SK9152003A3 - Aniline derivatives useful as 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 (I): wherein R<1>, R<2>, R<3> and R<4> are as defined herein.

Description

Technical field

The present invention relates generally to the field of phosphodiesterase 4 (PDE4) inhibition. More specifically, the present invention relates to the selective inhibition of PDE4 using novel compounds, for example, N-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing them, and methods of using them.

BACKGROUND OF THE INVENTION

This application claims the priority of U.S. Provisional Application Ser. No. 60/262,651, filed Jan. 22, 2001, U.S. Provisional Application Ser. No. 60/267,196, filed Feb. 8, 2001, and U.S. Provisional Application Ser. 60/306 140, filed July 14, 2001.

Cyclic nucleotide specific 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 second mesengers in cells and transduce pulses from cell surface receptors, binding various hormones and neurotransmitters, as mesengers. PDE regulates the level of cyclic nucleotides in the cells and maintains cyclic nucleotide homeostasis by degrading such cyclic mononucleotides that lead to the termination of their role as a messenger.

PDE enzymes can be grouped into 11 families, depending on their specificity against cAMP or cGMP hydrolysis, their sensitivity to calcium, calmodulin or cGMP regulation and their selective inhibition by various compounds. For example, pDE1 is stimulated with Ca ²⁺ / calmodulin. PDE2 is cGMP-dependent and found to be found in the heart and adrenal gland. PDE3 is cGMP dependent and inhibition of this enzyme produces a positive inotropic activity. PDE4 is specific for cAMP and its inhibition causes airway relaxation, anti-inflammatory and anti-stress activity. PDE5 appears to be important in regulating cGMP content in vascular smooth muscle and therefore PDE5 inhibitors may have cardiovascular efficacy. Since PDEs exhibit significant biochemical properties, they are likely to be subject to different forms of regulation.

PDE4 has various kinetic properties, including a low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 family consists of four genes that produce four isoforms of PDE4, designated PDE4A, PDE4B, PDE4C, and PDE4D [see: Wang et al., Expression Purification and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C and D, Biochem. Biophys. Res. Comm., 234,320-324 (1997)]. Furthermore, different variants of each PDE4 isoform were identified.

PDE4 isoenzymes are found in the cytosol of cells and are not associated with any known membrane structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its nydrolysis to adenosine 5'-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. PDE4 isoenzyme inhibitors such as rolipram, piclamilast, CDP-840, and ariflo are potent anti-inflammatory agents and can therefore be used to treat diseases where inflammation is problematic, such as asthma or arthritis. Further, rolipram improves cognitive behavior in rats and mice in educational paradigms.

rolipram piclamilast

In addition to compounds such as rolipram, PDE4 inhibits xanthine new derivatives such as pentoxyphylin (pentoxifylline), denbufylin (denbufylline) and theophylline (teophylline), and has recently received considerable attention for their cognitive effects. cAMP and cGMP are second mesengers that mediate cellular responses to a variety of different hormones and neurotransmitters. Thus, therapeutically significant effects may result from inhibition of PDE and the resulting increase in intracellular cAMP and cGMP in key cells, such as those located in the nervous system and elsewhere in the body.

Rolipram, formerly developed as an antidepressant, selectively inhibits PDE4 and has become a standard agent in the classification of PDE subtypes. Earlier PDE4 work on depression and inflammation was subsequently extended to indications such as dementia [for a general review see The PDE IV Family of Calcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al., Drugs of the Future 1992, 17 (9): 799-807]. Further clinical investigations of rolipram and first generation PDE4 inhibitors have been discontinued due to the side effects of these compounds. The primary side effect in primates is vomiting, while the primary side effects in rodents are testicular degranulation, vascular smooth muscle weakness, psychotropic effects, increased gastric acid secretion and gastric erosion.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds, novel N-substituted aniline and diphenylamine compounds that inhibit PDE4 enzymes and which have in particular an improved side effect profile, such as relatively non-emetic (for example, as compared to the compounds discussed earlier in the art). Preferably, the compounds of the invention selectively inhibit PDE4 enzymes. At the same time, the compounds of the present invention facilitate entry into cells, particularly cells of the nervous system.

Still further, the present invention provides methods for synthesizing compounds with both activity and selectivity, as well as methods (and corresponding pharmaceutical compositions for) treating a patient, e.g., a mammal, including a human, in need of PDE inhibition, particularly PDE4 inhibition, in disease states that include intracellular PDE4 levels or decreased cAMP levels, for example, include neurological syndromes, particularly those related to memory impairment, especially long-term memory impairment, wherein such memory impairment is partially due to catabolism of intracellular cAMP levels by PDE4 enzymes or where such deterioration occurs. memory can be improved by effectively inhibiting PDE4 enzyme activity.

In a preferred aspect, the compounds of the invention ameliorate such diseases by inhibiting the PDE4 enzyme at doses that do not cause vomiting.

The present invention includes compounds of formula I:

R 'where

R ¹ is C 1 -C 4 alkyl, straight or branched chain, unsubstituted or substituted one or more times with a halogen atom (e.g. CH ₃ , CHF ₂ , CF ₃ , etc.);

R ² is an alkyl group having 1 to 12, preferably 1 to 3, carbon atoms, straight or branched chain, unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C 1 -C 4 alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH ₂ CH ₂ - is replaced in each case by -CH = CH- or -C = C- (for example CH ₃ ,

CHF ₂ , CF ₃ , methoxyethyl, etc. ), a cycloalkyl group having 3 to 10, preferably 3 to 8, carbon atoms which is unsubstituted or is substituted one or more times by atom, halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 atoms carbon or combinations thereof (e.g. cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12, carbon atoms which is unsubstituted or substituted in the cycloalkyl moiety and / or the alkyl moiety one or more times by halogen, oxo, cyano, hydroxy, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), (C 6 -C 14) aryl group which is unsubstituted or substituted one or more times by halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.), arylalkyl, wherein the aryl moiety contains 6 to 14 carbon atoms and the branched or unbranched alkyl moiety containing from 1 to 5 carbon atoms wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by a halogen atom, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy and combinations thereof or in the alkyl moiety, one or more -CH ₂ CH ₂ - is optionally replaced by -CH = CH- or -C = C- and one or more -CH ₂ - is replaced by -O- or -NH- and / or the alkyl moiety is optionally substituted with a halogen atom, an oxo group, a hydroxy group, a cyano group, or a combination thereof ciami (e.g., phenylethyl, nylpropyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenyl chlorophenylethyl, chlorophenylpropyl, phenyletenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), the partially unsaturated carbon-substituted 5-carbonated or unsubstituted carbocyclic ring or multiple times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.), a heterocyclic group which is saturated, partially saturated or unsaturated, containing 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, which is unsubstituted or substituted one or more times with a halogen atom, a hydroxy group, an aryl group, an alkyl group, an alkoxy group, a cyano group, a trifluoromethyl group, a nitro group, an oxo group or combinations thereof (e.g. 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or a heterocyclylalkyl group, wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, the heterocyclylalkyl group being unsubstituted or substituted in the heterocyclic moiety one or more times 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 - is optionally replaced by -CH = CH- or -C = Ca one or more -CH ₂ - is replaced by - O- or -NH- and / or the alkyl moiety is optionally substituted by halogen, oxo, hydroxy or co combinations (e.g., pyridylethyl, pyridylpropyl, methylpiperazinylethyl, etc.);

R ³ is H, an alkyl group 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 by halogen atom, cyano, alkoxy group having 1 to 4 carbon atoms or. combinations thereof (e.g. methyl, ethyl, propyl, etc.), a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms and which is unsubstituted or substituted in the carbocyclic ring moieties one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof; and wherein the alkyl moiety is optionally substituted by halogen, C1-C4alkoxy, cyano or combinations thereof (e.g. cyclohexenylmethyl, etc.). C7 -C19 arylalkyl, wherein the aryl moiety contains 6 to 14 carbon atoms and wherein the branched or unbranched alkyl moiety contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety either or o halogen, trifluoromethyl, CF ₃ O, nitro, air, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl (e.g. benzyl, phenylethyl, phenylpropyl, methylbenzyl, methylbenzyl, methylbenzyl, methylbenzyl, methylbenzyl, methylbenzyl) methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), or a heteroarylalkyl group, wherein the heteroaryl moiety may be partially or fully saturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, wherein the alkyl moiety which is branched or unbranched, wherein the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl part by a halogen atom, an alkyl group, an alkoxy group, a cyano group, a trifluoromethyl group, CF ₃ O, nitro, oxo, amino, alkylamino or dialkylamino groups; / or substituted in the alkyl moiety by halogen, cyano, methyl, or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, imidinylmethyl, imidazolylmethyl, imidinylmethyl, imidinylmethyl, imidazolylmethyl, imidazolylmethyl, imidinylmethyl);

R ⁴ is H, (C 6 -C 14) aryl and is unsubstituted or substituted one or more times with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, trifluoromethyl, ethylenedioxy, O, ethylenioxy, O , amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g. hydroxymethyl), hydroxamic acid, tetrazol-5-yl, 2- (heterocyclo) tetrazol-5-yl (e.g. 2- (2-tetrahydropyranyl) tetrazole) -5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, butyldimethylsilyloxyethyl (e.g., trialkylsilyloxy) R ⁵ -L- or combinations thereof (for example, substituted or unsubstituted phenyl, naphthyl and biphenyl such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl, dimethylphenyl) , aminophenyl, etc.) or a heteroaryl group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g. hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl u (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. tert-butyldimethylsilyloxy), R ⁵ -L- or pyridinyl, thienyl, , isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);

R ⁵ is H, an alkyl group having 1 to 8, preferably 1 to 4, carbon atoms which is unsubstituted or substituted one or more times with a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an oxo group or combinations thereof (e.g. methyl, ethyl, propyl, etc.), alkylamino or dialkylamino, wherein each alkyl moiety independently has 1 to 8, preferably 1-4 carbon atoms (e.g. dimethylamino, etc.), partially unsaturated carbocyclylalkyl, wherein the carbocyclic moiety it contains 5 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms and which is unsubstituted or substituted, preferably in the carbocyclic moiety one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof (e.g. cyclohexenylmethyl, etc.), a cycloalkyl group containing 3 a %, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times with a halogen atom, a hydroxy group, an oxo group, a cyano group, an alkoxy group, an alkyl group containing from 1 to 10 carbon atoms; 4 carbon atoms or combinations thereof (e.g. cyclopentyl), a cycloalkylalkyl group containing 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 by halogen, oxo, cyano, hydroxy , alkyl, alkoxy or combinations thereof (e.g. cyclopentyl, cyclopropylmethyl, etc.), aryl of 6 to 14 carbon atoms and unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, methoxy, nitro , ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g. hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkox yy, carboxy, alkoxycarbonyl (for example tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl (for example substituted or unsubstituted phenyl and naphthyl, methylphenyl, ethoxyphenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl moiety contains 6 to 14 carbon atoms and wherein the alkyl moiety which is branched or unbranched contains 1 to 5 carbon atoms wherein the arylalkyl is unsubstituted or substituted in the aryl moiety one or more times by halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in a a halogen atom, a cyano group or a methyl group (for example, benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), a heterocyclic group which is saturated, partially saturated or unsaturated in a ring containing 5 to 10 atoms wherein at least one ring atom is N, O or S which is substituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ecylenedioxy, trifluoromethyl, amino, , aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g. hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), acano alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.) or a heterocyclylalkyl group wherein the heterocyclic moiety is saturated or partially saturated, contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, the heterocyclylalkyl group being unsubstituted or substituted one or more times in the heterocyclic moiety halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, dialkylamino or combinations thereof, and / or the alkyl moiety is substituted by halogen, cyano or methyl or combinations thereof (e.g. pyridylmethyl, yridylpropyl, methylpyridylmethyl, etc.);

L is a single bond or a divalent aliphatic group containing 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups are optionally replaced by -O-, -S-, -NR ⁶ -, -SO 2 NH-, -NHSO 2 -, -C0-.

-NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH or -NHCSNH- (e.g. -O-, -CH ₂ -, -CO-, -CO- 0-, -0-C0-,

-NH-CO-, -CH ₂ CH ₂ CH ₂ -NH-CO-, -CH ₂ -CH ₂ -O-, -SO ₂ -NH-CH ₂ -CH ₂ -O-,

-O-CH ₂ -CH ₂ -O-, -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 H, an alkyl group 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 by a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 4 carbon atoms, oxo or combinations thereof (e.g. methyl, ethyl, propyl, etc.) wherein at least one of R ³ and R ⁴ is other than hydrogen; and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a group of novel compounds of formulas II and III

(II) (III) wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. The compounds of this subgroup of formula I not only have PDE4 inhibitory activity, but are also useful as intermediates for the preparation of compounds of formula I wherein R ³ and R ⁴ are in each case other than hydrogen.

Next, subgroups great IV compound of formula I are compounds Γ ABOUT \ I on the l ' ^IV > R ' R you

wherein R ¹ , R ² and R ⁴ are as defined in formula I and one of groups A, B and D is N and the other are C. Preferably, B is N. Also, R ⁴ is preferably pyridyl or phenyl, which is in each optionally substituted or unsubstituted.

The present invention also encompasses compounds of formula

where

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

R ² 'is C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted one or more times with halogen, oxo, cyano, or combinations thereof, C 2 -C 12 alkenyl, C 2 -C 12 alkenyl 2 to 12 carbon atoms substituted one or more times with halogen atom, oxo group, cyano group or combinations thereof, 2 to 12 carbon atom alkynyl group, 2 to 12 carbon atom alkynyl group substituted one or more times with halogen atom, oxo group , cyano or combinations thereof, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted one or more times by halogen, oxo, alkyl or combinations thereof, cycloalkylalkyl of 4 to 12 carbon atoms, C 4 -C 12 cycloalkylalkyl substituted one or more times with halogen, oxo, alkyl or combinations thereof, partially unsaturated carbocyclic group up to carbon atoms, partially unsaturated carbocyclic group up to carbon atoms, substituted one or more times with halogen atom , alkyl combinations, alkoxy, nicro, cyano, oxo, or arylalkyl of 7 to 26 carbon atoms, arylalkyl of 7 to 26 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano , oxo, trifluoromethyl, or combinations thereof, a 5-10 ring heteroarylalkyl group wherein at least one ring atom is a heteroatom or a 5-10 ring substituted heteroarylalkyl group a ring, wherein at least one ring atom is a heceroatom and which is substituted one or more times in the hetercaryl moiety by a halogen atom, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl moiety with a halogen atom, oxo group, cyano group or combinations thereof;

X is O or S;

R ³ 'is C 6 -C 14 aryl, C 6 -C 14 aryl substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, up to 10 ring atoms wherein at least one ring atom is a heteroatom or a substituted heteroaryl group containing 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is substituted once or more multiple times with a halogen atom, an aryl group, an alkyl group, an alkoxy group, a cyano group, a trifluoromethyl group, a nitro group, an oxo group, an amino group 16, an alkylamino group, a dialkylamino group or combinations thereof;

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

R ⁴ 'is C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted one or more times with halogen, oxo, cyano, or combinations thereof, C 6 -C 14 aryl unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, alkyl, carboxy, alkyl, cyano, acyloxy, , phenoxy or combinations thereof, a heteroaryl group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, a substituted heteroaryl group having 5 to 10 ring atoms, wherein at least one at m in the ring is a heteroatom which is substituted one or more times with a halogen atom, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl of 7 to 16 carbon atoms, a group containing from 7 to 16 carbon atoms which is substituted one or more times by a halogen atom, an alkyl group, an alkoxy group, a nitro group, a cyano group, an oxo group, a trifluoromethyl group or combinations thereof, a heteroarylalkyl group of 5 to 10 ring atoms; of the ring is a heteroatom, a substituted heteroarylalkyl group containing 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom and which is substituted one or more times in the heteroaryl moiety by a halogen atom, an aryl group, an alkyl group, an alkoxy group u, 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 PDE4 activity in animals, for example mammals, especially humans. These compounds exhibit neurological activity, particularly where this activity acts on cognition, including long-term memory. These compounds will also be effective in the treatment of diseases in which cAMP levels are involved. An example is, but is not limited to, inflammatory disease. These compounds may also act as antidepressants or may be useful in the treatment of cognitive and negative symptoms of schizophrenia.

Assays for determining PDE4 inhibitory activity as well as selectivity of PDE4 inhibitory activity and selectivity of PDE4 isoenzyme inhibition are known in the art. See, for example, U.S. Pat. 6,136,821, incorporated herein by reference.

According to another aspect, the present invention provides compounds that are useful as intermediates for the production of the PDE4 inhibitors disclosed herein (e.g., PDE4 inhibitors of Formula I) and / or for the synthesis of radiolabeled analogues of PDE4 inhibitors using this use.

The present invention provides intermediate compounds which correspond to compounds of formula I wherein R, R ³ and R ⁴ are as previously defined for formula I, but is H, tert-butyldimethylsilyl- or a suitable phenol protecting group. Suitable phenol protecting groups are described, for example, in Greene, TW and Wuts, PGM, Protective Groups in

Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, p.

