KR100856622B1 - Phosphodiesterase 4 Inhibitors - Google Patents

Abstract

PDE4 inhibition is achieved by novel compounds such as N-substituted anilines and diphenylamine analogs. Compounds of the present invention are compounds of Formula I, wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein.

<Formula I>

Phosphodiesterase 4, inhibitors, aniline, diphenylamine analogues, cAMP

Description

Phosphodiesterase 4 Inhibitors

This application is filed on US Provisional Patent Application No. 60 / 262,651, filed Jan. 22, 2001, US Provisional Patent Application No. 60 / 267,196, filed February 8, 2001, and on July 14, 2001. US Provisional Patent Application No. 60 / 306,140 is based on a claim of priority.

The present invention generally relates to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically, the present invention relates to selective PDE4 inhibition by novel compounds, such as N -substituted anilines and diphenylamine analogues, and methods of making such compounds, compositions comprising such compounds, and methods of using the same. will be.

Cyclic nucleotide specific phosphodiesterases (PDEs) represent a class of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides function as secondary messengers in the cell and deliver stimuli from cell surface receptors bound to various hormones and neurotransmitters as messengers. PDEs function to maintain cyclic nucleotide homeostasis by regulating the levels of cyclic nucleotides in cells and terminating their messenger roles by digesting the cyclic mononucleotides.                 

PDE enzymes can be classified into seven classes depending on the specificity for the hydrolysis of cAMP or cGMP, the sensitivity to regulation by calcium, calmodulin or cGMP, and the selective inhibition by various compounds. For example, PDE1 is stimulated by Ca ²⁺ / calmodulin. PDE2 is cGMP-dependent and is found in the heart and adrenal glands. PDE3 is cGMP-dependent and inhibition of this enzyme results in positive contractile activity. PDE4 is cAMP specific and its inhibition results in airway relaxation, anti-inflammatory and antidepressant activity. PDE5 is important for the regulation of cGMP content of vascular smooth muscle, so PDE5 inhibitors can have cardiovascular activity. Since PDEs have distinct biochemical properties, they appear to be controlled in many different forms.

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

PDE4 isoenzymes are localized to the cytoplasm of cells and are not associated with any known membrane structure. PDE4 isozymes in particular catalyze hydrolysis to adenosine 5′-monophosphate (AMP) to inactivate cAMP. Modulation of cAMP activity is important for many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are potent anti-inflammatory agents and therefore may be useful in the treatment of diseases with inflammation problems such as asthma or arthritis. In addition, rolipram improves cognitive performance of rats and mice in the learning paradigm.

In addition to compounds such as rolipram, xanthine derivatives such as pentoxifylline, denbuphylline and theophylline have recently received considerable attention for their cognitive enhancement effects by inhibiting PDE4. cAMP and cGMP are secondary messengers that mediate cellular responses to many other hormones and neurotransmitters. Thus, a therapeutically important effect may be due to PDE inhibition in key cells located elsewhere in the nervous system and body, and consequently an increase in intracellular cAMP or cGMP.

Rolipram, which was under development as an antidepressant in the past, selectively inhibited the PDE4 enzyme and became a standard drug for the classification of PDE enzyme subtypes. Early research in the field of PDE4 focused on depression and inflammation, and then expanded to include indications such as dementia (for a general overview, see The PDE IV Family Of Calcium-Phosphodiesterases Enzymes, John A. Lowe). , III, et al., Drugs of the Future 1992, 17 (9): 799-807). Subsequent clinical development of rolipram and other first generation PDE4 inhibitors was discontinued due to side effects of the compound. The primary side effects of rodents are vomiting, whereas the primary side effects are testicular degranulation, vascular smooth muscle weakness, psychoactive effects, increased gastric acid secretion and gastric erosion.

Detailed description of the invention
Summary of the Invention

The present invention inhibits PDE4 enzymes and in particular has a novel side effect profile, e. G. A relatively new compound which does not cause vomiting (e.g. compared to the compounds of the prior art discussed above), eg new N -substituted It relates to aniline and diphenylamine compounds. Preferably, the compound selectively inhibits the PDE4 enzyme. At the same time, the compounds of the present invention readily enter into cells, especially into cells of the nervous system.

Furthermore, the present invention further provides a method for the synthesis of compounds having said activity and selectivity, and disease states comprising elevated intracellular PDE4 levels or reduced cAMP levels, such as nervous system syndromes, specifically memory disorders, most particularly For long term memory impairment, PDE inhibition, in particular PDE4 inhibition, when the memory disorder is partly due to the degradation of intracellular cAMP levels by PDE4 enzyme or the memory disorder can be enhanced by effectively inhibiting PDE4 enzyme activity Is for a method of treating a mammal, including a patient, eg, a human, and a corresponding pharmaceutical composition therefor.

In a preferred aspect, the compounds of the present invention ameliorate the disease by inhibiting the PDE4 enzyme at a dose that does not cause vomiting.                 

The present invention includes compounds of formula (I) and pharmaceutically acceptable salts thereof:

Where

R ¹ is branched or unbranched, unsubstituted or substituted one or more times by halogen, alkyl having 1 to 4 carbon atoms (eg CH ₃ , CHF ₂ , CF _3, etc.);

R ² is branched or unbranched, and optionally one or more —CH ₂ CH ₂ — groups, unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo or combinations thereof In each case alkyl having 1 to 12 carbon atoms, preferably 1 to 8 or more carbon atoms, substituted with -CH = CH- or -C≡C- (e.g. CH ₃ , CHF ₂ , CF ₃ , Methoxyethyl, etc.)

3 to 10, preferably unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or combinations thereof Cycloalkyl having 3 to 8 carbon atoms (eg cyclopentyl),

4 to 16 unsubstituted or cycloalkyl moieties and / or alkyl moieties substituted one or more times with halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4- alkoxy or combinations thereof , Preferably cycloalkylalkyl having 4 to 12 carbon atoms (eg cyclopentylmethyl, cyclopropylmethyl, etc.),

Aryl having 6 to 14 carbon atoms, unsubstituted or substituted one or more times with halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano or combinations thereof (Eg methylphenyl, methoxyphenyl, chlorophenyl, etc.),

The aryl moiety has 6 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the arylalkyl radical is unsubstituted or the aryl moiety is halogen, CF ₃ , OCF ₃ , alkyl, Substituted one or more times with hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy or combinations thereof, wherein at least one -CH ₂ CH ₂ -group of the alkyl moiety is -CH = CH- or-in each case Optionally substituted with C≡C- and one or more -CH ₂ -groups are each optionally substituted with -0- or -NH-, and / or the alkyl moiety is optionally substituted with halogen, oxo, hydroxy, cyano or a combination thereof Arylalkyl (eg, phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxy Ethyl, chlorophenyl Mino ethyl, etc.),

Partially unsaturated carbocyclic groups having 5 to 14 carbon atoms unsubstituted or substituted one or more times with halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo or combinations thereof (eg cyclohexenyl, Cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),

5 to 10, wherein one or more ring atoms, unsubstituted or substituted one or more times with halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof are N, O or S atoms , Partially saturated or unsaturated heterocyclic groups having 3 ring atoms (eg 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or

The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms , Unsubstituted or heterocyclic moiety is substituted one or more times with halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo or combinations thereof, wherein 1 of the alkyl moiety The above -CH ₂ CH ₂ -groups are each optionally substituted with -CH = CH- or -C≡C- and at least one -CH ₂ -group is each optionally substituted with -O- or -NH-, and / or an alkyl moiety A heterocycle-alkyl group (eg, pyridylethyl, pyridylpropyl, methylpiperazinylethyl, etc.) optionally substituted with halogen, oxo, hydroxy, cyano or a combination thereof;

R ³ is H,

Alkyl having 1 to 8, preferably 1 to 4 carbon atoms, branched or unbranched, unsubstituted or substituted one or more times with halogen, cyano, C _1-4 -alkoxy or combinations thereof; For example methyl, ethyl, propyl, etc.),

The carbocyclic moiety has 5 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms and the unsubstituted or carbocyclic moiety is halogen, alkyl, alkoxy, nitro, cyano , A partially unsaturated carbocycle-alkyl group which is substituted one or more times with oxo or a combination thereof, and wherein the alkyl portion is optionally substituted with halogen, C _1-4 -alkoxy, cyano or a combination thereof (eg cyclohexenylmethyl, etc.) ),

The aryl moiety has 6 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the arylalkyl radical is unsubstituted or the aryl moiety is halogen, trifluoromethyl, CF ₃ 0 Arylalkyl having 7 to 19 carbon atoms, substituted one or more times with nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and / or substituted with halogen, cyano or methyl Benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), or

The heteroaryl moiety may be partially or fully saturated, having 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Unsubstituted or heteroaryl portion is substituted one or more times with halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ 0, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, and (Or) heteroarylalkyl groups in which the alkyl moiety is substituted by halogen, cyano, methyl or combinations thereof (e.g. pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienyl Methyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl and the like);

R ⁴ is H,

Unsubstituted or halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy dialkylamino , Hydroxyalkyl (eg hydroxymethyl), hydroxysamic acid, tetrazol-5-yl, 2 (-heterocycle) tetrazol-5-yl (eg 2- (2-tetrahydropyra) Yl) tetrazol-5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsul Aryl having 6 to 14 carbon atoms (eg, substituted one or more times with phenyl, phenoxy, trialkylsilyloxy (eg tert-butyldimethylsilyloxy), R ⁵ -L- or combinations thereof (eg Substituted or unsubstituted phenyl, naphthyl and biphenyls, for example phenyl, methylphenyl, chlorophenyl, fluoro Phenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or

Unsubstituted or halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g. For example, hydroxymethyl), hydroxysamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, One or more ring atoms, substituted one or more times with alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg, tert-butyldimethylsilyloxy), R ⁵ -L- or combinations thereof Heteroaryl having 5 to 10 ring atoms which are heteroatoms (eg pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);

R ⁵ is H,

Alkyl having 1 to 8, preferably 1 to 4 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof (eg For example methyl, ethyl, propyl, etc.),

Each alkyl moiety is independently alkylamino or dialkylamino having 1 to 8, preferably 1 to 4 carbon atoms (eg dimethylamino, etc.),

The carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety is unsubstituted or preferably at least one carbocyclic moiety substituted one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo or combinations thereof. Partially unsaturated carbocycle-alkyl groups having 1 to 5 carbon atoms (eg, cyclohexenylmethyl, etc.),

3 to 10, preferably 3 to 8 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms or a combination thereof Cycloalkyl having (eg cyclopentyl),

4 to 16, preferably 4 to 12 carbons, wherein the unsubstituted or cycloalkyl moiety and / or alkyl moiety is substituted one or more times with halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof. Cycloalkylalkyl having an atom (eg cyclopentylmethyl, cyclopropylmethyl, etc.),

Unsubstituted or halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g. For example, hydroxymethyl), hydroxysamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl Aryl having 6 to 14 carbon atoms, substituted one or more times with alkylthio, alkylsulfinyl, alkylsulfonyl (eg, substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluoro Phenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

The aryl moiety has 6 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms and the arylalkyl radical is unsubstituted or the aryl moiety is halogen, trifluoromethyl, CF ₃ Having from 7 to 19 carbon atoms, substituted one or more times with zero, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, and / or alkyl moieties substituted with halogen, cyano or methyl Arylalkyl (eg benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.),

Unsubstituted or halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g. For example, hydroxymethyl), hydroxysamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g. tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, Saturated, partially saturated or unsaturated hetero, having 5 to 10 ring atoms, at least one ring atom substituted at least once with alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or a combination thereof is an N, O or S atom. Cyclic groups (eg, pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

The heterocyclic moiety is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms , An unsubstituted or heterocyclic moiety is substituted one or more times with halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF ₃ 0, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, And / or the alkyl moiety is a heterocycle-alkyl group substituted with halogen, cyano, methyl or a combination thereof (eg, pyridylmethyl, pyridylpropyl, methylpyridylmethyl, etc.);

L is a single bond or one or more -CH ₂ -groups are each -O-, -S-, -NR ^6- , -SO ₂ NH-, -NHSO _2- , -CO-, -NR ⁶ CO-, -CONR ⁶ -A divalent aliphatic radical having 1 to 8 carbon atoms, optionally substituted with -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH- or -NHCSNH- (e.g. -O-, CH _2- , -CO-, -CO-O-, -O-CO-, -CO-NH-, -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-S0 _2- , -CH ₂ CH ₂ CH ₂ -SO ₂ -NH- and the like);

R ⁶ is H,

1 to 8, preferably 1 to 4, branched or unbranched, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or a combination thereof Alkyl having a carbon atom (eg methyl, ethyl, propyl, etc.);

Wherein at least one of R ³ and R ⁴ is other than H.

According to another aspect of the present invention, a novel compound genus according to formulas (II) and (III)                 

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. The compounds of the subgenus of formula (I) not only have PDE4 inhibitory activity, but are also useful as intermediates for the preparation of compounds of formula (I) in which both R ³ and R ⁴ are other than H.

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

Wherein R ^{1 ′} , R ² and R ⁴ are as defined in Formula I, A, B and D are N and others are C. Preferably, B is N. In addition, R ⁴ is preferably in each case substituted or unsubstituted pyridyl or phenyl.

The present invention also includes compounds of Formula I 'and pharmaceutically acceptable salts:                 

Where

R ^{1 ′} is methoxy, F, Cl, CHF ₂ or CF ₃ ;

R ^{2 '} is alkyl having 1 to 12 carbon atoms,

Alkyl having 1 to 12 carbon atoms, substituted one or more times with halogen, oxo, cyano or combinations thereof,

Alkenyl having 2 to 12 carbon atoms,

Alkenyl having 2 to 12 carbon atoms, substituted one or more times with halogen, oxo, cyano or a combination thereof,

Alkynyl having 2 to 12 carbon atoms,

Alkynyl having 2 to 12 carbon atoms, substituted one or more times with halogen, oxo, cyano or a combination thereof,

Cycloalkyl having 3 to 10 carbon atoms,

Cycloalkyl having 3 to 10 carbon atoms, substituted one or more times with halogen, oxo, alkyl or a combination thereof,

Cycloalkylalkyl having 4 to 12 carbon atoms,                 

Cycloalkylalkyl having 4 to 12 carbon atoms, substituted one or more times with halogen, oxo, alkyl or a combination thereof,

Partially unsaturated carbocyclic groups having 5 to 14 carbon atoms,

Partially unsaturated carbocyclic groups having 5 to 14 carbon atoms, substituted one or more times with halogen, alkyl, alkyloxy, nitro, cyano, oxo or combinations thereof,

Arylalkyl having 7 to 26 carbon atoms,

Arylalkyl having 7 to 26 carbon atoms, substituted one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl or combinations thereof,

Heteroarylalkyl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, or

At least one ring atom having 5 to 10 ring atoms wherein the heteroaryl moiety is halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof Is substituted heteroarylalkyl substituted one or more times and / or the alkyl moiety is substituted with halogen, oxo, cyano or combinations thereof;

X is O or S;

R ^{3 ′} is aryl having 6 to 14 carbon atoms,

Halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, Aryl having 6 to 14 carbon atoms, substituted one or more times with alkylsulfinyl, alkylsulfonyl, phenoxy, unsubstituted or substituted with halogen, alkyl or alkoxy, or a combination thereof,

Heteroaryl having 5 to 10 ring atoms wherein at least one ring atom is a heteroatom, or

5-10 rings in which at least one ring atom is heteroatom, substituted one or more times with halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or a combination thereof Substituted heteroaryl with an atom;

L is -NH-, -NR ^{4 '} -, -NHCH _2- , -NR ^4' CH ₂ -or -CH ₂ NR ^{4 '} -;

R ^{4 '} is alkyl having 1 to 12 carbon atoms,

Alkyl having 1 to 12 carbon atoms, substituted one or more times with halogen, oxo, cyano or combinations thereof,

Unsubstituted or halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl Aryl having 6 to 14 carbon atoms, substituted one or more times with alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or a combination thereof,

Heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom,                 

Having 5 to 10 ring atoms, at least one ring atom being a heteroatom, once with halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or a combination thereof Substituted heteroaryl substituted with more than one,

Arylalkyl having 7 to 16 carbon atoms,

Arylalkyl having 7 to 16 carbon atoms, substituted one or more times with halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl or combinations thereof,

Heteroarylalkyl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, or

At least one ring atom has 5 to 10 ring atoms wherein the heteroaryl moiety is halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or A substituted heteroarylalkyl substituted one or more times in combination, and / or in which the alkyl moiety is substituted with halogen, oxo, cyano or combinations thereof.

