of brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica (35 g RediSep® column) using linear gradient ethyl acetate and hexanes as eluent (50% ethyl acetate to 70% ethyl acetate for 20 minutes) to obtain 4.8 g of a yellow solid after vacuum drying. 12 hours at 60 ° C.

1 H NMR (CDCl ₃ ) δ 11.15 (bs, 1H), 8.70 - 8.55 (m. 2H), 7.77 - 6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H ), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65 *** 1.45 (m, 2H).

The following compounds are prepared in a similar manner to those described above:

a) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid

b) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -1H- (3-pyridylmethyl) -3-aminobenzoic acid

c) N- [4-Difluoromethoxy-3- (3-tetrahydrofuranyloxy) phenyl]] - N- (3-pyridylmethyl) -3-aminobenzoic acid

d) b1-3,4-bis (difluoromethoxy) phenyl) -1H- (3-pyridylmethyl) -3-aminobenzoic acid

e) N- [4-Methoxy-3 - ((3 R) -tetaxidophenylphenyl) phenyl)] -N- (3-pyridylmethyl) -3-aminobenzoic acid

f) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid

g) b [- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid

11) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid

i) N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (365-pyridylmethyl) -3-aminobenzoic acid

j) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid

k) N- [3- (2-indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid

l) N- [4-Methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid

m) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -T4- (3-pyridylmethyl) -3-aminobenzoic acid ** · n) N- [3- (2-methoxyethoxy) -4- methoxyphenyl] -L- (3-pyridylmethyl) -3-aminobenzoic acid

o) N- [4-methoxy-3- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid.

Example 6

14- (3-Cyclopentyloxy-4-methoxyphenyl) -L [- (3-pyridylmethyl) -2-aminobenzoic acid

T-Butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 ml of 98% formic acid and heated at 40 ° C for 4 hours . Formic acid was removed in vacuo and the residue was loaded onto a silica gel column (RediSep®, 4.2 g). The product was eluted with a linear gradient of 40% ethyl acetate in hexanes to 60% ethyl acetate in hexanes for 15 minutes to give 16 mg of the product as a brown solid.

1 H NMR (CDCl ₃ ) δ 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8) 7.67 (d, J = 7.8 Hz), 7.56 (m. 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 ( p, 1H, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).

The following compounds are prepared in a similar manner to those described above:

a) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid

b) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinic acid Example 7

3-cyclopropylmethoxy-4-difluoromethoxy-T4- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine 3-cyclopropylmethoxy-4-difluoromethoxy-L- (3-pyridylmethyl) -4' [2- (2 -tetrahydropyranyl) -2H-tetrazol-5-yl] diphenylamine (1.5 g, 0.26 mmol) was dissolved in tetrahydrofuran (5 ml) and 3 ml of IN HCl were added. After 6 hours at room temperature, the mixture was neutralized to pH 5 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 50 ml). The ethyl acetate extracts were combined, washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude residue was loaded onto a RediSep column (sub silica gel) and the product was eluted using a linear gradient from 0% methanol in ethyl acetate to 5% methanol in ethyl acetate for 20 minutes to give 0.96 g of the product as a white powder.

_u ^! H NMR (CD ₃ OD) δ 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H, 8 = 0)

Hz), 7.21 (dd, 1H,> 4.9 Hz, 8.0 Hz), 7.18 (d, 1H,> 8.9 Hz), 7.10 - 6.90 (m, 8H), 6.87 (dd, 1H,> 8.6 Hz, 2.5 Hz) , 6.75 (t, 1H,> 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H,> 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H) .

The following compounds are prepared in a similar manner to those described above:

a) (3-Cyclopentyloxy-4-methoxy-L- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenyl amine

b) (3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenylamine

c) 4-Methoxy-L1- (3'-pyridylmethyl) -3 - ((3R) -tetrahydrofuranyloxy) - 4'67 (2H-tetrazol-5-yl) diphenylamine

d) (3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine

e) 4-difluoromethoxy-L- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuranyloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine

f) (3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine

g) (3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenylamine

h) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5yl) diphenyl amine.

Example 8 (Method A)

3-cyclopentyloxy-4-methoxydiphenylamine

Method A (Ref. Chan, D. Μ. Τ; Monaco, L. L.; Wang, R. Ο .; Winters, Μ. Ρ., Tetrahedron Lett., 1998, 39, 2933 - 2936). A suspension of 207 mg of 4-methoxy-3-cyclopentyloxyaniline, 280 mg of phenylboronic acid, 182 mg of Cu (OAc) ₂ , 280 µl of triethylamine and 4.0 ml of methylene chloride was stirred for 20 hours at room temperature. The black mixture was filtered through silica gel eluting with methylene chloride, concentrated and purified by chromatography on silica gel using ethyl acetate / hexanes as eluent (15/85) to obtain 75 mg of the desired product.

1 H NMR (CDCl ₃ ) δ 7.26 - 7.20 (m, 2H), 6.94 - 6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89 - 1.54 (m, 8H).

The following compounds are prepared in a similar manner to those described above:

a) 3-Cyclopentyloxy-3 ', 4-dimethoxydiphenylamine

b) 3'-chloro-3-cyclopentyloxy-4-methoxydiphenylamine

c) 3- Cyclopentyloxy-4-methoxy-3'-methyldiphenylamine

d) 3-cyclopentyloxy-4 &apos; -fluoro-4-methoxydiphenylamine

e) 3-cyclopentyloxy-4-methoxy-4'-vinyldiphenylamine

f) 3'-cyano-3-cyclopentyloxy-4-methoxydiphenylamine

g) 4′-chloro-3-cyclopentyloxy-4-methoxydiphenylamine

h) 3-cyclopentyloxy-4,4'-dimethoxydiphenylamine

i) 3-cyclopentyloxy-4-methoxy-2'-methyldiphenylamine

j) 3-cyclopentyloxy-4-methoxy-4'-methyldiphenylamine

k) 2'-chloro-3-cyclopentyl oxy-4-methoxydiphenylamine

l) 3-cyclopentyloxy-2 ', 4-dimethoxydiphenylamine

t) 3-Cyclopentyloxy-4-methoxy-3'-trifluoromethyldiphenylamine

n) 3-cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine

o) 3-cyclopentyloxy-2 ', 5'-dimethyl-4-methoxydiphenylamine.

Example 8 (Method B)

3-cyclopentyloxy-4-methoxydiphenylamine

Method B (Angerw. Chem. Int. Ed. 1995, 34 (17), 1348 - 1351). A mixture of 207 mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of NaOtBu, 9 mg of Pd2 (dba) ₃ , 12 mg of P (oxo) 3 and 7 ml of toluene was heated under stirring at 100 ° C for 4 hours. The mixture was cooled to room temperature, diluted with 25 ml of ethyl acetate and washed with 10 ml of water, 10 ml of brine, dried over magnesium sulfate, concentrated. The residue was purified by chromatography on silica gel using ethyl acetate / hexanes (5/95) as eluant to give 84 mg of the desired product.

The following compounds are prepared in a similar manner as described above:

a) 3-Cyclopentyloxy-4-methoxy-2 ', 4' -dimethyldiphenylamine

b) 3-cyclopentyloxy-2 ', 5'-dimethyl-4-methoxydiphenylamine

c) 3-cyclopentyloxy-2 ', 3'-dimethyl-4-methoxydiphenylamine

d) 3-cyclopentyloxy-3 ', 4'-dimethyl-4-methoxydiphenylamine

e) 3-cyclopentyloxy-3 ', 4'-methylenedioxydiphenylamine

f) 4'-tert-butyl-3-cyclopentyloxy-4-methoxydiphenylamine

g) 3-cyclopentyloxy-3 ', 4'-dichloro-4-methoxydiphenylamine

h) 3-Cyclopentyloxy-2 ', 3' -dichloro-4-methoxydiphenylamine

Example 8 (Method C)

-cyclopentyloxy-2 ', 4,5' -trimethoxidiphenyl amine

Method C. To a mixture of Pd (dppf) C12 (0.025 mmol, 5 mol%), dppf (0.075 mmol, 3dppf7Pd), NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 ml of tetrahydrofuran was added 1-bromo-2.5- dimethoxybenzene (0.55 mmol, 1.1 eq) followed by 1.0 ml of a 0.5 M solution of 3-cyclopentyloxy-4 methoxyaniline in tetrahydrofuran. The mixture was heated at 60 ° C for 3 hours and diluted with ether. It is washed with water and brine, dried over magnesium sulfate and concentrated. The crude residue was purified by chromatography on silica gel (Biotage Flash 12) eluting with 15% ethyl acetate in hexanes.

The following compounds are prepared in a similar manner as described above:

a) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-pyridylamine

b) 3-cyclopentyloxy-2 ', 4', 4-trimethoxydiphenylamine

c) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyridylamine

d) N- (3-cyclopentyloxy-4-methoxyphenyl) -8-quinolinylamine

e) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-naphthylamine

f) T4- (3-cyclopentyloxy-4-methoxyphenyl) -1-naphthylamine

g) 3-cyclopentyloxy-4'-ethyl-4-methoxydiphenylamine

11) 3-cyclopentyloxy-2'-fluoro-4-methoxy-5'-methyldiphenylamine

i) 3-cyclopentyloxy-3'-fluoro-4-methoxy-4'-methyldiphenylamine

j) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrimidinylamine

k) 3-cyclopentyloxy-3 ', 5'-dichloro-4-methoxydiphenylamine

l) 3-Cyclopentyloxy-2 &apos; -ethyl-4-methoxydiphenylamine

w) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxydiphenylamine

n) N- (3-cyclopentyloxy-4-methoxyphenyl) -4-isoquinolinylamine

o) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrazinylamine

ρ) N- (3-cyclopentyloxy-4-methoxyphenyl) -5-pyrimidinylamine

q) N- (3-cyclopentyloxy-4-methoxyphenyl) -1-isoquinolinylamine

d) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-quinolinylamine

s) N- (3-cyclopentyloxy-4-methoxyphenyl) -4-pyridylamine

t) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -3-pyridylamine

u) N- (3-cyclopropylmethyl oxy-4-methoxyphenyl) -3-pyridylamine

v) N- (3-cyclopropylmethyloxy-4-difluoromethoxyphenyl) -3-pyridylamine

w) N- (4-methoxy-3- (31 <) - tetrahydrofuryloxyphenyl) -3-pyridylamine

x) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -3-pyridylamine

y) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoate

z) 3-cyclopentyloxy-4 '- (N, N-dimethylamino) -4-methoxydiphenylamine aa) N- (3-cyclopentyloxy-4-methoxyphenyl) -3- (6-methoxypyridyl) amine bb) methyl N- (3-cyclopentyloxy-4- methoxyphenyl) -2'-aminonicotinate cc) tert-butyl N- (3-cyclopentyl oxy-4-methoxyphenyl) -6-aminonicotinate dd) 2'-amino-3-cyclopentyloxy-4-methoxydiphenylamine e) 3-cyclopentyloxy-4-methoxy- 3 '- (1-phthalimido) diphenylamine ff) 3-cyclopentyloxy-4-methoxy-3' - [2- (2-tetrahydropyranyl) -2Htetrazol-5-yl] diphenylamine.

Example 9 (Method A)

3-cyclopentyloxy-4-methoxy-N-methyldiphenylamine

To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 ml of tetrahydrofuran at 0 ° C was added 0.55 ml of 0.5 M KN (TMS) ₂ in toluene. The solution was stirred at 0 ° C for 0.5 hours, 2.0 equivalents of iodomethane were added and the reaction mixture was allowed to warm to room temperature. After completion of the reaction by TLC check, 10 ml of ethyl acetate were added and the mixture was washed with 3 ml of water, 3 ml of brine, dried over magnesium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage Flash 12) eluting with 5% ethyl acetate in hexanes.