246-293. These intermediates are also useful for the preparation of radiolabeled compounds, such as where R ¹ is ³ H ³ C-, ¹⁴ CH ₃ - or CH ₃ -, for example by deprotection and reaction of the resulting compound wherein R ¹ is H with preferred radiolabeled reagents. Such radiolabeled compounds are useful for determining the tissue distribution of a compound in mammals, in PET imaging studies, and for in vivo, ex vivo and in vitro binding studies.

Also provided are intermediate compounds which correspond to compounds of formula I wherein R ¹ , R ³ and R ⁴ are as defined for formula I but R ² is H, tert -butyldimethylsilyloxy or a suitable protecting group of an enol group. Suitable phenol protecting groups are described, for example, in Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, p. 246-293. Compounds in which R ² is H are useful as intermediates, for example as backbones for parallel or combinatorial chemical applications. Further, these compounds are useful for introducing radiolabeling such as ³ H, ¹⁴ C or ^U C.

As described above, compounds of formula II wherein R ¹ , R ² and R ⁴ are as described above are useful intermediates for the preparation of compounds of formula I wherein R ¹ is other than hydrogen.

Also, as described above, compounds of formula III wherein R ¹ , R ² and R ³ are as previously described are useful intermediates for the preparation of compounds of formula I wherein R 1 'is other than hydrogen.

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

An alkyl group, as a group or substituent, or as part of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight or branched chain alkyl group containing 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 up to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. Other examples of suitable alkyl groups include 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, dimethyl and the like.

Substituted alkyl groups are alkyl groups as described above which are substituted at one or more positions by halogen, oxo, hydroxyl, C 1 -C 4 alkoxy and / or cyano. Preferred substituents are halogen atoms, especially F and Cl.

Alkoxy means alkyl-O- and alkoxyalkoxy means alkyl-O-alkyl-O-, wherein alkyl is as previously defined. 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 -O-CO-, wherein alkyl is as defined above. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

Cycloalkyl means a monocyclic, bicyclic or tricyclic non-aromatic saturated hydrocarbon group containing 20 cu 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbonyl, 1-decalin, adamant-1-yl and adamant-2-yl. Other suitable cycloalkyl groups include spiropentyl, oicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, spiro [2.4] heptyl, spiro- [2.5] octyl, bicyclo [5.1.0] octyl, spiro [2.6] nonyl, oicyclo [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 halogen atoms and / or alkyl groups.

Cycloalkylalkyl means a cycloalkylalkyl group wherein the cycloalkyl and alkyl moieties are as previously defined. Examples are cyclopropylmethyl and cyclopentylmethyl.

Aryl as a group or substituent, male or as part of a group or substituent, means an aromatic carbocyclic group containing 6 to 14 carbon atoms, winning 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the aforementioned aryl groups which are substituted one or more times with, for example, aromatic. halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, anuno, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, alkyl, phenoxy, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl;

Arylalkyl refers to an arylalkyl group in which the aryl and alkyl moieties are as previously defined. Preferred examples are benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and naphthylmethyl.

Heteroaryl refers to an aromatic heterocyclic group containing one or two rings and a total of 5 to 10 ring atoms, at least one ring atom being a heteroatom. Preferably the heteroaryl group contains 1 to 3, especially 1 or 2 ring heteroatoms selected from N, O or S. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, ditialyl, oxathialyl, isoxazolyl , oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, , benzoxazolyl, benzothiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, naphthyridinyl and benzoxazinyl, for example 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4- , 5-, 6-, 7- or 8-quinolinyl and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.

Substituted heteroaryl groups refer to heteroaryl groups described above that are substituted at one or more sites with a halogen atom, aryl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

Heterocycles include heteroaryl groups as described above and also non-aromatic cyclic groups containing at least one ring heteroatom, preferably selected from N, S and O atoms, for example tetrahydrofuranyl, piperidinyl and pyrrolidinyl.

Heterocyclylalkyl refers to heterocyclylalkyl groups wherein the heterocyclic and alkyl moieties are as previously defined. Preferred 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, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.

Alkenyl refers to a straight or branched chain alkenyl group having 2 to 12 carbon atoms in which one or more of the structures -CH ₂ -CH ₂ - is each replaced by -CH = CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methyletenyl, 1-butene, 2-butene, 1-pentenyl and 2-pentenyl.

An alkynyl group refers to a straight or branched chain alkynyl group containing 2 to 12 carbon atoms in which one or more of -CH 2 -CH 2 - is always replaced by -C nahradC-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl and 2-butynyl.

Acyl refers to alkanoyl groups having 1 to 13 carbon atoms, wherein the alkyl moiety may be substituted with a halogen atom, an alkyl group, an aryl group and / or an alkoxy group, or aroyl groups having 7 to 15 carbon atoms, wherein the aroyl moiety may be substituted with a halogen atom, an alkyl group and / or an alkoxy group. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.

Substituted groups preferably contain 1 to 3 substituents, in particular 1 or 2 substituents.

In the compounds of formula (I), R ¹ is a C 1 -C 4 alkyl group optionally substituted by a halogen atom, preferably a fluorine or chlorine atom. R ¹ is especially methyl or difluoromethyl.

R ² is preferably cycloalkyl, particularly cyclopentyl Kupina p.

R ² is also preferably an aryl or arylalkyl group, in particular a substituted or unsubstituted phenyl or phenylalkyl group such as phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenylethyl, phenylpropyl, phenylbutyl, phenyletenyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, chlorophenylethyl , chlorophenylpropyl, methoxyphenylpropyl, methoxyphenylbutyl, chlorophenylbutyl, nitrophenylbutyl, chlorophenylaminoethyl and the like.

^R2 is also preferably an unsaturated carbocyclic group which is unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl, and indan-2-yl.

^R2 is also preferably an alkyl group having 1 to 9 carbon atoms, especially 1 to 4 carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl, trifluoromethyl, and methoxyethyl.

R ² is also preferably a heterocyclic or heterocyclylalkyl group, especially a group wherein the heterocyclic group contains 5 to 6 ring atoms and 1 to 2 ring heteroatoms selected from N, O and S, for example tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl , piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like.

Preferably R ² comprises cyclopentyl, tetrahydrofuranyl, CHF 2, methoxyethyl, cyclopropylmethyl, phenylethyl, phenylpropyl, phenyletenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl and pyridylpropyl.

R ³ is preferably hydrogen, C 1 -C 4 alkyl (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, pyrimidinyl (methyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for the aryl and heteroaryl moieties of R ³ are F, Cl, CH ₃ , C 2 H 5,

OCH ₃ and CN.

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

Further, when R ⁴ is an aryl group, especially a phenyl group, 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 -SO 2 -NH-alkylene-O-, NH ₂ -alkyl-NH-CO-, R ⁵ -alkylene-NH-CO-, alkyl-CO-NH-alkyl-, also methyl, ethyl, Cl, F, CN, OCH ₃ , CF ₃ , amino, nitro, HOCH ₂ and COOH.

When R ⁴ is aryl substituted with R 1 -SO ₂ -NH-, preferably phenyl is substituted and R ⁵ is preferably methyl, ethyl, propyl or phenyl.

When ^R4 is aryl substituted by ^R: -SO2-NH-alkylene Ο-, preferably a substituted phenyl group. In such a case, R ^{5 is} preferably methyl, ethyl, propyl or phenyl and the alkylene group is preferably -CH 2 -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -.

When R ^{4 is} aryl substituted with R 1 -L-, preferably phenyl is substituted. In such cases, R ⁵ includes tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrolinyl, piperadinyl or methylpiperadinyl and L is preferably a single bond, -O-, -CO-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -ch ₂ -o-, -ch ₂ ch ₂ -o-, -CH ₂ CH ₂ CH ₂ -O-, -CH ₂ -NH-CH ₂ CH ₂ -O -, -CO-NH- or -NH-CO-.

Further preferred PDE4 inhibitors according to the invention are the compounds described by formulas Ia to Ih, which correspond to formula I but which contain the following preferred groups:

Ia R ¹ is methyl or CHF ₂ ;

R ² is an alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl or heterocyclic group, in each case substituted or unsubstituted;

R ³ is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted;

R ⁴ is aryl or heteroaryl, in each case substituted or unsubstituted.

Ib R ³ is a heteroarylalkyl group which is substituted or unsubstituted.

Ic R ¹ is methyl or CHF ₂ ; and

R ² 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 a heteroarylalkyl group, in each case substituted or unsubstituted; and

R ⁴ is a substituted or unsubstituted aryl or heteroaryl group.

Ie R ¹ is methyl;

R ² is cyclopentyl; and

R ³ is a heteroarylalkyl group which is substituted or unsubstituted.

If R ¹ is a methyl group;

R ² is cyclopentyl;

R ³ is a heteroaryl group which is substituted or unsubstituted; and

R ⁴ is a phenyl group which is substituted or unsubstituted.

Ig R ¹ is methyl;

R ^{2 e} j cyclopentyl;

R ^{3 e} j pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case substituted or unsubstituted or a methyl, ethyl or propyl; and

R ⁴ is phenyl or phenyl substituted with 1 to 3 substituents.

R ¹ is methyl;

R ² is cyclopentyl;

R ³ is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsubstituted or methyl, ethyl or propyl; and

R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl or isoquinolinyl, in each case substituted or unsubstituted.

In addition, preferred PDE4 inhibitors of the invention are those described by formulas (IIa) to (IId), which correspond to formula (II) but which contain the following preferred groups:

Ha and R ¹ is methyl or CHF ₂ ;

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

R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, which in each case is substituted or unsubstituted.

IIb, R ¹ is methyl or CHF _2;

R ^{2 e} j cyclopentyl, _CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (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 ethylsulfonamide or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.

R ¹¹ is a methyl group;

R ² is cyclopentyl; and

R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, which is in each case substituted or unsubstituted.

Ild R ¹ is methyl;

R ² is cyclopentyl; and

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

In addition, preferred PDE4 inhibitors of the invention are those described by formulas IIIa to IIId, which correspond to formula III but which contain the following preferred groups:

H ^1a R ¹ is methyl or CHF ₂ ;

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

R ³ is. benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isocninolinylmethyl, thiazolylmethyl or pyrrolylmethyl, which in each case is substituted or unsubstituted.

IIIb is R ¹ is methyl or CHF ₂ ;

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

R ³ is a pyrazinylmethyl group, a pyrimidinylmethyl group or a pyridylmethyl group which is in each case substituted or unsubstituted.

IIIc 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 in each case is substituted or unsubstituted.

R ¹¹ is a methyl group;

R ² is cyclopentyl; and

R ^J is pyrazinylmethyl or pyridylmethyl, which in each case unsubstituted or substituted.

Further, preferred PDE4 inhibitors of the invention are compounds described by formulas IVa-IVp, which all correspond to 29 of formula IV but which contain the following advantages:

IVa R ¹ is a methyl group or CHF ₂ ; IVb R ¹ is a methyl group or CHF ₂ , a B is a N. IVc R ¹ is a methyl group or CHF ₂ ;

R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl tetrahydrofuranyl (especially (3R) -tetrahydrc): IVd R ¹ is methyl or CHF 2;

B is N; and

^R2 is cyclopentyl, _CHF2, Cyclopropylmethyl pina, pyridyl-ethyl (notably 2-pyridylethylidene tetrahydrofuranyl (particularly (3R) -tetrahydrc:

IVe R ¹ is methyl or CHF ₂ ; and

R ⁴ is 3-pyridyl or phenyl, in each case substituted or unsubstituted

IVf R ¹ is methyl or CHF ₂ ;

B is N; and

R ⁴ is 3-pyridyl or phenyl, in each case substituted or unsubstituted IVg R ¹ is methyl or CHF ₂ ;

R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl tetrahydrofuranyl (especially (3R) -tetrahydrate); and

R ⁴ is 3-pyridyl or phenyl, in each case substituted or unsubstituted

IVh R ¹ is methyl or CHF ₂ ;

B is N;

days of skuka or uranium!).

sany or uranyl).

which is which is sku or uranyl) which is

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

R ⁴ is 3-pyridyl or phenyl, in each case substituted or unsubstituted

IVi

R ¹ is methyl or CHF ₂ ;

R ⁴ is a phenyl group which is substituted in

3- or

4-position.

IVj

R ¹ is methyl or CHF ₂ ;

R ⁴ is phenyl substituted in

3- or

4-position.

IVk

R ¹ is methyl or CHF ₂ ;

R ² is cyclopropylmercyclopentyl, CHF ₂ , pyridylethyl (especially 2-pyridinyl) or pina, tetrahydrofuranyl (especially (3R) -tetrahydranyl);

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

IVI R ¹ is methyl or CHF ₂ ;

B is N;

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

and

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

IV m R ¹ is methyl or CHF ₂ ;

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl,

3-ethylsulfonamidophenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyanophenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl.

IV n R ¹ is methyl or CHF ₂ ;

B is Na

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl, 3-ethylsulfonamidophenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 4-pyridyl, 4-COOH-phenyl 4-cyanophenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl.

R 10 R ¹ is methyl or CHF ₂ ;

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

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl, 3-ethylsulfonamidophenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 4-pyridyl, 4-COOH-phenyl 4-cyanophenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl.

IV p R ¹ is methyl or CHF ₂ ;

B is N;

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

R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl,

3-ethylsulfonamidophenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 3-nitrophenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyanophenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-yl-phenyl or

4-hydroxymethylphenyl.

Preferred aspects of the present invention include pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, and optionally another active agent, as set forth below; a method of inhibiting the PDE4 enzyme, in particular isoenzyme, for example, as determined by conventional restraints or as described herein, either in vitro or in vivo (in an animal, e.g., animal model, or in a mammal, e.g., human); a method of treating a neurological syndrome, such as memory loss, particularly long-term memory, cognitive impairment or impairment, memory impairment, etc .; a method of treating a disease state modulated by PDE4 activity in a mammal, for example a human, for example, those disclosed herein.

The compounds of the invention may be prepared in a conventional manner. Some of the procedures that can be used have been described below. All starting materials are known or can be prepared from known starting materials.

Scheme 1

13) R2Br. K ₂ CO 3 DMF 1b) R 2 OH. PPh ₃ . DIAO, THF 1c) TBDMSCI. DMF 1d) R-, B (OH) ₇ . Cu (OAc) _; . ^ NO.

4) Pd.dba ,. NaOtBu.

P (tBu) 3, R 4 -I

X

R 2

I I

R2 R4

The starting nitrophenols of type 1 are either commercially available (e.g. R ¹ = CH 3) or can be prepared according to published procedures (e.g. R ¹ = CHF 2 or both R ¹ and Pv = CHF 2 see Mueller, Klaus-Helmut, Eur. Pat. Appl. (1994), 8 pp. C0DEN: EPXXDW EP 626361A1, Touma, Toshihiko, Asai, Tomoyuki Jpn, Kokai Tokkyo Koho (1999), 6 pp. CODEN: JKXXAF JP 11071319 A2;

Plato, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Wind. Int. Symp. Wood. Pulping Chem., 1995, Th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs Steven; Karpinski, Josef M. International Patent Application (1996), 12 p. CODEN: PIXXD2 (WO 9623754 A1, 08.08.1996). The aniline intermediates 3 are obtained in two steps; the first addition reaction affords intermediate 2, followed by reduction of the nitro group. Intermediate nitro compounds 2 can be prepared by a number of published procedures, such as a Mitsunobu reaction or a standard alkylation reaction. Compounds where R ² is aryl or heteroaryl may be prepared by copper catalysed reactions with aryl or heteroaryl iodides under (Jman conditions or condensation of aryl, vinyl or heteroaryl boronic acids with phenol 2 in the presence of a copper catalyst (e.g. Cu (OAc) ₂ )) and bases such as TEA The Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using an azodicarboxylate (e.g. DEAD, DLAD) and a suitable phosphine (e.g. Ph ₃ P, Bu ₃ P) provides alkylated nitrophenols 2. Mitsunobu reactions are usually performed in a Alternatively, alkylation may be performed by reaction between an appropriately substituted nitrophenol and an alkyl halide, in the presence of a base (e.g. K ₂ CO ₃ or NaH) in a polar aprotic solvent (e.g. DMF or CH ₃ CN).

The nitrocatechols 2 are then reduced to the corresponding anilines 3 by standard methods known in the art, such as hydrogenation using a suitable catalyst (e.g. Pd on carbon), in a polar solvent (e.g. MeOH or EtOH) at atmospheric hydrogen pressure. Alternatively, nitrocatechols 3 can be reduced using a hydride source (e.g. NaBH ₄ ) and a transition metal catalyst (e.g. NiCl ₂ , Pd on carbon) or using metals (e.g. Zn, Sn, Fe) in a mineral acid solution (e.g. HCl) ) to form the corresponding anilines. In general, polar pro-solvents such as methanol or ethanol are used in these reactions.