The compounds of the present invention are effective in inhibiting or modulating the activity of PDE4 in animals, for example mammals, especially humans. The compound has nervous system activity, in particular the activity affects cognition, including long-term memory. The compounds are also effective in the treatment of diseases associated with a decrease in cAMP levels. This includes, but is not limited to, inflammatory diseases. The compounds may also function as antidepressants or may be useful in the treatment of cognitive and negative symptoms of schizophrenia.

Assays for determining PDE inhibitory activity, and selectivity of PDE4 inhibitory activity and PDE4 isoenzyme inhibition, are known in the art. See, for example, US Pat. No. 6,136,821, the disclosure of which is incorporated herein by reference.

According to another aspect of the invention, it is useful as an intermediate for the preparation of the PDE4 inhibitors described herein (eg, PDE4 inhibitors of Formula I), and / or in the synthesis of radio-labeled analogs of the PDE4 inhibitors herein Useful compounds are provided.

Thus, intermediate compounds are provided which correspond to compounds of formula I, wherein R ² , R ³ and R ⁴ are as defined above for formula I, but R ¹ is H, tert-butyldimethylsilyl- or a suitable phenolic protecting group. Suitable phenolic protecting group is, for example, literature [Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 246-293. The intermediate may also react, for example, by removing a protecting group and reacting the resulting compound with R ¹ as H with an appropriate radiolabeling reagent such that radioactivity with R ¹ as ³ H ₃ C-, ¹⁴ CH ₃ -or ¹¹ CH _3-. Useful for synthesizing labeling compounds. The radio-labeled compound is useful for determining the tissue distribution of the compound in animals by PET imaging techniques for in vivo, ex vivo and in vitro binding studies.

Also provided are intermediate compounds corresponding to compounds of formula I, wherein R ¹ , R ³ and R ⁴ are as defined above for formula I but R ² is H, tert-butyldimethylsilyloxy- or a suitable phenolic protecting group. . Suitable phenolic protecting group is, for example, literature [Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 3 ^rd Edition, John Wiley & Sons, 1999, pp. 246-293. Compounds in which R ² is H are useful as intermediates, for example as a backbone for application in parallel or combinatorial chemistry. The compounds are also useful for the introduction of radio-labels such as ³ H, ¹⁴ C or ¹¹ C.

As described above, compounds of formula (II) in which R ¹ , R ² and R ⁴ are described above are useful as intermediates for the preparation of compounds of formula (I) in which R ³ is not H.

In addition, as described above, compounds of formula III wherein R ¹ , R ² and R ³ have been described above are useful as intermediates for the preparation of compounds of formula I in which R ⁴ is not H.

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

Alkyl (eg, alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), as a group or substituent itself, or as part of a group or substituent, is 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. It represents a carbon atom, in particular a straight or branched chain aliphatic hydrocarbon radical having 1 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, dimethylbutyl and the like.

Substituted alkyl groups are those alkyl groups in which one or more positions are substituted with halogen, oxo, hydroxyl, C _1-4 -alkoxy and / or cyano. Halogen is the preferred substituent, in particular F and Cl.

Alkoxy represents an alkyl-O- group and alkoxyalkoxy represents an alkyl-O-alkyl-O- group, wherein the alkyl moiety is as mentioned above. Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy and methoxyethoxy Include. Preferred alkoxy groups are methoxy and ethoxy. Likewise, alkoxycarbonyl represents alkyl-O-CO-, wherein the alkyl moiety is as mentioned above. For example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

Cycloalkyl denotes monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radicals having 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, norbornyl, 1-decalin, adamant-1-yl and adamant-2-yl. Other suitable cycloalkyl groups are spiropentyl, bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, spiro [2.4] heptyl, spiro [2.5] octyl, bicyclo [5.1.0] octyl, spiro [2.6 ] Nonyl, bicyclo [2.2.0] hexyl, spiro [3.3] heptyl, bicyclo [4.2.0] octyl and spiro [3.5] nonyl. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl. Cycloalkyl groups can be substituted, for example halogen and / or alkyl groups.

Cycloalkylalkyl refers to a cycloalkyl-alkyl radical in which the cycloalkyl and alkyl moieties are as defined above. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

Aryl, either as a group or substituent itself, or as part of a group or substituent, is an aromatic carbocyclic radical comprising 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, in particular 6 to 10 carbon atoms. Indicates. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups are for example halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, And those aryl groups substituted one or more times with alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and phenoxy.

Arylalkyl refers to aryl-alkyl-radicals in which the aryl and alkyl moieties are according to the above. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, pentyl and naphthylmethyl.                 

Heteroaryl refers to an aromatic heterocyclic group having one or two rings in which at least one ring atom is a heteroatom and a total of 5 to 10 ring atoms. Preferably, the heteroaryl group comprises 1 to 3, in particular 1 or 2 hetero-ring atoms, selected from N, O and S. Suitable heteroaryl groups are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, diallyl, oxatiallyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Oxatriazolyl, Dioxazolyl, Oxathiazolyl, Tiadiazolyl, Pyridyl, Pyridazinyl, Pyrimidinyl, Pyrazinyl, Triazinyl, Oxazinyl, Isoxazinyl, Oxathiazinyl, Oxadiazinyl, Benzofura Nil, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindoleyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, furinyl, benzopyranyl, Quinolinyl, isoquinolinyl, cynolinyl, 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 inclusive .

Suitable heteroaryls are those heteroaryls in which at least one portion is substituted with, for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino and dialkylamino Group.

The heterocycle is a heteroaromatic group, and preferably a non-aromatic cyclic group comprising at least one hetero-ring atom selected from N, S and O, for example tetrahydrofuranyl, piperidinyl and pyrrolidinyl It includes.

Heterocycle-alkyl refers to heterocycle-alkyl groups where the heterocyclic and alkyl moieties are as described above. Suitable examples include pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl and isoquinolinylmethyl.

Partially unsaturated carbocyclic structures are nonaromatic monocyclic or bicyclic structures containing from 5 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, wherein the ring structure comprises one or more C═C bonds . Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.

Alkenyl refers to a straight or branched chain aliphatic radical containing 2 to 12 carbon atoms, each of which at least one -CH ₂ -CH ₂ -structure is substituted with CH═CH—. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl and 2-pentenyl.

Alkynyl refers to a straight or branched chain aliphatic radical containing 2 to 12 carbon atoms, each of which at least one -CH ₂ -CH ₂ -structure is substituted with -C≡C-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl and 2-butynyl.

Acyl is an alkanoyl radical having 1 to 13 carbon atoms where the alkyl moiety may be substituted by halogen, alkyl, aryl and / or alkoxy, or the aryl moiety may be replaced by halogen, alkyl and / or alkoxy, for example. Aroyl radicals having from 7 to 15 carbon atoms which may be present. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.

Substituted radicals preferably have 1 to 3 substituents, in particular 1 to 2 teeth.

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

R ² is preferably cycloalkyl, in particular cyclopentyl.

R ² is also preferably aryl or arylalkyl, especially substituted or unsubstituted phenyl or phenylalkyl, for example phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl Phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenylethyl, chlorophenylethenyl, chlorophenoxyethyl, chlorophenylpropyl, methoxyphenpropyl, methoxyphenbutyl, chlorophenbutyl, Nitrophenbutyl, chlorophenylaminoethyl and the like.

R ² is also preferably an unsubstituted or substituted partially unsaturated carbocyclic group, in particular cyclohexenyl, cyclohexadienyl, indan-2-yl.

R ² is also preferably an alkyl group having 1 to 8 carbon atoms, in particular 1 to 4 carbon atoms, substituted or unsubstituted, for example methyl, difluoromethyl, trifluoromethyl and methoxyethyl to be.

R ² is also preferably a heterocyclic or heterocycle-alkyl group, in particular a heterocyclic group having from 5 to 6 ring atoms and from 1 to 2 hetero-ring atoms selected from N, O and S, for example Tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like.

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

R ³ is preferably hydrogen, alkyl having 1 to 4 carbon atoms (eg methyl, ethyl, n-propyl or n-butyl), arylalkyl (eg substituted or unsubstituted benzyl, pen Ethyl and phenpropyl), or heteroarylalkyl groups (eg, substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinyl Methyl and quinolinylmethyl). Preferred substituents for the aryl and heteroaryl portions of R ³ are F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ and CN.

R ⁴ is preferably aryl or heteroaryl, in particular phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl and isoquinolinyl, in each case unsubstituted or Replaced more than once. Preferred substituents are OH, F, Cl, CF ₃ , alkyl (eg methyl or ethyl), alkoxy (eg methoxy and ethoxy), CN, vinyl, CH ₂ OH, CONHOH, CONH ₂ , methylene Deoxy, COOH and combinations thereof.

In addition, when R ⁴ is aryl, in particular phenyl, preferred substituents are R ⁵ -L-, for example R ^5- , R ⁵ -O-, R ⁵ -CO-, R ⁵ -NH-CO-, R ⁵ -S0 ₂ -NH-, R ⁵ -SO ₂ -NH-alkylene-O-, NH ₂ -alkyl-NH-CO-, R ⁵ -alkylene-NH-CO-, alkyl-CO-NH-alkyl And methyl, ethyl, Cl, F, CN, OCH ₃ , CF ₃ , amino, nitro, HOCH ₂ and COOH.

When R ⁴ is aryl substituted with R ⁵ -S0 ₂ -NH-, it is preferably a substituted phenyl group and R ⁵ is preferably methyl, ethyl, propyl or phenyl.

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

When R ⁴ is aryl substituted with R ⁵ -L-, it is preferably substituted phenyl. Preferred R ⁵ groups in this case include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl or methylpiperadinyl, 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-.

Preferred PDE4 inhibitors according to the invention are also compounds which correspond to formula I but are described by sub-formulas la-h with the following preferred groups.

Ia: R ¹ is methyl or CHF ₂ ; R ² is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl or heterocyclic, respectively; R ³ is substituted or unsubstituted H, alkyl, arylalkyl or heteroarylalkyl, respectively; R ⁴ is substituted or unsubstituted aryl or heteroaryl, respectively.

Ib: R ³ is substituted or unsubstituted heteroarylalkyl.

Ic R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydrofuranyl).

Id: R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl; Each R ³ is substituted or unsubstituted heteroarylalkyl; R ⁴ is substituted or unsubstituted aryl or heteroaryl.

Ie: R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted heteroarylalkyl.

If R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted heteroarylalkyl; R ⁴ is substituted or unsubstituted phenyl.

Ig R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl or pyrazinylmethyl, or methyl, ethyl or propyl, respectively; R ⁴ is phenyl or phenyl substituted with 1 to 3 substituents.

Ih R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl or pyrazinylmethyl, or methyl, ethyl or propyl, respectively; R ⁴ is substituted or unsubstituted phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl or isoquinolinyl, respectively.

Preferred PDE4 inhibitors according to the invention are also compounds represented by the formulas IIa-IId which correspond to formula II but which have the following preferred groups.

IIa: R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydrofuranyl); R ⁴ is substituted or unsubstituted phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, respectively.

IIb: R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydrofuranyl); R ⁴ is phenyl unsubstituted or substituted with methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido or substituted with carboxy or alkoxycarbonyl or Unsubstituted 3-pyridyl.

IIc: R ¹ is methyl; R ² is cyclopentyl; R ⁴ is substituted or unsubstituted phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, respectively.

IId: R ¹ is methyl; R ² is cyclopentyl; R ⁴ is phenyl unsubstituted or substituted with methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl or ethylsulfonamido or substituted with carboxy or alkoxycarbonyl or Unsubstituted 3-pyridyl.

Preferred PDE4 inhibitors according to the invention are also compounds represented by the subformulas IIIa-IIId which correspond to formula III but have the following preferred groups.

IIIa: R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydrofuranyl); R ³ is substituted or unsubstituted benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl or pyrrolylmethyl, respectively .

IIIb: R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydrofuranyl), and R ³ is each substituted or Unsubstituted pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl.

IIIc: R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl Isisoimidazolyl, thiazolylmethyl or pyrrolylmethyl.

IIId: R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted pyrazinylmethyl or pyridylmethyl, respectively.

Furthermore, preferred PDE4 inhibitors according to the invention are compounds which correspond to formula IV but are represented by the subformulas IVa-IVp having the following preferred groups.

IVa: R ¹ is methyl or CHF ₂ .

IVb: R ¹ is methyl or CHF ₂ and B is N.

IV: R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydro Furanyl).

IVd: R ¹ is methyl or CHF ₂ , B is N, R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly ( 3R) -tetrahydrofuranyl).

IVe: R ¹ is methyl or CHF ₂ and R ⁴ is substituted or unsubstituted 3-pyridyl or phenyl, respectively.

IVf: R ¹ is methyl or CHF ₂ , B is N and R ⁴ is substituted or unsubstituted 3-pyridyl or phenyl, respectively.

IV: R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydro Furanyl) and R ⁴ is substituted or unsubstituted 3-pyridyl or phenyl.

IVh: R ¹ is methyl or CHF ₂ , B is N, R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly ( 3R) -tetrahydrofuranyl), and R ⁴ is substituted or unsubstituted 3-pyridyl or phenyl.

IV: R ¹ is methyl or CHF ₂ and R ⁴ is phenyl substituted at the 3- or 4- position.

IVj: R ¹ is methyl or CHF ₂ , B is N and R ⁴ is phenyl substituted at the 3- or 4- position.

IVk: R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydro Furanyl) and R ⁴ is phenyl substituted at the 3- or 4- position.

IVl: R ¹ is methyl or CHF ₂ , B is N, R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly ( 3R) -tetrahydrofuranyl), and R ⁴ is phenyl substituted at the 3- or 4- position.

IVm: R ¹ is methyl or CHF ₂ , R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetra Zol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5- Mono-phenyl or 4-hydroxymethyl-phenyl.

IVn: R ¹ is methyl or CHF ₂ , B is N, R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido- Phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4- Tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl.

IVo: R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly (3R) -tetrahydro Furanyl), and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl- Phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl or 4- Hydroxymethyl-phenyl.

IV: R ¹ is methyl or CHF ₂ , B is N, R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl) or tetrahydrofuranyl (particularly ( 3R) -tetrahydrofuranyl), R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazole -5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4- Tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl.