The following compounds are prepared in a similar manner as described above:

a) 3-cyclopentyloxy-1,1-ethyl-4-methoxydiphenylamine

b) 3-cyclopentyloxy-4-methoxy-N- (1-propyl) diphenylamine

c) 3-cyclopentyloxy-4-methoxy-14- [1- (3-phenpropyl)] diphenylamine

d) T4-benzyl-3-cyclopentyloxy-4-methoxydiphenylamine

e) 3-Cyclopentyloxy-4-methoxy-14- (4-pyridylmethyl) diphenylamine

f) 3-cyclopentyloxy-4-methoxy-L- (2-pyridylmethyl) diphenylamine

g) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

11) 3-cyclopentyloxy-4-methoxy-N- [3- (3-pyridyl) -1propyl] diphenylamine

i) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-ethyl-4 isoquinolinylamine

j) N- (3-cyclopentyloxy-4-methoxyphenyl) -1H-benzyl-4 isoquinolinylamine

k) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-methyl-4-isoquinolinylamine

l) X- (3-cyclopentyloxy-4-methoxyphenyl) -1H-propyl-4-isoquinolinylamine

m) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -L4 (4-pyridylmethyl) amine

η) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N (3-pyridylmethyl) amine

o) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -N (5-pyrimidinyl) amine

p) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyrazinyl) -N- (3-pyridylmethyl) amine

q) N- (3-cyclopentyloxy-4-methoxyphenyl) -1H- (2-pyridyl) -N- (3-pyridylmethyl) amine

d) N- (3-cyclopentyloxy-4-methoxyphenyl) -L [- (3-pyridyl) -N- (3-pyridylmethyl) amine

s) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-pyridyl) -N- (3-pyridylmethyl) amine

t) tert-butyl

14- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinate

i) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -1H- (3-pyridyl) -N- (3-pyridylmethyl) amine

v) N- (4-methoxy-3- (3R) -tetrahydrofuranyloxyphenyl) -N- (3-pyridyl) N- (3-pyridylmethyl) amine

w) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -1 '1- (3-pyridyl) N- (3-pyridylmethyl) amine

x) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine

y) N- (4-difluoromethoxy-3- (31 &apos; -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine

z) N- (4-chloro-3-pyridylmethyl-N- (3-cyclopentyloxy-4methoxyphenyl) -N- (2-pyridyl) amine aa) b1- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4- methyl-3-pyridylmethyl) -N- (2-pyridyl) amine bb) 3-cyclopentyloxy-4-methoxy-L- (2-thiazolylmethyl) diphenylamine c) N- (2-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxydiphenylamine dd) L- (6-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxydiphenylamine.

Example 9 (Method B)

L1-4-chloro-3-pyridylmethyl-N- (3-cyclopentyl-4-methoxyphenyl) -L1 (pyridyl) amine

To a solution of (3-cyclopentyloxy-4-methoxyphenyl) -2-pyridylamine (30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol) dissolved in dimethylformamide (1 ml) was added in small portions of sodium. hydride (50 mg of 60% dispersion in mineral oil, 1.3 mmol). After stirring for 1 hour at room temperature, the mixture was poured into 25 ml of ice water. The mixture was extracted with ethyl acetate (2x15 ml) and the ethyl acetate extracts were combined, washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g silica gel) and the product was eluted with 15% ethyl acetate in hexanes to give 20 mg of a yellow crystalline solid.

1 H NMR (CDCl ₃ ) δ 8.61 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33 (m, 1H), 7.25 (m, 1H) , 6.83 (d, 1H,> 8.5), 6.75 (d, 1H,> 8.5), 6.71 (s, 1H), 6.62 (m, 2H), 6.42 (d, 1H,> 8.6), 5.31 (s, 2H) ), 4.63 (p, 1H, > 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds are prepared in a similar manner to those described above:

a) 3,4-bis (difluoromethoxy) -N- (4-chloro-3-pyridylmethyl) -3 '(tetrahydropyran-2-yl) -2H-tetrazol-5-yl) diphenylamine

b) 3,4-bis (difluoromethoxy) -N- (4-chloro-3-pyridylmethyl) -3'- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) diphenylamine.

Example 10

3-Cyclopentyloxy-4-methoxyanilino) -N- (3-pyridylmethyl) -14-3- (4pyridyl) benzamide

To a solution of N- (3-cyclopentyloxy-4-methoxyphenyl) -N (pyridylmethyl) -3-aminobenzoic acid (20 mg, 0.05 mmol) and ruBOP (40 mg, 0.08 mmol) in methylene chloride (2 ml) at room temperature. added diisopropylethylamine (20 mL, 0.11 mmol). After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added w and the mixture was stirred for 16 h.

The mixture was diluted with ethyl acetate (25 ml) and washed with water (2x15 ml) and brine (15 ml), dried over magnesium sulfate and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g silica gel) and the product was eluted linearly gradient from 40% ethyl acetate in hexanes to 60% ethyl acetate in hexanes for 15 min to give 22 mg of the substance.

1 H NMR (CDCl ₃ ) δ 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, > 8.5), 6.80 - 6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, > 4.1 Hz), 3.86 (s, 3H), 1.86 - 1.70 (m, 6H), 1.65 -1.45 (m, 2H).

The following compounds are prepared in a similar manner to those described above:

a) 3- (3-Cyclopentyloxy-4-methoxyanilino) -N- (3-pyridylmethyl) -L1-

- [3- (N, N-dimethylamino) prop-1-yl] benzamide

b) 3-cyclopentyloxy-4-methoxy-3 '- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine

c) 3-cyclopentyloxy-4-difluoromethoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) -1H- (3-pyridylmethyl) diphenylamine

d) 3-cyclopentyloxy-4-methoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenylamine.

Example 11

The following compounds were prepared in a similar manner to those described in Example 2:

a) 4′-amino-3-cyclopentyloxy-4-methoxy-L- (3-pyridylmethyl) diphenylamine

b) 3 '-amino-3-cyclopentyloxy-4-methoxy-PM- (3-

W pyridylmethyl) diphenylamine

c) 3'-amino-3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

d) 3'-amino-4-methoxy-N- (3-pyridylmethyl) -3 - [(3I) tetrahydrofuranyloxy] diphenylamine

Example 12 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine

To a solution of 4 &apos; -amino-3-cyclopentyloxy-4-methoxy-N, N-pyridylmethyl) diphenylamine (47 mg, 0.12 mmol) in methylene chloride (2 mL) was added pyridine (20 μl, 0.24 mmol) at room temperature followed by methanesulfonyl (2 mL). 15 µl, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16 hours. The mixture was diluted with ether (50 ml), washed with water (25 ml), brine (25 ml), dried over magnesium sulfate and concentrated. The crude residue was purified by flash column chromatography (RediSep column (4.2 g silica gel) and the product was eluted linearly gradient from 45% ethyl acetate in hexanes to 60% ethyl acetate in hexanes for 20 min to give 41 mg of the substance.

1 H NMR (CDCl ₃ ) δ 8.51 (s, 1H), 8.41 (d, 1H,> 4.8 Hz), 7.56 (d, 1H,> 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H. > 9.0), 6.80 - 6.60 (m, 6H), 4.82 (s, 2H), 4.56 (p,

1H, 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 are prepared in a similar manner to those described above:

a) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine

c) 3 '- (1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

d) 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

e) 3'-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

f) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-L1- (3-pyridylmethyl) diphenylamine

g) 3-cyclopentyloxy-4-methoxy-4 '- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine) h) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-b1- (3w pyridylmethyl) diphenylamine

i) 4-Difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) - 3- [(31 <) - tetrahydrofuryloxy] diphenylamine

Example 13

-cyclopentyl oxy-4-methoxy-3'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine

To a solution of ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate (50 mg, 0.11 mmol) in tetrahydrofuran (5 ml) at 0 ° C was added dropwise under stirring. , 2.5 M solution of 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 removed by adding 5 drops of ethyl acetate to the mixture. The mixture was concentrated and the residue partitioned between methylene chloride (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2x10 ml). The organic extracts were combined and washed with brine (50 ml), dried over magnesium sulfate and concentrated. The crude residue was purified by flash column chromatography on a RediSep column (4.2 g of silica gel) and the product was eluted with 300 ml of 50% ethyl acetate in hexanes and then with 100% ethyl acetate to give 15 mg of the substance.

C * H NMR (CDCl ₃ ) δ 8.51 (s, 1H), 8.40 (br, 1H), 7.58 (d, 1H, J = 7.9 Hz),

7.25 - 7.05 (m, 3H), 6.80 - 6.60 (m, 5H), 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 compound was prepared in a similar manner to that described above:

a) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine.

Example 14

3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol5-yl) diphenylamine

To a solution of L [- (3-cyclopentyloxy-4-methoxyphenyl) -L- (3-pyridylmethyl) -3-aminobenzonitrile (100 mg, 0.25 mmol) in dimethylformamide (3 ml) was added NaN ₃ (163 mg, 2.5 mmol) and ammonium chloride (135 mg, 2.5 mmol) and the mixture was stirred at 120 ° C for 6 hours. The mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2 x 25 ml). The ethyl acetate extracts were combined, washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was loaded onto a RediSep column (4.2 g silica gel) and the product was eluted linearly gradient with 50% to 75% ethyl acetate in hexanes to afford 12 mg of the substance.

1 H NMR (CDCl ₃ ) δ 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H,> 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

-cyclopentyloxy-4-methoxy-4 '- (4-methyl-1-piperazinylmethyl) -N (3-pyridylmethyl) diphenylamine

To a solution of 3-cyclopentyloxy-4-methoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) diphenylamine (100 mg, 0.20 mmol) in tetrahydrofuran (5 ml) was carefully added with stirring lithium aluminum hydride (50 mg, 1.3 mmol). . The mixture was stirred for 15 minutes and a few drops of ethyl acetate were carefully added to remove excess hydride. Water (50 ml) and methylene chloride (50 ml) were added and the mixture filtered through Celite. The methylene chloride layer was separated, washed with brine (25 ml), dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g silica gel) eluting gradient from 5% methanol in ethyl acetate to 15% methanol in ethyl acetate to afford 60 mg of the product as a light yellow oil.

¹ H NMR (CDCl 3) δ 8.59 (s, 1H), 8.47 (d, 1H,> 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J-4.8 Hz, 7.9 Hz). 7.11 (d, 2H,> 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 compound was prepared in a similar manner to that described above:

a) 3-cyclopentyloxy-4-methoxy-3'-4-methyl-1-piperazinylmethyl) -181 (3-pyridylmethyl) diphenylamine.

Example 16

3'-Aminomethyl-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

To a solution of N- (3-cyclopentyloxy-4-methoxyphenyl-N- (3pyridylmethyl) -3-aminobenzonitrile (50 mg, 0.12 mmol) in tetrahydrofuran (5 ml) was carefully added with stirring lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 hours and gently added a few drops of water to remove excess hydride. Water (50 ml) and methylene chloride (50 ml) were added and the mixture filtered through celite. The methylene chloride layer was separated, washed with water. brine (25 ml), dried over magnesium sulfate and concentrated in vacuo The crude residue was purified on ISCO Redi Sep column (4.2 g silica gel) eluting with 10% methanol in ethyl acetate to give 20 mg of the substance.