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

The N-arylalkylanilines 4 are readily subjected to N-arylation by standard methods known in the art, including Ullman condensation, metal catalyzed condensation, or aromatic nucleophilic substitution reaction. For example, a metal catalyzed reaction between N-benzylaniline and an aryl halide using a palladium catalyst (e.g. Pd2dba3), an electron-rich zincine ligand (e.g. tributylphosphine), and a suitable base (e.g. NaOtBu) provides N-arylalkyldiphenylamines. Nickel and copper catalysts may also be used. Solvents used in this reaction include non-polar organic solvents such as toluene, benzene, xylenes, tetrahydrofuran and ether. When synthesizing compounds of type 5 wherein R ⁴ is alkoxycarbonylphenyl, it is preferred that the amine 4 is condensed with 1.1 equivalents of tert-butyl-3-iodobenzene and 22 mol% (tBu) 3P, 5.5 mol% Pd 2 is used. (dba) ₃ and 1.3 equivalents of tBuONa.

Scheme 2

Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7. For example, the ethyl ester (R ⁵ = Et) can be hydrolyzed using a mixture of an aqueous base (e.g. NaOH, KOH) and a water miscible solvent (e.g. EtOH , THF). If necessary, tert-butyl esters (R ⁵ = tert-butyl) can be hydrolyzed using aqueous acid (e.g. HCl, formic acid, TFA) in a water-miscible organic solvent.

Scheme 3

Condensation of protected tetrazol bromine or iodobenzenes (e.g. 5- (3-iodophenyl) -2- (2-tetrahydropyran) tetrazole with N-substituted aniline derivatives 4) affords THP-protected tetrazoles 8. Hydrolysis of THP-protected tetrazoles 8 can be accomplished using aqueous acids such as HCl in water and a water miscible solvent such as THF or EtOH to give tetrazoles 9. Furthermore, THP tetrazoles 8 can be oxidatively cleaved using reagents such as CAN and DDQ in halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and the like to give the tetrazoles 9.

Alternatively, tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with an azide ion (e.g. KN ₃ , NaN ₃ , etc.) and a proton source (e.g. NH ₄ Cl) in a polar aprotic solvent such as DMF. They can also be obtained by treatment with an azide ion and a Lewis acid (e.g. ZnBr?) In water, if necessary, using a water-miscible solvent such as isopropanol. Another method of preparation involves treating the nitrile with tin or silicone azide (e.g. Me ₃ SiN ₃ , Bu ₃ SnN ₃ ) in an aprotic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF and the like.

Scheme 4

3A) R4-3 (OH). Cu (OAc).

· L. N CH ₂ Cl ₂

8B) R4- | NaOtBu. Toluene (Pd / d), P (otcl) ₃

8C) R 4 -Sr, Pd (ofOoflCl 3, dDDĹNaOBu. · NH).

Ϊ

R 2

(9A) CN (TMS) ₂ . R3-I,

THF. 0 C

98) R 3 -Cl, NaH, DMF

R2 R * ¹ ·

Diphenylamines 10 can be prepared by condensation of suitably substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyaniline, with an arylboronic acid in the presence of a base such as triethylamine and a copper catalyst such as copper acetate (as described by Chan et al., Tetrahedron Lett. 39, 2933-2936 (1998)). In general, halogenated solvents such as dichloromethane, chloroform, dichloroethane and the like, as well as apolar aprotic solvents such as benzene, toluene or xylene may be used. Such diphenylamines (e.g., 10) can be advantageously synthesized by metal catalyzed amination reactions. For example, reacting an appropriately substituted aniline 3 with an aryl halide in the presence of a base (e.g. K ₃ PO ₄ , Cs ₂ CO ₃ or NaOtBu) and a palladium or nickel catalyst such as Pd (dppf) Cl ₂ , Uganda (e.g. dppf) and a base (e.g. NaOtBu) (JCAS. 1986, 118, 7217) or with Pd ₂ dba ₃ , an electron-rich fossil such as P (tBu) ₃ and a base (e.g. NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired Diphenylamines 10. The solvents most commonly used in this type of reaction include non-polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether and the like.

The diphenylamines 10 may then 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 its salts, in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide to give substituted diphenylamines 5. Solvents suitable for this reaction are aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF and the like, .

Scheme 5

The carbocyclic acids 7 can be further processed to form carboxamides using methods known in the art. For example, a carbocyclic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable condensing agent such as BOP, pyBOP or DCC, and a base such as Et ₃ N or DIEA to form the carboxamide. These reactions are usually carried out in a non-polar aprotic solvent such as dichloromethane, chloroform or dichloroethane.

The carbocyclic esters 6 or acids 7 can be reduced using methods known in the art to give the corresponding carboxaldehyde or hydroxymethyl analogs. For example aryletylester (e.g., structure 6, ^R = ethyl) can be treated with a suitable reducing agent (e.g., LAH, DIBAL, etc.) in an aprotic solvent, such as ether aleo THF to form the corresponding carboxaldehyde or hydroxymethyl analogs. Such aldehydes and alcohols may be further derivatized by methods known in the art.

Similarly, carboxamides (e.g., structure 11) and nitriles can be reduced using methods known in the art to give the corresponding amines or aminomethyl analogs. For example, arylcarboxamide 11 can be reduced with a suitable reducing agent (e.g. LAH) in an aprotic solvent (e.g. benzene, toluene, ether, THF, etc.) to give the corresponding aminomethyl analog. While reducing the aryl nitrile, the corresponding primary aminomethyl analog is obtained.

Scheme 6

Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by methods known in the art, such as hydrogenation using a suitable catalyst (e.g. Pd on carbon) in a polar protic solvent (e.g. EtOH, MeOH, etc.). Nitrobenzenes 12 can also be reduced using a hydride source (e.g. NaBH ₄ ) and a transition metal catalyst (e.g. NiCl ₂ , Pd on carbon) in polar aprotic solvents such as EtOH to give the corresponding anilines 13. These anilines can then be further substituted by methods known in the art. For example, type 13 anilines can be alkylated, acylated or sulfonated to give the corresponding N-alkylamines, carboxamides (e.g., structure 15) or sulfonamides (e.g., structure 14). For example, the sulfonamide can be prepared from aniline and a suitable sulfonyl halide or sulfonic anhydride (e.g. MeSO ₂ Cl, EtSO ₂ Cl, BnSO ₂ Cl, PhSO ₂ Cl, etc.) in the presence of a base (e.g. Et ₃ N, pyridine, DIEA, etc.). .). Suitable solvents for this reaction are non-polar aprotic solvents such as dichloromethane, chloroform and the like.

Scheme 7

18A) R 2 -Br, K, CO ₃ , DMF 18B) DIAD, PPh ₃ , Imd ..

R 2 -OH, THF

R2 R4

Type 16 trialkylsilyl ethers are prepared as described in Scheme 1. The tert-butyl dimethylsilyl-protected catechol intermediates 16 are readily deprotected by a number of methods described in the literature (see Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 3). Ed., John Wiley & Sons, 1999, pp. 273-276), either using a fluoride ion source (e.g., Bu ₄ NF) in an aprotic solvent such as ether or THF; or under acidic conditions (e.g., KF, 48% HBr, DMF). The resulting phenol 17, which is a very useful synthetic intermediate, can then be alkylated by methods known in the art and in a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1. For example, Mitsunobu reaction, reaction with an alkyl halide in the presence of a base or Ullman aryl by condensation or by reaction with vinyl, aryl or heteroarylboronic acids in the presence of a copper catalyst.

Scheme 8

The haloalkoxy intermediates 18, of the corresponding phenol, can be alkylated with fatty amines, alcohols or thiols by reaction with a base in the presence of a base to form analogs such as 19. For example, an alkyl halide can be aminated with a suitable primary or secondary amine and base such as K ₂ CO ₃ a polar aprotic solvent such as THF, DMF or CH ₃ CN.

Many of these synthetic procedures are described in more detail in the examples below.

It will be apparent to those skilled in the art that some of the compounds of formulas I and I 'may exist in different geometric isomeric forms. Furthermore, some of the compounds of the invention have one or more asymmetric carbon atoms and may exist in the form of optical isomers as well as in the form of their racemic and non-racemic mixtures and in the form of diastereomers and diastereomeric mixtures. All of these compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, and substantially pure and pure enantiomers are within the scope of the present invention. The substantially pure enantiomers contain no more than 5% w / w. the corresponding opposite enantiomers, more preferably not more than 2%, most preferably not more than 1%.

Optical isomers may be obtained by resolution of the racemic mixtures by conventional means, for example by formation of diastereomeric salts, using an optically active acid or base, or by formation of covalent diastereomers. Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid, and camphorsulfonic acid. Mixtures of diastereoisomers may be separated into their individual diastereomers based on their physical and / or chemical differences by methods known to those skilled in the art, for example by chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. Various procedures for separation of optical isomers include the use of chiral chromatography (e.g., chiral column HPLC) with or without conventional derivatization, optimally selected to achieve maximum separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, for example among many others Chiracel OD and Chiracel OJ, all of which are usually selectable. Enzymatic separations with or without derivatization are also useful. Optically active compounds of formulas I and I 'may likewise be obtained 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 of the compounds of the present invention.

Pharmaceutically acceptable salts include those obtained by reacting a base compound as a base with an inorganic or organic acid to form a salt, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those where the parent compound acts as an acid, and the acid reacts with a suitable base, a salt, a potassium salt, a calcium salt, to form, for example, a sodium magnesium salt, an ammonium salt, and a choline salt.

One skilled in the art will appreciate that acid addition salts derived from the claimed compounds can be prepared by reaction with the appropriate inorganic or organic acid by methods known in the art. Alternatively, alkali metal or alkaline earth metal salts can be prepared by reacting the compounds of the invention with a suitable base, using known methods.

Further examples of acid salts that may be obtained by reaction with an inorganic or organic acid include: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, gamphates, digluconates, cyclopentane propionates, dodecylsulfates, glucansulfonates, glucansulfonates, ethanesulfonates , hemisulphates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxyethanesulphonates, lactates, maleates, methanesulphonates, nicotinates, 2-naphthalenesulphonates, oxalates, palmoates, pectinates, persulphates, 3-phenylpropionates, picin, propionates, piccin, propionates, piccin, propionates, piccin , thiocyanates, oosylates, mesylates and undecanoates.

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

The compounds of the invention may be administered alone or as an active ingredient of the formulation. The present invention also encompasses pharmaceutical compositions of compounds of Formula I or Z 'comprising, for example, one or more pharmaceutically acceptable carriers.

A variety of standard references are available for preparing various formulations suitable for administration of the compounds of the invention. Examples of potential formulations and compositions are found, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablecs (Liebeman, Lachman and Schwartz, ed.) Current edition, published by Marcel Dekker, Inc., also Remington's Pharmaceutical Sciences (Arthur Osol, ed.), 1553-1593 (current edition).

Because of their high degree of PDE4 inhibition, the compounds of the invention can be administered to anyone who requires PDE4 inhibition and / or improved cognition. Administration may be by the patient's needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, irradiantly and by infusion), by inhalation, rectally, vaginally, copically, topically, transdermally, and ocularly.

Various solid oral dosage forms can be used to administer the compounds of the invention, including such forms as tablets, gelatin capsules, caplets, granules, lozenges and bulk powders. The compounds of the invention may be administered alone or co-administered with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including, but not limited to, suspending agents, solubilizers, buffers , binders, disintegrants, preservatives, colorants, aromatics, lubricants and the like. Also suitable for the administration of the compounds of the invention are capsules, tablets and time release gels.

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

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

For topical administration, pharmaceutical compositions in the form of creams, ointments, ointments, lotions, emulsions, susceptions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eye, ear or nose can be used. Topical forms of administration may also include transdermal administration using compositions such as transdermal patches.

Aerosol formulations suitable for administration by inhalation may also be prepared. For example, for the treatment of respiratory-tract diseases, the compounds of the invention may be administered by inhalation in the form of a powder (e.g. micronized) or in the form of atomized solutions or suspensions. Aerosol formulations may be placed in a compressed suitable propellant.

The compounds of the invention may be administered as the sole active ingredient or in combination with other pharmaceutical agents, such as other agents used in the treatment of cognitive impairment and / or the treatment of psychoses, e.g. other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, receptor modifiers adenosine, amphakin NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (such as donepezil, rivastigimine and glanthanamine). In such combinations, the active ingredient may be administered either within their usual dosage range or at a dosage lower than the usual dosage.

The present invention further encompasses methods of treatment that include inhibiting PDE4 enzymes. The present invention encompasses methods of selectively inhibiting PDE4 enzymes in animals, for example mammals, particularly humans, where such inhibition has a therapeutic effect, such inhibition can alleviate conditions related to neurological syndromes such as memory loss, especially long-term memory loss. Such methods include administering to an animal in need thereof, in particular to a mammal, particularly a human, an inhibitory amount of the compound, alone or as part of a formulation, as described in the torrent document.

A memory deterioration condition is manifested by a deterioration in the ability to receive new information and / or recall previously learned information. Memory impairment is the primary dementia syndrome and may also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Hunoington's disease, Pick's disease, Creutzfeld-Jakob's disease, HIV, cardiovascular disease and head injury, as well as age-related reduction cognitive ability.

Dementias are diseases that include memory loss and other intellectual impairment separate from memory. The present invention encompasses methods of treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementia (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g. heart attacks, haemorrhage, heart disease), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob disease multiple sclerosis, traumatic dementia (e.g., subdural hematoma or traumatic brain damage), infectious (e.g., HIV), genetic (Down's syndrome), toxic (e.g., caused by heavy metals, alcohol, certain drugs), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g. depression and schizophrenia) and hydrocephalus.

The present invention encompasses methods for dealing with memory loss that is separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive impairment. The present invention includes methods of treating memory impairment resulting from a disease. In another application, the present invention provides methods of memory loss resulting from the use of general anesthetics, chemotherapy, radiation therapy, post-surgical trauma and therapeutic interventions.

The compounds of the chiatric conditions of the invention can be used to treat dogs including schizophrenia, bipolar or manic-depressive psychosis, major depression and drug addiction and morphine dependence. These compounds may increase alertness.

PDE4 inhibitors can be used to increase cAMP levels and protect neurons from apoptosis. PDE4 is also known to have an anti-inflammatory effect. Combinations of anti-apoptotic and anti-inflammatory properties make these compounds useful for the treatment of neurodegenerations resulting from any disease or injury, including stroke, spinal injury, neurogenesis,

Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS) and multiple system atrophy (MSA).

According to a preferred embodiment, the present invention includes methods of treating patients suffering from memory disorders due to, for example, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob's disease, depression, aging, head injury, stroke, CNS hypoxia, cerebral senility, multi-infarct dementia; and other neurological conditions, including acute neuronal diseases, also HIV and cardiovascular diseases, comprising administering an effective amount of a compound of Formula I or I ', or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can also be used in methods of treating patients suffering from conditions characterized by reduced NMDA function, such as schizophrenia. The compounds of the invention may also be used to treat psychoses characterized by elevated levels of PDE4, for example, various forms of depression, such as manic-depressive psychosis, severe depression, and depression associated with psychiatric and neurological diseases.

As mentioned above, the compounds of the present invention also exhibit anti-inflammatory activity. As a result, the compounds of the invention are useful for the treatment of a number of allergic and inflammatory diseases, in particular those characterized by decreased levels of cyclic ΆΜΡ and / or increased levels of phosphodiesterase 4. Thus, according to another embodiment of the invention is provided a method for treating allergic and inflammatory conditions comprising administering an effective amount of a compound of Formula I or I 'or a pharmaceutically acceptable salt thereof. Such diseases include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid septum, myocardial and brain damage, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyrosis, chronic obstruction, diabetes mellitus, diabetes mellitus, diabetes and allergic contact eczema, atopic eczema, seborrheic eczema, simple eczema, sunburn, itching in the genital ti, baldness, hypertrophic scars, discoid lupus e: tosus, systemic lupus erythematosus, follicular na and regional pyoderma, endogenous and exogenous acne, acne Beghet's disease, anaphylactoid purpura nephritis, bowel disease, leukemia, multiple sclerosis, gastroir.t; diseases, autoimmune diseases, and the like.

PDE4 inhibitors for the treatment of asthma, chronic brcn; psoriasis, allergic rhinitis, and other inflammatory reactions of tumor necrosis factor are known in the art. See, for example, WO 98/58901, JP 11-18957, JP 11WO 93/25517, WO 94/14742, US 5 814 651 and US 5 935 9773 references also disclose assays for the determination of inhibitory PDE4 and methods for preparing such compounds.