In a preferred aspect, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier and, optionally, other active agents discussed below; For example, PDE4 enzymes, in particular homogeneous, as measured in vitro or in vivo (in animals, for example in animal models or in mammals or in humans) or by conventional assays or those described herein. Methods of inhibiting enzymes; Methods of treating neurological syndromes, such as memory loss, especially long term memory, cognitive impairment or reduction, memory impairment, and the like; In mammals, for example in humans, for example, methods of treating disease states modulated by the PDE4 activity referred to herein.

The compounds of the present invention can be prepared conventionally. Some methods that can be used are shown below. All starting materials are known or conventionally prepared from known starting materials.

Type 1 starting nitrophenols are either commercially available (eg R1 = CH ₃ ) or prepared by known procedures (eg R1 = CHF ₂ or both R1 and R2 = CHF ₂ , literature [ Mueller, Klaus-Helmut.Eur. Pat. Appl. (1994), 8 pp.CODEN: EPXXDW EP 626361 A1; Touma, Toshihiko; Asai, Tomoyuki.Jpn.Kokai Tokkyo Koho (1999), 6 pp. A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor.Int.Symp.Wood.Pulping Chem. , 1995, 8th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 Al 19960808). Aniline intermediate 3 is prepared in two steps. First, the addition reaction gives intermediate 2, and then the nitro group is reduced. Intermediate nitro compound 2 can be prepared by a number of known procedures, such as a Mitsunobu reaction or a standard alkylation reaction. Compounds in which R ² is aryl or heteroaryl are either copper catalyzed with aryl or heteroaryl iodide under Ullman conditions or in the presence of bases such as copper catalysts (eg Cu (OAc) ₂ ) and TEA Under the coupling of aryl-, vinyl- or heteroaryl-boronic acid with phenol 2. Mitsunobu reactions between suitably substituted nitrophenols and primary or secondary alcohols with azodicarboxylates (eg DEAD, DIAD) and appropriate phosphines (eg Ph ₃ P, Bu ₃ P) are alkylated. Nitrophenol 2 which has been prepared. Mitsunobu reactions are generally carried out in aprotic solvents such as dichloromethane or THF. Alternatively, alkylation is a reaction between an appropriately substituted nitrophenol and an alkyl halide in a polar aprotic solvent (eg DMF or CH ₃ CN) in the presence of a base (eg K ₂ CO ₃ or NaH). It can be performed as.

Nitrocatechol 2 is followed by corresponding aniline by standard methods in the art, such as hydrogenation with a suitable catalyst (eg, Pd on carbon) in a polar protic solvent (eg MeOH or EtOH) under a hydrogen atmosphere. Reduced to three. Alternatively, nitrocatechol 3 can be prepared using a hydride source (e.g., NaBH ₄ ) and a transition metal catalyst (e.g., NiCl ₂ , Pd on carbon) or in an inorganic acid solution (e.g., HCl). For example, by using Zn, Sn, Fe) can be reduced to obtain the corresponding aniline. Generally, polar protic solvents such as ethanol or methanol are used in this reaction.

N-arylalkylaniline 4 can be synthesized by standard methods in the art such as reductive amination reactions, alkylation reactions or by reduction of the corresponding amides. For example, in the presence of a borohydride reducing agent such as NaBH ₄ or NaBH ₃ CN, together with an acid catalyst such as acetic acid or pTsOH, the reductive amination reaction of aryl or arylalkyl aldehydes with an appropriately substituted aniline is the desired N. -Arylalkylaniline is provided. In general, these reactions occur in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.

N-arylalkylaniline 4 is easily N-arylated by standard methods in the art, including Ullman coupling reactions, metal-catalyzed coupling or aromatic nucleophilic substitution reactions. For example, using a palladium catalyst (eg Pd ₂ dba ₃ ), a bulk electron rich phosphine ligand (eg tributylphosphine) and an appropriate base (eg NaOtBu) , N-arylalkyldiphenylamine is obtained by metal catalyzed reaction between N-benzylaniline and aryl halide. Nickel and copper catalysts have also been used. Solvents useful for this reaction include nonpolar aprotic solvents such as toluene, benzene, xylene, tetrahydrofuran and ether. When synthesizing compounds of type 5 wherein R 4 is alkoxycarbonylphenyl, it is advantageous to couple the amine 4 with 1.1 equivalents of tert-butyl 3-iodobenzene, 22 mol% of (tBu) ₃ P, 5.5 mol It is advantageous to use% Pd ₂ (dba) ₃ and 1.3 equivalents of tBuONa.

Carboxylic ester intermediate 6 can be hydrolyzed under acidic or basic conditions to yield the corresponding carboxylic acid 7. For example, ethyl ester (R5 = Et) can be hydrolyzed using a mixture of an aqueous base (eg NaOH, KOH) and a water miscible solvent (eg EtOH, THF). On the other hand, t-butyl ester (R 5 = t-butyl) can be hydrolyzed in water miscible organic solvents using aqueous acids (eg HCl, formic acid, TFA) if necessary.                 

THP by coupling a protected tetrazole bromo or iodobenzene (eg 5- (3-iodophenyl) -2- (2-tetrahydropyran) tetrazole) with an N-substituted aniline derivative 4 Obtained protected tetrazole 8 Hydrolysis of THP-protected tetrazole 8 can be carried out by using an aqueous acid such as HCl in water and a miscible solvent such as THF or EtOH to give tetrazole 9. THP tetrazole 8 can also be oxidatively segmented using reagents such as DDQ and CAN in halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and the like to obtain tetrazol 9.

Alternatively, tetrazol analog 9 can be prepared from the corresponding nitrile by treatment with azide ions (e.g., KN ₃ , NaN _3, etc.) and a positive source (e.g., NH ₄ Cl) in a polar aprotic solvent such as DMF. Can be prepared. They can also be prepared by treating with azide ions and Lewis acids (eg, ZnBr ₂ ) in water, if necessary, using a water miscible cosolvent such as isopropanol. Another process is the treatment of nitriles with tin or silicon azide (e.g. Me ₃ SiN ₃ , Bu ₃ SnN ₃ ) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like. will be.

Diphenylamine 10 is prepared by coupling an appropriately substituted aniline 3 such as 3-cyclopentyloxy-4-methoxyaniline with arylboronic acid in the presence of a base such as triethylamine and a copper catalyst such as copper acetate. (As described in Chan et al, Tetrahedron Lett. , 39, 2933-2936 (1998)). Generally, nonpolar aprotic solvents such as benzene, toluene or xylene, as well as halogenated solvents such as dichloromethane, chloroform, dichloroethane and the like are used. Such diphenylamines (eg 10) may be more preferably synthesized by metal catalyzed amination reactions. For example, bases (eg K ₃ PO ₄ , CsC0 ₃ or NaOtBu) and palladium or nickel catalysts such as Pd (dppf) Cl ₂ , ligands (eg dppf) and bases (eg Reaction of an appropriately substituted aniline 3 with an arylhalide in the presence of NaOtBu) (see JACS . 1996, 118 , 7217) or an appropriately substituted aniline 3 with Pd ₂ dba ₃ , P (tBu Reaction with a bulk electron rich phosphine and a base (e.g. NaOtBu) such as ₃ ) (see J. Org. Chem. 1999, 64, 5575) gives the desired diphenylamine 10. The solvents most commonly used in this type of reaction include nonpolar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether and the like.

Diphenylamine 10 is then iodomethane, ethylbromide, benzylchloride, 3- (chloromethyl) pyridine in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide. , N-substituted by alkylation with various alkyl halides or arylalkyl halides, or salts thereof, such as, but not limited to, 4- (chloromethyl) -2,6-dichloropyridine and 4- (bromomethyl) benzoic acid Diphenylamine 5 can be obtained. Solvents useful in this reaction include aprotic solvents such as benzene, toluene, tetrahydrofuran, ethers, DMF and the like.

Carboxamide 11 can be formed by further treatment of carboxylic acid 7 using standard methods in the art. For example, the carboxylic acid can be treated with an appropriate primary or secondary amine in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC and a base such as Et ₃ N or DIEA to obtain a carboxamide. In general, these reactions occur in nonpolar aprotic solvents such as dichloromethane, chloroform or dichloroethane.

Carboxyl ester 6 or acid 7 can be reduced using standard methods in the art to obtain the corresponding carboxaldehyde or hydroxymethyl analogs. For example, aryl ethyl esters (e.g. Formula 6, R5 = ethyl) are treated with the appropriate reducing agent (e.g. LAH, DIBAL, etc.) in an aprotic solvent such as ether or THF to give the corresponding carboxaldehyde or hydroxide Roxymethyl analogs can be obtained. Such aldehydes and alcohols can be further derived by using standard methods in the art.

Similarly, carboxamides (eg, formula 11) and nitriles can be used to obtain the corresponding substituted amine or aminomethyl analogs using standard methods in the art. For example, aryl carboxamide 11 is reduced in an aprotic solvent (e.g. benzene, toluene, ether, THF, etc.) with an appropriate reducing agent (e.g. LAH) to obtain the corresponding substituted aminomethyl analogue. Can be. On the other hand, reduction of the aryl nitrile yields the corresponding primary aminomethyl analog.

Reduction of the nitrobenzene compound 12 to the corresponding aniline 13 by standard methods in the art, such as hydrogenation, using an appropriate catalyst (e.g. Pd on carbon) in a polar protic solvent (e.g. EtOH, MeOH, etc.). Can be. In addition, in a polar protic solvent such as EtOH, the nitrobenzene 12 is reduced using a hydride source (e.g., NaBH ₄ ) and a transition metal catalyst (e.g., NiCl ₂ , Pd on carbon) to obtain the corresponding aniline 13 You can get it. These anilines can then be further substituted by standard methods in the art. For example, type 13 aniline may be alkylated, acylated or sulfonylated to yield the corresponding N-alkyl amines, carboxamides (eg, Formula 15) or sulfonamides (eg, Formula 14), respectively. You can get it. For example, in the presence of a base (e.g., Et ₃ N, pyridine, DIEA, etc.), aniline and an appropriate sulfonyl halide or sulfonic anhydride (for example, MeSO ₂ Cl, EtSO ₂ Cl, BnSO ₂ Cl, PhSO ₂ Sulfonamide) can be prepared from Cl and the like. Suitable solvents for this reaction include nonpolar aprotic solvents such as dichloromethane, chloroform, ethers and the like.

Type 16 trialkylsilyl ethers are prepared as described in Scheme 1. tert-Butyldimethylsilyl protected catechol intermediate 16 is prepared by the use of a fluoride ion source (eg Bu ₄ NF) in an aprotic solvent such as ether or THF or under acidic conditions (eg KF, 48% HBr). , DMF) with ease by the method of the number of documents, such as (see the literature [Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1999, pp. 273-276]) Deprotected. The resulting phenol 17, a very useful synthetic intermediate, can then be alkylated by methods that are standard in the art and by methods similar to those described for alkylation of nitrophenol 2 in Scheme 1. For example, by reaction with a vinyl-, aryl- or heteroaryl-boronic acid by Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by ulman type aryl coupling or in the presence of a copper catalyst By

Haloalkoxy intermediate 18 prepared by alkylation of the corresponding phenol can be alkylated by reaction with a substituted amine, alcohol or thiol in the presence of a base to obtain an analogue such as 19. For example, alkyl halides can be aminated with a suitable primary or secondary amine and a base such as K ₂ CO _{3 in a} polar aprotic solvent such as THF, DMF or CH ₃ CN.

Many of these synthesis procedures are described in more detail in the Examples below.

Those skilled in the art will appreciate that some compounds of formulas (I) and (I ′) may exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention have one or more asymmetric carbon atoms, and therefore not only in the form of optical isomers, but also in the form of racemic or non-racemic mixtures thereof, and inter alia, in the form of diastereomers and diastereomeric mixtures. May exist. All such compounds are within the scope of the present invention, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers and substantially pure and pure enantiomers. Substantially pure enantiomers comprise less than or equal to 5% w / w, preferably less than or equal to 2%, most preferably less than or equal to 1% of the corresponding opposite enantiomer.

Optical isomers can be obtained by cleavage of the racemic mixture according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases or by forming covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, dytoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of physical and / or chemical differences by methods known to those skilled in the art, for example by chromatography or fractionation. The optically active base or acid is then released from the separated diastereomeric salt. Other methods of separation of optical isomers include the use of chiral chromatography (eg, chiral HPLC columns) with or without conventional induction, optimally selected to maximize separation of the enantiomers. Suitable chiral HPLC columns are prepared by Diacel, all of which can be selected in general, for example, but especially Chilacel OD and Chilacel OJ are suitable. Also useful are enzymatic separations with or without derivatives. Likewise, optically active compounds of formula (I) and (I ′) can be obtained by chiral synthesis using optically active starting materials.

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

The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrate, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, diglucose Nate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2 Hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, Pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

Preferably, the resulting salt is a pharmaceutically acceptable salt for administration to a mammal. However, pharmaceutically unacceptable salts of the compounds are suitable for converting the salts back to free base compounds by isolating the compounds as intermediates, for example as salts, and then treating the alkaline reagents. If necessary, the free base can then be converted to a pharmaceutically acceptable acid addition salt.

The compounds of the present invention can be administered alone or as active ingredients of the formulation. Thus, the present invention also encompasses pharmaceutical compositions of compounds of formula (I) or (I ′), for example comprising one or more pharmaceutically acceptable carriers.

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

In view of the high degree of PDE4 inhibition, the compounds of the present invention may be administered to anyone who requires or wants to inhibit PDE4 and / or enhance cognition. Administration can be effected according to the needs of the patient, for example orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, into the skin and by infusion), by inhalation, rectally, intravaginally, locally, Topically, it may be performed transdermally and by ocular administration.

Various solid oral dosage forms can be used for the administration of the compounds of the invention, including solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. Compounds of the present invention may include, but are not limited to, suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavors, lubricants, and the like, and various pharmaceutically acceptable compounds known in the art. And carriers, diluents (eg sucrose, mannitol, lactose, starch) and excipients. In addition, sustained release capsules, tablets and gels are advantageous for administering the compounds of the present invention.

In addition, various liquid oral dosage forms can be used to administer the compounds of the present invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms also include suitable inert diluents and preservatives known in the art such as water, wetting agents, sweeteners, flavoring agents, as well as suitable known in the art such as emulsifiers and / or suspending agents of the compounds of the invention. Excipients may be included. The compounds of the present invention can be injected intravenously, for example in the form of isotonic sterile solutions. Other manufactures are also possible.

Suppositories for rectal administration of a compound of the present invention may be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylate and polyethylene glycol. Formulations for vaginal administration may be present in the form of accessories, tampons, creams, gels, pastes, foams or sprays which comprise, in addition to the active ingredient, suitable carriers known in the art.

Pharmaceutical compositions for topical administration may be in the form of creams, ointments, stains, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eyes, ears or nose. In addition, topical administration may include transdermal administration via means such as transdermal patches.                 

In addition, aerosol formulations suitable for administration via inhalation may be prepared. For example, for the treatment of airway disorders, the compounds according to the invention can be administered via inhalation in the form of powders (eg micronized) or in the form of granular solutions or suspensions. Aerosol formulations may be placed in pressurized acceptable sandpaper.

The compound may be used as the sole active agent or in other drugs used in the treatment of cognitive disorders and / or in the treatment of psychosis, for example other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators, ampakine NMDAR modulators, mGluR It may be administered in combination with other pharmaceutical agents such as modulators and cholinesterase inhibitors (eg donepezil, rivastimine and glantanamin). In such mixtures, each active ingredient may be administered according to their usual dosage range or at a dosage below the usual dosage range.