1 H NMR (CDCl ₃ ) δ 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H,> 7.8 Hz),

7.26 - 7.10 (m, 2H), 6.90 - 6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, 1H,> 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H). 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

Example 17

3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

To a solution of 3- (tert-butyldimethylsiloxy) - N, N-pyridylmethyl) 4-methoxydiphenylamine (1.20 g, 2.85 mmol) in tetrahydrofuran (40 ml) was added at 0 ° C 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (10 ml, 10 ml). ). The mixture was stirred at 0 ° C for 30 minutes. 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 brine (25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with hexanes and filtered under vacuum to give 0.85 g of the substance.

^! H NMR (CDCl ₃ ) δ 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H,> 7.8 Hz),

7.26 - 7.10 (m, 3H), 6.90 - 6.65 (m, 5H), 6.64 (dd, 1H,> 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s. 3H).

The following compounds were prepared in a similar manner to those described above:

a) 3 '-chloro-3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) ethyl N- (3-hydroxy-4-methoxyphenyl) -N- (3-pyridylmethyl) diphenylamine

Example 18 (Method B)

The following compounds were prepared in a similar manner to those described in Example 1B:

a) 3- [3- (4-chlorophenyl) prop-1-yloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) 3- [3- (4-chlorophenyl) ethoxy] -D-methoxy-N- (3-pyridylmethyl) diphenylamine

c) 4-methoxy-3- (4-phenoxybut-1-yl) oxy-N- (3-pyridylmethyl) diphenylamine

d) 4-methoxy-L- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine

e) 4-Methoxy-3- [3- (4-methoxyphenyl) prop-1-wyloxy] -N- (3-pyridylmethyl) diphenylamine

f) 4-methoxy-3- [3- (4-pyridyl) prop-1-h] oxch-N- (3-pyridylmethyl) diphenylamine

g) 4-Methoxy-3- [2- (4-methoxyphenyl) ethoxy] -14- (3-pyridylmethyl) diphenylamine

N) 4-methoxy-3- (4-phenylbut-1-yl) oxy-L- (3-pyridylmethyl) diphenylamine

i) 4-Methoxy-3- [4- (4-methoxyphenyl) but-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine

j) 4-methoxy-3- [4- (4-nitrophenyl) but-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine

k) 4-Methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine

1) 4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenyl amine

m) 4-methoxy-3- [3- (2-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine

n) 4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine

o) 3-cyclopropylmethoxy-4-methoxy-L- (3-pyridylmethyl) diphenylamine

p) 4-methoxy-3- (1-methylpyrrolidin-3-yl) oxy-N- (3-pyridylmethyl) diphenylamine

q) 4-Methoxy-3- (1-methylpiperidin-4-yl) oxy-L1- (3-pyridylmethyl) diphenylamine

d) 4-methoxy-N- (3-pyridylmethyl) -3 - [(3S) -tetrahydrofuryloxy] diphenylamine

s) 4-Methoxy-N- (3-pyridylmethyl) -3 - [(31 &apos; -tetrahydrofuryloxy] diphenylamine

t) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine

i) 3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine

v) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine

w) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - [(ZK) tetrahydrofuryloxy] diphenylamine

x) 3-cyclohexyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

y) 3-cycloheptyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

z) 3- (2-cyclopropylethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine aa) 3-cyclononylmethoxy-N, 3-pyridylmethyl) diphenylamine bb) ethyl N- [3- (4-chlorophenyl) prop-1-yloxy- 4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoate c) ethyl 1 N- [3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate dd) ethyl L- [3-cyclopropylmethoxy-4- difluoromethoxyphenyl) -1H- (3-pyridylmethyl) -3-aminobenzoate) ethyl N- [3- (2-indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) 3-aminobenzoate ff) ethyl L [- [4- methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3W pyridylmethyl) -3-aminobenzoate (g) ethyl N- [4-methoxy-3 - ((3 N) -tetrahydrofuranyloxy) phenyl] -1 '[- (3pyridylmethyl) -3-aminobenzoate hh) ethyl N' [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3pyridylmethyl) -3-aminobenzoate ii) ethyl - [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -L- (3-pyridylmethyl) -3-aminobenzoate.

Example 18 (Method C)

The following compounds were prepared in a similar manner to those described in

In Example 8A, but when phenolic acid was boiled with boric acid instead of boronic acid aniline coupled:

a) 4-methoxy-3- (4-methoxyphenoxy) -1 N- (3-pyridylmethyl) diphenylamine

B) 4-methoxy-3-phenoxy-N- (3-pyridylmethyl) diphenylamine

c) 4-methoxy-3- (4-methylphenoxy) - N- (3-pyridylmethyl) diphenylamine

d) 3- (4-chlorophenoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine

f) 3 [2- (4-chlorophenyl) ethenyloxy] 4-methoxy-N- (3-pyridylmethyl) diphenylamine.

Example 19

The following compounds were prepared in a similar manner to those described in Example 17:

a) 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

c) 3-cycle propylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 20 (Method A)

The following compound was prepared by a similar method to that described in Example 1A:

w) 3 '- (2-bromoethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 20 (Method B)

The following compounds were prepared by a similar method to that described in Example 1B:

a) 3-cyclopentyloxy-4 '- (2-methoxyethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4 '- (3-methyl-1-butoxy) -4-methoxy-L1- (3-pyridylmethyl) diphenylamine

c) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- [(38) tetrahydrofuranyloxy] diphenylamine

d) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- [(3R) tetrahydrofuranyloxy] diphenylamine

e) 3-cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-L1- (3-pyridylmethyl) diphenylamine

f) 4 '-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-b1- (3-pyridylmethyl) diphenylamine

g) 4'-cyclopentylethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

h) 3-cycle of opentyloxy-4-methoxy-4 '- (1-methylpiperidin-4-yloxy-N (3-pyridylmethyl) diphenylamine

i) 3-Cyclopentyloxy-4-methoxy-4 '- (1-methylpiperidin-3-yloxy-N (3-pyridylmethyl) diphenylamine

j) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-methylpyrrolidin-2yl) ethoxy] - N- (3-pyridylmethyl) diphenylamine

k) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-pyrrolidinyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine

l) 3-Cyclopentyloxy-4-methoxy-4 '- [2- (6-methylpyridyl) methoxy] - N- h * (3-pyridylmethyl) diphenylamine

m) 3-cyclopentyloxy-4-methoxy-4 '- [3- (1-methylpiperidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine

n) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1 methylpiperidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine

o) 3-cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine

p) 4 '- [1- (3-bromopropyl) oxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine _z q) 3-cyclopentyloxy-4-methoxy-4' - [2- (R- phthalimido) ethoxy] -H- (3-pyridylmethyl) diphenylamine

Example 21

3-cyclopentyloxy-4-methoxy-3 '- [2- (1-piperidinyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine

To a solution of 3 '- (2-bromoethoxy) -3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl) diphenylamide (17 mg, 0.03 mmol) in acetonitrile (1 ml) was added potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 μl, 0.05 mmol) and the mixture was stirred at 60 ° C for 4 hours. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic layer was washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was loaded onto an ISCO RediSep column (4.2 g silica gel) eluting linearly gradient with 5% methanol in ethyl acetate to 15% methanol in ethyl acetate to give 11 mg of the substance.

1 H NMR (CDCl ₃ ) δ 8.59 (s, 1H), 8.48 (d, 1H,> 4.7 Hz), 7.64 (d, 1H,> 8.2 Hz), 7.26 - 7.20 (m, 1H), 7.06 (d. 1H,> 8.6 Hz), 6.81 (d, 1H,> 9.2 Hz), 6.75 6.68 (m, 2H), 6.45 - 6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H,> 4.1) Hz), 4.00 (t, 2H,> 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H,> 6.2 Hz), 2.47 (m, 4H), 1.86 - 1.70 (m, 6H), 1.65 - 1.45 (m, 2H).

W The following compounds are prepared in a similar manner to the method described above:

a) 3-cyclopentyloxy-3 '- [2- (1-imidazolyl) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4-methoxy-3 '- [2- (1-methylpiperazin-4-yl) ethoxy] - N- (3-pyridylmethyl) diphenylamine

c) 3-cyclopentyloxy-4-methoxy-4 '- [3- (2-methylpiperazin-4yl) propoxy] - N- (3-pyridylmethyl) diphenylamine

d) 3-cyclopentyloxy-4-methoxy-4 '- (3- (1-methylpiperazin-4yl) propoxy] -N- (3-pyridylmethyl) diphenylamine

e) 3-Cyclopentyloxy-4-methoxy-4 '- [3- (2-morpholin-4ylethylamino) propoxy] -N- (3-pyridyl methyl) diphenyl amine

f) 4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine

g) 3- [2- (4-chlorophenoxy) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine

11) 4-methoxy-3- (2-pyrrolidin-1-yl) ethoxy-1 N - [(3-pyridylmethyl) diphenylamine

i) 4-Methoxy-3- (2- (4-methylpiperazin-1-yl) ethoxy) -N- (3-pyridylmethyl) diphenylamine

j) 3- [2- (4-Chlorophenylamino) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenyl amine.

Example 22

4'-aminoethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

To a solution of L1- (3-pyridylmethyl) -3 '- [2- (2-phthalimido) ethoxy] -3cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol) in methanol (5 ml) was added hydrazine hydrate (1.0 ml. 20 mmol). After 6 h at room temperature ethyl acetate (50 ml) was added and the precipitate was filtered off. C * The filtrate was washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was loaded onto an ISCO RediSep column (10 g silica gel). The column was washed with 10% methanol in ethyl acetate to give 0.21 g of the substance.

¹ H NMR (CDCl ₃ ) δ 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,> 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 6.70 (d, 1H,> 8.6 Hz), 6.50 - 6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p , 1H,> 4.1 Hz), 3.90 (t, 2H,> 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86 - 1.70 (m, 8H), 1.65 - 1.45 (m, 2H) .

g Example 23

The following compounds were prepared by a method similar to that described in Example 12:

a) 3-Cyclopentyloxy-4 '- (2-methanesulfonylamino) ethoxy-4-methoxy-1- (3-pyridylmethyl) diphenylamine

b) 3-cyclopentyloxy-4 '- (2-ethanesulfonylamino) ethoxy-4-methoxy-N (3-pyridylmethyl) diphenylamine

c) 3-cyclopentyloxy-4-methoxy-4 '- [2- (2-propanesulfonylamino) ethoxy] -1H- (3-pyridylmethyl) diphenylamine

d) 3-Cyclopentyloxy-4-methoxy-4 '- [2- (1-propanesulfonylamino) ethoxy] - 14- (3-pyridylmethyl) diphenylamine

f) 4 '- [2- (1-butanesulfonylamino) ethoxy] -3-cyclopentyloxy-4methoxy No. (3-pyridylmethyl) diphenylamine

Example 24

Measurement of type 4 phosphodiesterase inhibitory activity in vitro

Human PDE4 is derived from baculovirus-infected Sf9 cells that express the recombinant enzyme. The cDNA encoding 11PDE-4D6 is subcloned into a baculovirus vector. Insect cells (Sf9) are infected with the baculovirus and the cells are cultured until protein is expressed. Baculovirus-infected cells are lysed and the lysate is used as the source of the 11PDE-4D6 enzyme. The enzyme was partially purified using DEAE ion exchange chromatography. This procedure can be repeated using cDNA encoding other PDE4 enzymes.