Full descriptions of these documents are incorporated herein by reference;

PDE4 inhibitors can be used to prevent or treat osteoporosis, as an antibiotic, to treat cardiovascular disease by releasing cholesterol from atherosclerotic drugs, to treat rheumatoid arthritis (RA), for long-term inhibition. mesenchymal cell fermentation after transplantation, to treat national obstruction secondary to benign hyperplasia p: to suppress chemotaxis and to reduce invasion of cancer ^- some bowel, to treat chronic lymphocytic (B-CLL) cells, to inhibit uterine contractions, to alleviate national vascular ischemic reperfusion injury to corneal hydration, to inhibit IL-2R expression, and to promote the import of nuclear HIV-1 DNA into memory T cells, to increase glucose-induced insulin secretion, to p: and to treat colitis, and to inhibit mast cell degranulation:

The compounds of the invention may be administered as a single component, or in combination with other pharmaceutical agents, other agents used in the treatment of cognitive disorders for the treatment of psychoses, for example, with other PDE4 inhibitors, oblaszythemascarcorrhea, inflammatory estinal shitis, are known.

-072415,

These acts3. FROM .

decay of evil evils, at the prole: bu urir o s t o th, of buleukemia e pulmo: (IRI), by echo, to seizure.

active agents such as and / or block 49 calcium channel receptors, cholinergic drugs, adenosine receptor modulators, amphakin NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (such as donepezil, rivastigmine and glantanamine). In such combinations, the active ingredient may be administered either within their usual dosage range or at a dosage lower than the usual dosage.

The dosages of the compounds of the present invention depend on a number of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosing interval, the particular compound employed, the toxicological profile, the pharmacokinetic profile of the compound, and the presence of any adverse effects.

The compounds of the present invention are typically administered at the dosage levels that are common in a mammal for PDE4 inhibitors than the known compounds mentioned above. For example, the compounds may be administered in one or more doses by oral administration at a dosage level of, for example, 0.01-100 mg / kg / day, preferably 0.170 mg / kg / day, especially 0.5-10 mg / kg / day. Unit dosage forms may contain, for example, 0.1-50 mg of the active compound. For intravenous administration, the compounds may be administered in one or more doses at a dosage level of, for example, 0.001 - 50 mg / kg / day, preferably 0.001 - 10 mg / kg / day, especially 0.01 - 1 mg / kg / day. Unit dosage forms may contain, for example, 0.1-10 mg of the active compound.

In carrying out the processes of the present invention, however, it is to be understood that references to particular buffers, media, reagents, cells, culture conditions, and the like may not be limiting, but should be understood to include all related materials that are known to those skilled in the art and which are of interest or valuable in the particular context in which the discussion takes place. For example, it is often possible to replace one buffer or one culture medium and achieve similar or identical results. The skilled artisan will have sufficient knowledge of such systems and methodologies to carry out, without undue experimentation, such substitutes that are optimal.

The present invention is further described by the following examples, which in no way limit the scope of the invention.

In applying these examples, it will be appreciated that further embodiments of the methods disclosed by the present invention will undoubtedly be suggested by those skilled in the art.

In the foregoing and the following examples, all temperatures indicated are uncorrected in degrees Celsius and, unless otherwise indicated, all parts and percentages are by weight. The abbreviation bs for NMR means broad.

All disclosures of all applications, patents and publications cited above and hereinafter are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

Example 1A 1-Cyclopentyloxy-2-methoxy-5-nitrobenzene

To a suspension of 2-methoxy-5-nitrophenol (525 g, 3.104 mcl; and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 L) under N ₂ protection was added cyclopentyl bromide (499.2 mL, 4 mL). The suspension was heated at 100 ° C for 6 hours and then potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. C. over 4 hours TLC indicated complete reaction (9: 1 DCM: MeOH) 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 reextracted. The combined organic layers were washed with 1 N NaOH (2 L), water (2 L) and brine (2 L), and the organic layer was dried over sodium sulfate, filtered and evaporated. azeotroped with toluene (2 x 300 mL) to give 736.7 g (99.6%) of the product as a yellow solid.

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

(a) 1-cyclopropylmethoxy-2-methoxy-5-nitrobenzene,

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

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

Example 1B

2-Methoxy-5-nitro-l - ((3R) -tetrahydrofuryloxy) benzene

To a mixture of 2-methoxy-5-nitrophenol (1.69 g, 10 mmol), triphenylphosphine (5.24 g, 20 mmol) and 3- (R) -hydroxytetrahydrofuran (1.80 g, 20 mmol) in anhydrous tetrahydrofuran ( 40 mL) was added dropwise with stirring diisopropylazodicarboxylan (4.0 mL, 20 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL) and brine (50 mL), (MgSO ₄ ), and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product.

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

(a) 2-methoxy-5-nitro-1- (3-tetrahydrofuryloxy) benzene;

(b) 2-methoxy-5-nitro-1 - ((3S) -tetrahydrofuryloxy) benzene;

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

(d) 2-difluoromethoxy-5-nitro-1 - ((3R) -tetrahydrofuryloxy) benzene;

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

(f) 2-methoxy-5-nitro-1- (3-phenylpropyloxy) 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 DMF (40 mL) was added tert-butyldimethylsilyl chloride (2 mL) with stirring. 05 g, 13.6 mmol) and allowed to stir at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was dissolved in 40 mL of 50% eoylacetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexanes and the ficrates were combined and concentrated in vacuo to give 2.01 g of the product as a brownish crystalline solid. ¹ 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

Cyclopentyloxy-4-methoxyaniline

To a suspension of 10% Pd on activated carbon (25 g) in ethanol (4 L) was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250 g, 1.054 mol) under nitrogen protection. The reaction mixture was degassed three times in vacuo. The reaction mixture was stirred vigorously while hydrogen gas was passed through the reaction mixture. After 4 hours the reaction is complete as determined by TLC (5: 1 hexanes: EA). The reaction mixture was filtered through a pad of diatomaceous earth (Celite) and the celite was rinsed with additional ethanol. The solvent was removed in vacuo to give 208.38 g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. ¹ H NMR (CDCl 3) δ 6.85 (d, J = 8.4 Hz, 1H), 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 were prepared in a similar manner as 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-tetrahydrofuryloxy) aniline;

(h) 4-difluoromethoxy-3 - ((3R) -tetrahydrofuryloxy) aniline;

(i) 4-difluoromethoxy-3 - ((3S) -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 then cooled to 0 ° C and sodium boron hydride (37.64 g, 2.3 mol) was added portionwise over 4 hours. The reaction mixture was allowed to warm to room temperature with stirring over 16 hours. TLC indicated complete reaction (1: 3 hexanes: EA). The solvent was evaporated to give 0.5 L of a slurry. The slurry was diluted with water (1 L) and extracted with ethyl acetate (2x21). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to 300 g (100% yield) of the desired product as a viscous liquid. 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, J = 8.4Hz, 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 were prepared in a similar manner as described above:

a) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) aniline, b) 3-cyclopentyloxy-4-methoxy-N- (4-pyridylmethyl) aniline, c) 3-Cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxyethoxy- tench, d) 3-cyclopentyloxy-4-methoxy-N- (2-quinolinylmethyl) aniline, e) 3-cyclopentyloxy-4-Menox-N- (3-quinolinylmethyl) aniline, f) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) aniline, g) 3-cyclopentyloxy-4-methoxy-N- (2-pyrazinylmethyl) aniline, h) 4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy.anilín, i) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) aniline, j) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3S) -tetrahydrofuryloxy) aniline, k) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl); tench, D 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmetyl'anilín, m) 4-Difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydronaryloxy) - aniline, n) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3 R) -tetrahyorofuryl- oxy) aniline, about) 3,4-Bis (difluoromethoxy) -N- (3-pyridylmethyl) aniline, P) 3-t-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) aniline, q) 3-cyclopentyloxy-4-Merox-N- (2-pyridylmethyl) aniline, r) 3-cyclopentyloxy-4-methoxy-N- [1- (2-phenylethyl)] aniline, with) N-benzyl-3-cyclopentyloxy-4-methoxyaniline, t) N - [(cyclohex-l-en-l-yl) methyl] -3-cyclopentyloxy-4-methoxyanilino

lin,

(u) 3-cyclopentyloxy-4-methoxy-N- (3,4,5-trimethoxybenzyl) 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-N- (2-methylbenzyl) aniline;

y) 3-cyclopentyloxy-4-methoxy-N- (2-trifluoromethylbenzyl) aniline;

z) 3-cyclopentyloxy-4-methoxy-N - ((3,4-methylenedioxy) benzyl) aniline, aa) 3-cyclopentyloxy-N- (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, ee) 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-phenylpropyloxy) -N- (4-pyridylmethyl) 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-phenylpropyloxy) aniline, mm) 4-methoxy-3- (3-phenylpropyloxy) -N- (3-pyridylmethyl) aniline, nn) 3-cyclopentyloxy-4-methoxy-N- (2-thienylmethyl) aniline, oo) 3- (2-indanyloxy) -4-methoxy-N- (3-thienylmethyl) aniline, pp) 4-methoxy- 3- (3-phenylpropyloxy) -N- (3-thienylmethyl) aniline, qq) 3- (2-indanyloxy) -4-methoxy-N- (2-pyridylmethyl) aniline, rr) 3- (2-indanyloxy) - 4-methoxy-N- (3-pyridylmethyl) aniline, ss) 3- (2-indanyloxy) -4-methoxy-N- (4-pyridylmethyl) aniline, mp) 3-cyclopentyloxy-4-methoxy-N- (3 (piperidinomethyl) aniline, uu) 3-cyclopentyloxy-4-methoxy-N- (3- (1-tert-butyloxycarbonyl) piperidinomethyl) aniline, vv) 3-cyclopentyloxy-4-methoxy-N- (6-methyl-2- aniline, ww) N- (2-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline, xx) N- (2-chloro-5-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline, yy) 3-Cyclopentyloxy-4-methoxy-N- (2-1-thiazolylmethyl) aniline.

Example 4

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

To a 100 mL dry argon purged flask was charged 0.59 g (6.10 mmol) NaOtBu, 360 mg Pd ₂ dba ₃ , 20 mL toluene, 0.14 mL P (tBu) 3 and 20 mL solution 1 in the following order. 3 g (4.36 mmol) of N- (pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline in toluene. While stirring, 3.1 g (15 mmol) of iodobenzene are added dropwise and the mixture is stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with water and extracted with 3 x 15 mL 3N HCl. The combined acidic extracts were washed with 15 mL of EtOAc and then carefully neutralized to pH greater than 12 with 6N NaOH. The basic solution was extracted with 2 x 15 mL of EtOAc and the combined organic fractions were then washed with 15 mL of water and brine, dried (MgSO4). ₄ ) and concentrate. The residue was purified by silica gel chromatography (Biotage Flash 40M) eluting with 25% EtOAc in hexanes. The material was further purified by crystallization from hexanes to give 550 mg of a white solid.

^X 1 HNMR (CDCl ₃₎ δ 8.61 (s, 1H), 8.49 (d, 1 H, J = 4.2 Hz), 7.67 (d,

1H, J = 7.9Hz), 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, J = 4.1 Hz), 3.84 (s, 3H),

1.86-1.70 (m, 6H); 1.65-1.45 (m, 2H).

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

(a) 3-cyclopentyloxy-4-methoxy-2'-methyl-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'-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;

(h) 3-cyclopentyloxy-3 ', 4-dimethoxy-N- (3-pyridylmethyl) diflyylamine;

(i) 3-cyclopentyloxy-4,4'-dimethoxy-N- (3-pyridylmethyl) diphenylamine; (j) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'-trifluoromethyldiphenylamine;

(k) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4-trifluoromethyldiphenylamine;

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

(m) 3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine;

(n) 3-cyclopentyloxy-4-methoxy-3'-phenyl-N- (3-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;

(r) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate,

(s) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoate;

t) 3-cyclopentyloxy-4-methoxy-3'-nitro-N- (3-pyridylmethyl) diphenylamine;

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

(v) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -1-naphthylamine;

(w) 3-cyclopentyloxy-2 ', 3'-dimethyl-4-methoxy-N- (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-methoxy-N- (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-N- (3-pyridylmethyl) diphenylamine, dd) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl-) tulle) diphenylamine, ee) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl-) tulle) diphenylamine, ff) 4'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'-tri- fluórmetyldifenylamín. gg) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) diphenylamine, hh) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-thienylmethyl) -1-naphthylamine, ii) 3-cyclopentyloxy-2 ', 3'-dichloro-4-methoxy-N- (3-thienylmezyl) diphenylamine, jj) 3-cyclopentyloxy-4-methoxy-4'-methyl-N- (4-pyridylmethyl ₎ diphenylamine, kk) 3-Cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3'- -metyldifenylamín. 11) 2'-chloro-3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmeryl) -4- -metoxydifenylamín. mm) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-mesoxydiphenylamine, nn) 3-Cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) diphenyl- amine, oo) 3-cyclopentyloxy-4-methoxy-N- (3-quinolinylmethyl) diphenylamine, PP) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) diphenylamine, qq) 3-cyclopentyloxy-4-methoxy-N- (2-pyrazinylmethyl) diphenylamine, rr) 4-Methoxy-3'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryl- oxy) diphenylamine, ss) 4-Methoxy-4'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryl-

oxy) diphenylamine, mp) 4,4'-dimethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine, uu) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - (3-tetrahydrofuryloxy) diphenylamine, vv) 4-methoxy-4'- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine, ww) 3'-cyano -4-methoxy-N- (3-pyridylmethyl) - ((3R) -tetrahydrofuryloxy) diphenylamine, xx) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, yl) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine, zz) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine, aaa) 4-difluoromethoxy-N- (3 pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine, bbb) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine, ccc) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- ( (3R) -tetrahydrofuryloxy) diphenylamine, ddd) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, eee) 3'-chloro-4-difluoromethoxy -N- (3-pyridylmethyl) -3 - ((3R) -retrahydrofuryloxy) diphenylamine, ff f) ethyl N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate, ggg) 3-cyclopentyloxy-4-methoxy-3 '- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine, hhh) 3-cyclopentyloxy-4-methoxy-4 '- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine, iii) 3'-tert- butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, ij) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, (kk) tert-butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-oyridylmetyl) -3-aminobenzoate,

111) ethyl N- (3-cyclopentyloxy) -4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate, mmm) ethyl N- (4-difluoromethoxy-3- (3-tetranydrofuryloxy) phenyl) - N- (3-pyridylmethyl) -3-aminobenzoate, nnn) ethyl N- (3,4-bis (difluoromethoxy) phenyl) -N- (3-pyridylmeryl) -3aminobenzoate, ooo) ethyl N- (4-methoxy 3 - ((3R) -tetrahydrofuryloxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoate, ppp) ethyl N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3 (aminobenzoate, qqq) 3-cyclopentyloxy-4-methoxy-4'- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine, rr) 3-cyclopentyloxy -4-methoxy-3'- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine, sss) 4-methoxy-4'- (2- ( tetrahydropyran-2-yl) -2H-tetrazol-5-yl) N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofuryloxy) diphenylamine, mp) 3-cyclopropylmethoxy-4-methoxy-4'- (2 - (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine, uuu) 4-difluoromethoxy-4 '- (2-tetrahydropyran-2-yl) -2H-tetrazol-5 yl) -N- (3-pyridylmethyl l) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, vvv) 3-cyclopropylmethoxy-4-difluoromethoxy-4'- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- ( 3-cyclopentyloxy-4-difluoromethoxy-4'- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine, 3-pyridylmethyl) diphenylamine; xxx) 3-cyclopropylmethoxy-4-difluoromethoxy-3'- (2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylaminoyl) bis - ( 3,4-difluoromethoxy) -3'- (2- (tetrahydro-pyran-2-yl ⁾ -2H-tetrazol-5'-yl) -N- (3-pyridylmethyl) diphenylamine, zzz) 3-tert- butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmecyl) diphenylamine, aaaa) 3-tert-butyldimethylsilyloxy-3'-chloro-4-methoxy-N- (3-oyridylmethyl) diphenylamine, bbbb) ethyl-N- (3- tert-butyldimethylsilyloxy-4-methoxyphenyl; N - (3-pyridylmethyl) -3-aminobenzoate, cccc) 3-cyclopentyloxy-2'-chloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine, dddd) 3- (2-indanyloxy) -4-methoxy N- (3-pyridylmethyl) difenylsmín.

Example 5

N- (3-Cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-amznobenzoic acid

A solution of 6.5 g of ethyl N- (3-cyclopentyloxy-4-methoxyphenyl; -N- (3-pyridylmethyl) -3-aminobenzoate) in 50 ml of EtOH is treated with 10 ml of 6N NaOH and the mixture is allowed to stand for 6 hours. The mixture was extracted with 2 x 50 mL of ether, acidified with AcOH to pH 3 and extracted with 2 x 50 mL of EtOAc, the combined EcOAc fractions were washed with 25 mL of water and 25 mL of brine, dried ( _MgSO4) and concentrated. the residue was purified by chromatography over SiC (35 g, column RediSep ®) using a linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc for 20 Minucia) and dried in vacuo for 12 hours at 60 DEG C., 4.8 g of solid product. ¹ 1 HNMR (CDCl ₃₎ δ 11.15 (bs, 1H), 8.70 to 5.55 (m,

2Η), 7.77-6.71 (m, 9Η), 4.99 (s, 2Η), 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 were prepared in a similar manner as described above:

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

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

c) N- [4-difluoromethoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,

d) N-3,4-bis (difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,

(e) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid;

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

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

(h) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid;

(i) N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-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-aminobezoic acid;

m) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,

n) N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -364

-aminobenzoic acid,

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

Example 6

N- (3-cyclopenthyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoic acid tert-Butyl-N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2- The aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL of 98% formic acid and heated at 40 ° C for 4 hours. The 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 from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 minutes to give 16 mg of the product as a brown solid.