The present invention further includes a method of treatment comprising inhibition of PDE4 enzyme. Thus, the present invention encompasses methods for the selective inhibition of PDE4 enzymes in animals, for example in mammals, in particular humans, in which case such inhibition will alleviate conditions involving neurological syndromes such as memory loss, especially long term memory loss. Can have a therapeutic effect. Such methods include, as disclosed herein, administration to an animal, in particular a mammal, most particularly a human, in need thereof, alone or as part of a formulation.

Memory impairment states appear to be impaired in the ability to learn new information and / or inability to come up with previously learned information. Memory disorders are the primary symptoms of dementia and are also associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Crutzfeldt-Jakob disease, HIV, cardiovascular disease, and head trauma, as well as senile dementia. It may be a symptom.

Dementia is a disease that involves memory loss and additional intellectual disabilities separate from memory. The present invention includes methods of treating patients suffering from memory disorders in all forms of dementia. Dementia is classified according to its cause, neurodegenerative dementia (eg Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease), vascular disorders (eg infarction, bleeding, heart disorder), mixed vascular and Alzheimer's disease, bacterial meningitis , Creutzfeldt-Jakob disease, multiple sclerosis, traumatic (eg subdural hematoma or traumatic brain injury), infectious (eg HIV), hereditary (Down syndrome), toxicity (eg heavy metals, alcohol, some Drugs), metabolism (eg vitamin B12 or folic acid deficiency), CNS hypoxia, Cushing's disease, psychiatry (eg depression and schizophrenia) and hydrocephalus.

The present invention includes methods of treating memory loss separate from dementia, including mild cognitive impairment (MCI) and aging cognitive decline. The present invention includes a method of treating a memory disorder that is the result of a disease. In another application, the present invention includes methods of treating memory loss resulting from the use of general anesthesia, chemotherapy, radiation therapy, postoperative trauma and therapeutic procedures.

The compounds can be used to treat psychiatric conditions including schizophrenia, bipolar depression or mood swings, major depression and drug addiction and morphine dependence. These compounds can enhance arousal. PDE4 inhibitors can be used to elevate cAMP levels and prevent neurons from apoptosis. In addition, PDE4 inhibitors are known to be anti-inflammatory. Combinations of anti-apoptotic and anti-inflammatory properties can cause these compounds to include strokes, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and multiple systems atrophy (MSA) or It is useful for treating neurodegeneration resulting from injury.

Thus, according to a preferred embodiment, the invention comprises administering an effective amount of a compound according to formula (I) or (I ′) or a pharmaceutically acceptable salt thereof, for example Alzheimer's disease, schizophrenia, Parkinson's disease HIV and cardiovascular diseases, as well as other neurological conditions including Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarction dementia and acute neuronal disease Methods of treating a patient suffering from a memory disorder caused.

In addition, the compounds of the present invention can be used in methods of treating patients suffering from disease states characterized by reduced function of NMDA, such as schizophrenia. In addition, the compounds can be used to treat various forms of depression, such as psychosis characterized by elevated PDE4 levels, such as mood swings, major depression and depression associated with psychiatric and neurological disorders.

As mentioned, the compounds of the present invention also exhibit anti-inflammatory activity. As a result, the compounds of the present invention are useful for the treatment of various allergic and inflammatory diseases, in particular disease states characterized by a decrease in the amount of cyclic AMP and / or an increase in the amount of phosphodiesterase 4. Thus, according to a further embodiment of the present invention there is provided a method of treating allergic and inflammatory disease states comprising administering an effective amount of a compound according to formula (I) or (I ′) or a pharmaceutically acceptable salt thereof. . These disease states include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis , Crohn's disease, myocardial and brain reperfusion injury, chronic tetramyelitis, endotoxin shock, adult respiratory distress syndrome, cyst fibrosis, artery restenosis, arteriosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, fever (pyresis), diabetes , Pneumoconiosis, chronic obstructive airway disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple gland, sunburn, itching in the anal area, alopecia areata, hypertrophic scar, disc lupus erythema, Systemic lupus erythematosus, follicular and extensive purulent dermatosis, endogenous and exogenous acne, acne strawberry nose, Behcet's disease, anaphylactic purpura kidney , Including inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune disease, etc.

PDE4 inhibitors for inhibiting tumor necrosis factor for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis and other inflammatory diseases are known in the art. See, for example, WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 and US 5,935,9778. In addition, these references describe assays for the determination of PDE4 inhibitory activity and methods of synthesizing such compounds. The entire disclosure of these documents is incorporated herein by reference.

PDE4 inhibitors are antibiotics to prevent or ameliorate osteoporosis, to treat cardiovascular disease by aggregating cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), and to prolong the long-term inhibition of mesenchymal-cell proliferation after transplantation. For the treatment of urinary obstruction, which is secondary to benign prostatic hyperplasia, uterine contractions, to treat B cell chronic lymphocytic leukemia (B-CLL), to inhibit chemotaxis and reduce the invasion of colon cancer cells To suppress, to reduce pulmonary vascular ischemic perfusion injury (IRI), to corneal hydration, to inhibit IL-2R expression and to prevent the entry of HIV-1 DNA nuclei into memory T cells, to increase glucose-induced insulin secretion Can be used for both prevention and treatment of colitis and to inhibit breast cell degranulation.

The compounds of the present invention may be used alone or as other substances used in the treatment of cognitive disorders and / or in the treatment of psychosis, for example other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amparkin NMDA It can be administered in conjunction with other pharmaceutical agents such as -R modulators, mGluR modulators and cholinesterase inhibitors (e.g. donepezil, rivastimine and glantanamin). In such mixtures, each active ingredient may be administered according to their usual dosage range or at a dosage below the usual dosage range.

The dosage of a compound of the invention can be determined, among other considerations, in particular the particular syndrome to be treated, the depth of symptoms, the route of administration, the frequency of the interval of administration, the specific compound used, the efficacy, the toxicological profile of the compound, and the pharmacokinetic profile of the compound. And the presence of harmful side effects.

Typically, compounds of the present invention are administered to a mammal at a dosage typical for PDE4 billion agents, such as the known compounds mentioned above. For example, the compound may be administered once or in multiple doses, for example at a dose of 0.01-100 mg / kg / day, preferably 0.1-70 mg / kg / day, in particular 0.5-10 mg / kg / day By oral administration. Unit dosage forms may comprise, for example, 0.1-50 mg of active compound. For intravenous administration, the compound may be administered once or in multiple doses, for example 0.001-50 mg / kg / day, preferably 0.001-10 mg / kg / day, in particular 0.01-1 mg / kg / day. It may be administered in a dosage. Unit dosage forms may comprise, for example, 0.1-10 mg of active compound.

In carrying out the process of the present invention, references to particular buffers, media, reagents, cells, culture conditions, etc., are not intended to be limiting but all that one of ordinary skill in the art would recognize would be advantageous or valuable in the specific context in which the discussion is presented. Of course, it should be interpreted as including the relevant substances. For example, often one buffer system or culture may be replaced with another, and similar results may still be obtained if they are not identical. Those skilled in the art will have sufficient knowledge of these systems and methodologies to ensure that such substitutions optimally achieve their purpose in using the methods and procedures disclosed herein without undue experimentation.

The invention will now be further described through the following non-limiting examples. In applying the content of these examples, it should be borne in mind that other and various embodiments of the method disclosed in accordance with the present invention can certainly be presented to those skilled in the art.

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

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

Example 1A

1-cyclopentyloxy-2-methoxy-5-nitrobenzene

Under N ₂ protection, 499.2 mL (4.66 mol) of cyclopentyl bromide was added to a suspension of 525 g (3.104 mol) of 2-methoxy-5-nitrophenol and 643.5 g (4.66 mol) of potassium carbonate in 1 L of dimethylformamide. It was. The suspension was heated to 100 ° C. for 6 hours. 85.8 g (0.62 mol) of potassium carbonate and 50 mL (0.46 mol) of cyclopentyl bromide were added. The suspension was heated to 100 ° C. for 4 hours. TLC showed the reaction was complete (9: 1 DCM: MeOH). The reaction mixture was cooled to room temperature and diluted with 3 L of water and 3 L of ether. The layers were separated and the aqueous layer was reextracted with 2 L of ether. The combined organic layers were washed with 2 L 1 N NaOH, 2 L water and 2 L brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The solid thus obtained was azeotropically mixed with 300 mL of toluene twice to give 736.7 g (99.6% yield) as a yellow solid.

The following compounds were prepared in a similar manner to the 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-1-((3R) -tetrahydrofuryloxy) benzene

1.69 g (10 mmol) of 2-methoxy-5-nitrophenol, 5.24 g (20 mmol) of triphenylphosphine and 1.80 g (20 mmol) of 3- (R) -hydroxytetrahydrofuran in 40 mL of anhydrous tetrahydrofuran To this mixture was added dropwise stirring 4.0 mL (20 mmol) of diisopropylazodicarboxylate, and the mixture was stirred at rt for 16 h. The mixture was diluted with 150 mL of ether, washed with 50 mL of 2 N NaOH (3 times) and 50 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane as eluent (Biotage flash 40 M) to give 1.05 g of product.

The following compounds were prepared in a similar manner to the 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-phenpropyloxy) benzene

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

Example 1C

1- (tert-butyldimethylsilyl) oxy-2-methoxy-5-nitrobenzene

To a mixture of 1.53 g (9.0 mmol) of 2-methoxy-5-nitrophenol and 1.08 g (15.9 mmol) in imidazole in 40 mL of anhydrous DMF, 2.05 g (13.6 mmol) of tert-butyldimethylsilyl chloride are added with stirring, The mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was further washed with 200 mL of 50% ethyl acetate in hexanes, and the filtrates were combined and concentrated in vacuo to give 2.01 g of the product as a tan crystalline solid. ¹ H NMR (CDC1 ₃ ) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Example 2

3-cyclopentyloxy-4-methoxyaniline

Under N ₂ protection, 250 g (1.054 mol) of 1-cyclopentyloxy-2-methoxy-5-nitrobenzene were added to a suspension of 25 g of 10% Pd on activated carbon in 4 L of ethanol. The reaction mixture was degassed three times under vacuum. The reaction mixture was stirred vigorously with hydrogen gas flowing over the reaction mixture. After 4 hours, the reaction was confirmed to be complete by TLC (5: 1 hexanes: ethyl acetate). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in vacuo to 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 to the 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 106.55 g (0.995 mol) of 3-pyridinecarboxaldehyde in 5 L of methanol was added 208.38 g (1.005 mol) of 3-cyclopentyloxy-4-methoxyaniline and 200 mg of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred for 4 hours. The flask was then cooled to 0 ° C. and 37.64 g (2.3 mol) of sodium borohydride were added in portions over 4 hours. The reaction mixture was allowed to warm to room temperature with stirring over 16 hours. TLC showed the reaction was complete (1: 3 hexanes: ethyl acetate). The solvent was evaporated until approximately 0.5 L of slurry remained. The slurry was diluted with 1 L of water and extracted twice with 2 L of ethyl acetate. The combined organic layers were washed with 500 mL brine, dried over sodium sulfate and concentrated to afford 300 g (100% yield) of the desired product as a brown viscous liquid. ¹ H NMR (CDC1 ₃ ) δ 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 ( s, 1H), 6.13 (dd, J = 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 ( m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner to the 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-methoxyaniline

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

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

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

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

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

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) aniline

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

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

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

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

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

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

r) 3-cyclopentyloxy-4-methoxy-N- [1- (2-pentethyl)] aniline

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

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

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

v) N-[(cyclohex-3-en-l-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-methoxyxylbenzyl) -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-phenpropyloxy) -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

1l) N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3- (3-phenpropyloxy) aniline

mm) 4-methoxy-3- (3-phenpropyloxy) -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-phenpropyloxy) -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                 

tt) 3-cyclopentyloxy-4-methoxy-N- (3-piperidinemethyl) aniline

uu) 3-cyclopentyloxy-4-methoxy-N- (3- (l-tert-butyloxycarbonyl) piperidinemethyl) aniline

vv) 3-cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) aniline

ww) N- (2-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline

xx) N- (2-chloro-5-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline

yy) 3-cyclopentyloxy-4-methoxy-N- (2-thiazolylmethyl) aniline

Example 4

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

0.59 g (6.10 mmol) of NaOtBu, 360 mg of Pd ₂ dba ₃ , 20 mL of toluene, 0.14 mL of P (tBu) ₃ and N- (3-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline in toluene In a sequence of 20 mL of 1.3 g (4.36 mmol) of solution, 100 mL of oven dried and added to an argon flushed flask. 3.1 g (15 mmol) of iodobenzene was added dropwise with stirring, and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc, washed twice with H ₂ 0 and extracted three times with 15 mL of 3 N HCl. The combined acid extracts were washed with 15 mL of EtOAc and then carefully neutralized with 6 N NaOH to exceed pH 12. The basic solution was extracted twice with 15 mL of EtOAc, then the combined organic fractions were washed with 15 mL of H ₂ 0 and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (Biotage Flash 40 M) using 25% EtOAc in hexane as eluent. The material was further purified by crystallization with hexanes to give 550 mg of a white solid. ¹ H NMR (CDC1 ₃ ) δ8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30-7.10 (m, 3H), 6.90-6.80 (m, 4H), 6.80-6.60 (m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2 H).

The following compounds were prepared in a similar manner to the 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) diphenylamine

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) diphenylamine

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

ff) 4'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'-trifluoromethyldiphenylamine

gg) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) diphenylamine

hh) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-thienylmethyl) -l-naphthylamine

ii) 3-cyclopentyloxy-2 ', 3'-dichloro-4-methoxy-N- (3-thienylmethyl) diphenylamine

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

kk) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3'-methyldiphenylamine

1l) 2'-chloro-3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine

mm) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine

nn) 3-cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) diphenylamine                 

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-tetrahydrofuryloxy) diphenylamine

ss) 4-methoxy-4'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine

tt) 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) -3-((3R) -tetrahydrofuryloxy) diphenylamine

xx) 3′-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine

yy) 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) -tetrahydrofuryloxy) diphenylamine

fff) 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

jjj) 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3 pyridylmethyl) diphenylamine

kkk) tert-butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate                 

11l) ethyl N- (3-cyclopentyloxy) -4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate

mmm) ethyl N- (4-difluoromethoxy-3- (3-tetrahydrofuryloxy) phenyl) -N- (3 pyridylmethyl) -3-aminobenzoate

nnn) ethyl N- (3,4-bis (difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoate

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) diphenyl Amine

rrr) 3-cyclopentyloxy-4-methoxy-3 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenyl Amine

sss) 4-methoxy-4 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) -3-((3R)- Tetrahydrofuryloxy) diphenylamine

ttt) 3-cyclopropylmethoxy-4-methoxy-4 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) di Phenylamine

uuu) 4-difluoromethoxy-4 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) -3-((3R ) -Tetrahydrofuryloxy) diphenylamine                 

vvv) 3-cyclopropylmethoxy-4-difluoromethoxy-4 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl Diphenylamine

www) 3-cyclopentyloxy-4-difluoromethoxy-4 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) Diphenylamine

xxx) 3-cyclopropylmethoxy-4-difluoromethoxy-3 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl Diphenylamine

yyy) bis- (3,4-difluoromethoxy) -3 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) Diphenylamine

zzz) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

aaaa) 3-tert-butyldimethylsilyloxy-3'-chloro-4-methoxy-N- (3-pyridylmethyl) 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) diphenylamine

Example 5

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

A solution of 6.5 g of ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6 N NaOH. The mixture was left for 6 hours, concentrated and diluted with 50 mL of H ₂ O. The aqueous mixture was extracted twice with 50 mL of ether, acidified with AcOH to pH 3 and extracted twice with 50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL H ₂ O and 25 mL brine, dried (MgSO ₄ ) and concentrated. The residue was purified by chromatography on Si0 ₂ (35 g Redisep® column) using a linear gradient of EtOAc and hexane as eluent (50% EtOAc to 70% EtOAc over 20 minutes). 4.8 g of a yellow solid product after drying in vacuo at 60 ° C. for 12 hours. ¹ H NMR (CDC1 ₃ ) δ 11. 15 (bs, 1H), 8.70-8.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H) , 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner to the 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) N- (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-aminobenzoic 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) -3-aminobenzoic acid

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

Example 6

N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoic acid

60 mg (0.13 mmol) of Tert-butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoate were taken up in 2 mL of 98% formic acid Heated at 40 ° C. for 4 h. Formic acid was removed in vacuo and the residue was charged to a silica gel column (RediSef, 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 product as a brown solid. ¹ H NMR (CDC1 ₃ ) δ 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, lH, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H) , 4.54 (p, 1H, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).