Testing:

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5′-adenosine monophosphate (5′-AMP). Nucleotidase converts 5'AMP to adenosine. Therefore, the combined activity of PDE4 and nucleotidase convert cAMP into adenosine. Adenosine is easily separated from cAMP by neutral aluminum oxide columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this trial; therefore, PDE4 inhibitors cause a decrease in adenosine.

Cell lysates (40 μl) expressing hPDE-4D6 were combined with 50 μl of the test mixture and 10 μl of inhibitors and incubated for 12 minutes at room temperature. The final test compound concentration is: 0.4 μg enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl ₂ , 3 μM cAMP, 0.002 U 5'-nucleatidase and 3 x 10 ⁴ cpm [ ³ H] cAMP. The reaction was quenched by the addition of 100 µl of boiling 5 mN HCl. Aliquots of 75 µl of the reaction mixture were transferred from each well to an alumina column (Multiplate; Millipore). Labeled adenosine was eluted in OptiPlate by rotation at 2000 rpm for 2 min; 150 µl scintillation fluid per well in OptiPlate was added. The plate was sealed, shaken for about 30 minutes, and the [ ³ H] adenosine was determined using Wallac Triflux®.

All test compounds were dissolved in 100% DMSO and diluted in the test so that the final concentration in DMSO was 1%. DMSO does not affect enzyme activity at this concentration.

Decrease in adenosine concentration indicates inhibition of PDE activity. pIC50 values were determined by checking 6 to 12 concentrations of the compound in the range of 0.1 nM to 10,000 nM and then comparing the drug concentration with respect to the [ ³ H] adenosine concentration. A nonlinear regression software device (Assey Explorer®) is used to determine the pIC 50 values.

Example 25 (Method A)

Passive avoidance in rats and in vivo testing for learning and memory

The assay was performed as previously described (Zhang, N.-T., Crissman, A. M., Dorairaj, NR, Chandler, LJ , and O'Donnell, JM, r Neuropsychopharmacology, 2000, 23, 198-204 ). The apparatus (Model E10-16SC,

Coulbourn Instruments, Allentown, PA) consists of a two-room camera with a illuminated room sealed to a darkened room with a guillotine door. The floor of the darkened room is made up of stainless steel rods through which a direct current source of electricity can flow. All experimental groups are initially accustomed to the apparatus the day before the experiment begins. During training, the downspout (male Spraque-Dawley (Harlan), weighing 250 to 350 g) is placed in the illuminated room by looking at the guillotine sides of the closed door for 1 minute before lifting the door. Latency is reported before entering the darkened room. After the rat enters the darkened room, the door is closed and 0.5 mA electrical current is passed for 3 seconds. After 24 hours, the rat was administered 0.1 mg / kg MK801 or saline solution, 30 minutes before injection of the saline solution or test compound (at a dose of 0.1 to 2.5 mg / kg peritoneally), which was performed 30 minutes before the delay time began. . The rat is again placed in the illuminated room with the guillotine door open. The latency to enter the darkened room is counted up to 180 seconds, at which point the trial switches.

All data are analyzed by variant (ANOVA); individual w comparisons are made using the Kewman - Keuls tests. Naïve rats slow for less than 30 seconds on average to cross from the illuminated to the darkened room. However, 24 hours after exposure to electric shock, most pre-treated rats do not re-enter the darkened room; mean latency increased to 175 seconds (p <0.001). Pre-treated with MK-801 (0.1 mg / kg) markedly reduced the latency compared to the vehicle (p <0.001). This MK-801 amnesia effect was counteracted in a statistically dependent manner by the test compounds in a dose-dependent manner (e.g., 3-cyclopentyloxy-4-methoxy-L- (3-pyridylmethyl) diphenylamine, effective dose in the range = 0.5 to 2.5 mg / kg ip and N- (3cyclopentyloxy-4-methoxyphenyl) - N- (pyridylmethyl) -3-aminobenzoic acid, effective dose in the range = 0.1 to 2.5 mg / kg ip).

Example 25 (Method B)

Radial arm maze test in rats and in vivo learning and memory test

The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, NR, Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198 - 204) . Five days after initial placement, rats (male Spraque-Dawley (Harlan) weighing 250 to 350

d) placed in an eight-arm radial labyrinth (each lobe is 60 x 10 x 12 cm high; the labyrinth is raised 70 cm above the floor) for acclimatization for two days. The rats were then placed individually in the center of the maze for 5 minutes with food pellets placed close to the feed wells and then, on the following day, in the wells at the end of the sleeves; two sessions a day. In the next four randomly selected sleeves a bait of one food pellet is placed. The rat was confined to the center of the platform (26 cm in diameter) for 15 seconds and then allowed to move freely through the maze until it collected all food pellets or until 10 minutes had elapsed. Four parameters are considered: 1) working memory errors, ie entering the sleeves with bait already visited during the same attempt; 2) orientation memory errors, ie entering the sleeveless sleeves; 3) total number of sleeves visited is 4) test duration (seconds), ie. time spent collecting all the pellets from the maze. If the working memory error is zero and the orientation memory error is less than one in five consecutive tests, the rat is tested for the drug. MK-801 or saline is injected 15 minutes before the vehicle or test agent, which is given 45 minutes before the test. The experiments were conducted in a lighted room containing several visual maze additions.

All data are analyzed by variance (ANOVA); individual comparisons are made using the Kewman - Keuls tests. Compared with the control, MK-801 (0.1mg / kg, i.p.) increased the frequency of working and orientation memory errors (p <0.01). This effect of MK-801 amnesia on working memory is reversed in a statistically significant way by administering the test compounds in a dose-dependent manner (e.g., 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, effective dose = 2.5 mg / kg ip p <0.01).

The above examples can be repeated with similar success by replacing the reagents and / or operating conditions of the present invention with those used in the foregoing examples.

The invention has been illustrated with respect to the preparation of specific compounds. It is clear, however, that variations and modifications can be made without departing from the spirit and scope of the invention.

Claims (70)