⁴ H NMR (CDCl _3)? ,) δ 8.47 (D, 1H, J = 4.9), 8.43 (s, 1 H), 8.10 (d, 1H, J = 7.8), 7.67 (D, 1H, J = 7, ( $ Hz ), 7.56 (m, 1H) .7, 40-7.20 (m, 3H), 6.75 (d, 1 H, J 8 / 7), 6.57 (D, 1 H, J = 8, 7), 6.47 (s, 1H), 4.72 (with, 2H), 4.54 ( pz 1H, J = 4.3 ) 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m , 2H ) ·

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

(a) 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-Cyclopropylmethyl-4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine

3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4'65

[2- (2-tetrahydropyranyl) -2H-tetrazol-5-yl] diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF (5 mL) and 3 mL of 1N HCl was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 50 mL). Combine the EtOAc extracts, wash with brine (50 mL), dry (MgSO ₄ ) and concentrate in vacuo. The crude residue was placed on a RediSep column (10 g, silica gel) and the product eluted using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc over 5 minutes to give 0.96 g of the product as a white powder. ¹ 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, J = 4.9Hz, 8.0Hz), 7.18 (d, 1H, J = 8.9Hz), 7.10-6.90 (m, 3H), 6, 37 (dd, 1H, J = 8.6Hz, 2.5Hz), 6.75 (t, 1H, J = 75.5Hz), 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m,

2H).

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

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

b) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 '-( 227-cetrazol-5-yl) diphenylamine;

c) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -4 ' -

- (2H) -tetrazol-5-yl) diphenylamine,

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

(e) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -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 '- (2'-tetrazol-5-)

yl) diphenylamine.

Example 8 (method A)

3- Cyclopentyloxy-4-methoxydiphenylamine

Method A. (Ref. Chan, D.M.T .; Monaco, K.L .; Wang, R.P .; Winters, M.P., Tetrahedron Lett., 1998, 39, 2933-2936). Mash 207 mg

4-methoxy-3-cyclopentyloxyaniline, 280 mg phenylboronic acid, 182 mg 4-methoxy-3-cyclopentyloxyaniline, 280 mg phenylboronic acid j, 182 mg Cu (0Ac) _{2 from} 280 μΐ Et ₃ N and 4.0 ml CH ₂ Cl ₂ is stirred for 20 hours at room temperature. The dark mixture was filtered through silica eluting with CH ₂ Cl ₂ , concentrated and purified by chromatography over SiO ₂ using EtOAc / hexanes (15/85) as eluent to give 75 mg of the desired product. 1 H NMR (CDCl ₃ ) δ 7.26-7.20 (m, 2H), 6.64-6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m 1H, 3.82 (s, 3H), 1.89-1.54 (m, 8H).

The following compounds were prepared in a similar manner as 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'-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-cyclopentyloxy-4-methoxydiphenylamine,

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

(m) 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-metoxydifenylamín

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 (o-tol) ₃ and 7 ml of toluene was combined and heated to 100 ° with stirring. C for 4 hours. The mixture was cooled to room temperature, diluted with 25 mL EtOAc and washed with 10 mL water, 10 mL brine, dried (MgSO ₄ ) and concentrated. The residue was purified by chromatography over SiO 2 using EtOAc / hexanes (5/95) as eluent to give 84 mg of the desired product.

The following compounds were 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)

3-Cyclopentyloxy-2 ', 4,5'-trimethoxydiphenylamine

Method C. To a mixture of Pd (dppf) Cl ₂ (0.025 mmol, 5 mol%), dppf (0.075 mmol, 3dppf / Pd) and NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 mL of THF was added 1-bromo-2,5-dimethoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a 0.5 M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated at 60 ° C for 3 hours and diluted with ether and washed with water and brine, dried (MgSO 4 and concentrated. The crude product was purified by silica gel chromatography (Biotage Flash 12), eluting with 15% EtOAc in hexanes.

The following compounds were 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) N- (3-cyclopentyloxy-4-methoxyphenyl) -1-naphthylamine;

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

(h) 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'-ethyl-4-methoxydiphenylamine;

(m) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxydiphenylamine,

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

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

p) N- (3-cyclopentyloxy-4-methoxyphenyl) -5-pyrimidinylamine,

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

(r) 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-cyclopropylmethyloxy-4-methoxyphenyl) -3-pyridylamine;

(v) N- (3-cyclopropylmethyloxy-4-difluoromethoxyphenyl) -3-pyridyl amine;

(w) N- (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -3-pyridylamine;

(x) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -3-pyridyl amine;

(y) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoar;

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-cyclopentyloxy-4-methoxyphenyl) -6-aminonicotinate, dd) 2'-amino-3-cyclopentyloxy-4- methoxydiphenylamine, ee) 3-cyclopentyloxy-4-methoxy-3 '- (1-phthalimido) diphenylamine, ff) 3-cyclopentyloxy-4-methoxy-3' - [2- (2-tetrahydropyranyl) -2H-tetrazole-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 THF at 0 ° C was added 0.55 mL 0.5 M KN (TMS) 2 in toluene. The solution was stirred at 0 ° C for 0.5 h and 2.0 equivalents of iodomethane were added and the mixture was warmed to room temperature. After completion of the reaction (indicated by TLC), 10 mL of EtOAc was added and the mixture was washed with 3 mL of water, 3 mL of brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by column chromatography (Biotage flash 12), using 5% EtOAc in hexanes as eluent.

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

(a) 3-cyclopentyloxy-N-ethyl-4-methoxydiphenylamine,

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

c) 3-cyclopentyloxy-4-methoxy-N- [1- (3-phenylpropyl)] diphenylamine;

(d) N-benzyl-3-cyclopentyloxy-4-methoxydiphenylamine,

(e) 3-cyclopentyloxy-4-methoxy-N- (4-pyridylmethyl) diphenylamine;

(f) 3-cyclopentyloxy-4-methoxy-N- (2-pyridylmethyl) diphenylamine;

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

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

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

j) N- (3- (cyclopentyloxy-4-methoxyphenyl) -N-benzyl-4-isoquinolinylamine),

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

(l) N- (3- (cyclopentyloxy-4-methoxyphenyl) -N-propyl-4-isoquinolinylamine);

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

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

- (3-pyridylmethyl) amino,

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-pyridylmethyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine),

(r) N- (3- (cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine),

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

t) tert-butyl N- (3- (cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinate),

u) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,

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

w) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N-

- (3-pyridylmethyl) amine,

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

y) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N-3-pyridyl) -N- (3-pyridylmethyl) amine,

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

Example 9 (method B)

N-4-chloro-3-pyridylmethyl-N- (3-cyclopentyl-4-methoxyphenyl) -N- (212

pyridyl) amine

A solution of (3-cyclopentyloxy-4-methoxyphenyl) -2-pyridylamine (30 mg, 0.10 mmol) and 4-chloro-picolyl chloride hydrochloride (50 mg, 0.25 mmol) was dissolved in DMF (1 mL) and added in small portions. sodium hydride (50 mg, 60% dispersion in mineral oil, 1.3 mmol). The mixture was stirred at room temperature for 1 hour and then poured into 25 ml of ice water. Extract the mixture with EtOAc (2 x 15 mL) and combine the EtOAc extracts, wash with brine (15 mL), dry (MgSO ₄ ) and concentrate in vacuo. The crude residue was transferred to a RediSep column (4.2 g, silica gel) and the product eluted with 15% EtOAc in hexanes to give 20 mg of the product as

yellow crystalline solid . NMR (CDC1 ₃ ) δ 8, 61 (s, 1 H, 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, J = 8.5); 6.75 (D, 1H, J = 8.5), 6.71 (s, 1 H), 6, 62 (m, 1 H), 6.42 (d, 1 H, J = 8, 6), 5.31 (with, 2H), 4.63 (P / 1H,

J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

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

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

b) 3,4-bis (difluoromethoxy) -N- (4-methyl-3-pyridylmethyl) -3'- (2-

- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) diphenylamine.

Example 10

3-cyclopentyloxy-4-methoxyaniline-N- (3-pyridylmethyl) -N-3- (4-pyridyl) benzamide

To a solution of N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid (20 mg, 0.05 mmol) and PyBOP (40 mg, 0.08 mmol) in CH ₂ C1 ₂ (2 mL) was added diisopropylethylamine (20 μΐ, 0.11 mmol) at room temperature. After stirring for 15 minutes, 4-aminopyridine (15 mg, 0.15 mmol) was added and the mixture was stirred for hours. The mixture was diluted with EtOAc (25 mL) and washed with water (2 x 15 mL) and brine (15 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was transferred to a RediSep column (4.2 g, silica gel) and the product eluted with a linear gradient of 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 minutes to afford

with 22 mg of the product . ^X H NMR (CDCl ₃ ) δ 8.70 -8.40 (M, 3H ), 8.24 (with, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30 to 7, 20 (m, 1H), 6.88 (d, 2H, J = 8); 5), 6.80-6.65 (m, 3H); 4.98 (s, 2H) ), 4.66 (P, 1 H, J = 4.1 Hz), 3, 86 (s, 3H), 1.86-1.70 (M, 6H), 1 65 to 1.45 (M,

2H).

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

(a) 3- (3-cyclopentyloxy-4-methoxyanilino) -N- (3-pyridylmethyl) -N-3- [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) -N- (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 that described in Example 2:

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

(b) 3'-amino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine;

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

4

d) 3'-amino-4-methoxy-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine.

Example 12

3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N- (3-pyricylmetyl) diphenylamine

To a solution of 4'-amino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine (47 mg, 0.12 mmol) in CH 2 Cl 2? (2 mL) was added at room temperature pyridine (20 microliters, 0.24 mmol then methanesulfonyl chloride (15 microliters, 0.18 mmol) and allowed to stand at room temperature for 16 hours. The mixture was diluted with ether (50 mL). and washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated.The crude residue was transferred to a RediSep column (4.2 g, silica gel) and the product eluted with a linear gradient of 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 minutes to give 41 ^{mg.; H-NMR} (CDCl) δ 3.51 (s,

IH), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 16.1 m, 1H), 6, 98 (d, 2H, J = 9.0 Hz), 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, 2 H). The following compounds were prepared in a similar way as is a

described earlier:

(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'-benzylsulphonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine;

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

f) 3-cyclopentyl yloxy-4'-et. Lansulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,

(g) 3-cyclopentyloxy-4-methoxy-4 '- (1-propanesulfonylamino) -X- (3-

pyridylmethyl) diphenylamine,

(h) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine;

i) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3-

- [(3 R) -tetrahydrofuryloxy] diphenylamine.

Example 13

3-Cyclopentyloxy-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 THF (5 mL) was added at 0 ° C and with stirring, 2.5 M diisobutylaluminum hydride in toluene (0.4 mL, 1.00 mmol). The mixture was stirred at 0 ° C for 1 hour and excess diisobutylaluminium hydride was quenched by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between CH ₂ Cl ₂ (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 10 mL). Combine the organic extracts and wash with brine (50 mL), dry (MgSO ₄ ) and concentrate. The residue was separated by flash chromatography (RediSep column, 4.2 g silica gel) eluting with 300 mL of 50% EtOAc in hexanes

followed by 100% EtOAc to give 15 mg product. ¹ H NMR (COC1 ₃ ) δ 8.51 (s, 1H), 8.40 (br, 1H); 7.58 (d, 1H, 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 as described above:

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

Example 14

3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-( 2H-tetrazole-5)

-yl) diphenylamino-3-aminobenzonitrile (100 mg, 0.25 mmol) in DMF (3

2.5 mmol) and NH ₄ Cl (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

Combine the EtOAc extracts, wash with water and brine (25 mL), dry (MgSO ₄ ) and concentrate in vacuo.

into the column

The remainder is transferred

sa s linear gradient from 50% to 75% EtOAc in he xánoch with obtained sa 12 mg of product. ¹ H NMR (CDC1 ₃₎ δ 12.50 (Br, 1H ) 8, 64 with, 1H), 8.54 (br, 1H); 7.86 (d, 2H, J = 8.8 Hz), 7.75 ( d. 1H, '8 Hz), 7,36 (m, 1H), 6.80-6.60 (m, 5H) 4, 99 (with, 2H) 1, 4.66 ^: P, 'w - - - f J = 4.1 Hz), 3.84 (s, 3H) , 86-1,70 ( m, 7 H) 1, 1, 65- 1 4 5 (m, 2H ).

Example 15

3-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 THF (5 mL) was added cautiously with stirring 11-aluminum aluminum hydride (50 mg, 1, 3 mmol). The mixture was stirred for 15 minutes and a few drops of EtOAc were added to quench excess hydride. Water (50 mL) and CH ₂ Cl ₂ (50 mL) were added and the mixture was filtered through Celite. The CH ₂ Cl ₂ layer was separated, washed with brine (25 mL), dried (MgSO ₄ ), and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g silica gel), eluting with a gradient of 5% MeOH in EcOAc to 15% MeOH in EtOAc to give 60 mg of the product as a yellow oil. ¹ HNMR (CDCl ₃ ) δ 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 ( dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3H), 6.70- 6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz), 3.82 (s, 3H), 3.41 (s, 2H) 1.75-2.20 (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 as described above:

a) 3-cyclopentyloxy-4-methoxy-3 '- (4-methyl-1-piperazinylmethyl) -N- (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- (3-pyridylmethyl) -3-aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was added cautiously with stirring lithium aluminum hydride (20 mg). , 0.52 mmol). The mixture was stirred for 4 hours and a few drops of water were carefully added to quench the excess hydride. Water (50 mL) and CH 2 Cl 2 (50 mL) were added and the mixture was filtered through Celite. The CH ₂ Cl ₂ layer was separated, washed with brine (25 mL), dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified on an ISCO RediSep column (4.2 g, silica gel), eluting with 10% MeOH in EtOAc to give 20 mg of the product. ^T H NMR (CDCl3) 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, 6E), 4.94 (s, 2H), 4.63 (p, 1H, J = 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-butyldimethylsilyloxy) -N- (3-pyridylmethyl) -4-methoxydiphenylamine (1.20 g, 2.85 mmol) in THF (40 mL) was added 1.0 M tetrabutylammonium fluoride in THF (40 mL) at 0 ° C. THF (10 mL, 10 mmol). 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 (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with hexanes and collected by vacuum filtration to yield

0.85 g of product. ¹ H NMR (CHCl 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, 5F),

6.64 (dd, 1H, J = 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 as described above:

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

(b) ethyl N- (3-hydroxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate,

Example 18 (method B)

The following compounds were prepared in a similar manner to that described in Example IB:

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

(b) 3- [2- (4-chlorophenyl) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine;

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

(d) 4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine;

(e) 4-methoxy-3- [3- (4-methoxyphenyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine;

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

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

(h) 4-methoxy-3- (4-phenylbut-1-yl) oxy-N- (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;

(l) 4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine;

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

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

o) 3-cyclopropylmethoxy-4-methoxy-N- (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-N- (3-pyridylmethyl) diphenylamine;

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

(s) 4-methoxy-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine;

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

u) 3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) -80-diphenylamine,

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

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

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

y) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,

z) 3- (2-cyclopropylethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine, aa) 3-cyclopentylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, bb) ethyl N- [3] - (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoate, cc) ethyl N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3- dri) ethyl N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate, ee) ethyl N- [3- (2-indanyloxy) - 4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoate, ff) ethyl N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3 (gg) ethyl N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoate, hh) ethyl N- [3- (2- methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoate; ii) ethyl N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3) -pyridylmethyl) -3-aminobenzoate.

Example 18 (method C)

The following compounds were prepared in a manner similar to that described in Example 8A by condensation of phenol with boronic acid rather than condensation of aniline with boronic acid:

(a) 4-methoxy-3- (4-methoxyphenoxy) -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;

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

Example 19

The following compounds were prepared in a similar manner to that 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-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine.

Example 20 (method A)

The following compound was prepared in a similar manner to that described in Example IA:

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

Example 20 (method B)

The following compounds were prepared in a similar manner to that described in Example 1B.