The following compounds were prepared in a similar manner to the 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-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine

3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '-[2- (2-tetrahydropyranyl) -2H-tetrazol-5-yl] diphenyl 1.5 g (0.26 mmol) of amine was dissolved in 5 mL of THF and 3 mL of 1 N HCl was added. After 6 hours at room temperature, the mixture was neutralized with saturated sodium bicarbonate solution to pH = 5 and extracted three times with 50 mL of EtOAc. EtOAc extracts were combined together, washed with 50 mL brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was charged into a Readysef column (10 g, silica gel) and the product was eluted over 20 minutes using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc to give 0.96 g of the product as a white powder. Got it. ¹ H NMR (CDC1 ₃ ) 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 = 4.9 Hz, 8.0 Hz ), 7.18 (d, 1H, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.87 (dd, 1H, J = 8.6 Hz, 2.5 Hz), 6.75 (t, 1H, J = 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H).

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

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

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

Example 8 (Method A)

3-cyclopentyloxy-4-methoxydiphenylamine

Method A (see Chan, DMT; Monaco, KL; Wang, RP; Winters, MP, Tetrahedron Lett ., 1998, 39, 2933-2936). A slurry of 207 mg of 4-methoxy-3-cyclopentyloxyaniline, 280 mg of phenylboronic acid, 182 mg of Cu (OAc) ₂ , 280 μL of Et ₃ N and 4.0 mL of CH ₂ CI ₂ was stirred at room temperature for 20 hours. . The black mixture was filtered through silica, eluted with CH ₂ Cl ₂ , concentrated and purified by chromatography on Si0 ₂ using EtOAc / hexane (15/85) as eluent to afford 75 mg of the desired product. . ¹ H NMR (CDC1 ₃ ) δ 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8 H).

The following compounds were prepared in a similar manner to the 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-methoxydiphenylamine

Method B (see Angerw Chem. Int. Ed., 1995, 34 (17), 1348-1351) 3-cyclopentyloxy-4-methoxyaniline 207 mg, iodobenzene 204 mg, NaOtBu 115 mg, A mixture of 9 mg Pd ₂ (dba) ₃ , 12 mg P (o-tol) ₃ and 7 mL of toluene were combined together and warmed to 100 ° C. with stirring for 4 h. The mixture was cooled to rt, diluted with 25 mL of EtOAc, washed with 10 mL of H ₂ O, 10 mL of brine, dried (MgSO ₄ ) and concentrated. The residue was purified by chromatography on Si0 ₂ using EtOAc / hexane (5/95) as eluent to afford 84 mg of the desired product.

The following compounds were prepared in a similar manner to the 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. 1-bromo-2,5-dimethoxy in a mixture of 0.025 mmol (5 mol%) of Pd (dppf) Cl ₂ , 0.075 mmol (3dppf / Pd) of dppf and 0.70 mmol (1.4 equiv) of NaOtBu and 1.0 mL of THF To 0.55 mmol (1.1 equiv) of benzene was added followed by 1.0 mL of a 0.5M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated to 60 ° C. for 3 h, diluted with ether, washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by chromatography on silica gel (Biotage Flash 12) using 15% EtOAc in hexane as eluent.

The following compounds were prepared in a similar manner to the 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) -l-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-pyridylamine

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

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

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

z) 3-cyclopentyloxy-4 '-(N, N-dimethylamino) -4-methoxydiphenylamine

aa) N- (3-cyclopentyloxy-4-methoxyphenyl) -3- (6-methoxpyridyl) amine

bb) methyl N-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-tetrazol-5-yl] diphenylamine

Example 9 (Method A)

3-cyclopentyloxy-4-methoxy-N-methyldiphenylamine

To a solution of 70 mg (0.25 mmol) of 3-cyclopentyloxy-4-methoxydiphenylamine in 3 mL of THF at 0 ° C. was added 0.55 mL of 0.5 M KN (TMS) ₂ in toluene. The solution was stirred at 0 ° C. for 0.5 h, 2.0 equivalents of iodomethane were added and the reaction mixture was allowed to warm to room temperature. After confirming the reaction was complete by TLC, 10 mL of EtOAc was added and the mixture was washed with 3 mL of H ₂ O, 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 to the 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-pentpropyl)] 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) amine

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

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

q) N- (3-cyclopentyloxy-4-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- (2-pyridyl) amine

A solution of 30 mg (0.10 mmol) of (3-cyclopentyloxy-4-methoxyphenyl) -2-pyridylamine and 50 mg (0.25 mmol) of 4-chloropicolinyl chloride hydrochloride was dissolved in 1 mL of DMF and hydrogenated. Sodium (50 mg of 60% inorganic oil dispersion, 1.3 mmol) was added in portions. After stirring for 1 hour at room temperature, the mixture was poured into 25 mL of ice water. The mixture was extracted twice with 15 mL of EtOAc, the EtOAc extracts were combined together, washed with 15 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was charged into a Readysef column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline solid. ¹ H NMR (CDC1 ₃ ) δ 8.61 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33 (m, 1H), 7.25 (m, 1H) , 6.83 (d, IH, J = 8.5), 6.75 (d, 1H, J = 8.5), 6, 71 (s, 1H), 6.62 (m, 1H), 6.42 (d, 1H, J = 8.6), 5.31 (s, 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 to the 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-methoxyanilino-N- (3-pyridylmethyl) -N-3- (4-pyridyl) benzamide

20 mg (0.05 mmol) and pyBOP 40 mg (N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid in 2 mL of CH ₂ Cl ₂ at room temperature) 0.08 mmol) was added 20 L (0.11 mmol) of diisopropylethylamine. After stirring for 15 minutes, 15 mg (0.15 mmol) of 4-aminopyridine were added and the mixture was stirred for 16 hours. The mixture was diluted with 25 mL of EtOAc, washed with 15 mL of water (twice) and 15 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was charged into a Readysef column (4.2 g, silica gel) and the product eluted over 15 minutes with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes to give 22 mg of product. ¹ H NMR (CDC1 ₃ ) δ 8.70-8.40 (m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H ), 6.88 (d, 2H, J = 8.5), 6.80-6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.86 (s, 3H), 1.86- 1.70 (m, 6 H), 1.65-1.45 (m, 2 H).

The following compounds were prepared in a similar manner to the 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 as 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

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

Example 12

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

20 microns of pyridine in a solution of 47 mg (0.12 mmol) of 4'-amino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -diphenylamine in 2 mL of CH ₂ Cl ₂ at room temperature. To liter (0.24 mmol) was added 15 microliters (0.18 mmol) of methanesulfonyl chloride and the mixture was left at room temperature for 16 hours. The mixture was diluted with 50 mL of ether, washed with 25 mL of water and 25 mL of brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by flash column chromatography (4.2 g Readysef column, silica gel) eluting with a linear gradient from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 minutes to give 41 mg of product. ¹ H NMR (CDC1 ₃ ) δ 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 7.16 (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, 6 H), 1.65-1.45 (m, 2 H).

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

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

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

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

d) 3′-benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

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

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

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

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

i) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine

Example 13

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

Toluene 0.4 in a solution of 50 mg (0.11 mmol) of ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoate in 5 mL of THF at 0 ° C. 2.5M diisobutylaluminum hydride in mL (1.00 mmol) was added dropwise with stirring. The mixture was stirred at 0 ° C. for 1 h and excess diisobutylaluminum hydride was quenched by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between 50 mL of CH ₂ C1 _{2 and} 50 mL of water. The layers were separated and the aqueous layer was extracted twice with 10 mL of CH ₂ C1 ₂ . The organic extracts were combined together, washed with 50 mL brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by flash column chromatography (4.2 g Readysef column, silica gel) using 300 mL of 50% EtOAc in hexane followed by 100% EtOAc as eluent to afford 15 mg of product. ¹ H NMR (CDC1 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, 2 H).

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

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

Example 14

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

163 mg (2.5 mg) of NaN _{3 in} a solution of 100 mg (0.25 mmol) of N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzonitrile in 3 mL of DMF mmol) and NH ₄ C1 135 mg (2.5 mmol) were added and the mixture was stirred at 120 ° C. for 6 h. The mixture was cooled to rt, diluted with 50 mL of water and extracted twice with 25 mL of EtOAc. The EtOAc extracts were combined together, washed with 25 mL of water and 25 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was charged into a Readysef column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes to give 12 mg of product. ¹ H NMR (CDC1 ₃ ) δ 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz) , 7.36 (m, 1H), 6.80-6.60 (m, SH), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H ), 1.65-1.45 (m, 2H).

Example 15

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

To a solution of 100 mg (0.20 mmol) of 3-cyclopentyloxy-4-methoxy-4 '-(4-methylpiperazin-1-ylcarbonyl) diphenylamine in 5 mL of THF, 50 mg of lithium aluminum hydride (1.3) mmol) was added carefully with stirring. The mixture was stirred for 15 minutes, and a few drops of EtOAc were carefully added to quench the excess hydride. 50 mL of water and 50 mL of CH ₂ Cl ₂ were added and the mixture was filtered through celite. The CH ₂ Cl ₂ layer was separated, washed with 25 mL brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified on an ISCO Readysef column (4.2 g, silica) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 60 mg of product as a light yellow oil. ¹ H NMR (CDC1 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), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

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

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

Example 16

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

To a solution of 50 mg (0.12 mmol) of N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzonitrile in 5 mL of THF, 20 mg of lithium aluminum hydride ( 0.52 mmol) was added carefully with stirring. The mixture was stirred for 4 hours, and a few drops of water were carefully added to quench excess hydride. 50 mL of water and 50 mL of CH ₂ Cl ₂ were added and the mixture was filtered through celite. The CH ₂ Cl ₂ layer was separated, washed with 25 mL brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified on an ISCO Readysef column (4.2 g, silica) using 10% MeOH in EtOAc as eluent to afford 20 mg of product. ¹ H NMR (CDC1 ₃ ) δ 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, 1H, 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, 2 H).

Example 17

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

At 0 ° C., in a solution of 1.20 g (2.85 mmol) of 3- (tert-butyldimethylsiloxy) -N- (3-pyridylmethyl) -4-methoxydiphenylamine in 40 mL of THF, 10 mL of THF (10 mmol) 1.0M tetrabutylammonium fluoride in) was added. The mixture was stirred at 0 ° C. for 30 minutes. 50 mL of water was added and the mixture was extracted three times with 25 mL of ether. The ether extracts were combined together, washed with 25 mL of water (3 times) and 25 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dispersed with hexanes and collected by vacuum filtration to give 0.85 g of product. ¹ H NMR (CDC1 ₃ ) δ 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-6.65 (m, 5H), 6.64 (dd, 1H, 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 to the 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 similar to the manner described in Example 1B:                 

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) diphenylamine

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-pyridylmethyl) 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- (l-methylpiperidin-4-yl) oxy-N- (3-pyridylmethyl) diphenylamine

r) 4-methoxy-N- (3-pyridylmethyl) -3-[(35) -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) 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-cycloheptyloxy-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-pyridylmethyl) -3-aminobenzoate

dd) 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-aminobenzoate

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)

By coupling phenol and boronic acid rather than aniline and boronic acid, the following compounds were prepared in a manner similar to that described in Example 8A:

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 an analogous manner to those described in Example 17:                 

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

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

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

Example 20 (Method A)

The following compounds were prepared in a similar manner as described in Example 1A:

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

Example 20 (Method B)

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

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

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

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

d) 3-cyclopentyloxy-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 '-(l-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-pyridylmethyl) 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- (l-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine

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

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

p) 4 '-[1- (3-bromopropyl) oxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

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

Example 21

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

Potassium carbonate in a solution of 17 mg (0.03 mmol) of 3 '-(2-bromoethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine in 1 mL of acetonitrile 25 mg (0.18 mmol) and 5 μL (0.05 mmol) of piperidine were added and the mixture was stirred at 60 ° C. for 4 hours. The mixture was partitioned between 50 mL of water and 50 mL of EtOAc. The layers were separated and the organic layer was washed with 25 mL of water and 25 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was charged to an ISCO Readysef column (4.2 g, silica) and eluting the column with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc gave 11 mg of product. ¹ H NMR (CDC1 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 = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 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, 2H).

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

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

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

c) 3-cyclopentyloxy-4-methoxy-4 '-[3- (2-methylpiperazin-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

0.39 g (0.69 mmol) of N- (3-pyridylmethyl) -3 '-[2- (2-phthalimido) ethoxy] -3-cyclopentyloxy-4-methoxydiphenylamine in 5 mL of MeOH To the solution was added 1.0 mL (20 mmol) of hydrazine hydrate. After 6 hours at room temperature, 50 mL of EtOAc was added and the precipitate was filtered off. The filtrate was washed with 25 mL of water and 25 mL of brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was charged to an ISCO Readysef column (10 g, silica). The column was washed with 200 mL of 10% MeOH in EtOAc and the product eluted with 50% MeOH in EtOAc to give 0.21 g. ¹ H NMR (CDC1 ₃ ) δ 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10 (m, lH), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 6.70 (d, 1H, J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 ( p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6. 1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 ( m, 2H).

Example 23

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

a) 3-cyclopentyloxy-4 '-(2-methanesulfonylamino) 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- (l-butanesulfonylamino) ethoxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 24

In vitro measurement of type 4 phosphodiesterase inhibitory activity

Human PDE4 was obtained from baculovirus-infected Sf9 cells expressing recombinant enzymes. cDNA encoding hPDE-4D6 was subcloned into the baculovirus vector. Insect cells (Sf9) were infected with baculovirus and cells were cultured until protein was expressed. Baculovirus-infected cells were lysed and the lysates were used as the hPDE-4D6 enzyme source. The enzyme was partially purified using DEAE ion exchange chromatography. This process can be repeated using cDNA encoding another PDE-4 enzyme.

Assay:

Type 4 phosphodiesterase converts cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5′-AMP to adenosine. Thus, the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. Adenosine is easily separated from cAMP by neutral alumina columns. In this assay, the phosphodiesterase inhibitor prevents the conversion of cAMP to adenosine, and consequently, the PDE4 inhibitor causes a reduction of adenosine.

Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitor and incubated at room temperature for 12 minutes. Final concentrations of assay components were 0.4 ug enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl ₂ , 3 uM cAMP, 0.002 U 5′-nucleotidase and 3 × 10 ⁴ cpm [3H] cAMP . The reaction was stopped by adding 100 μl of boiling 5 mN HCl. An aliquot of 75 μl of the reaction mixture was transferred from each well to an alumina column (Multiplate; Millipore). Labeled adenosine was eluted into the OptiPlate by spinning at 2000 rpm for 2 minutes and 150 μl scintillation fluid per well was added to the Optiplate. The plate was sealed, shaken for about 30 minutes, and the cpm of [ ³ H] adenosine was measured using Wallac Triflux®.

All test compounds were dissolved in 100% DMSO and assayed by diluting the final concentration of DMSO to 0.1%. DMSO does not affect enzyme activity at this concentration.

Reduction of adenosine concentrations indicates inhibition of PDE activity. pIC ₅₀ values were determined by screening 6-12 concentrations of compounds ranging from 0.1 nM to 10,000 nM, followed by plotting drug concentration versus ³ H-adenosine concentration. Nonlinear regression estimation software (Assay Explorer®) was used to estimate the pIC50 value.

Example 25 (Method A)

Passive evasion in rats, an in vivo test for learning and memory

Tests were performed as previously described in Zhang, H.-T., Crissman, AM, Dorairaj, NR, Chandler, LJ and O'Donnell, JM, Neuropsychopharmacology , 2000, 23, 198-204. The device (model E10-16SC, Coulbourn Instruments, allentown, PA) consisted of two compartment rooms with illuminated compartments connected to darkened compartments by guillotine doors. The bottom of the dark compartment consists of stainless steel rods through which the electric sole-shock can be delivered from a constant current source. First, all experimental groups were familiar with the device one day before the start of the experiment. During training, rats (250-350 g male Spraque-Dawley (Harlan)) were placed in a lighted compartment with the guillotine door closed for one minute before raising the door. The incubation period into the dark compartment was recorded. After the rat entered the dark compartment, the door was closed and subjected to an electric shock of 0.5 mA for 3 seconds. After 24 hours, rats were given 0.1 mg / kg MK-801 or saline 30 minutes prior to injecting saline or test compound (dose from 0.1 to 2.5 mg / kg, intraperitoneal) 30 minutes before starting the retention test. Administered. Again, the mice were placed in illuminated compartments with the guillotine doors open. The incubation period into the dark compartment was recorded for up to 180 seconds, at which point the test was terminated.

All data were analyzed by analysis of variance (ANOVA) and individual comparisons were made using the Keewman-Keuls test. Natural mice took an average of less than 30 seconds to cross from the illuminated compartment to the dark compartment. However, most of the mice pretreated with vehicle 24 hours after being exposed to electric shock did not enter the dark compartment again, and the mean latency was increased to a maximum of 175 seconds (p <0.001). Pretreatment with MK-801 (0.1 mg / kg) significantly reduced this latency when compared to vehicle (p <0.001). This memory loss effect of MK-801 is effective in a dose-dependent manner (eg, 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, depending on the actual test compound). Dose range = 0.5-2.5 mg / kg, intraperitoneal; and N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, effective dosage range = 0.1 to 2.5 mg / kg, intraperitoneally) in a statistically significant manner.

Example 25 (Method B)

Radial maze task in rats, an in vivo test for learning and memory

Tests were performed as previously described in Zhang, H.-T., Crissman, AM, Dorairaj, NR, Chandler, LJ and O'Donnell, JM, Neuropsychopharmacology , 2000, 23, 198-204. Five days after the first entry, rats (250-350 g male Sprague-Dauray species) were placed in a radial maze with eight arms (each arm was 60 × 10 × 12 cm long). Maze, 70 cm above the bottom) and acclimated for 2 days. The mice were then placed in the middle of the maze for 5 minutes with food pellets placed close to each food well, then placed in the well at the end of the arm, and performed twice a day. Next, one food pellet was placed as a bait on each of four randomly selected arms. The rats were kept in the central platform (26 cm in diameter) for 15 seconds and then allowed to move freely through the maze until all pellets of food were collected or reached 10 minutes later. Four parameters were recorded: l) working memory error, ie entry into the bait arm already visited during the same test; 2) reference memory error, ie entry into the arm without bait; 3) total arm position; And 4) test period in seconds, ie the time spent collecting all pellets in the maze. In five consecutive trials, when the working memory error was 0 and the mean reference memory error was less than 1, the drug test was started in the rat. MK-801 or saline was injected 15 minutes prior to injection of the vehicle or test agent provided 45 minutes prior to the test. The experiment was performed in a lit room with several visible signals outside the maze.

All data were analyzed by analysis of variance (ANOVA). Individual comparisons were made using the Kyuman-Cools test. Compared to the control group, MK-801 (0.1 mg / kg, intraperitoneal) increased the frequency of both working and reference memory errors (p <0.01). This amnestic effect of MK-801 on working memory is dependent on the dose of the actual test compound (eg, 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) di. Phenylamine, effective dose = 2.5 mg / kg, intraperitoneally; p <0.01), inverted in a statistically significant manner.

The above examples can be repeated with similar success by substituting (substituting) or reacting the reactants described generally or specifically and implementing the conditions of the invention used in the examples above.

While the invention has been illustrated with respect to the production of certain compounds, it is clear that changes and modifications of the invention can be made without departing from the scope of the invention.

Claims (70)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: <Formula I>

Where R ¹ is alkyl having 1 to 4 carbon atoms, branched or unbranched, unsubstituted or substituted one or more times with halogen; R ² is branched or unbranched, unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo or combinations thereof, wherein one or more —CH ₂ CH ₂ — groups Alkyl having 1 to 12 carbon atoms, each of which may be substituted by -CH = CH- or -C≡C-, 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a combination thereof Cycloalkyl having, 4 to 16 unsubstituted or substituted once or more by cycloalkyl moiety, alkyl moiety or both by halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy or combinations thereof Cycloalkylalkyl having a carbon atom, The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, and the unsubstituted or aryl moiety is halogen, CF ₃ , OCF ₃ , 1 to 4 carbon atoms. Substituted one or more times with alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, having one to four carbon atoms, wherein one or more -CH ₂ CH of the alkyl moiety ₂ -groups can be substituted with -CH = CH- or -C≡C-, respectively, and one or more -CH ₂ -groups can be substituted with -O- or -NH-, respectively, with the alkyl moiety unsubstituted or Arylalkyl substituted with oxo, hydroxy, cyano or a combination thereof, 5 to 14 carbons, unsubstituted or substituted one or more times with halogen, alkyl with 1 to 4 carbon atoms, alkoxy, hydroxy, nitro, cyano, oxo or a combination thereof with 1 to 4 carbon atoms Partially unsaturated carbocyclic groups having atoms, Unsubstituted or halogen, hydroxy, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, nitro, oxo Or a saturated, partially saturated or unsaturated heterocyclic group having 5 to 10 ring atoms, at least one ring atom substituted at least once by a combination thereof, is an N, O or S atom, or The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms , Unsubstituted or heterocyclic moiety is halogen, OCF ₃ , hydroxy, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano , Trifluoromethyl, nitro, oxo or one or more combinations thereof, wherein one or more -CH ₂ CH ₂ -groups of the alkyl moiety can each be substituted with -CH = CH- or -C≡C-, One or more -CH ₂ -groups may each be substituted with -O- or -NH- and a heterocyclic alkyl group unsubstituted with an alkyl moiety or substituted with halogen, oxo, hydroxy, cyano or a combination thereof ego; R ³ is The carbocyclic moiety has 5 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, and the unsubstituted or carbocyclic moiety is halogen, 1 to 4 carbon atoms. Alkyl at least one time, substituted with one or more carbon atoms having 1 to 4 carbon atoms, nitro, cyano, oxo, or a combination thereof, the alkyl moiety being unsubstituted or halogen, C _1-4 -alkoxy, cyano or a combination thereof A partially unsaturated carbocyclic alkyl group substituted with The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the unsubstituted or aryl moiety is halogen, trifluoromethyl, CF ₃ O, nitro, Is substituted one or more times with amino, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, C _1-4 -alkylamino, diC _1-4 -alkylamino or a combination thereof Arylalkyl having 7 to 19 carbon atoms, unsubstituted or substituted with halogen, cyano or methyl, or Heterocyclic moieties may be aromatic, partially saturated or fully saturated, having at least 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, and branched or unbranched alkyl moieties are 1 to 5 carbons. Atom, unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, CF ₃ O, nitro, oxo , amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, cyano, methyl, or substituted heteroaryl when a combination thereof Click alkyl group ego; R ⁴ is Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms , C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, DiC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxysamic acid, tetrazol-5-yl, 2- (heterocycle) tetrazol-5-yl, hydroxyC _1-4 -alkoxy , Carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, phenoxy, triC _{1- 4-alkyl-silyloxy,} R ⁵ -L-, or substituted one or more times by combinations thereof, aryl having 6 to 14 carbon atoms, or Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl hydroxamic acid, tetra Sol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C ₁ Heteroaryl having 5 to 10 ring atoms wherein at least one ring atom is a heteroatom, substituted one or more times with _-4 -alkylsulfonyl, phenoxy, triC _1-4 -alkylsilyloxy or a combination thereof ego; R ⁵ is H, Alkyl having 1 to 8 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof, 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms or a combination thereof Cycloalkyl having, Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, Tetrazol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C Aryl having 6 to 14 carbon atoms, substituted one or more times with _1-4 -alkylsulfonyl or a combination thereof, Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, Tetrazol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C Saturated, partially saturated or unsaturated heterocyclic groups having 5 to 10 ring atoms wherein at least one ring atom is N, O or S atom, substituted one or more times with _1-4 -alkylsulfonyl, phenoxy or a combination thereof, or The heterocyclic moiety is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms , Unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, cyano, methyl, or a combination of a substituted heterocyclic group ego; L represents 1-8 carbon atoms in which a single bond or one or more -CH ₂ -groups can be substituted with -O-, -NR ^6- , -SO ₂ NH-, -CO- or -NR ⁶ CO-, respectively Is a divalent aliphatic radical having; R ⁶ represents 1 to 8 carbon atoms, H, or branched or unbranched, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof Having alkyl; Here, when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. delete The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; C _1-12 -alkyl, C _2-12 -alkenyl, C _2-12 -alkynyl, C _3-10 -cycloalkyl, C _{6-14 -arylC} wherein R ² is substituted or unsubstituted in each case _1-5 -alkyl, C _{5-10 -heterocyclicC 1-5} -alkyl, C _4-16 -cycloalkylalkyl or C _{5-10 -heterocyclic} ; R ³ is in each case substituted or unsubstituted C _{6-14 -arylC 1-5} -alkyl or C _{5-10 -heterocyclicC 1-5} -alkyl. The compound of claim 1, wherein R ³ is substituted or unsubstituted C _{5-10 -heterocyclicC 1-5} -alkyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or (3R) -tetrahydrofuranyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl; R ³ is substituted or unsubstituted C _{5-10 -heterocyclicC 1-5} -alkyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ in each occurrence is substituted or unsubstituted C _{6-14 -arylC 1-5} -alkyl or C _{5-10 -heterocyclicC 1-5} -alkyl; R ⁴ is substituted or unsubstituted C _6-14 -aryl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted C _{5-10 -heterocyclicC 1-5} -alkyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted or unsubstituted C _{5-10 -heterocyclicC 1-5} -alkyl; R ⁴ is substituted or unsubstituted phenyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is in each case substituted or unsubstituted pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl or pyrazinylmethyl; R ⁴ is phenyl or phenyl substituted with 1 to 3 substituents. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ in each occurrence is substituted or unsubstituted pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl; R ⁴ is in each case substituted or unsubstituted, phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl or isoquinolinyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl; 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 ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl; R ⁴ is unsubstituted or unsubstituted or substituted with methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl, ethylsulfonamido or combinations thereof Or 3-pyridyl substituted with carboxy, C _1-4 -alkoxycarbonyl, or a combination thereof. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; 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 ⁴ is unsubstituted or unsubstituted or substituted with methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl, ethylsulfonamido or combinations thereof Or 3-pyridyl substituted with carboxy, C _1-4 -alkoxycarbonyl, or a combination thereof. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl; When the R ³ each substituted or unsubstituted, benzyl, phenethyl, cyclohexenyl methyl, furanyl-methyl, thienylmethyl, pyridylmethyl, quinolinyl-methyl, isoquinolinyl-methyl, thiazolyl methyl or blood A compound which is rollylmethyl. The compound of claim 1, wherein R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl; R ³ is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, in each case substituted or unsubstituted. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is substituted in each case, or unsubstituted, benzyl, phenethyl, cyclohexenyl methyl, furanyl-methyl, thienylmethyl, pyrazinyl-methyl, pyrimidinyl, methyl, pyridylmethyl, quinolinyl-methyl, isoquinolinyl Nolinylmethyl, thiazolylmethyl or pyrrolylmethyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; R ³ is pyrazinylmethyl or pyridylmethyl, in each case substituted or unsubstituted. The compound of claim 1 selected from a compound of formula IV and a pharmaceutically acceptable salt thereof: <Formula IV>