Claims A compound of formula I R2 (I) in which: R ¹ is alkyl having from 1 to 4 carbon atoms which may be branched or unbranched and may be unsubstituted or substituted one or more times with halogen; R is alkyl of 1 to 12 which may be branched or unbranched and may be substituted or unsubstituted one or more times by halogen, hydroxy, cyano, C1-4 alkoxy, oxo or a combination thereof and where optionally one or more -CH ₂ CH _{The 2} groups are in each case substituted by -CH = CH- or -C = C-, cycloalkyl having from 3 to 10 which may be unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl with 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or a combination thereof, cycloalkylalkyl having 4 to 16 which is unsubstituted or substituted in the cycloalkyl moiety and / or in the alkyl moiety one or more times by halogen, oxo, cyano, hydroxy, C 1-6 alkyl, C 1-4 alkoxy or a combination thereof, aryl having 6 to 14 carbon atoms which is unsubstituted or substituted by one or more times with halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or a combination thereof, arylalkyl having in the aryl moiety 6 to 14 carbon atoms and in an alkyl moiety which may be branched or unbranched, there are 1 to 5 carbon atoms, wherein the arylalkyl radical is is unsubstituted or substituted on the aryl moiety one or more times by halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy or a combination thereof and where in the alkyl moiety one or more -CH ₂ CH ₂ groups are in each case substituted by -CH = CH- or -OC- and one or more - CH ₂ groups may each be replaced by -O- or NH- and / or the alkyl moiety is optionally substituted by halogen, oxo, hydroxy, cyano or combinations thereof, a partially unsaturated carbocyclic group having from 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, saturated or unsaturated having 5 to 10 ring atoms in which at least 1 ring atom is N, O or S which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof or a heterocyclic-alkyl group in which the heterocyclic part is saturated, partially saturated or unsaturated and theirs 5 to 10 ring atoms of which at least 1 ring atom is N, O or S and the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms, the heterocyclic-alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof, wherein in the alkyl moiety one or more -CH ₂ CH ₂ groups are optionally substituted in each case by -CH = CH- or -OC- and one or more CH ₂ groups each of which may be optionally substituted is -O- or -NH and / or the alkyl moiety is optionally substituted by halogen, oxo, hydroxy, cyano or combinations thereof; R ³ is hydrogen, alkyl having 1 to 8, preferably 1 to 4, carbon atoms which is branched or unbranched and which may be unsubstituted or substituted one or more times by halogen, cyano, C 1-4 alkoxy or a combination thereof, partially unsaturated a carbocyclic-alkyl group in which the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms and which is unsubstituted or substituted on the carbocyclic moiety one or more times by halogen, alkyl, alkoxy , nitro, cyano, oxo or combination and the alkyl moiety is optionally substituted by halogen, C 1-4 alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety which may be branched or unbranched has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted on the aryl moiety one or more times by halogen, CF ₃ , OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl or heteroarylalkyl group, where the heteroaryl moiety may be partially or fully saturated and having 5 to 10 ring atoms in which at least 1 ring atom is N, O or S, the alkyl moiety 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 moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety by halogen, cyano or methyl or combinations thereof, R ⁴ is hydrogen, 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, OCF ₃ , amino, OCF ₃ , amino aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthiofluoxyalkylthiosulfonylamino; -butyldimethylsilyloxy), R ⁵ -L-, or combinations thereof or heteroaryl having from 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, trifluoromethyl, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonylthinylsilyl trifluoro R ⁵ is hydrogen, alkyl having 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with halogen, Oalkyl, C 1-4 alkoxy, oxo or a combination thereof, aliclamino or dialkylamino, where each alkyl moiety has independently 1 to 8 carbon atoms , a partially unsaturated carbocyclic alkyl group, wherein the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms which is unsubstituted or substituted, preferably in the carbocyclic moiety, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof, cycloalkyl having 3 to 10 which is unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkoxy, alkyl of 1 to 4 carbon atoms or combinations thereof, cycloalkyl alkyl having 4 to 16, which is unsubstituted or substituted on the cycloalkyl moiety and / or in the alkyl moiety one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, an aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted by one or repeatedly with halogen, alkyl, hydroxy, alkoxy, alkoxy coke, nitroxy, ethylenedioxy, trifluoromethyl, amino, aminoalkyl, aminoalkyl, hydroxyalkyl, hydroxyl, hydroxyalkyl, carboxylic acid arylalkyl having 7 to 19 carbon atoms in which the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms, the arylalkyl radical being unsubstituted or substituted on the aryl moiety one or more times by halogen, trifluoromethyl, OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl, a heterocyclic group which is saturated, partially saturated or unsaturated, having 5 to 10 rings having 5 to 10 rings of which at least 1 ring atom is N, O or S which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl group, amino, aminomethyl, aminoalkyl , aminoalkoxy, dialkylamino, hydroxyalkyl, hyd oxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, or a heterocyclic-alkyl group, wherein the heterocyclic moiety is not the nasite portion, the nasite moiety is the nasite moiety, 10 ring atoms in which at least 1 ring atom is N, O or S and the alkyl moiety which is branched or unbranched and having 1 to 5 carbon atoms, the heterocyclic alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen , para Ki, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or is substituted in the alkyl moiety by halogen, cyano or methyl or combinations thereof; L means a single bond or a bivalent aliphatic radical having 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups, each of which may be optionally substituted by -O-, -S-, -NR ⁶ -, -SO ₂ NH-, -NHSO ₂ - CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH, -NHCOO-, SCONH-, SCSNHor -NHCSNH- and R ⁶ is hydrogen or alkyl having 1 to 8 which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, C 1-4 alkyl, C 1. dalkoxy, oxo or a combination thereof; and wherein at least one of R ³ and R ⁴ is other than hydrogen and their pharmaceutically acceptable salts. The compound of claim 1, wherein R ⁴ is other than hydrogen. The compound of claim 1, wherein R is methyl or CHF ₂ ; R is an alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycloalkyl, cycloalkylalkyl, aryl or heterocyclic group which may be substituted or unsubstituted; R ³ is hydrogen, arylalkyl or heteroarylalkyl, which may be substituted or unsubstituted, and R ⁴ is aryl or heteroaryl, which may be substituted or unsubstituted. The compound of claim 1, wherein R ³ is heteroarylalkyl which is substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ and R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl or (3R) tetrahydrofuranyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ , R ² is cyclopentyl, R ³ is heteroarylalkyl, in each case substituted or s * unsubstituted, and R ⁴ is substituted or unsubstituted aryl or heteroaryl. The compound of claim 1, wherein R is methyl; R ³ is cyclopentyl, R ³ is arylalkyl or heteroarylalkyl which are substituted or unsubstituted and R ⁴ is substituted or unsubstituted aryl. The compound of claim 1, wherein R is methyl; R ³ is cyclopentyl, R ³ is heteroarylalkyl which is substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl, R ³ is heteroarylalkyl which is substituted or unsubstituted and R ⁴ is phenyl which is substituted or unsubstituted. The compound of claim 1, wherein R is methyl; Re h »β cyclopentyl; R is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl or pyrazinylmethyl, which may be substituted or unsubstituted or methyl, ethyl or propyl and R ⁴ is phenyl or phenyl substituted with 1 to 3 substituents. The compound of claim 1, wherein R ¹ is methyl; R ² is β cyclopentyl; R is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which may be substituted or unsubstituted or methyl, ethyl or propyl, and R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyridyl, pyridyl, pyridyl or isoquinolinyl, in each case substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl or CHF 2; R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl; R ³ is hydrogen and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl which may be substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl or CHF 2; R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl; R ³ is hydrogen and R ⁴ is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF 3, vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido or is 2-pyridyl which is unsubstituted W or substituted with carboxy or alkoxycarbonyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is hydrogen and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl which may be substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is hydrogen and R ⁴ is phenyl which is unsubstituted or substituted with methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido or is 3-pyridyl which is unsubstituted or substituted with carboxy or alkoxycarbonyl. d " The compound of claim 1, wherein R ¹ is methyl or CHF 2; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl; R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl or pyrrolylmethyl, which may be substituted or unsubstituted and R ⁴ is hydrogen. The compound of claim 1, wherein R ¹ is methyl or CHF 2; R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl; R ³ is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, which may be unsubstituted or substituted and R ⁴ is hydrogen. 100 1 2 The compound of claim 1, wherein R is methyl; R is cyclopentyl; R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl or pyrrolylmethyl, which may be substituted or unsubstituted and R ⁴ is unsubstituted and ⁴ . The compound of claim 1, wherein R is methyl; R is cyclopentyl; R ³ is pyrazinylmethyl or pyridylmethyl which may be substituted or unsubstituted and R ⁴ is hydrogen. A compound of claim 1 having the general formula IV: t A wherein R and R are as defined in Formula I and one of A, B or D is N and the other is CH and R ⁴ is pyridyl or phenyl which may be substituted or unsubstituted and their pharmaceutically acceptable salts. The compound of claim 20, wherein R ¹ is methyl or CHF 2. The compound of claim 21, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF 2 and R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl. The compound of claim 23, wherein B is N. The compound of claim 19, wherein R ¹ is methyl or CHF ₂ and R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted. The compound of claim 25, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF 2, R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl and R ⁴ is 3-pyridyl or phenyl which may be substituted or unsubstituted. 101 The compound of claim 27, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ , and R ⁴ is phenyl which is substituted at the 3 or 4 position. The compound of claim 29, wherein B is N. The compound of claim 19, wherein R ¹ is methyl or CHF 2, R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl and R ⁴ is phenyl which is substituted at the 3 or 4 position. The compound of claim 31, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ , R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3- tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4- hydroxymethyl-phenyl. The compound of claim 33, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ Λ R is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-C1-phenyl, 3-cyanophenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl- phenyl, 3-hydroxymethylphenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl. The compound of claim 35, wherein B is N. The compound of claim 1, selected from: a) 3-cyclopentyloxy-4'-ethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-3 ', 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine c) 3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) - 3'-trifluoromethyldiphenylamine 102 d) 3-cyclopentyl oxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine e) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-T4- (3-pyridylmethyl) diphenylamine f) 3-cyclopentyloxy-4-methoxy-3'-phenyl-N- (3-pyridylmethyl) diphenylamine g) 4'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine 11) 3-cyclopentyloxy-4-methoxy-3'-nitro-18 [- (3w pyridylmethyl) diphenylamine i) 4'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) - 3 '-trifluoromethyldiphenylamine j) 4-Methoxy-3'-methyl- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine k) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine l) N- (3-cyclopentyl oxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinic acid m) 18 [- (3-cyclopentyloxy-4-methoxyphenyl) -1 '1- (2-pyrazinyl) -N- (3-pyridylmethyl) amine n) 3'-benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine o) 3- [3- (4-chlorophenyl) prop-1-yloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine p) 4-Methoxy-3- [3- (4-methoxyphenyl) prop-1-yl] oxy-L- (3-pyridylmethyl) diphenylamine q) 4-Methoxy-3- [3- (2-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4 '- (2-methoxyethoxy) -4-methoxy-N- (3103 pyridylmethyl) diphenylamine s) 3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- [(3R) -tetrahydrofuranyloxy] diphenylamine t) 3-Cyclopentyloxy-4-methoxy-4 '- (1-methylpiperidin-4-yloxy) -L1 (3-pyridylmethyl) diphenyl amine i) 3-cyclopentyloxy-4-methoxy-4 '- (1-methylpyrrolidin-3-yloxy) -1H (3-pyridylmethyl) diphenyl amine v) 3-cyclopentyloxy-4-methoxy-4 '~ [2- (1-pyrrolidinylethoxy)] - N (3-pyridylmethyl) diphenylamine w) 3-cyclopentyloxy-4-methoxy-4 '- [2 ~ (6-methylpyridyl) methoxy] -T4 (3-pyridylmethyl) diphenylamine x) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-methylpiperidinyl) methoxy] - N- (3-pyridylmethyl) diphenyl amine y) 3-Cyclopentyloxy-4-methoxy-3 '- [2- (1-piperidinyl) ethoxy] -1H (3-pyridylmethyl) diphenylamine z) 3-cyclopentyloxy-3 '- [2- (1-imidazolyl) ethoxy] -4-methoxy-N (3-pyridylmethyl) diphenyl amine aa) 3-cyclopentyloxy-4-methoxy-4' - [3- (2 -methylpiperazin-4yl) propoxy] -N- (3-pyridylmethyl) diphenylamine