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

(b) 3-cyclopentyioxy-4'- (3-methyl-1-butoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine;

(c) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 &apos; - [(3S) -tetrahydrofuranyloxy] diphenylamine;

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

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

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

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

h) 3-cyclopentyloxy-4-methoxy-4 '- (1-methylpiperidin-4-yloxy) -N-

- (3-pyridylmethyl) diphenylamine,

i) 3-cyclopentyloxy-4-methoxy-4 '- (1-methylpyrrolidin-3-yloxy) -N-

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

k) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-pyrrolidinylethoxy) -N- (3-pyridylmethyl) diphenylamine,

l) 3-cyclopentyloxy-4-methoxy-4 '- [2- (6-methylpyridyl) methoxy] -N-

- (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-pyrazinylmethyl) diphenylamine,

q) 3-cyclopentyloxy-4-methoxy-4'- [2- (N-phthalimido) ethoxy] -N- (3-pyridylmethyl) diphenylamine,

Example 21

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

To a solution of 3 '- (2-bromomethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine (17 mg, 0.03 mmol) in acetonitrile (1 mL) was added potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 μΐ, 0.05 mmol) and the mixture was stirred at 60 ° C for 4 hours. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was transferred to an ISCO RediSep column (4.2 g, silica gel) and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg of the product. ¹ H NMR (CDCl 3) δ 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7 20 (m, 1H), 7.06 (t, 1H, J = 8.6Hz), 6.81 (d, 1H, J = 9.2Hz), 6.75-6.68 (m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H,

J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H,

J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70 (m, 6H), 1.86-1.70 (m, 6H),

1.65-1.45 (m, 2 H).

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

(a) 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-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine;

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

e) 3-cyclopentyloxy-4-methoxy-4 '- [3- (2-morpholin-4-ylethylamino) -propoxy] -N- (3-pyridylmethyl) diphenylamine,

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

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

(h) 4-methoxy-3- (2-pyrrolidin-1-yl) ethoxy-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) diphenylamine.

Example 22

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

To a solution of N- (3-pyridylmethyl) -3 '- [2- (2-phthalimido) -oxy] -3-cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol in MeOH (5 mL)) is added hydrazine hydrate (1.0 mL, 20 mmol) After 6 hours at room temperature, EtOAc (50 mL) was added and the precipitate was filtered off, and the filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ). The residue was transferred to an ISCO RediSep column (10 g, silica gel), washed with 10% MeOH in EtOAc (200 mL) and the product eluted with 50% MeOH in EtOAc.

to give 0.21 g of product. ^X H NMR (CDC1 ₃₎ δ 8.55 (s, 1H); 8.42 (d, 1H, J = 3.8Hz), 7.62 (D, 1H, 7.7 Hz), 7.20-7.10 (m, 1 H), 6.91 (d, 2H, J = 9.0 Hz); 78 (D, 2H, J = 9.0 Hz), 6.70 (d, 1 H,

J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, 1H,

J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H),

1.86-1.70 (m, 8H); 1.65-1.45 (m, 2H).

Example 23

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

a) 3-Cyclopentyloxy-4'- (2-methanesulfonylamino) ethoxy-4-methoxy-N-

- (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] -N- (3-pyridylmethyl) diphenylamine,

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

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

Example 24

In vitro measurement of phosphodiesterase type 4 inhibitory activity

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

Test

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. Thus, the combined activity of PDE4 and nucleo86 tidase converts cAMP to adenosine. Adenosine is readily separated from cAMP on neutral aluminum columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine.

Cell lysates (40 μΐ) expressing hPDE-4D6 were combined with 50 μΐ of the assay mixture and with 10 μΐ inhibitors and incubated for 12 minutes at room temperature. The final concentrations of the test components are: 0.4 μς enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl ₂ , 3 μΜ cAMP, 0.002 5'-nucleotidase units and 3 x 10 ⁴ cpm [3 H] cAMP. The reaction was stopped by adding 100 µL of boiling 5 mM HCl. An aliquot of 75 μΐ reaction mixture from each well was transferred to an aluminum column (Multiplate; Millipore). Labeled adenosine was eluted into OptiPlate by centrifugation at 2000 rpm for two minutes. 150 μΐ per well of scintillation fluid was added to OptiPlate. The plate was sealed, shaken for about 30 minutes and the cpm of [ ³ H] adenosine was determined using Wallac Triflux®.

All test compounds were dissolved in 100% DMSO and diluted to a final DMSO concentration of 0.1%. DMSO does not affect enzyme activity at this concentration.

A decrease in adenosine concentration indicates inhibition of PDE activity. PIC ₅₀ values were determined by monitoring 6 to 12 concentrations of the compound in the range of 0.1 nM to 10,000 nM and then plotting drug concentrations versus ³ H-adenosine concentrations. Non-linear regression software (Assay Explorer®) was used to determine pIC ₅₀ values.

Example 25 (Method A)

Passive avoidance test in rats, in vivo test for learning and memory

The assay is performed as described (Zhang, H.T., Crissman,

A.M., Dorairaj, N.R., Chandler, L.J. and O'Donnell, J.M. Neuropsychopharmacology, 2000, 23, 198-204). The device (Model E10-16SC, Coulbourn Instruments, Allentown, PA) consists of a chamber and two compartments, the illuminated compartment being connected to the dark compartment by a guillotine door. The dark compartment floor consists of stainless steel bars which could be supplied with an electric shock from a constant power source. All experimental groups were first placed on the device the day before the experiment began to get used to the environment. During training, rats (male Sprague-Dawley (Harlan) weighing 250-350 g) were placed in an illuminated puffed compartment from a closed guillotine door for 1 minute before the door was raised. The latency time to enter the dark compartment was recorded. After the rats crawled into the dark compartment, the door was closed and received an electrical shock with 0.5 mA for 3 seconds. After 24 hours, rats were administered 0.1 mg / kg MK-801 or saline. After 30 minutes, the rats received saline or test compound (0.1-2.5 mg / kg, i.p.) and after a further 30 minutes the test was started. The rats were again placed in an illuminated compartment with an open guillotine door. The latency time to enter the dark compartment was recorded for 180 seconds when analysis was complete.

All data were analyzed by analysis of variance (ANOVA ;; individual comparisons were performed using Kewman-Keuls tests. Naive rats needed less than 30 seconds on average to switch from illuminated to dark compartment. However, 24 hours after exposure to electric shock most vehicle-treated rats did not enter the dark compartment, mean latency increased to 175 seconds (p <0.001), and with pretreatment MK-801 (0.1 mg / kg), this latency against vehicle decreased significantly (p <0.001). the effect of MK-801 is reversed in a statistically significant manner by the current test compounds in a dose-dependent manner (e.g. 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, the effective dose range being 0.5 to 2.5 mg / kg , ip, and N- (3-cyclopentyloxy-1-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, effective dose range 0.1-2.5 mg / kg, ip).

Example 25 (method B)

Maze test with radially placed arms with paws, in vivo test for learning and memory

The assay was performed as described previously (Zhang, H.T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M. Neuropsychopharmacology, 2000, 23, 198-204). Five days after immediate placement, rats (male Sprague-Dawley Harlan) weighing 250-350 g) are transferred to an eight-arm radial maze (each arm is 60x10x12 cm high; maze; e 70 cm above the floor) to acclimate for two days. The rats were then placed individually at the center of the maze for 5 minutes with food placed near the food wells and then the following day in the wells at the end of the maze arms. Two attempts were made per day. In the next step, feed was placed in only four randomly selected branches of the maze. The rat gets stuck! to the center of the maze (26 cm in diameter) for 15 seconds and afterwards he was allowed to move until he had found all the food or 10 minutes had passed (which was done earlier). 4 parameters were recorded: 1) errors in the working memory, ie entry into branches that were previously visited; 2) errors in the reference memory, i.e. entry into the arms where there was no food; 3) total number of inputs; and 4) the duration of the test (sec.), that is, the time spent in the maze to eat all the baits in the maze. If the working memory error was zero and the mean reference memory error was less than one in five consecutive analyzes, then a drug test was started in rats. MK-801 or saline was injected, after 15 minutes vehicle or test compound was administered, and after 45 minutes the test began. The experiments were carried out in an illuminated room containing several pointers located outside the maze.

All data were analyzed by analysis of variance (ANOVA); individual comparisons were performed using Kewman-Keuls tests. Compared to the control, administration of MK-801 (0.1 mg / kg, i.p.) resulted in an increase in error rates in both working and reference memory (p <0.01). This amnestic effect of MK-801 is reversed in a statistically significant manner by the administration of the test compounds in a dose-dependent manner (e.g. 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, the effective dose range being 2.5 mg / kg, ip; p <0.01).

The foregoing examples may be repeated with similar success by substituting generically or specifically described substances or conditions of the invention.

Claims (55)