Wherein R ¹ and R ² are as defined in claim 1, at least one of A, B and D is N and the other is CH and R ⁴ is in each case substituted or unsubstituted pyridyl or phenyl When the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ . The compound of claim 21, wherein B is N. 23. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl. 24. The compound of claim 23, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ and R ⁴ is in each case substituted or unsubstituted 3-pyridyl or phenyl. The compound of claim 25, wherein B is N. 27. The 3-pyri according to claim 20, wherein R ¹ is methyl or CHF ₂ , R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl, and R ⁴ in each occurrence is substituted or unsubstituted. Compound that is dill or phenyl. The compound of claim 27, wherein B is N. 29. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ and R ⁴ is phenyl substituted at the 3- or 4-position. 30. The compound of claim 29, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ , R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl, and R ⁴ is phenyl substituted at the 3- or 4-position. 32. 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-cyano-phenyl, 3-ethyl-sulfonamido- Phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfone Amido-phenyl, 4-tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl. 34. The compound of claim 33, wherein B is N. The compound of claim 20, wherein R ¹ is methyl or CHF ₂ , R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl or tetrahydrofuranyl, and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3- Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl , 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl. 36. The compound of claim 35, wherein B is N. The method of claim 1, 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-amino-nicotinic acid m) N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (2- pyrazinyl) - N - (3- pyridylmethyl) amine n) 3'-benzylsulfonylamino-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine o) 3- [3- (4-chlorophenyl) prop-1-yloxy] -4-methoxy- N- (3-pyridylmethyl) diphenylamine p) 4-methoxy-3- [3- (4-methoxyphenyl) prop-1-yl] oxy- 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 s) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -4 '-[(3R) -tetrahydrofuranyloxy] -diphenylamine t) 3- cyclopentyloxy-4-methoxy-4 '- (1-methyl-piperidin-4-yloxy) - N - (3- pyridylmethyl) diphenylamine u) 3- cyclopentyloxy-4-methoxy-4 '- (1-methyl-pyrrolidin-3-yloxy) - N - (3- pyridylmethyl) diphenylamine v) 3- cyclopentyloxy-4-methoxy-4 '- [2- (1-pyrrolidinyl-ethoxy) - N - (3- pyridylmethyl) diphenylamine w) 3- cyclopentyloxy-4-methoxy-4 '- [2- (6-methyl-pyridyl) methoxy) - N - (3- pyridylmethyl) diphenylamine x) 3- cyclopentyloxy-4-methoxy-4 '- [2- (1-methyl-piperidinyl) methoxy] - N - (3- pyridylmethyl) diphenylamine y) 3- cyclopentyloxy-4-methoxy-3 '- [2- (1-piperidinyl) ethoxy] - N - (3- pyridylmethyl) diphenylamine z) 3-cyclopentyloxy-3 '-[2- (1-imidazolyl) ethoxy] -4-methoxy- N- (3-pyridylmethyl) diphenylamine aa) 3-cyclopentyloxy-4-methoxy-4 '- [3- (2-methylpiperazin-l-yl) propoxy] - N - (3-pyridylmethyl) diphenylamine bb) 3-cyclopentyloxy-4-methoxy-4 '- [3- (2-morpholin-4-yl-ethylamino) 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 kk) 3-cyclopentyloxy-3 ', 4'-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine ll) 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy- N- (3-pyridylmethyl) diphenylamine mm) 3-cyclopentyloxy- N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine nn) 4-methoxy-4'-methyl- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine oo) 4,4'-dimethoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine pp) 3-indanyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine qq) N - [4- methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid 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 tt) N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (2- pyridyl) - N - (3- pyridylmethyl) amine uu) N - (4- methoxy -3- (3R) - tetrahydrofuryl oxyphenyl) - 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-yl-carbonyl) - N - (3- pyridylmethyl) diphenylamine xx) 3- cyclopentyloxy-4-difluoromethoxy-4 '- (4-methylpiperazin-1-yl-carbonyl) - N- (3- pyridylmethyl) diphenylamine yy) 4-Methoxy-4 '- (4-methylpiperazin-1-yl-carbonyl) - N - (3-pyridylmethyl) - (3- (3-tetrahydrofuryl oxy) diphenylamine zz) 3 '-(1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine aaa) 3'-acetamido-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine bbb) 4-methoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine ccc) 4-Methoxy-3- [2- (4-pyridyl) ethoxy] - N - (3- pyridylmethyl) diphenylamine ddd) 4- methoxy-3- (2-methoxyethoxy) - N - (3- pyridylmethyl) diphenylamine eee) 3-cyclopropylmethoxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine fff) 4-methoxy- N- (3-pyridylmethyl) -3-[(3S) -tetrahydrofuryloxy] diphenylamine ggg) 3'- chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] - N - (3- pyridylmethyl) diphenylamine hhh) 3- [2- (4-chlorophenyl) ethenyloxy] -4-methoxy- N- (3-pyridylmethyl) diphenylamine iii) 3-cyclopentyloxy-3'-hydroxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine jjj) 3-cyclopentyloxy-4'-hydroxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine kkk) 4'-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine lll) 3- cyclopentyloxy-4-methoxy-4 '- [2- (1-methylpyrrolidin-2-yl) ethoxy] - N - (3-pyridylmethyl) diphenylamine mmm) 3-cyclopentyloxy-4-methoxy-4 '- [3- (1-piperidinyl) methoxy] - N - (3-pyridylmethyl) diphenylamine nnn) 3-cyclopentyloxy-4-methoxy-4 '- [3- (1-piperazin-4-yl) propoxy] - N - (3-pyridylmethyl) diphenylamine ooo) 4- methoxy-3- (2-phenoxy-ethoxy upon) - N - (3- pyridylmethyl) diphenylamine ppp) 3- cyclopentyloxy-4-methoxy-4 '- [2- (2-propane sulfonyl amino) ethoxy] - N - (3- pyridylmethyl) diphenylamine qqq) 3'-cyano-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine rrr) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy- N- (3-pyridylmethyl) diphenylamine sss) 3-cyclopropylmethoxy-4-difluoromethoxy- N- (3-pyridylmethyl) diphenylamine ttt) 3- cyclopentyloxy-4-methoxy-4 '- (2- (tetrahydropyran-2-yl) 2H- tetrazol-5-yl) - N - (3- pyridylmethyl) diphenylamine uuu) 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) -diphenylamine vvv) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl- N- (3-pyridylmethyl) diphenylamine www) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl- N- (3-pyridylmethyl) diphenylamine xxx) 4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy- N- (3-pyridylmethyl) diphenylamine yyy) 3'- chloro-4-methoxy-3- (2-methoxyethoxy) - N - (3- pyridylmethyl) diphenylamine zzz) 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine aaaa) 3-cyclopentyloxy-4 '-(2-ethanesulfonylamino) ethoxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine bbbb) 3- cyclopentyloxy-4-methoxy-4 '- [2- (1-propane-sulfonyl-amino) 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-tetrahydrofuryloxy) diphenylamine eeee) 3'-cyano-4-methoxy- N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine ffff) 4-difluoromethoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) 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 kkkk) 4'- tert - butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy - N - (3- pyridylmethyl) diphenylamine llll) 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-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid oooo) N- [4- methoxy-3- (3-tetrahydrofuryl) 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) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid rrrr) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -4-aminobenzoic acid ssss) N- (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -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- indanyl) -4- methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid xxxx) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid yyyy) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid zzzz) N - [3- (2- ethoxy) methoxy-4-methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid aaaaa) 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-tetrazol-5-yl) diphenylamine fffff) 4-difluoromethoxy- N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(2H-tetrazol-5-yl) diphenylamine ggggg) 3-cyclopentyloxy-4-difluoromethoxy- N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine hhhhh) 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 jjjjj) N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine kkkkk) N - (3- cyclopentyloxy-4-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine lllll) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine mmmmm) N - (4- difluoromethoxy--3- (3R) - tetrahydrofuryl oxyphenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine nnnnn) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine ooooo) 3- cyclopentyloxy-4-methoxy-3 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine ppppp) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine qqqqq) 3- cyclopentyloxy-4-methoxy-4 '- (1-propane-sulfonyl-amino) - 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 ttttt) 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'-chloro-4-methoxy- N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine xxxxx) 3- cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidin pyridinyl) methoxy] - N - (3- pyridylmethyl) diphenylamine A compound selected from: or a pharmaceutically acceptable salt thereof, wherein when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or a single enantiomer or a single diastereomer Compounds or pharmaceutically acceptable salts thereof, which may be in the form of isomers. The method of claim 1, a) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-3'-methyl- N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-4'-methyl- N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4'-nitro- N- (3-pyridylmethyl) diphenylamine e) 3-cyclopentyloxy-3 ', 4'-dichloro-4-methoxy- 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) - tetrahydrofuryl oxyphenyl) - 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-yl-carbonyl) - N- (3- pyridylmethyl) diphenylamine r) 3- cyclopentyloxy-4-difluoromethoxy-4 '- (4-methylpiperazin-1-yl-carbonyl) - N - (3- pyridylmethyl) diphenylamine s) 4-methoxy-4 '- (4-methylpiperazin-1-yl-carbonyl) - N - (3-pyridylmethyl) -3- (3-tetrahydrofuryl oxy) diphenylamine 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-piperidinyl) methoxy] - N - (3-pyridylmethyl) diphenylamine hh) 3-cyclopentyloxy-4-methoxy-4 '- [3- (1-piperazin-4-yl) propoxy] - N - (3-pyridylmethyl) diphenylamine ii) 4- methoxy-3- (2-phenoxy-ethoxy upon) - N - (3- pyridylmethyl) diphenylamine jj) 3- cyclopentyloxy-4-methoxy-4 '- [2- (2-propane sulfonyl amino) ethoxy] - N - (3-pyridylmethyl) diphenylamine kk) 3'-cyano-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine ll) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy- N- (3-pyridylmethyl) diphenylamine mm) 3-cyclopropylmethoxy-4-difluoromethoxy- N- (3-pyridylmethyl) diphenylamine nn) 3- cyclopentyloxy-4-methoxy-4 '- (2- (tetrahydropyran-2-yl) -2H- tetrazol-5-yl) - N - (3- pyridylmethyl) diphenyl Amine oo) 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) -diphenylamine pp) 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl- N- (3-pyridylmethyl) diphenylamine qq) 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl- N- (3-pyridylmethyl) diphenylamine rr) 4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy- N- (3-pyridylmethyl) diphenylamine ss) 3'- chloro-4-methoxy-3- (2-methoxyethoxy) - N - (3- pyridylmethyl) diphenylamine 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-propane-sulfonyl-amino) ethoxy] - N - (3- pyridylmethyl) diphenylamine ww) 3'-chloro-3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine xx) 3'-chloro-4-methoxy- N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine yy) 3'-cyano-4-methoxy- N- (3-pyridylmethyl) -3-((3R) -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) -tetrahydrofuryloxy) diphenylamine ccc) 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-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid iii) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid jjj) N -3,4- bis (difluoromethoxy) phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid kkk) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid lll) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -4-aminobenzoic acid mmm) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid ooo) N - [3- (4- chlorophenyl) prop-1-yloxy-4-methoxyphenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid ppp) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid qqq) N - [3- (2- indanyl) -4- methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid rrr) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid sss) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid ttt) N - [3- (2- ethoxy) methoxy-4-methoxy-phenyl] - 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 '-(2H-tetrazol-5-yl) diphenylamine www) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -3 '-(2H-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-((3R) -tetrahydrofuryloxy) -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 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 eeee) N - (3- cyclopentyloxy-4-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine ffff) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine gggg) N - (4- difluoromethoxy--3- (3R) - tetrahydrofuryl oxyphenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine hhhh) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine iiii) 3- cyclopentyloxy-4-methoxy-3 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine jjjj) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine kkkk) 3- cyclopentyloxy-4-methoxy-4 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine llll) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine mmmm) 4-difluoromethoxy-3'-ethanesulfonylamino- N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine nnnn) 4- methoxy-3- [2- (2-pyridyl) ethoxy] - N- (3- pyridylmethyl) diphenylamine oooo) 4-methoxy- N- (3-pyridylmethyl) -3-[(3R) -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 rrrr) 3- cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidin pyridinyl) methoxy] - N - (3- pyridylmethyl) diphenylamine A compound selected from: or a pharmaceutically acceptable salt thereof, wherein when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or a single enantiomer or a single diastereomer Compounds or pharmaceutically acceptable salts thereof, which may be in the form of isomers. The method of claim 1, 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) diphenyl Amine 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-propane-sulfonyl-amino) ethoxy] - N - (3- pyridylmethyl) diphenylamine 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-((3R) -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-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid y) N - [4- methoxy-3- (3-tetrahydrofuryl) 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) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid bb) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -4-aminobenzoic acid cc) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -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- indanyl) -4- methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid hh) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid ii) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid jj) N - [3- (2- ethoxy) methoxy-4-methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid kk) 3-cyclopropylmethyloxy-4-difluoromethoxy- N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine ll) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine mm) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -3 '-(2H-tetrazol-5-yl) diphenylamine 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 rr) 3-cyclopropylmethyloxy-4-difluoromethoxy- N- (3-pyridylmethyl) -3 '-(2H-tetrazol-5-yl) diphenylamine ss) bis-3,4-difluoromethoxy- N- (3-pyridylmethyl) -4 '-(2H-tetrazol-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) amine vv) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine ww) N - (4- difluoromethoxy--3- (3R) - tetrahydrofuryl oxyphenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine xx) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine yy) 3- cyclopentyloxy-4-methoxy-3 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine zz) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine aaa) 3- cyclopentyloxy-4-methoxy-4 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine bbb) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine ccc) 4-difluoromethoxy-3'-ethanesulfonylamino- N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine ddd) 4- methoxy-3- [2- (2-pyridyl) ethoxy] - N - (3- pyridylmethyl) diphenylamine eee) 4-methoxy- N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine fff) 3'- chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] - N - (3- pyridylmethyl) diphenylamine ggg) 3'-chloro-4-methoxy- N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine hhh) 3- cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidin pyridinyl) methoxy] - N - (3- pyridylmethyl) diphenylamine A compound selected from: or a pharmaceutically acceptable salt thereof, wherein when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or a single enantiomer or a single diastereomer Compounds or pharmaceutically acceptable salts thereof, which may be in the form of isomers. The method of claim 1, 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) -tetrahydrofuryloxy) diphenylamine i) 4'- tert - butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy - N - (3- pyridylmethyl) diphenylamine j) N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid k) N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -4-aminobenzoic acid l) N - (3- cyclopentyloxy-4-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid m) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid n) N -3,4- bis (difluoromethoxy) phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid o) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid p) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -4-aminobenzoic acid q) N - (3- cyclopropylmethoxy-4-difluoromethoxy-phenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid s) N - [3- (4- chlorophenyl) prop-1-yloxy-4-methoxyphenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid t) N - (3- cyclopropylmethoxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid u) N - [3- (2- indanyl) -4- methoxy-phenyl] - N - (3- pyridylmethyl) -3-aminobenzoic acid v) N - [4- methoxy-3- (3-tetrahydrofuryl) phenyl] - N - (3-pyridylmethyl) -3-aminobenzoic acid w) N - [4- methoxy -3 - ((3R) - tetrahydro-furyl) 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-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine z) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine aa) 3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) -3 '-(2H-tetrazol-5-yl) diphenylamine bb) 4-methoxy- N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(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-((3R) -tetrahydrofuryloxy) -4 '-(2H-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 '-(2H-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-difluoromethoxy-phenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine kk) N - (4- difluoromethoxy--3- (3R) - tetrahydrofuryl oxyphenyl) - N - (3- pyridyl) - N - (3- pyridylmethyl) amine ll) 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine mm) 3- cyclopentyloxy-4-methoxy-3 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine nn) 3-cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine oo) 3- cyclopentyloxy-4-methoxy-4 '- (1-propane-sulfonyl-amino) - N - (3- pyridylmethyl) diphenylamine pp) 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy- N- (3-pyridylmethyl) diphenylamine 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) -3-[(3R) -tetrahydrofuryloxy] diphenylamine vv) 3- cyclopentyloxy-4-methoxy-4 '- [2- (5-oxopyrrolidin pyridinyl) methoxy] - N - (3- pyridylmethyl) diphenylamine A compound selected from: or a pharmaceutically acceptable salt thereof, wherein when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or a single enantiomer or a single diastereomer Compounds or pharmaceutically acceptable salts thereof, which may be in the form of isomers. A compound of formula (I ') or a pharmaceutically acceptable salt thereof: <Formula I '>