bb) 3-cyclopentyloxy-4-methoxy-4 '- [3- (2-morpholin-4ylamino) propoxy] -N- (3-pyridylmethyl) diphenylamine cc) 3- [2- (4-chlorophenoxy) ethoxy] -4-methoxy-L- (3-pyridylmethyl) diphenylamine dd) 3- [2- (4-chlorophenylamino) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine ee) 3-cyclopentyloxy-4 '- (2-methanesulfonylamino) ethoxy-4-methoxyN- (3-pyridylmethyl) diphenylamine ff) 4' - [2- (1-butanesulfonylamino) ethoxy] -3-cyclo entiloksi-4-methoxy-Y1- (3-pyridylmethyl) diphenylamine 104 gg) 3-cyclopentyloxy-4-methoxy-b1- (3-pyridylmethyl) diphenylamine hh) 3-cyclopentyloxy-4-methoxy-3 '-methyl-N- (3 pyridylmethyl) diphenylamine ii) 3-cyclopentyloxy-4- methoxy-4'-methyl-N- (3-pyridylmethyl) diphenylamine jj) 3-cyclopentyloxy-4-methoxy-4'-methyl-diphenylamine kk) 3-cyclopentyloxy-3 ', 4'-dichloro-4- methoxy-N- (3-pyridylmethyl) diphenylamine 11) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine mm) 3-cyclopentyloxy-14- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine PP) 4 -methoxy-4'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenylamine oo) 4, 4'-dimethoxy-L1- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) -diphenylamine pp) 3- indanyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine qq) N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid rg) b [ - (3-cyclopentyloxy-4-methoxyphenyl) - N- (4-isoquinolinyl) - N (3-pyridylmethyl) amine ss) N- (3-cyclopentyloxy-4-methoxyf enyl) - N- (3-pyridylmethyl) - N (5-pyrimidinyl) amine t) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) - N- (3-pyridylmethyl) amine uu) M - (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -1 N- (3-pyridyl) N- (3-pyridylmethyl) amine 105 w) 3-cyclopentyloxy-4-methoxyanilino) -N- (3-pyridylmethyl) -1H- (3 (4-pyridyl) benzamide ww) 3-cyclopentyloxy-4-methoxy-3 '- (4-methylpiperazin-1 ylcarbonyl) - N- (3-pyridylmethyl) diphenylamine xx) 3-cyclopentyloxy-4-difluoromethoxy-4 '- (4-methylpiperazin-1 ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine yy) 4-methoxy-4' - (4 -methylpiperazin-1-ylcarbonyl) -1H- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenylamine zz) 3 '- (1-butanesulfonylamino) -3-cyclopentyloxy-4 m ethoxy-N- (3-pyridylmethyl) diphenyl) diphenyl aaa) 3'-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine bbb) 4-methoxy and - N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine ccc) 4-methoxy-3- [2- (4-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine ddd) 4-methoxy-3- ( 2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine ee) 3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine fff) 4-methoxy-N- (3-pyridylmethyl) -3 - [(35) tetrahydrofuryloxy] diphenylamino] ggg) 3'-chloro-4-methoxy -3- [2- (4-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine chloro) 3- [2- (4-chlorophenyl) ethyloxy] -4-methoxy-N - (3-pyridylmethyl) diphenylamine iii) 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine jjj) 3-cyclopentyloxy-4'-x Hydroxy-4-methoxy-N- (3106 pyridylmethyl) diphenylamine KKK) 4'-Cyclohexyl-3-cyclopentyloxy-4-methoxy-N- (3piridilmetil) diphenylamine 111) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-methylpyrrolidin-2-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine mmin) 3-cyclopentyloxy-4-methoxy -4' - [3- (1methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine PPP) 3-cyclopentyloxy-4-methoxy -4 '- [3- (1-methylpiperazin-4yl) propoxy] - N- (3-pyridylmethyl) diphenylamine ooo) 4-methoxy-3- (2-phenoxyethoxy) - N- (3-pyridylmethyl) diphenylamine ppr) 3-cyclopentyloxy-4-methoxy -4 '- [2- (2-propanesulfonylamino) ethoxy] - N- (3-pyridylmethyl) diphenylamine qqq) 4'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine pt) 4'-chloro-3-cyclopentyloxy-3'-fluo ro-4-methoxy-N- (3-pyridylmethyl) diphenylamine sss) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine ttt) 3-cyclopentyloxy-4-methoxy-4 '- (2- (tetrahydropyran-2-yl) ) -2H-tetrazol-5-yl) - N- (3-pyridylmethyl) diphenylamine uuu) 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine vw) 3-cyclopentyloxy-4-methoxy -3 ' -hydroxymethyl-N- (3-pyridylmethyl) diphenylamine www) 3-cyclopentyloxy-4-methoxy -4'-hydroxymethyl-N - (3-pyridylmethyl) diphenylamine xxx) 4-methoxy-3 '- [3- (4-pyridyl) prop-1 -yl] oxy-N- (3-pyridylmethyl) diphenylamine 107 yy) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine zzz) 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine aaaa) 3 -cyclopentyloxy-4 '- (2-ethanesulfonylamino) ethoxy-4methoxy-N- (3-pyridylmethyl) diphenylamine bbbb) 3-cyclopentyloxy-4-methoxy-4' - [2- (1-propanesulfonylamino) ethoxy] - N- (3- pyridylmethyl) diphenylamine ccc) 3'-chloro-3-cyclopentyloxy-4-methoxy-T4- (3-pyridylmethyl) diphenylamine ddd) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenylamine diphenylamine 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3- ((3R) tetrahydrofuryl) si) diphenylamine ffff) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 (tetrahydrofuryloxy) diphenylamine yyyy) 3,4-bis (difluoromethoxy) N- (3-pyridylmethyl) diphenylamine hilyl) 4-difluoromethyloxy (4-difluoromethyloxy) 3-pyridylmethyl) -3- ((3R) tetrahydrofuryloxy) diphenylamine iiii) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3- ((3R) tetrahydrofuryloxy) diphenylamine jjjj) 3'-chloro-4 -difluoromethoxy-N- (3-pyridylmethyl) -3- ((3R) tetrahydrofuryloxy) diphenylamine kkkk) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4methoxy-N- (3-pyridylmethyl) diphenylamine 1111) T4- (3-Cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid mmmm) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -4-aminobenzoic acid 108 Nnn) N- (3-Cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid oooo) N- [4-methoxy-3- (3-tetrahydrofuranyloxy) phenyl] -L- (3-pyridylmethyl) - 3-Aminobenzoic acid pprr) T4-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid qqqq) b1- [4-methoxy-3 - ((3R) -tetrahydrofurloxy) phenyl] - N- (3-pyridylmethyl) 3-aminobenzoic acid ptg) b1- (3-cyclopropylmethoxy-4-methoxyphenyl) -B1- (3-pyridylmethyl) -4-aminobenzoic acid ssss) b1- (3-cyclopropylmethoxy-4-difluoxy-4-difluoxy) 3-pyridylmethyl) -4-aminobenzoic acid ttt) N- (3-cyclops) ntyloxy-4-methoxyphenyl) -3-aminobenzoic acid (N- (3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl) -T4- (3-pyridylmethyl) 3-aminobenzoic acid ww) N- (3- cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid wwww) 14- [3- (2-indanyloxy) -4-methoxyphenyl] -N [- (3-pyridylmethyl) 3-aminobenzoic acid xxxx) b1 - [ 4-Methoxy-3- (3-tetrahydrofuranyloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid UUU) b1- [4-methoxy-3 - ((3R) tetrahydrofuryloxy) phenyl] -L [- (3-pyridylmethyl) -3-aminobenzoic acid zzzz) N - [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid aAAAA) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine bbbbb) 3-cyclopentyloxy-4-cyclopentyloxy -L1- (3,109 pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine cccc) 3- cyclopentyloxy -4-methoxy-L1- (3pyridylmethyl) -3' - (2H-tetrazol-5-yl) diphenylamine ddddd) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine eee) 3-cycloprop lmethoxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2Htetrazol-5-yl) diphenylamine fffff) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3 R) tetrahydrofuryloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine w ggggg) 3-cyclopentyloxy-4-difluoromethoxy-L- (3-pyridylmethyl) 4' - (2H-tetrazol-5-yl) diphenylamine hihlihli) 3-cyclopropylmethyloxy} -difluoromethoxy-N- (3-pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenylamine iiiii) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4' - (2H-tetrazol-5-yl) ) diphenylamine jjjj) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine kkkkk) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) ) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine 11111) L [- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine mmmmm) - N - (difluoromethoxy-3- (3R) -tetaxid-3-yl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-yl-phenyl-3-phenyl-3-yl-phenyl-3-yl pyridyl) - N- (3-pyridylmethyl) amine introduction (3) -cyclopentyloxy-3'-ethanosulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine oooo) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanol) N- (3-pyridylmethyl) diphenylamine pyrrrr) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine 110 qqqqq) 3-cyclopentyloxy-4-methoxy-4 '- (1-propanesulfonylamino) N- (3-pyridylmethyl) diphenylamine (Rrr) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridyl) methylmethyl) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine tert) 4-methoxy-3- [2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine uuuuu) 4-methoxy-N- (3-pyridylmethyl) -3 - [(3S) tetrahydrofuryloxy] diphenylamine vww) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] - N- ( 3pyridylmethyl) diphenylamine wwwww) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - [(3R) tetrahydrofuryloxy] di phenylamine xxxxx) 3-cyclopentloxy-4-methoxy-4 '- [2- (5 oxopyrrolidinyl) methoxy] - L [- (3-pyridylmethyl) diphenylamine and their pharmaceutically acceptable salts. The compound of claim 1, selected from: a) 3-Cyclopentyloxy-4-methoxy - N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-3'-methyl-N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-4'-methyl-N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4'-nitro-N- (3-pyridylmethyl) diphenylamine e) 3-cyclopentyloxy-3 ', 4'-dichloro-4-methoxy-T4- (3-pyridylmethyl) diphenylamine f) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine Ill g) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine h) 4-Methoxy-4'-methyl- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine i) 4,4'-dimethoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine j) 3-indanyloxy-4-methoxy-14- (3-pyridylmethyl) diphenylamine k) 14- [4-Methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid l) N- (3-cyclopentyloxy-4-methoxyphenyl) -1H- (4-isoquinolinyl) - N- (3-pyridylmethyl) amine m) N- (3-cyclopentyloxy-4-methoxyphenyl) -L [- (3-pyridylmethyl) - N (5-pyrimidinyl) amine n) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (2-pyridyl) - N- (3-pyridylmethyl) amine o) N- (4-methoxy-3- (31 <) - tetrahydrofuranyloxyphenyl) - N '1- (3-pyridyl) N- (3-pyridylmethyl) amine p) 3-Cyclopentyloxy-4-methoxyanilino-N- (3-pyridylmethyl) - N-3 (4-pyridyl) benzamide q) 3-cyclopentyloxy-4-methoxy-3 '- (4-methylpiperazin-1 ylcarbonyl) - L1- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-difluoromethoxy-4 '- (4-methylpiperazin-1 ylcarbonyl) - N- (3-pyridylmethyl) diphenylamine s) 4-Methoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) - N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine t) 3 '- (butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine i) 3'-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine 112 v) 4-methoxy-14- (3-pyridylmethyl) - (3- (3-tetrahydrofuryloxy) diphenylamine w) 4-methoxy-3- [2- (4-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine x) 4-Methoxy-3- (2-methoxyethoxy) - N- (3-pyridylmethyl) diphenylamine y) 3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine z) 4-Methoxy-S-3-pyridylmethyl) -3 - [(3S) tetrahydrofuryloxy] diphenylamine aa) 3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine bb) 3- [2- (4-chlorophenyl) ethenyloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine cc) 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N- (3dd) pyridylmethyl) diphenylamine e) 3-cyclopentyloxy-4'-hydroxy-4-methoxy-N- (3ff) pyridylmethyl) diphenylamine e) 4'-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy- N- (3pyridylmethyl) diphenylamine gg) 3-cyclopentyloxy-4 -methoxy-4 '- [2- (1-methylpyrrolidin-21111) yl) ethoxy] -L- (3-pyridylmethyl) diphenylamine gg) 3-cyclop ntyloxy-4-methoxy-4 '- [3- (1-methylpyrrolidin-2-yl) methoxy] -1' [- (3-pyridylmethyl) diphenylamine 1 ') 3-cyclopentyloxy-4-methoxy-4' - [3- (1 -methylpiperazin-4-yl) propoxy] -L1- (3-pyridylmethyl) diphenylamine n) 4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine jj) 3-cyclopentyloxy-4-methoxy-4 '- [2- (2-propanesulfonylamino) ethoxy] - N - (3- pyridylmethyl) diphenylamine 113 kk) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine 11) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine mm) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine PP) 3-cyclopentyloxy 4-methoxy-4 '- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamino) 3-cyclopentyloxy-4' -methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine pp) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine qq) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N (3-pyridylmethyl) diphenylamine-4-methoxy-4-methoxy-4-methoxy) methoxy-3- [2- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) ) diphenylamine ss) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) - N- (3-pyridylmethyl) diphenylamine (t) 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine uu) 3-cyclopentyloxy-4 '- (ethanesulfonylammonium) ethoxy-4-methoxy-N (3-pyridylmethyl-) diphenylamine w) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-propanesulfonylmino) ethoxy] - N- (3-pyridylmethyl) diphenylamine ww) 3'-chloro-3-cyclopentyloxy-4-methoxy-L- ( 3-pyridylmethyl) diphenylamine xx) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine yu) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3- ( (3S) 114 'Whose *' tetrahydrofuryloxy) diphenylamine zz) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3tetrahydrofuryloxy) diphenylamine aaa) bis-3,4- (difluoromethoxy) - N - (3-pyridylmethyl) diphenylamine bbb) 4-difluoromethoxy-b1- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine cc) 3'-cyano-4- difluoromethoxy-L- (3-pyridylmethyl) -3 - ((31 <) tetrahydrofuryloxy) diphenylamine ddd) 3'-chloro-4-difluoromethoxy-L [- (3-pyridylmethyl) -3 - ((31 <) tetrahydrofuryloxy) diphenylamine eee) 3'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy- (3-pyridylmethyl) diphenylamine fff) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3aminobenzoic acid gg N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -4-aminobenzoic acid hhh) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid iii) N - [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl ] - N- (3-pyridylmethyl) -3-aminobenzoic acid jjj) N-3,4-bis (difluoromethoxy) phenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid kkk) N - [4-methoxy-3 - (( 3 R) -tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid 111) N- (3-Cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) 4-aminobenzoic acid mmin) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminopenzoicbenzoic acid N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid 115 Acid Ooo) N - [3- (4-Chlorophenyl) prop-1-yloxy-4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid ppr) N- (3-cyclopropylmethoxy-4-methoxyphenyl) - N - (3-pyridylmethyl) -3-aminobenzoic acid qqq) N - [3- (2-indanyloxy) -4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid pt) N - [4-methoxy-3- (3 -tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid w sss) N - [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid ttt) N - [3- (2-methoxyethoxy) -4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid uuu) 3-cyclopropylmethyl l-oxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenyl-amine vw) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4' - (2H -tetrazol-5-yl) diphenylamine www) 3-cyclopentyloxy-4-methoxy-N- (3d pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenylamine xxx) 4-methoxy-N- (3-pyridylmethyl) ) -3 - ((3R) -tetrahydrofuranyloxy) 4 '- (2H-tetrazol-5-yl) diphenyl amine yy) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4' - (2H-tetrazol-5) (yl) diphenylamine zzz) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((31 <) tetrahydrofuryloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine aaaa) 3-cyclopentyloxy-4-difluoro ethoxy-N- (3-pyridylmethyl) -4 '- (2 H-tetrazol-5-yl) diphenyl amine bbbb) 3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3' - (2 H-tetrazol-5 -yl) diphenylamine 116 ccc) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine dddd) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridyl) - 181- (3-pyridylmethyl) amine eee) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine ffff) N- (3-cyclopropylmethoxy-4-difluoromethoxy) -methoxy-phenyloxymethoxy N- (3-pyridyl) -N- (3-pyridylmethyl) amine yyyy) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxy) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine hhhh) 3- cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine iiii) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanesulfonylamino-N- (3p ridilmetil) diphenylamine jii j) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3piridilmetil) diphenylamine kkkk) 3-cyclopentyloxy-4-methoxy-4 '- (1-propansulfonilamino-N (H-pyridylmethyl) diphenylamine 1111) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine mmmm) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydrofluoro Nnnn) 4-methoxy-3- [2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine oooo) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine pyrrr) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine qqqq) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- ( (3R) 117 Tertrahydrofuryloxy) diphenylamine pg) 3-cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidinyl) methoxy] - N- (3-pyridyl) ethyl) diphenylamine and their pharmaceutically acceptable salts. The compound of claim 1, which is: a) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine c) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4 '- (2- (tetrahydropyran-2-yl) -2Htetrazol-5-yl) - N- (3-pyridylmethyl) diphenylamine e) 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine f) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine g) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine 11) 4-methoxy-3- [3- (4-pyridyl) prop-1-yl] okch-N- (3-pyridylmethyl) diphenylamine i) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) - N- (3-pyridylmethyl) diphenylamine j) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-L1- (3-pyridylmethyl) diphenylamine k) 3-cyclopentyloxy-4 '- (2-ethanesulfonylamino) ethoxy-4-methoxy- (3-pyridylmethyl) diphenylamine l) 3-Cyclopentyloxy-4-methoxy-4 '- [2- (1 propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine 118 m) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine η) 3′-chloro-4-methoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine o) 3'-cyano-4-methoxy- N- (3-pyridylmethyl) -3 - ((ZK) tetrahydrofuryloxy) diphenylamine p) 4-difluoromethoxy-T4- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenyl q) 3,4-bis (difluoromethoxy) - N- (3-pyridylmethyl) diphenylamine d) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine s) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) - 3 - ((3R) tetrahydrofuryloxy) diphenylamine t) 3′-chloro-4-difluoromethoxy-14- (3-pyridylmethyl) - 3 - ((3R) tetrahydrofuryloxy) diphenylamine and) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl) diphenylamine v) N- (3-cyclopentyloxy-4-methoxyphenyl) -1H- (3-pyridylmethyl) -3-aminobenzoic acid w) N- (3-cyclopentyloxy-4-methoxyphenyl) - N - (3-pyridylmethyl) -4-aminobenzoic acid x) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid y) N - [4-Methoxy-3- (3-tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid z) N-3,4-bis (difluoromethoxy) phenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid aa) N - [4-methoxy-3 - ((3R) -tetaxoxypropyloxy) phenyl] -methyl ) -3-Aminobenzoic acid 119 bb) b1- (3-cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -4-aminobenzoic acid cc) 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 b1- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid ff) N- (3-cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid gg) N - [3- (2-indanyloxy) -4-methoxyphenyl] - N- (3-pyridylmethyl) -3 - aminobenzoic acid Illi) N - [4-methoxy-3- (3-tetrahydrofuranyloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid π) N - [4-methoxy-3 - ((3R) -tetrahydrofuranyloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid jj) N - [3- (2-methoxyethoxy) -4-methoxyphenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid kk) 3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine II) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine mm) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3' - (2H -tetrazol-5-yl) diphenylamine PP) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3S) -tetrahydrofuryloxy) 4 '- (2H-tetrazol-5-yl) diphenylamine (O) 3-cyclopropylmethyloxy -4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine pp) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((31 <) 120 tetrahydrofuryloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine qq) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4' - (2H-tetrazol-5-yl) diphenyl amine 2 ') 3-cyclopropylmethyl si-4-difluoromethoxy-N- (3-pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenyl amine ss) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4' - (2H -tetrazol-5-yl) diphenylamine t) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine uu) 14- (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridyl) -N 3 -pyridylmethyl) amine w) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridyl) - N- (3-pyridylmethyl) amine ww) L1- (4-difluoromethoxy-3- (3S) -tetrahydrofuryloxy) - N- ( 3-pyridyl) - N- (3-pyridylmethyl) amine xx) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine yy) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine zz) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine aaa) 3-cyclopentyloxy-4-methoxy-4 '- (1-propanesulfonylamino) -N-3-4-methoxy-4-methoxy -pyridylmethyl) diphenylamine bbb) 3-cyclopropylmethoxy-3'-ethanesulfonyl ino-4-methoxy-N- (3-pyridylmethyl) diphenylamine x cc) 4-difluoromethoxy-3'-ethanesulfonylamino-L1- (3-pyridylmethyl) -3 - ((3 H) -tetrahydrofuryloxy) diphenylamine ddd) 4-methoxy-3- [ 2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine 121 eee) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuranyloxy) diphenylamine fff) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] - N- (3pyridylmethyl) diphenylamine yyyy) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - ((3 R) tetrahydrofuryloxy) diphenylamine hhh) 3-cyclopentyloxy-4-methoxy-4 '- [2- ( 5-Oxopyrrolidinyl) methoxy] - L- (3-pyridylmethyl) diphenylamine and their pharmaceutically acceptable salts. The compound of claim 1 selected from: a) 3 '-chloro-3-cyclopentyloxy-4-methoxy-1' - [(3-pyridylmethyl) diphenylamine b) 3'-chloro-4-methoxy- N- (3-pyridylmethyl) -3- (3tetrahydrofuryloxy) diphenylamine c) 3'-cyano-4-methoxy- N- (3-mipnawiMeTmi) -3 - ((3R) tetrahydrofuryloxy) diphenylamine d) 4-difluoromethoxy-1 \ [- (3-pyridylmethyl) -3- (3-tetrahydrofuranyloxy) diphenyl e) 3,4-bis (difluoromethoxy) - N- (3-pyridylmethyl) diphenylamine f) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine g) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) - 3 - ((3R) tetrahydrofuryloxy) diphenylamine h) 3′-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) - 3 - ((3R) tetrahydrofuryloxy) diphenylamine i) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl) diphenylamine j) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid 122 k) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -4-aminobenzoic acid l) No. (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid m) N - [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid n) N-3,4-bis (difluoromethoxy) phenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid ο) N - [4-Methoxy-3 - ((31 <) - tetrahydrofuranyloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid p) N- (3-cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -4-aminobenzoic acid q) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid d) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid s) N - [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid t) N- (3-cyclopropylmethoxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoic acid u) N - [3- (2-indanyloxy) -4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid v) N - [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid w) N - [4-Methoxy-3 - ((31 <) - tetrahydrofuranyloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid x) N - [3- (2-methoxyethoxy) -4-methoxyphenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid y) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N- (3123 pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine z) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine aa) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3' - ( 2H-tetrazol-5-yl) diphenyl amine bb) 4-methoxy-N- (3-pyridylmethyl) -3 - ((31 &apos; -tetrahydrofuryloxy) 4 '- (2H-tetrazol-5-yl) diphenyl amine cc) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine dd) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((31 <) tetrahydrofuranyloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4' - (2H-tetrazol-5-yl) diphenylamine ft) 3- cyclopropylmethylox and-4-difluoromethoxy-N- (3-pyridylmethyl) -3 '- (2H-tetrazol-5-yl) diphenylamine (g) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4' - (2H-tetrazol-5 h) N- (3-cyclopentyloxy-4-methoxyphenyl) - N- (3-pyridyl) -N- (3-pyridylmethyl) amine n) b1- (3-cyclopentyloxy-4-difluoromethoxyphenyl) - N- (3pyridyl) - N- (3-pyridylmethyl) amine jj) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) - N- (3-pyridyl) - N- (3-pyridyl) (3-pyridylmethyl) amine kk) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxy) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine 11) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine mm) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanesulfonylamino-N (3-pyridylmethyl) diphenylamine) 124 nn) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamino) 3-cyclopentyloxy-4-methoxy-4 '- (1-propanesulfonylamino-N- (3-pyridylmethyl) diphenylamine pp) 3- cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine qq) 4-difluoromethoxy-3'-ethanesulfonylamino-L- (3-pyridylmethyl) -3 - ((3 K) -tetrahydrofuranyloxy) dihydroxyglyloxy) -3- [2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenylamine ss) 4-methoxy-HC3-pyridylmethyl) -3 - ((3R) tetrahydrofuryloxy) diphenylamine tt) 3'-chloro-4-methoxy -3- [2- (2-pyridyl) ethoxy] - N- (3-pyridylmethyl) diphenes amine uu) 3'-Chloro-4-methoxy YTSZ-pyridylmethyl) - 3 - ((3R) tetrahydrofuryloxy) diphenylamine w) 3-Cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine and their pharmaceutically acceptable salts. 41. A compound of formula D R ¹ ' R ² ' R ¹ is methoxy, F, Cl, CHF ₂ or CF ₃ ; R ² is alkyl having 1 to 12 carbon atoms; 125 alkyl having 1 to 12 carbon atoms which is substituted one or more times with 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 with 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 with halogen, oxo, cyano or combinations thereof; cycloalkyl having 3 to 10 carbon atoms; cycloalkyl having 3 to 10 carbon atoms which is substituted one or more times with 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 with 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 with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof; arylalkyl having 7 to 26 carbon atoms; arylalkyl having 7 to 26 carbon atoms which is substituted one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof; heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom or a 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 moiety aryl, alkyl, alkoxy, cyano, 126 trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety by halogen, oxo, cyano or combinations thereof; X is O or S; R ³ is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, , carboxy, 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 having at least one ring atom is a heteroatom or a substituent a tan heteroaryl having from 5 to 10 ring atoms in which at least one ring atom is a heteroatom which is substituted one or more times with halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations from them; L is -NH-, -NR ⁴ -, -NHCH ² -, -NR ⁴ CH 2 - or -CH ₂ NR ⁴ -, and R is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times with halogen, oxo, cyano or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, ethylsulfonyl, alkylsulfinyl, alkylthiol 5 to 10 rings and atoms in which at least 1 ring atom is a heteroatom, 127 substituted heteroaryl having from 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times with 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 with halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having up to 10 ring atoms in which at least 1 a Rosten 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 moiety by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety by halogen, oxo, cyano or combinations thereof and pharmaceutically acceptable salts thereof. Use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of mammals to improve their cognitive ability, wherein an effective amount of the compound is administered to the mammal in need of such treatment. The use of claim 42, wherein the compound is administered in an amount of 0.01-100 mg / kg body weight per day. The use of claim 42, wherein the mammal is a human. The use of claim 42, wherein the medicament is administered for the treatment of cognitive impairment. The use of claim 45, wherein the medicament is administered to a human. 