R ¹ is a straight or branched chain alkyl group and mono- or polysubstituted by up to 4 carbon atoms with non-branching is unsubstituted by a halogen atom; R ² is a C 1 -C 12 alkyl group, straight or branched chain, unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C 1 -C 4 alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH ₂ CH ₂ - is in each case replaced by -CH = CH- or -C = C-, a cycloalkyl group containing 3 to 10 carbon atoms which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or combinations thereof, (C 4 -C 16) cycloalkylalkyl which is unsubstituted or substituted one or more times in the cycloalkyl moiety and / or the alkyl moiety , oxo, cyano, hydro amino, sulfhydryl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, _{CF3, OCF3,} alkyl , hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or combinations thereof, arylalkyl wherein the aryl moiety contains from 6 to 14 carbon atoms and the alkyl moiety that is branched or unbranched contains 1 to 5 carbon atoms, wherein the arylalkyl is unsubstituted or unsubstituted substituted in the aryl portion one or more times by halogen, _{CF3, OCF3,} alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups is optionally replaced by -CH = CH- or -C = C-, and one or more -CH ₂ - is replaced by -0- or -NH- and / or the alkyl moiety is optionally substituted by halo, oxo, hydroxy, cyano or combinations thereof , partially unsaturated carbocyclic group containing 5 to 14 carbon atoms which is unsubstituted or sub-substituted one or more times by halogen atom, alkyl, alkoxy, hydroxy, nitro, cyano, oxo or combinations thereof, heterocyclic group which is saturated or partially saturated unsaturated containing 5 to 10 ring atoms, wherein at least one 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, heterocyclylalkyl wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, the heterocyclylalkyl group being unsubstituted or substituted in the heterocyclic moiety one or more times by a halogen atom, 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 - is optionally replaced by -CH = CH- or -C-c and one or more -CH ₂ - is replaced by -O- or the -NH- and / or the alkyl moiety is optionally substituted by a halogen atom, an oxo group, a hydroxy group, or combinations thereof; R ³ is H, an alkyl group containing 1 to 8, preferably 1 to 4, carbon atoms which is branched or unbranched and which is unsubstituted or substituted one or more times by a halogen atom, a cyano group, an alkoxy group containing 1 to 4 carbon atoms or a combination thereof, partially unsaturated carbocyclylalkyl, wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms and which is unsubstituted or substituted in the carbocyclic moiety one or more times by halogen, alkyl, alkoxy, nitro , cyano, oxo, or combinations thereof, and wherein the alkyl moiety is optionally substituted with a halogen atom, a (1-4C) alkoxy, a cyano, or combinations thereof, an arylalkyl group containing 7 to 19 carbon atoms, wherein the aryl moiety contains 6 to 14 atoms and wherein the branched or unbranched alkyl moiety contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by halogen atom, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy , alkylamino, dialkylamino and / or substituted in the alkyl part by halogen, cyano or methyl, or heteroarylalkyl, wherein the heteroaryl part may be partially or fully saturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, wherein the alkyl moiety which is branched or unbranched, wherein the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl moiety by a halogen atom, an alkyl group, an alkoxy group, a cyano group, a trifluoromethyl group, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, and / or substituted in the alkyl portion by halogen, cyano, methyl, or combinations thereof; R ⁴ is H, a (C 6 -C 14) aryl group which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, , amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2- (heterocyclyl) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, alkyl, acy, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g., tert-butyldimethylsilyloxy), R ⁵ -L-, or combinations thereof, a 5-10 ring heteroaryl group wherein at least one ring atom is a heteroatom which is is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, aminoalkoxy, 5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilylcxy or combinations thereof; R ⁵ is H, an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an oxo group or combinations thereof, alkylamino or a dialkylamino group wherein each alkyl moiety independently has 1 to 8 carbon atoms, a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms and which is unsubstituted or substituted, preferably in the carbocyclic moiety once or several times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof, the cycloalkyl group containing r is unsubstituted or substituted by a halogen atom, hydroxy group, alkyl group 3 to 10 carbon atoms in which an oxo group or more than an alkoxy group, a group or a combination thereof, a cyano group, up to 4 carbon atoms containing 4 to 4 carbon atoms, which is unsubstituted or substituted by parts and / or alkyl moieties one or more times of halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl of 6 to 14 carbon atoms and which is unsubstituted or substituted one or more by halogen, alkyl, hydroxy , alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxy, n-hydroxy, carboxylic acid, hydroxy, an alkoxycarbonyl group with an acyl group, an alkylthio group, an alkyl sulfinyl group, an alkylsulfonyl group, or a combination thereof, an arylalkyl group containing 7 to 19 carbon atoms, wherein the aryl moiety contains 6 to 14 carbon atoms, and wherein the branched or unbranched alkyl moiety contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by halogen atom, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl part by halogen, cyano or methyl, a heterocyclic group which is saturated, partially saturated or unsaturated, containing 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ecylenedioxy, trifluoromethyl, amino, aminomethyl, dialkylalkyl, aminoalkyloxy, amino, hydroxyalkyl, hydroxy group, hydroxyl group, group, acid, tetrazol-5-yl, hydroxyalkoxycarboxy, alkoxycarbonyl, cyano acyl, alkylthio, alkylsulfinyl alkylsulfonyl, phenoxy, or combinations thereof, or heterocyclic, the heterocyclic moiety is saturated, partially saturated or unsaturated and contains 5 to 10 ring atoms wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, the heterocyclylalkyl group is unsubstituted or substituted in the heterocyclic moiety one or more times by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, dialkylamino or combinations thereof, and / or the alkyl moiety is substituted with h allogene, cyano or methyl or combinations thereof; L is a single bond or a divalent aliphatic group containing 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups are optionally replaced by -C-, -S-, -NR 0 -, -SO ₂ NH-, -NHSO ₂ - , -C0-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH or -NHCSNH-; and R ⁶ is H, a C 1 -C 8 alkyl group which is branched or unbranched and which is unsubstituted or substituted one or more times by a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, an oxo group or combinations thereof, wherein at least one of R ³ and R ⁴ is other than hydrogen; and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ⁴ is other than hydrogen. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; R ² is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; R ³ is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R ⁴ is an aryl or heteroaryl group, in each case substituted or unsubstituted. The compound of claim 1, wherein R ³ is a heteroarylalkyl group which is substituted or unsubstituted. A compound according to claim 1, wherein R ¹ is methyl or CHF 2; and R ² is cyclopentyl, CHF 2, cyclopropylmethyl, pyridylethyl or (3R) -tetrahydrofuranyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; R ⁴ is a cyclopentyl group; R ³ is a heteroarylalkyl group, in each case substituted or unsubstituted; and R ⁴ is a substituted or unsubstituted aryl or heteroaryl group. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is an arylalkyl group or a heteroarylalkyl group which is in each case substituted or unsubstituted; and R ⁴ is a substituted or unsubstituted aryl group. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; and R ³ is a heteroarylalkyl group which is substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is a heteroarylalkyl group which is substituted or unsubstituted; and R ⁴ is a phenyl group which is substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which is in each case substituted or unsubstituted or methyl, ethyl or propyl; and R ⁴ is phenyl or phenyl substituted with 1 to 3 sub-substituents. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is pyridylmethyl, pyrimidinylmethyl, phenylethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, in each case substituted or unsubstituted or methyl, ethyl or propyl; and R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl or isoquinolinyl in each case substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl or CHF 2; ^R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R ³ is H; and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, in each case substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl or CHF 2; ^R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R ³ is H; and R ⁴ is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamide or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is H; and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, in each case substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is H; and R ⁴ is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymecyl or ethylsulfonamide or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. The compound of claim 1, wherein R ¹ is methyl, or CHF 2; ^R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R ³ is benzyl, phenethyl, cyclohexenyl100 methyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl or pyrrolylmethyl, in each case substituted or unsubstituted; and R ⁴ is H. 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 a pyrazinylmethyl group, a pyrimidinylmethyl group or a pyridylmethyl group which is in each case substituted or unsubstituted; and R ⁴ is H. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl, or a substituted or unsubstituted or substituted methyl group; and R ⁴ is H. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is a pyrazinylmethyl group or a pyridylmethyl group which is in each case unsubstituted or substituted; and R ⁴ is H. A compound according to claim 1, wherein said compound has the general formula IV ABOUT I R (IV) Wherein R ¹ and R ² are as defined above, at least one of A, B and D is N and the others are CH and R ¹¹ is a pyridyl or phenyl group which is in each case substituted or unsubstituted, and pharmaceutically acceptable salts thereof . 21st compound according to of claim 20, wherein R ¹ is a methyl group or chf ₂ • 22nd compound by of claim 21, wherein B is a N. 23rd compound by of claim 20, wherein R ¹ is a methyl group or chf ₂ and R ² is a cyclopentyl group, CHF ₂ , cyclopropylme tylová a group, a pyridylethyl group or a tetrahydrofuranyl group. 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 a 3-pyridyl or phenyl group which is in each case substituted or unsubstituted. The compound of claim 25, wherein B is N. A compound according to claim 20, wherein R ¹ is methyl or CHF 2; ^R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is a 3-pyridyl or phenyl group which is in each case substituted or unsubstituted. 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 a phenyl group which is substituted in 3- or 2-carboxy 102 4-position. The compound of claim 29, wherein B is N. The compound of claim 19, wherein R ¹ is methyl or CHF 2; ^R2 is cyclopentyl, CHF2, cyklopropylmeuylová, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is a phenyl group 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 ; and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl, 3-ethylsulfonamidophenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethylphenyl, 3-nitrophenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyanophenyl, 4-ethylsulfonamidophenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl. The compound of claim 33, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF 2; ^R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyanophenyl, 3-ethylsulfonamidophenyl, 3-tetrazol-5-ylphenyl, 3-hydroxymethylphenyl, 3-nitrophenyl, 4-pyridyl, 4-COOH-phenyl, 4 -cyanophenyl group, 4-ethylsulfonamidophenyl, 4-tetrazol-5-ylphenyl or 4-hydroxymethylphenyl. 103 The compound of claim 35, wherein B is N. A compound according to claim 1, selected from the group consisting of: (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, (d) 3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (e) 3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (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, (h) 3-cyclopentyloxy-4-methoxy-3'-nitro-N- (3-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-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinic acid; (m) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyrazinyl) -N- (3-pyridylmethyl) amine; 104 η) 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl dylmethyl) diphenylamine, ο) 3- [3- (4-Chloro-phenyl) -prop-1-yloxy] -4-methoxy-N- (3-pyridylmethyl) -diphenylamine, ρ) 4-methoxy-3- [3- (4-methoxyphenyl) prop-l-yl] oxy-N- (3-pyridylmethyl) diphenylamine, q) 4-Methoxy-3- [3- (2-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine, r) 3-cyclopentyloxy-4'- (2-methoxyethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine, with) 3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4' - [(3R) -tetrahydrofuranyloxy] diphenylamine, t) 3-Cyclopentyloxy-4-methoxy-4'- (1-methylpiperidin-4-yloxy) -N- - (3-pyridylmethyl) diphenylamine, u) 3-Cyclopentyloxy-4-methoxy-4'- (1-methylpyrrolidin-3-yloxy) -N- - (3-pyridylmethyl) diphenylamine, in) 3-Cyclopentyloxy-4-methoxy-4 '- [2- (1-pyrrolidinylethoxy) -N- - (3-pyridylmethyl) diphenylamine, w) 3-Cyclopentyloxy-4-methoxy-4'- [2- (6-methylpyridyl) methoxy] -N- - (3-pyridylmethyl) diphenylamine, x) 3-Cyclopentyloxy-4-methoxy-4'- [2- (1-methylpiperidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine, y) 3-Cyclopentyloxy-4-methoxy-3'- [2- (1-piperidinyl) ethoxy] -N- (3- pyridylmethyl) diphenylamine, from) 3-cyclopentyloxy-3 '- [2- (1-imidazolyl) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine, aa) 3-cyclopentyloxy-4-methoxy-4'- [3- (2-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine, bb) 3-Cyclopentyloxy-4-methoxy-4 '- [3- (2-morpholin-4-ylethylamino) - 105 Propoxy] -N- (3-pyridylmethyl) diphenylamine, cc) 3- [2- (4-chlorophenoxy) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine, dd) 3- [2- (4 (chlorophenylamino) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine, ee) 3-cyclopentyloxy-4'- (2-methanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, ff) 4 '- [2- (1-butanesulfonylamino) ethoxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, gg) 3-cyclopentyloxy-4-methoxy-N- (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'-nitro-N- (3-pyridylmethyl diphenylamine) 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-N- (2,6-dichloro-4-pyridylmethyl) -4 mecoxydiphenylamine, nn) 4-methoxy-4'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine, oo) 4,4'-dimethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryioxy) 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, 106 (rr) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N- (3-pyridylmethyl) amine, ss) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3 pyridylmethyl) -N- (5-pyrimidinyl) amine; m) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine; -methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, vv) 3-cyclopentyloxy-4-methoxyanilino-N- (3-pyridylmethyl) -N-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, yl) 4-methoxy-4'- (4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) - ( 3- (3-tetrahydrofuryloxy) diphenylamine, zz) 3'- (1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, aaa) 3'-acetamido-3-cyclopentyloxy-4- methoxy-N- (3-pyridylmeryl) diphenylamine, bbb) 4-methoxy-N- (3-pyridyimethyl) -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, eee) 3-cyclopropylmethoxy-4-methoxy-N- (3- (f) 4-Methoxy-N- (3-pyridylmethyl) -3 - [(3S) -tetrahydrofuryloxy] diphenylamine, ggg) 3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, 107 hhh) 3- [2- (4-chlorophenyl) ethenyloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine, iii) 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N- (3-pyridylmethyl) dif- -benzyloxycarbonylamine. j j j) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenyl- -benzyloxycarbonylamine. kkk) 4'-cyclohexylethoxy-3-cyklopentyloxv-4-methoxy-N- (3-pyridylme- tyl) diphenylamine, 111) 3-Cyclopentyloxy-4-methoxy-4'- [2- (1-methylpyrrolidin-2-yl) et- oxy] -N- (3-pyridylmethyl) diphenylamine, mmm) 3-Cyclopentyloxy-4-methoxy-4 '- [3- (1-methylpiperidinyl) methoxy] - N- (3-pyridylmethyl) diphenylamine, nnn) 3-cyclopentyloxy-4-methoxy-4'- [3- (1-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine, ooo) 4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine, PPP) 3-cyclopentyloxy-4-methoxy-4'- [2- (2-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine, qQQ) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) dif- -benzyloxycarbonylamine. rrr) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl-) tyl) diphenylamine, sss) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) dif- -benzyloxycarbonylamine. 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, VVV) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N- (3-pyridylme- tyl) diphenylamine, 108 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) di-phenylamine, yyy) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine, zzz) 3-cyclopropylmethoxy-4-hydroxy-4-methoxy-N- (3-pyridylmethyl) - diphenylamine, äääa) 3-Cyclopentyloxy-4'- (2-ethanesulfonylamino) ethoxy-4-methoxy-N- - (3-pyridylmethyl) diphenylamine, bbbb) 3-cyclopentyloxy-4-methoxy-4'- [2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine, cccc) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, dddd) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyl oxy) diphenylamine, eeee) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofu- ryloxy) diphenylamine, ffff) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyl oxy) diphenylamine, gggg! 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine, hHHH) 4-difluoromethoxy-N- (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, k) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- ( 3-pyridylmethyl) diphenylamine, 109 1111) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, mmmm) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4 -aminobenzoic acid, nnnn) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, ooo) N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid, pppp) N-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid, qqqq) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, rrrr) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid , ssss) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, mtt) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid, uuuu) N - [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, vvvv) N- (3-cyclopropylmethoxy) -4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, wwww) N- [3- (2-indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, xxxx) N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] - N- (3-pyridylmethyl) -3-aminobenzoic acid, yyl) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, zzzz) N - [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, 110aaaaa) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, bbbbb) 3-Cyclopentyloxy-4-methoxy-N- (3- pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, ccccc) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'- (2H-tetrazol-5-yl) diphenylamine ddddd) 4-Methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -4'- (2H-tetrazol-5-yl) diphenylamine, eeeee) 3-cyclopropylmethyloxy-4-methoxy-N - (3-pyridylmethyl) -4'- (2H-cetrazol-5-yl) diphenylamine, fffff) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -4'- (2H 3-Cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 &apos;-( 2H-tetrazol-5-yl) diphenylamine, b) 3-cyclopropylmethyloxy-4-difluoromethoxy N- (3-pyridylmethyl) -3'- (2H-tetrazol-5-yl) diphenylamine, iiiii) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5) yl) diphenylamine, 3 jjj j) ^N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amino, kkkkk) N- (3-cyclopentyloxy-4-difluoromethoxy-phenyl ) - N- (3-pyridyl) -N- (3-pyridylmethyl) amino, 11111) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, mmmmm; N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, nnnn) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, ooooo) 3-cyclopentyloxy-4-methoxy-3'- (1-propanesulfonylamino) -N- (3111) (pyridylmethyl) diphenylamine, ppppp) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, qqqqq) 3-cyclopentyloxy-4-methoxy-4'- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine, rrrrr) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, sssss) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) - 3 - [(3R) -tetrahydrofuryloxy] diphenylamine, mp) 4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, uuuuu) 4-methoxy-N- (3- pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine, vvvvv) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, wwwww) 3 1-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine, xxxxx) 3-cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidinyl) methoxy] N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable salts thereof. 38. The compound of claim 1 selected from the group consisting of: (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; 112 e) 3-cyclopentyloxy-3 ', 4'-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (f) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (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-N- (3-pyridylmethyl) diphenylamine; (k) N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid; (l) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N- (3-pyridylmethyl) amine; (m) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -N- (5-pyrimidinyl) amine; (n) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine; o) N- (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (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) -N- (3-pyridylmethyl) diphenylamine, (r) 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), 113 t) 3 '- (1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, u) 3'-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (v) 4-methoxy-N- (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-N- (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- (3-pyridylmethyl; diphenylamine, dd) 3-cyclopentyloxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, ee) 4'-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N - (3-pyridylmethyl) diphenylamine, ff) 3-cyclopentyloxy-4-methoxy-4'- [2- (1-methylpyrrolidin-2-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, gg) 3-cyclopentyloxy -4-methoxy-4 '- [3- (1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine, hh) 3-cyclopentyloxy-4-methoxy-4'- [3- (1-methylpiperazine-4) (ii) 4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine; 114 j j) 3-cyclopentyloxy-4-methoxy-4'- [2- (2-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine, kk) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) dif- phenylamino, 11) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine, mm) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) dif- phenylamino, nn) 3-Cyclopentyloxy-4-methoxy-4'- (2- (tetrahydropyran-2-yl) -2H- tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine, oo) 3-cyclopentyloxy-4-metánsulfony1amino-4-methoxy-N- (3-pyridylmethyl dylmethyl) diphenylamine, PP) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N- (3-pyridylme- tyl) diphenylamine, qq) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine, rr) 4-methoxy-3- [3- (4-pyridyl) prop-l-yl] oxy-N- (3-pyridylmethyl) di- phenylamine, ss) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) dif- phenylamino, tt) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) - diphenylamine, uu) 3-Cyclopentyloxy-4'- (2-ethanesulfonylamino) ethoxy-4-methoxy-N- - (3-pyridylmethyl) diphenylamine, vv) 3-cyclopentyloxy-4-methoxy-4 '- [2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine, ww) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) dif- phenylamino, XX) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuranyl 115 oxy) diphenylamine, yl) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofuryloxy) diphenylamine, zz) 4-difluoromethoxy-N- (3-pyridylmethyl) - 3- (3-tetrahydrofuryloxy) diphenylamine, aaa) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine, bbb) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) - c) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, ddd) 3'-chloro-4-difluoromethoxy-N- (3 pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, eee) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, fff) N- (3-cyclopentyloxy- 4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, ggg) 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, j) N-3,4-bis (difluoromethoxy) phen yl-N- (3-pyridylmethyl) -3-aminobenzoic acid, k) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, 111) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid, mmm) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3 -aminobenzoic acid, 116 ηηη) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid, οοο) N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, ΡΡΡ) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, qQQ) N- [3- (2-indanyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, rrr) N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, 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-Cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ' - (2H-tetrazol-5-yl) diphenylamine, VVV) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ' tetrazol-5-yl) diphenylamine, www) 3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 ' tetrazol-5-yl) diphenylamine, XXX) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -4 ' - (2H-tetrazol-5-yl) diphenylamine, yyy) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, zzz) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofuryl- oxy) -4 '- (2H-tetrazol-5-yl) diphenylamine, aaaa) 3-Cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H- tetrazol-5-yl) diphenylamine, BBBB) ) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) - -3 '- (2H-tetrazol-5-yl) diphenylamine, 117 cccc) Bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, dddd) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- ( 3-pyridyl) -N- (3-pyridylmethyl) amine, ee) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, ffff) N- ( 3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, gggg) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3 -pyridyl) -N- (3-pyridylmethyl) amine, hhh) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, iiii) 3-cyclopentyloxy- 4-methoxy-3'- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine, ij) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, kkkk) 3 -cyclopentyloxy-4-methoxy-4'- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine, 1111) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, mmmm) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3 - [(3 R)] tetrahydrofuryloxy] diphenylamine, nnn) 4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, 100o) 4-methoxy-N- (3-pyridylmethyl) -3- [ (3 R) -tetrahydrofuryloxy] diphenylamine, pppp) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, qqqq) 3'-chloro-4 -methoxy-N- (3-pyridylmethyl) -3- [(3R) -tetrahydrofuryloxy] diphenylamine, 118 (trans) 3-Cyclopentyloxy-4-methoxy-4'- [2- (5-oxopyrrolidinyl) methoxy [-N- (3-pyridylmethyl) diphenylamine], and pharmaceutically acceptable salts thereof. 