Where R ^{1 ′} is methoxy; R ^{2 '} is Alkyl having 1 to 12 carbon atoms, unsubstituted or substituted one or more times with halogen, oxo, cyano or combinations thereof, Alkenyl having 2 to 12 carbon atoms, unsubstituted or substituted one or more times with halogen, oxo, cyano or combinations thereof, Alkynyl having 2 to 12 carbon atoms, unsubstituted or substituted one or more times with halogen, oxo, cyano or combinations thereof, Cycloalkyl, having 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, oxo, alkyl having 1 to 4 carbon atoms or a combination thereof, Cycloalkylalkyl, having 4 to 12 carbon atoms, unsubstituted or substituted one or more times with halogen, oxo, alkyl having 1 to 4 carbon atoms or a combination thereof, Having 5 to 14 carbon atoms, unsubstituted or substituted one or more times with halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, nitro, cyano, oxo or a combination thereof Partially unsaturated carbocyclic groups, 7 to 26, unsubstituted or substituted one or more times with halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, nitro, cyano, oxo, trifluoromethyl or a combination thereof Arylalkyl having 3 carbon atoms, or Unsubstituted or heteroaryl moiety is halogen, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, nitro, amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, oxo, cyano, or substituted with a combination thereof, one or more Heteroarylalkyl having 5 to 10 ring atoms wherein the ring atom is heteroatom ego; X is O; R ^{3 '} is Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, C _1-4 -alkylamino, di C _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxyC _1-4 -alkoxy, carboxy, cyano, acyl, C _1-4 -alkoxycarbonyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, phenoxy, unsubstituted or substituted with halogen, alkyl with 1 to 4 carbon atoms, or alkoxy with 1 to 4 carbon atoms Aryl having 6 to 14 carbon atoms, substituted one or more times with heteroaryl or a combination thereof, or Unsubstituted or halogen, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times by combinations thereof, heteroaryl having a ring atoms are hetero atoms of 5 to 10 ring atoms one or more ego; L is -NR ^{4 '} -or -NR ^4' CH _2- ; R ^{4 '} is Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, having 6 to 14 carbon atoms, unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, 2 to 4 carbon atoms, C _1-4 -alkylamino, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxyC _1-4 -alkoxy, carboxy, cyano, acyl, C _1-4 -alkoxycarbonyl , C _1-4 - alkylthio, C _1-4 - alkyl sulfinyl, C _1-4 - alkylsulfonyloxy, phenoxy or substituted aryl or more times with a combination thereof, or Having 5 to 10 ring atoms, at least one ring atom being heteroatom, unsubstituted or halogen, C _6-14 -aryl, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl , Heteroaryl substituted one or more times with nitro, oxo, amino, C _1-4 -alkylamino, diC _1-4 -alkylamino or a combination thereof, Here, when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. delete delete delete delete delete Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick disease, Infarction, Bleeding, Heart disorder, Bacterial meningitis, Crutzfeldt-Jakob disease, Multiple sclerosis, Subdural hematoma, Traumatic, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier Pharmaceutical compositions for treating memory disorders due to dementia resulting from brain injury, HIV, Down syndrome, heavy metal toxicity, alcohol toxicity, vitamin B12 deficiency, folic acid deficiency, CNS hypoxia, Cushing's disease, depression, schizophrenia or hydrocephalus. delete Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Crutzfeldt-Jakob disease, depression, head trauma, stroke, CNS hypoxia, multi-infarction dementia or HIV, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical compositions for treating memory disorders caused by. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, eosinophilic granulomas, psoriasis, inflammatory arthritis, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier , Rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, cyst fibrosis, artery restenosis, arteriosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, fever (pyresis), Diabetes mellitus, pneumoconiosis, chronic obstructive airway disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple gland, sunburn, alopecia areata, discoid lupus erythema, systemic lupus erythematosus, follicular And from extensive purulent dermatosis, endogenous and exogenous acne, acne strawberry nose, Behcet's disease, Anaphylactic antagonist nephritis, leukemia and multiple sclerosis A pharmaceutical composition for treating a disease associated with lowered cAMP levels, which is selected. delete delete delete A pharmaceutical composition for treating a memory disorder due to a neurodegenerative disease, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating a memory disorder due to an acute neurodegenerative disease, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. delete Compounds of the formula: or pharmaceutically acceptable salts thereof

Where R ¹ is H, tert-butyldimethylsilyl, ³ H ₃ C-, ¹⁴ CH ₃ -or ^ll CH _3- ; R ² is branched or unbranched and unsubstituted or substituted one or more times with halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo or combinations thereof, wherein one or more —CH ₂ CH ₂ — groups are each Alkyl having 1 to 12 carbon atoms, which may be substituted by -CH = CH- or -C≡C-, 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a combination thereof Cycloalkyl having, 4 to 16 unsubstituted or substituted once or more by cycloalkyl moiety, alkyl moiety or both by halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy or combinations thereof Cycloalkylalkyl having a carbon atom, The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, and the unsubstituted or aryl moiety is halogen, CF ₃ , OCF ₃ , 1 to 4 carbon atoms. Substituted one or more times with alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, having one to four carbon atoms, wherein one or more -CH ₂ CH of the alkyl moiety ₂ -groups can be substituted with -CH = CH- or -C≡C- respectively, and one or more -CH ₂ -groups can be substituted with -O- or -NH- respectively, the alkyl moiety being unsubstituted or halogen Arylalkyl substituted with oxo, hydroxy, cyano or a combination thereof, Partially unsaturated car having 5 to 14 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, hydroxy, nitro, cyano, oxo or combinations thereof Clicking, Unsubstituted or halogen, hydroxy, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, nitro, oxo Or a saturated, partially saturated or unsaturated heterocyclic group having 5 to 10 ring atoms, at least one ring atom substituted at least once by a combination thereof, is an N, O or S atom, or The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, the alkyl moiety is branched or unbranched and has 1 to 5 carbon atoms , Unsubstituted or heterocyclic moiety is halogen, OCF ₃ , hydroxy, aryl having 6 to 14 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano , One or more times substituted with trifluoromethyl, nitro, oxo or combinations thereof, wherein one or more -CH ₂ CH ₂ -groups of the alkyl moiety can each be substituted with -CH = CH- or -C≡C-, Heterocyclic alkyl groups in which one or more —CH ₂ — groups may each be substituted with —O— or —NH— and the alkyl moiety is unsubstituted or substituted with halogen, oxo, hydroxy, cyano or combinations thereof. ego; R ³ is The carbocyclic moiety has 5 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the unsubstituted or carbocyclic moiety is halogen, C _1-4 -alkyl, Partially unsaturated carbosubstituted one or more times with C _1-4 -alkoxy, nitro, cyano, oxo or combinations thereof, with the alkyl moiety unsubstituted or substituted with halogen, C _1-4 -alkoxy, cyano or combinations thereof Bocyclic alkyl group, The aryl moiety has 6 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms and the unsubstituted or aryl moiety is halogen, trifluoromethyl, CF ₃ O, nitro, Alkyl moiety, substituted one or more times with amino, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, C _1-4 -alkylamino, diC _1-4 -alkylamino or a combination thereof Arylalkyl having 7 to 19 carbon atoms, unsubstituted or substituted with halogen, cyano or methyl, or Heterocyclic moieties may be aromatic, partially saturated or fully saturated, and have 5 to 10 ring atoms where at least one ring atom is an N, O or S atom, and branched or unbranched alkyl moieties are 1 to 5 carbons Atom, unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, CF ₃ O, nitro, oxo , amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, cyano, cyclic substituted heteroaryl as methyl or combinations thereof Alkyl group ego; R ⁴ is Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms , C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, DiC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxysamic acid, tetrazol-5-yl, 2- (heterocycle) tetrazol-5-yl, hydroxyC _1-4 -alkoxy , Carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, phenoxy, triC _{1- 4-alkyl-silyloxy,} R ⁵ -L-, or substituted one or more times by combinations thereof, aryl having 6 to 14 carbon atoms, or Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl hydroxamic acid, tetra Sol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C ₁ One or more rings, substituted one or more times with _-4 -alkylsulfonyl, phenoxy, triC _1-4 -alkylsilyloxy, R ⁵ -L-, diC _1-4 -alkylamino-L- or combinations thereof Heteroaryl having 5 to 10 ring atoms in which the atom is heteroatom ego; R ⁵ is H, Alkyl having 1 to 8 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof, Cycloalkyl having 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, C _1-4 -alkoxy, alkyl having 1 to 4 carbon atoms or a combination thereof , Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, Tetrazol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C Aryl having 6 to 14 carbon atoms, substituted one or more times with _1-4 -alkylsulfonyl or a combination thereof, Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, C _1-4 -alkoxy, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, tri Fluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, tetrazole- 5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C _1-4 A saturated, partially saturated or unsaturated heterocyclic group having 5 to 10 ring atoms wherein at least one ring atom is N, O or S atom, substituted one or more times with alkylsulfonyl, phenoxy or a combination thereof, or Heterocyclic moieties are saturated, partially saturated or unsaturated, and have 5 to 6 ring atoms where one or two ring atoms are each N or O atoms, and a branched or unbranched alkyl moiety may contain 1 to 5 carbon atoms And unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, C _1-4 -alkoxy, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, C ₁ Heterocyclic alkyl group substituted one or more times with _-4 -alkylamino, diC _1-4 -alkylamino or a combination thereof and unsubstituted or substituted with halogen, cyano, methyl or a combination thereof. ego; L is 1-8 carbon atoms in which a single bond or one or more -CH ₂ -groups can be substituted with -O-, -NR ^6- , -SO ₂ NH-, -CO- or -NR ⁶ CO-, respectively Divalent aliphatic radicals having; R ⁶ represents 1 to 8 carbon atoms, H, or branched or unbranched, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof Having alkyl; Here, when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Compounds of the formula: or pharmaceutically acceptable salts thereof

Where R ¹ is alkyl having 1 to 4 carbon atoms, branched or unbranched, unsubstituted or substituted one or more times with halogen; R ² is H or tert-butyldimethylsilyloxy-; R ³ is The carbocyclic moiety has 5 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, and the unsubstituted or carbocyclic moiety is halogen, 1 to 4 carbon atoms. May be substituted one or more times with alkyl having, alkoxy having 1 to 4 carbon atoms, nitro, cyano, oxo or combinations thereof, and the alkyl moiety may be substituted with halogen, C _1-4 -alkoxy, cyano or combinations thereof Partially unsaturated carbocyclic alkyl group, The aryl moiety has 6 to 14 carbon atoms and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms and the unsubstituted or aryl moiety is halogen, trifluoromethyl, CF ₃ O, nitro, Alkyl moiety, substituted one or more times with amino, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, C _1-4 -alkylamino, diC _1-4 -alkylamino or a combination thereof Arylalkyl having 7 to 19 carbon atoms, unsubstituted or substituted with halogen, cyano or methyl, or Heterocyclic moieties may be aromatic, partially saturated or fully saturated, and have 5 to 10 ring atoms where at least one ring atom is an N, O or S atom, and branched or unbranched alkyl moieties are 1 to 5 carbons Atom, unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, CF ₃ O, nitro, oxo , amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, cyano, methyl, or substituted heteroaryl when a combination thereof Click alkyl group ego; R ⁴ is Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, nitro, trifluoromethyl, OCF ₃ , Amino, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, hydroxamic acid, tetrazol-5-yl, 2- (heterocycle) tetrazol-5-yl, carboxy, C _1-4 -alkoxy 6 to 12 carbons, substituted one or more times with carbonyl, cyano, acyl, C _1-4 -alkylsulfonyl, phenoxy, triC _1-4 -alkylsilyloxy, R ⁵ -L- or combinations thereof Aryl having an atom, or 1 or 2 ring atoms unsubstituted or substituted one or more times with alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, carboxy, C _1-4 -alkoxycarbonyl or a combination thereof Heteroaryl having 5 to 6 ring atoms being N ego; R ⁵ is H, Alkyl having 1 to 8 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof, Cycloalkyl having 3 to 10 carbon atoms, unsubstituted or substituted one or more times with halogen, hydroxy, oxo, cyano, C _1-4 -alkoxy, alkyl having 1 to 4 carbon atoms or a combination thereof , Unsubstituted or halogen, C _1-4 -alkyl, hydroxy, C _1-4 -alkoxy, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl , Amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, tetrazol-5-yl , HydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C _1-4 -alkylsul Aryl having 6 to 14 carbon atoms, substituted one or more times with ponyls or combinations thereof, Unsubstituted or halogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, C _1-4 -alkoxyC _1-4 -alkoxy, nitro, methylenedioxy, ethylenedi Oxy, trifluoromethyl, amino, aminomethyl, aminoC _1-4 -alkyl, aminoC _1-4 -alkoxy, diC _1-4 -alkylamino, hydroxyC _1-4 -alkyl, hydroxamic acid, Tetrazol-5-yl, hydroxyC _1-4 -alkoxy, carboxy, C _1-4 -alkoxycarbonyl, cyano, acyl, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl, C Saturated, partially saturated or unsaturated heterocyclic groups having 5 to 10 ring atoms wherein at least one ring atom is N, O or S atom, substituted one or more times with _1-4 -alkylsulfonyl, phenoxy or a combination thereof, or The heterocyclic moiety is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms wherein at least one ring atom is an N, O or S atom, and the branched or unbranched alkyl moiety has 1 to 5 carbon atoms , Unsubstituted or heterocyclic moiety is halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, trifluoromethyl, CF ₃ O, nitro, oxo, amino, C _1-4 - alkylamino, di C _1-4 - alkylamino or substituted one or more times with a combination thereof, the alkyl moiety is unsubstituted or substituted by halogen, cyano, methyl, or a combination of a substituted heterocyclic group ego; L is 1-8 carbon atoms in which a single bond or one or more -CH ₂ -groups can be substituted with -O-, -NR ^6- , -SO ₂ NH-, -CO- or -NR ⁶ CO-, respectively Divalent aliphatic radicals having; R ⁶ is H, or branched or unbranched, 1 to 8 carbon atoms, unsubstituted or substituted one or more times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo or combinations thereof Alkyl having; Here, when the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. 3- tert - butyldimethylsilyloxy-4-methoxy - N - (3- pyridylmethyl) diphenylamine; 3- tert - butyldimethylsilyloxy-3'-chloro-4-methoxy - N - (3- pyridylmethyl) diphenylamine; Ethyl N - (3- tert - butyldimethylsilyloxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoate; 3-cyclopentyloxy-4-methoxydiphenylamine; 3-hydroxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine; 3'-chloro-3-hydroxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine; Ethyl N - (3- hydroxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoate; 3 '-(2-bromoethoxy) -3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine; 4 '-[1- (3-bromopropyl) oxy] -3-cyclopentyloxy-4-methoxy- N- (3-pyridylmethyl) diphenylamine; And 4-hydroxy-3-cyclopentyloxy- N- (3-pyridylmethyl) diphenylamine A compound selected from the above, wherein if the compound exhibits chirality, it may be a mixture of enantiomers, such as racemates, or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer . The compound of claim 1, wherein the compound is N- 3,4-bis (difluoromethoxy) phenyl- N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound is N - (3- cyclopentyloxy-4-methoxyphenyl) - N - (3- pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt of the compound. A pharmaceutical composition for treating depression, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 63. The method according to any one of claims 47, 49, 50, 54 and 62, wherein the calcium channel blocker, cholinergic drug, adenosine receptor modulator, ampacin, NMDAR modulator, mGluR modulator, cholines A pharmaceutical composition further comprising one or more pharmaceutical agents selected from thease inhibitors or any combination thereof. 63. The pharmaceutical composition of any one of claims 47, 49, 50, 54 and 62, wherein the compound is administered in an amount of 0.01-100 mg / kg body weight / day. 63. The pharmaceutical composition of any one of claims 47, 49, 50, 54 and 62, wherein the pharmaceutical composition is in unit dosage form comprising 0.1-50 mg of the compound. 63. The pharmaceutical composition of any one of claims 47, 49, 50, 54 and 62, wherein the pharmaceutical composition is in unit dosage form comprising 0.1-10 mg of the compound. 63. The compound of any one of claims 47, 49, 50, 54 and 62, wherein the compound is N- 3,4-bis (difluoromethoxy) phenyl- N- (3-pyriy). Pharmaceutical composition, which is dilmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 63. The compound of any one of claims 47, 49, 50, 54 and 62, wherein the compound is N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3- Pharmaceutical composition which is pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 51. The pharmaceutical composition of claim 50, wherein said disease is asthma. 51. The pharmaceutical composition of claim 50, wherein the disease is chronic obstructive pulmonary disease (COPD).