128 Use according to claim 46, wherein the medicament is used in the treatment of memory impairment. Use according to claim 45, wherein the compound is administered in an amount of 0.01-100 mg / kg body weight per day. Use according to claim 47, wherein the patient suffering from memory impairment is due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob's disease, depression, age, trauma head, stroke, central nervous system hippos, cerebral senility, multi-infarct dementia, HIV, or cardiovascular disease. Use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of a disease comprising reduced cAMP levels, wherein an effective amount of the compound is administered to a human or animal in need of such treatment. Use of a compound of formula I according to claim 1 for the preparation of a medicament for inhibiting PDE4 enzyme activity, wherein an effective amount of the compound is administered to a human or animal in need of such treatment. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A composition according to claim 52, containing 0.1 to 50 mg of the compound. Use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of memory impairment due to a neurodegenerative disorder. The use of claim 54 wherein the memory impairment is due to an acute neurodegenerative disorder. Use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of mammals suffering from 129 an allergic or inflammatory disease, wherein an effective amount of the compound is administered to a mammal in need of such treatment. 57. A compound of formula R (I) in which: R ¹ is hydrogen, tert-butyldimethylsilyl, ³ H ₃ C-, ¹⁴ CH 3 - or ^{and a} CH 3 - or phenolic protecting group; R ² is alkyl of 1 to 12 which may be branched or unbranched and 4 '''may be unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C _1-4 alkoxy, oxo or a combination thereof and where optionally one or more -CH 2 CH 2 - groups are substituted in each case by -CH = CH- or -C 1 -C-, cycloalkyl having from 3 to 10 which may be unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or a combination thereof, cycloalkylalkyl having 4 to 16 which is unsubstituted or substituted on the cycloalkyl moiety and / or alkyl h ast one or more times with halogen, oxo, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy or a combination thereof, an aryl having 6 to 14 carbon atoms which is unsubstituted or substituted one or more times with halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or a combination thereof, arylalkyl having in the aryl moiety 6 to 14 carbon atoms and in an alkyl moiety which may be branched or unbranched there are from 1 to 5 130 carbon atoms, wherein the aralkyl radical is unsubstituted or substituted on the aryl moiety by one or more halogens, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy or a combination thereof and where in the alkyl part one or more -CH ₂ CH ₂ groups are in each case substituted by -CH = CH- or -C ^ C- and one or more CH2- groups each may optionally be replaced by -O- or ΝΗ - and / or the alkyl moiety is optionally substituted by halogen, oxo, hydroxy, cyano or combinations thereof, a partially unsaturated carbocycle a group having 5 to 14 'w 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, saturated or saturated, or unsaturated having from 5 to 10 ring atoms in which at least 1 ring atom is Ν, O or S, which is substituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro , oxo or combinations thereof or a heterocyclic-alkyl group in which heterocyclic the unsaturated moiety is saturated, partially saturated or unsaturated and has 5 to 10 ring atoms of which at least 1 ring atom is Ν, O or S, and the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms, heterocyclic-alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof, wherein in the alkyl moiety one or more -CH 2 CH 2 - groups are optionally substituted in each case by -CH = CH- or -C = C- and one yl more -CH ₂ - groups each of which may optionally be replaced by -O- or -NHi / or the alkyl portion is optionally substituted with halogen, oxo, hydroxy, cyano or combinations thereof; 131 R ³ is hydrogen, alkyl having 1 to 8, preferably 1 to 4, carbon atoms which is branched or unbranched and which may be unsubstituted or substituted one or more times by halogen, cyano, C 1-4 alkoxy or a combination thereof, partially unsaturated a carbocyclic-alkyl group in which the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms and which is unsubstituted or substituted on the carbocyclic moiety one or more times by w halogen, alkyl, alkoxy, nitro, cyano, oxo or comb and the alkyl moiety is optionally substituted by halogen, C 1-4 alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl moiety is 6 to 14 carbon and the alkyl moiety which may be branched or unbranched has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted on the aryl moiety one or more times by halogen, CF ₃ , OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methane * or heteroarylalkyl group, e.g. wherein the heteroaryl moiety may be partially or fully saturated and having 5 to 10 ring atoms in which at least 1 ring atom is N, O or S, the alkyl moiety 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 moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety by halogen, cyano or methyl or combinations thereof, R ⁴ is hydrogen, 132 aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, aminoalkyl, aminoalkyl dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (heterocycle) tetrazol-5-yl, hydroxycarbonyl, cyano, acyl, alkylthio, alkylsulfonyl, alkylsulfonyl R ⁵ -L-, or combinations thereof, or hetero eroaryl having from 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, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxyalkyl, phenyloxy, phenyloxy; R ⁵ is hydrogen, alkyl having 1 to 8, which is unsubstituted or substituted one or whose * multiple times by halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo or a combination thereof, aliclamino or dialkylamino, where each alkyl moiety has independently 1 to 8 carbon atoms, a partially unsaturated carbocyclic alkyl group, wherein the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms which is unsubstituted or substituted, preferably in the carbocyclic moiety, one or more times by halogen, alkyl , alkoxy, nitro, cyano, oxo or co binatsii of them 133 cycloalkyl having 3 to 10 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, cycloalkyl alkyl having 4 to 16 which is unsubstituted or substituted in the cycloalkyl moiety and / or in the alkyl moiety one or more times with 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, methylenedioc and, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acylalkyl, alkyl, alkylthio, alkyl, alkylthio, 19 carbon atoms in which the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms, the arylalkyl radical is unsubstituted or substituted in the aryl moiety, one or more times by halogen, trifluoromethyl OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl, a heterocyclic group which is saturated, partially saturated or unsaturated having 5 to 10 ring atoms, of which -almost 1 ring atom is Ν, O or S which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl group, amino, aminomethyl, aminoalkyl, aminoalkyl, aminoalkyl, amino , hydroxyalkyl, hydroxamic acid, tetra sol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, or 134 heterocyclic-alkyl group wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and has 5 to 10 ring atoms in which at least 1 ring atom is N, O or S and an alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms, the heterocyclic alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted the alkyl moiety with halogen, cyano or m ethyl or combinations thereof; h *, L means a single bond or a bivalent aliphatic radical having 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups, each of which may be optionally substituted by -O-, -S-, -NR ⁶ - , -SO2NH-, -NHSO2- CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH, -NHCOO-, SCONH-, SCSNHor-NHCSNH- and R ⁶ is hydrogen or alkyl having 1 to 8 which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, C 1-4 alkyl, C 1. ₄ alkoxy, oxo or a combination thereof; and wherein at least one of R ³ and R ⁴ is other than hydrogen and their pharmaceutically acceptable salts. 58. A compound of the formula: R ¹ is alkyl of 1 to 4 carbon atoms, which may be branched or unbranched and may be unsubstituted or substituted once or more times by halogen; 135 R is hydrogen, a tert-butyldimethylsilyloxy or phenolic protecting group ;, R ³ is hydrogen, alkyl having 1 to 8, preferably 1 to 4, carbon atoms which is branched or unbranched and which may be unsubstituted or substituted one or more times by halogen, cyano, C 1-4 alkoxy or a combination thereof, partially unsaturated a carbocyclic-alkyl group in which the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms and which is unsubstituted or substituted on the carbocyclic moiety one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or comb optionally substituted by halogen, C 1-4 alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl moiety has 6 to 14 carbons and an alkyl moiety which may be branched or unbranched has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted on the aryl moiety one or more times by C halo, CF ₃ , OCF ₃ , nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety with a halogen, cyano or methane or heteroarylalkyl group, k if the heteroaryl moiety can be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is N, O or S, the alkyl moiety 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 moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro, oxo, amino, alkylamino, dialkylamino or 136 combinations thereof and / or substituted in the alkyl moiety by halogen, cyano or methyl, or combinations thereof, R ⁴ is hydrogen, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthiofluoxyalkylthiosulfonylamino; butyldimethylsilyloxy), R ⁵ -L-, or combinations a moiety or heteroaryl having from 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, trifluoromethyl , aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl; R ⁵ is hydrogen, alkyl having 1 to 8, which is unsubstituted or substituted one or more times with halogen, C 1-4 alkyl, C 1-4 alkoxy, oxo or a combination thereof, aliclamino or dialkylamino, wherein each alkyl moiety has independently 1 to 8 carbon atoms, a partially unsaturated carbocyclic alkyl group, wherein the carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms which is unsubstituted or substituted, preferably 137 in the carbocyclic moiety, one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof, cycloalkyl having from 3 to 10 which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl of 1 to 4 carbon atoms or combinations thereof, cycloalkylalkyl having 4 to 16 which is unsubstituted or substituted on the cycloalkyl moiety and / or in the alkyl moiety one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, A aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkyl , tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl or combinations thereof, arylalkyl having 7 to 19 carbon atoms in which the aryl moiety has 6 to 14 carbon atoms, is unfolded on or unbranched, has 1 to 5 carbon atoms, the arylalkyl radical is unsubstituted or substituted on the aryl moiety, one or more times by halogen, trifluoromethyl, OCF3, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in alkyl with halogen, cyano or methyl, a heterocyclic group which is saturated, partially saturated or unsaturated having from 5 to 10 ring atoms, of which at least 1 ring atom is N, O or S which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl group, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 'hydroxyalkoxy, carboxy, 138 alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof or a heterocyclic-alkyl group wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and has 5 to 10 ring atoms in which at least 1 ring atom is present N, O or S and the alkyl moiety which is branched or unbranched has 1 to 5 carbon atoms, the heterocyclic alkyl group is unsubstituted or substituted one or more times in the heterocyclic moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, OCF ₃ , nitro , oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L means a single bond or a bivalent aliphatic radical having 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups, each of which may be optionally substituted by -O-, -S-, -NR ⁶ -, -SO ₂ NH-, -NHSO ₂ - CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH, -NHCOO-, SCONH-, SCSNHor-NHCSNH- and R ⁶ is hydrogen or alkyl having 1 to 8 which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, C _1-4 alkyl, C 1-6. ₄ alkoxy, oxo or a combination thereof; and wherein at least one of R ³ and R ⁴ is other than hydrogen and their pharmaceutically acceptable salts. 59. Compound selected from: a) 3-cyclopentyl-4-methoxy-14- (3-pyridylmethyl) aniline b) 3-tert-butyldimethyl silyl oxy-4-methoxy-N- (3-pyridylmethyl) aniline c) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine d) 3-tert-butyldimethylsilyloxy-3'-chloro-4-methoxy-N- (3139 pyridylmethyl) diphenylamine e) ethyl N- (3-tert-butyldimethylsilyloxy-4-methoxyphenyl) - N- (3-pyridylmethyl) -3-aminobenzoate f) 3-cyclopentyloxy-4-methoxydiphenylamine g) 3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine h) 3'-chloro-3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine i) ethyl N- (3-hydroxy-4-methoxyphenyl) - T4- (3-pyridylmethyl) -3aminobenzoate j) 3 '- (2-bromoethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine k) 4 '- [1- (3-bromopropyl) oxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine and l) 4-hydroxy-3-cyclopentyloxy-N- (3-pyridylmethyl) diphenylamine. 60. Compounds according to claim 1, which is N-3,4bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 61. Compounds according to claim 1, which is N- (3cyclopentyloxy-4-methoxyphenyl) -1H- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. The use of claim 44, wherein the compound is N- 3.4- bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. The use of claim 50, wherein the compound is N- 3,4-bis (difluoromethoxy) phenyl-L- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. The use of claim 63, wherein the disease is depression. 140 The use according to claim 44, wherein the compound is N (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 66. A composition according to claim 52, comprising the compound N-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 67. A composition according to claim 52, which comprises the compound N- (3-cyclopentyloxy-4-methoxyphenyl) -L [- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 68. The composition of claim 52, wherein the composition also comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakine NMDA-R modulators, mGluR modulators, cholinesterase inhibitors, and any combination thereof. 69. The composition of claim 66, wherein the composition also comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakin NMDA-R modulators, mGluR modulators, cholinesterase inhibitors, and any combination thereof. The composition of claim 67, wherein the composition also comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakine NMDA-R modulators, mGluR modulators, cholinesterase inhibitors, and any combination thereof.