39. The compound of claim 1 selected from the group consisting of: (a) 3'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (b) 4'-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) -2H-tetrazol-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; (h) 4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine; (i) 3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine; (j) 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; k) 3-Cyclopentyloxy-4'- (2-ethanesulfonylamino) ethoxy-4-methoxy-N- - (3-pyridylmethyl) diphenylamine, (l) 3-cyclopentyloxy-4-methoxy-4'- [2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine; 119 (m) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (n) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine; o) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, p) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine; q) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine, (r) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofuryloxy) diphenylamine; (s) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine; t) 3'-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine, u) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, (v) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (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-tetrahydro-furyloxy) -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) -tetrahydrofuryloxy) phenyl] -N - (3-pyridylmethyl) -3-aminobenzoic acid, bb) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4120 (cc) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, dd) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid, ee) N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -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, hh) N- [4 -methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, ii) N- [4-methoxy-3 - ((3R) -tetrahydrofuryloxy) phenyl] -N- ( 3-pyridylmethyl) -3-aminobenzoic acid, j) N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, k) 3-cyclopropylmethyloxy-4-difluoromethoxy N- (3-pyridylmethyl ·) -4 '- (2H-tetrazol-5-yl) diphenylamine, 11) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-( 2H-thrazrazol-5-yl) diphenylamine, mm) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) - 3'- (2H-tetrazol-5-yl) diphenylamine, nn) 4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) -4 '- (2H-tetrazol-5-yl) diphenylamine, oo) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, pp) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- ((3R) -tetrahydrofuryloxy) -4'- (2H-tetrazol-5-yl) diphenylamine, qq) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-) yl) diphenylamine, 121 rr) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 ' - (2H-tetrazol-5-yl) diphenylamine, ss) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazole-5- yl) diphenylamine, tt) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, uu) N- (3-cyclopentyloxy-4-difluoromethoxy-phenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amino, w) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, ww) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyfenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amino, 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-pyridylmethyl) diphenylamine, bbb) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, ccc) 4-Difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3- - [(3 R) -tetrahydrofuryloxy] diphenylamine, ddd) 4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenyl amine eee) 4-Methoxy-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] di- fff) phenylamine, 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) - DPA, 122 ggg) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3 - [(3R} -tetrahydrofuryloxy] diphenylamine, hhh) 3-cyclopentyloxy-4-methoxy-4'- [2- (5- oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable salts thereof. 40. The compound of claim 1 selected from the group consisting of: (a) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; (b) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine; (c) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3 - ((3R) -tetrahydrofuryloxy) diphenylamine; (d) 4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine; (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) -cecrahydrofuryloxy) 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, (k) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid; (l) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid; 123 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, about) N- [4-methoxy-3- ((3R) -tetrahydrofuryloxy) 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, r) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid, with) 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, in) N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, w) N- [4-methoxy-3 - ((3 R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid, x) N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl-3-aminobenzoic acid), y) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmetyl.-4 ' - (2H-tetrazol-5-yl) diphenylamine, FROM) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-( 2H-terrazol-5-yl) diphenylamine, aa) 3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'- (2H-resra- tetrazol-5-yl) diphenylamine, bb) 4-Methoxy-N- (3-pyridylmethyl) -3 - ((R) -tetrahydrofuryloxy) -4'- 124 - (2H-tetrazol-5-yl) diphenylamine, cc) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, dd) 4-difluoromethoxy- N- (3-pyridylmethyl) -3 - ((3 R) -tetrahydrofuryloxy) -4'- (2 H -tetrazol-5-yl) diphenylamine, ee) 3-cyclopentyloxy-4-difluoromethoxy-N- (3- pyridylmethyl) -4'- (2H-tetrazol-5-yl) diphenylamine, ff) 3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3'- (277-tetrazol-5-yl) diphenylamine, gg (bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 '- (2H-tetrazol-5-yl) diphenylamine, hh) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3- pyridyl) -N- (3-pyridylmethyl) amine, ii) N- (3-cyclopentyloxy-4-difluoromethoxy-phenyl) -N- (3-pyridyl) -N ^_ (3-pyridylmethyl) amine jj) N- (3- cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine, N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3- pyridyl) -N- (3-pyridylmethyl) amine, 11) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, mm) 3-cyclopentyloxy-4-methoxy-3 '- (1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine, nn) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, oo) 3-cyclopentyloxy-4-methoxy-4'- (1-propanesulfonylamino) -N- (3- pyridylmethyl) diphenylamine, pp) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine, 125 qq) 4-Difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine, rr) 4-Methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, ss) 4-methoxy-N- (3-pyridylmethyl) -3 - [(3R) -tetrahydrofuryloxy] diphenylamine> tt) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine, uu) 3'-chloro-4-methoxy-N- (3-pyridylmethyl) 13 - [(3R) -tetrahydrofuryloxy] diphenylamine, vv) 3-cyclopentyloxy-4-methoxy-4'- [2- (5-oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable salts thereof. 41. A compound of formula I ': where R ¹ 'is methoxy, F, Cl, CHF ₂ or CF ₃ ; (C 1 -C 12) alkyl, (C 1 -C 12) alkyl substituted one or more times with halogen, oxo, cyano, or combinations thereof, C 2 -C 12 alkenyl, C 2 -C 12 alkenyl substituted one or more times with halogen, oxo, cyano, or combinations thereof, C 2 -C 12 alkynyl, C 2 -C 12 alkynyl carbon atoms substituted one or more times by halogen atom, oxo group, cyano group or combinations thereof, cycloalkyl group containing 3 to 10 carbon atoms, cycloalkyl group containing 3 to 10 carbon atoms, substituted one or more times by halogen atom, oxo group, alkyl group or theirs combinations, a C 4 -C 12 cycloalkylalkyl group, a C 4 -C 12 cycloalkylalkyl group which is substituted one or more times by a halogen atom, an oxo group, an alkyl group or combinations thereof, a partially unsaturated carbocyclic group and containing 5 to 14 carbon atoms, a partially unsaturated carbocyclic group 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl with a group, alkyloxy, nitro, cyano, oxo or combinations thereof, arylalkyl having 7 to 26 carbon atoms, arylalkyl having 7 to 26 carbon atoms which is substituted once or multiple times with a halogen atom, an alkyl group, an alkoxy group, a nitro group, a cyano group, an oxo group, a trifluoromethyl group or combinations thereof, a heteroarylalkyl group containing 5 to 10 atoms in the ring 127 hu, wherein at least one ring atom is a heteroatom or a substituted heteroarylalkyl group containing 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom and which is substituted one or more times in the heteroaryl moiety by a halogen atom, an aryl group, an alkyl group, alkoxy, cyano, 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 an aryl group having 6 to 14 carbon atoms, an aryl group having 6 to 14 carbon atoms, which is substituted one or more times with halogen atoms, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, dialkylamino, alkylamino, alkylamino hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy groups containing 5 to 10 carbon atoms, ring atoms, wherein at least one ring atom is a heteroatom or a substituted heteroaryl group containing 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is substituted once or several times with halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or their 128 combinations; L is -NH-, -NR ⁴ '-, -NHCH 2 -, -NR ⁴ ' CH 2 - or -CH ₂ NR ⁴ '-; and R ⁴ 'is C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted one or more times with halogen, oxo, cyano, or combinations thereof, C 6 -C 14 aryl which is unsubstituted or substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, alkyl, carboxy, alkyl, cyano, alkyl, cyano, acyloxy, , phenoxy or combinations thereof, a heteroaryl group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, a substituted heteroaryl group having 5 to 10 ring atoms, wherein at least one at m in the ring is a heteroatom which is substituted one or more times with a halogen atom, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl of 7 to 16 carbon atoms, a group containing from 7 to 16 carbon atoms which is substituted one or more times by a halogen atom, an alkyl group, an alkoxy group, a nitro group, a cyano group, an oxo group, a trifluoromethyl group or combinations thereof, 129 a heteroarylalkyl group containing 5 to 10 ring atoms wherein at least one ring atom is a heteroatom, a substituted heteroarylalkyl group containing 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, and which is substituted one or more times in the heteroaryl moiety by an atom 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. 42. A method of increasing cognition in a patient in whom such an increase is desirable to a daily patient by administering an effective amount of a compound of Formula I. 43rd The method of claim 42, wherein said compound is administered in an amount of 0.01-100 s by mg / kg body weight / day. The method of claim 42, wherein such patient is a human. 45. A method of treating a patient suffering from a deterioration or loss of cognition, comprising administering to said patient an effective amount of a compound of claim 1. The method of claim 45, wherein said patient is a human. The method of claim 46, wherein said patient is suffering from memory impairment. 130 48. The method of claim 45, wherein said compound is administered in an amount of 0.01-100 mg / kg body weight / day. The method of claim 47, wherein said patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob's disease, depression, age, head injury, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease. 50. A method of treating a patient with a disease in which the level of cAMP is reduced, comprising administering to said patient an effective amount of a compound of claim 1. 51. A method of inhibiting PDE4 enzyme activity in a patient, comprising administering to said patient an effective amount of a compound of claim 1. 52. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 53. The composition of claim 51, wherein said composition comprises 0.1-50 mg of said compound. 54. A method of treating a patient suffering from memory impairment due to a neurodegenerative disease, comprising administering to said patient an effective amount of a compound of claim 1. 55. A method of treating a patient suffering from memory impairment due to acute neurodegenerative disease, comprising administering to said patient an effective amount of a compound of claim 1. 56. A method of treating a patient suffering from an allergic or inflammatory disease, comprising administering to said patient an effective amount of a compound according to claim 1. A compound of the formula wherein R ¹ is H, tert-butyldimethylsilyl, ³ H ³ C-, ¹⁴ CH 3 -, ¹¹ CH _3, or a phenyl protecting group; R ² is a C 1 -C 12 alkyl group, straight or branched chain, unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C 1 -C 4 alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH 2 CH 2 - is in each case replaced by -CH = CH- or -C = C-, a cycloalkyl group containing 3 to 10 carbon atoms which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl (C 1 -C 4) group, (C 1 -C 4) alkoxy or combinations thereof, (C 4 -C 16) cycloalkylalkyl which is unsubstituted or substituted in cycloalkyl 132 moieties and / or alkyl moieties one or more times by halogen, oxo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or combinations thereof, C 6 -C 14 aryl group which is unsubstituted or substituted one or more times by halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or combinations thereof, arylalkyl, wherein the aryl moiety contains from 6 to 14 carbon atoms and alkyl; is branched or unbranched containing 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by a halogen atom, CF 3, OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, ethylenedioxy or combinations thereof and wherein in the alkyl moiety one or more -CH 2 CH 2 - is optionally replaced by -CH = CH- or -OC- and one or more -CH ₂ - is 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 containing 5 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, , oxo or combinations thereof, a heterocyclic group which is saturated, partially saturated or unsaturated, containing 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, which is unsubstituted or substituted one or more times by halogen , hydroxy, aryl, alkyl, alkoxy, cyano u, trifluoromethyl, nitro A heterocyclylalkyl group wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and containing 1 to 5 carbon atoms, the heterocyclylalkyl group being unsubstituted or substituted in the heterocyclic moiety one or more times by halogen atom, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro or oxo groups, oxo groups wherein in the alkyl moiety one or more -CH ₂ CH ₂ - is optionally replaced by -CH = CH- or -C = C-. and one or more -CH ₂ - is replaced by -O- or -NH- and / or the alkyl moiety is optionally substituted by a halogen atom, an oxo group, a hydroxy group, or combinations thereof, R ³ is H, an alkyl group 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 by halogen atom, cyano, alkoxy group having 1 to 4 carbon atoms or combinations thereof, a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms and which is unsubstituted or substituted in the carbocyclic moiety one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof, and wherein the alkyl moiety is optionally substituted with a halogen atom, a C 1 -C 4 alkoxy group, a cyano group or a combination thereof, an arylalkyl group containing 7 to 19 carbon atoms, wherein The aryl moiety contains 6 to 14 carbon atoms and wherein the alkyl moiety that is branched or unbranched contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by halogen, trifluoromethyl, CF ₃ O, nitro , amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl, or heteroarylalkyl, wherein the heteroaryl moiety may be partially or fully saturated and contains 5 to 10 ring atoms, wherein at least one ring atom is N, O or S, wherein the branched or unbranched alkyl moiety contains 1 to 5 carbon atoms, wherein the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl moiety by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and / or substituted in the alkyl portion by halogen, cyano, methyl or combinations thereof; R ⁴ is H, a (C 6 -C 14) aryl group which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, ₃ , amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2- (heterocyclyl) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acy, acy, acy, acy , alkylsulfinyl, alkylsulfonyl, phenoxy, tri-35 alkylsilyloxy (e.g., tert-butyldimethylsilyloxy), R ⁵ -L- or combinations thereof, or a heteroaryl group of 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, aminoalkoxy, -5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R ⁵ -L-, dialkylamino-L-, or combinations thereof; R ⁵ is H, an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted one or more times by a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an oxo group or combinations thereof, alkylamino or a dialkylamino group wherein each alkyl moiety independently has 1 to 8 carbon atoms, a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms and which is unsubstituted or substituted, preferably in the carbocyclic moiety once or halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, unsubstituted or substituted one or more times 136 with a halogen atom, a hydroxy group, an oxo group, a cyano group, an alkoxy group, a carbon atom or an alkyl group thereof with combinations containing The 1 to 4 cycloalkylalkyl atoms which is unsubstituted or the 4 to 16 moieties and / or alkyl moieties are substituted one or more times with n, oxo, cyano, pin, alkoxy or hydroxy groups, combinations, carbon atoms, cycloalkyl to haloalkyl and haloalkyl groups. group containing 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, alkoxyalkoxy, indio, trifluoromethyl methylenedioxy, ethyl, amino, hydroxyalkylamino, aminoalkylamino, aminoalkylamino, aminoalkyloxy, hydroxamic roxyalkoxy, n, cyano, tetrazol-5-yl, coupled with cuvycarboxy, alkoxycarbonyl acyl, alkylthio, alkylsulphinyl, alkylsulphonyl with combinations of, up to 19 atoms arylalkyl group containing 7 aryl moieties containing 6 to 14 carbon atoms and wherein which is branched or unbranched, carbon wherein the alkyl moiety contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by halogen , trifluoromethyl, CF ₃ O, nitro, amino, alkyl. an alkoxy group, an alkylamino group, an alkylamino group and / or a halogen atom, a cyano group substituted in an alkyl moiety or a methyl group, a heterocyclic group, saturated or unsaturated, containing up to The 10 ring atoms at least one ring atom is an atom bold or substituted once N, or S, which is or more than one atom of unsubsthalogen, 137 alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkoxy, carboxylic acid, hydroxy, a cyano group, an acyl group, an alkylthio group, an alkylsulfonyl alkylsulfonyl group, a phenoxy group or combinations thereof, or a heterocyclylalkyl group wherein the heterocyclic moiety is saturated, partially saturated or unsaturated and contains from 8 to 10 ring atoms, wherein at least one the ring atom is N, C or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, the heterocyclylalkyl group being unsubstituted or substituted in the heterocyclic moiety once or several times with halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ O, nirro, oxo, amino, dialkylamino or combinations thereof, and / or the alkyl moiety is substituted with halogen, cyano or methyl or combinations thereof; L is a single bond or a divalent aliphatic group containing 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups is optionally replaced by -O-, -S-, -NR ⁶ -, -SO ₂ NH-, -nhso ₂ -, -CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH- or -NHCSNH-; and R ⁶ is H, alkyl group containing 1 to 8 atoms the carbon that is branched or unbranched and which is unsubstituted or substituted one or more times by a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, an oxo group or a combination thereof, wherein at least one of R ³ and R ⁴ is other than hydrogen; and pharmaceutically acceptable thereof A compound of the formula wherein R ¹ is an alkyl group containing from 1 to 5 carbon atoms; 4 carbon atoms which is branched or unbranched and which is unsubstituted or substituted one or more times by an atom R ² is H, t-butyldimetylsilyloxy- protecting group or a phenyl group; R ³ is H, an alkyl group 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 by halogen atom, cyano, alkoxy group having 1 to 4 carbon atoms or combinations thereof, a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms and which is unsubstituted or substituted in the carbocyclic moiety one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo or 139 combinations thereof, and wherein the alkyl moiety is optionally substituted with a halogen atom, a C 1-4 alkoxy group, a cyano group, or combinations thereof, a C 7-19 arylalkyl group wherein the aryl moiety contains 6-14 carbon atoms and wherein the alkyl moiety is branched or unbranched containing 1 to 5 carbon atoms, the arylalkyl group being unsubstituted or substituted in the aryl part one or more times by a halogen atom, a trifluoromethyl group, CF ₃ O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or in the alkyl moiety with a halogen atom, a cyano group or a methyl group, or a heteroarylalkyl group, wherein the heteroaryl moiety may be partially or fully saturated and contains 5 to 10 ring atoms wherein at least one ring atom is N, O or S, wherein the alkyl moiety, which is branched or unbranched, wherein the heteroarylalkyl group is unsubstituted or substituted in the heteroaryl moiety one or more times by a halogen atom, an alkyl group, an alkoxy group, a cyano group, a trifluoromethyl group, CF ₃ O, a nitro group, an oxo group, an amino group, an alkylamino group or a dialkylamino group; in the alkyl moiety with a halogen atom, a cyano group, a methyl group or combinations thereof; R ⁴ is H, a (C 6 -C 14) aryl group which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, ₃ , amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-3-yl 140, 2- (heterocyclyl) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy groups (e.g., t-butyldimetylsilylcxyskupinou), R ³ -L- or a combination thereof, or a heteroaryl group of 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by a halogen atom, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano u, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R ⁵ -L-, dialkylamino-L- or combinations thereof; R ⁵ is H, an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an oxo group or combinations thereof, alkylamino or a dialkylamino group wherein each alkyl moiety independently has 1 to 8 carbon atoms, a partially unsaturated carbocyclylalkyl group wherein the carbocyclic moiety contains 5 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms and which is unsubstituted or substituted, preferably in the carbocyclic moiety once or several times with a halogen atom, an alkyl group, an alkoxy group, a nitro group C 3 -C 10 -cycloalkyl which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, C 1 -C 4 -alkyl, or a phenyl, cyano, oxo or combinations thereof combinations, a C 4 -C 16 cycloalkylalkyl group which is unsubstituted or substituted in the cycloalkyl moiety and / or the alkyl moiety one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl of 6 to 6 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, hydroxamic roxyalkoxy, acids, tetrazol-5-yl, hydroxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylthio, alkylthio, alkylthio C7 -C19 arylalkyl, wherein the aryl moiety contains 6 to 14 carbon atoms and wherein the branched or unbranched alkyl moiety contains 1 to 5 carbon atoms, wherein the arylalkyl group is unsubstituted or substituted in the aryl moiety one or more times by an atom halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted in the alkyl moiety by halogen, cyano or methyl, 142 is a heterocyclic group which is saturated, partially saturated or unsaturated, containing up to 10 ring atoms wherein at least one ring atom is an atom bold or substituted once N, or S, which is unsubstituted or more than once by halogen, alkyl, hydroxy, alkoxy, nitro, oxy, trifluoromethyl alkoxy, methylenedioxy, amino, alkoxyethylenediaminomethyl, aminoalkyl, aminoalkoxy, aminoalkoxy, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl with alkylsulfonyl, phenoxy or combinations thereof, or heterocyclylalkyl, wherein the heterocyclic moiety is saturated or unsaturated or saturated, up to 10 ring atoms, wherein at least one ring atom is N, O or S, and the alkyl moiety is branched or unbranched and contains 1 to 5 carbon atoms, wherein the heterocyclylalkyl group is unsubstituted or substituted in the heterocyclic moiety one or more times by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ O, nicro, oxo, amino, dialkylamino or combinations thereof, and / or the alkyl moiety is substituted by halo, cyano or methyl or combinations thereof; L is a single bond or a divalent aliphatic group containing 1 to 8 carbon atoms, wherein one or more -CH ₂ - groups are optionally replaced by -O-, -S-, -NR ⁶ -, -SO ₂ NH-, -NHSO ₂ - , -CO-, -NR ⁶ CO-, -CONR ⁶ -, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH or -NHCSNH-; and R ⁶ is H, C 1 -C 8 alkyl which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, oxo group or combinations thereof, wherein at least one of R ³ and R ⁴ is other than hydrogen; and pharmaceutically acceptable salts thereof. 59. A compound selected from the group consisting of: (a) 3-cyclopentyl-4-methoxy-N- (3-pyridylmethyl) aniline; (b) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) aniline; c) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine; d) 3-tert-butyl-dimethylsilyloxy-3'-chloro-4-methoxy-N- (3-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) -N- (3-pyridylmethyl) -3-aminobenzoate; 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.