NO329548B1 - Aniline derivatives, pharmaceutical compositions comprising such a compound, and uses of the compounds for the manufacture of medications for the treatment of cognitive disorders, depression or allergic or inflammatory diseases - Google Patents

Description

Field of the invention

The present invention generally relates to the field of enzyme inhibition of phosphodiesterase 4 (PDE4). More specifically, this invention relates to selective PDE4 inhibition by means of new compounds which are N-substituted aniline analogues, pharmaceutical preparations containing such compounds, and uses thereof.

The background of the invention

The cyclic nucleoside-specific phosphodiesterases (PDEs) constitute a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers in cells and as messengers, carrying impulses from cell surface receptors with bound different hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides in cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides, resulting in termination of their messenger role.

PDE enzymes can be grouped into 11 families according to their specificity towards the hydrolysis of cAMP and cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by different 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 creates positive inotropic activity. PDE4 is cAMP-specific and its inhibition causes airway relaxation, anti-inflammatory and antidepressant activity. PDE5 appears to be important in regulating cGMP content in vascular smooth muscle, and PDE5 inhibitors may therefore have cardiovascular activity. As the PDEs have distinct biochemical properties, it is likely that they are subject to many different forms of regulation.

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

PDE4 isoenzymes are located in the cytosol of cells and are not associated with any known membrane structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine-5'-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes, such as rolipram, piclamilast, CDP-840 and ariflo, are strong anti-inflammatory agents and may therefore be useful in the treatment of diseases where inflammation is problematic, such as asthma or arthritis. Furthermore, rolipram improves the cognitive performance of rats and mice in learning paradigms.

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

Rolipram, previously under development as an antidepressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the passivation of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has since been expanded to include such indications as dementia. [See "The PDE IV Family Of Calcium-Phospho-diesterases Enzymes", John A. Lowe, III et al., Drugs of the Future 1992, 17(9):799-807 for a general overview). Further clinical developments of rolipram and other first-generation PDE4 inhibitors were terminated due to the side effect profile of these compounds. The primary side effect in primates is emesis, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotropic effects, increased gastric acid secretion and gastric emptying.

Summary of the invention

The present invention relates to new N-substituted aniline and diphenylamine compounds, which inhibit PDE4 enzymes, and which in particular have improved side effect profiles, e.g. are relatively non-emetic (e.g. as compared to the previously discussed prior art compounds). The compounds preferably selectively inhibit PDE4 enzymes. The compounds according to this invention simultaneously facilitate entry into cells, especially cells of the nervous system. Furthermore, the invention relates to pharmaceutical preparations comprising such a compound and a pharmaceutically acceptable carrier, and uses of the compounds for the manufacture of medicines.

Methods for synthesizing compounds with such activity and selectivity are discussed here, as well as methods for treating a patient, e.g. mammals, including humans, requiring PDE inhibition, particularly PDE4 inhibition, for a disease state involving elevated intracellular PDE4 levels or decreased cAMP levels, e.g. involving neurological syndromes, particularly those conditions associated with memory impairment, most particularly long-term memory impairment, and wherein such memory impairment is due in part to catabolism of intracellular cAMP levels by PDE4 enzymes, and wherein such memory impairment can be improved by effectively inhibiting PDE4- enzyme activity.

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

The present invention comprises compounds of formula I:

where

R<1> is alkyl with 1-4 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen;

R2 is alkyl with 1-12 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen,

cycloalkyl with 3-10 carbon atoms,

cycloalkylalkyl with 4-16 carbon atoms, or

methoxyethoxy, tetrahydrofuranyl or indanyl;

R 3 is benzyl, quinolinylmethyl, thienylmethyl or pyridyl C 1 -C 6 alkyl which is optionally substituted with halogen or C 1 -C 6 alkyl; R 4 is naphthyl or phenyl which is unsubstituted or substituted one or more times by halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkoxy, nitro, trifluoromethyl, hydroxy-C 1 -C6-alkyl, tetrazol-5-yl, 2-(tetrahydropyranyl)-tetrazol-5-yl, hydroxy-C1-C6-alkoxy, carboxy, C1-C6-alkyl-00C-, cyan, acetamido, C1-C6~ alkyl-sulfonylamino-, benzyl-sulfonyl-amino-, C1-C6-alkyl-sulfonylamino-C1-C6-alkoxy, pyrrolidinyl-oxy-, pyrrolidinyl-C1-C6-alkoxy which is optionally substituted with oxo or C1-C6-alkyl , Ci-C6-alkyl-carbonylamino-, piperazinyl-oxy-, piperazinyl-carbonyl which is optionally substituted with Ci-C6~alkyl, piperazinyl-Ci-C6-alkyl which is optionally substituted with

-Ci-C6-alkyl, pyridyl-Ci-C6-alkoxy which is optionally substituted with C1-C6-alkyl, pyridyl-aminocarbonyl-, C3-C10-cycloalkyl-Ci-C6-alkoxy, piperazinyl-C1-C6- alkoxy which optionally substituted with C 1 -C 6 -alkyl, piperidinyl C 1 -C 6 -alkyl which is optionally substituted with C 1 -C 6 -alkyl, imidazolyl C 1 -C 6 -alkyl, morpholinyl C 1 -C 6 -alkyl-amino-C 1 -C 6 - alkoxy, phenyl, tetrahydrofuranyl, tri-C 1 -C 6 alkylsilyloxy or combinations thereof, or

isoquinolinyl, pyrimidinyl, pyrazinyl or pyridyl which is unsubstituted or substituted by carboxy;

or a pharmaceutically acceptable salt thereof.

Additionally, preferred compounds of formula I are those of subformula IV

where at least one of A, B and D is N and the others are CH, and R<4> is pyridyl or phenyl which in each case is substituted or unsubstituted, or a pharmaceutically acceptable salt thereof.

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

Assays for determining PDE inhibitory activity as well as selectivity of PDE4 inhibitory activity and selectivity for inhibition of PDE4 isoenzymes are known in the art. See e.g. US Patent No. 6,136,821.

Compounds are also provided which can be used as intermediates for the production of the PDE4 inhibitors described here (e.g. PDE4 inhibitors of formula I) and/or can be used for the synthesis of radioactively labeled analogues of PDE4 inhibitors within this application.

Intermediate compounds corresponding to compounds of formula I have thus been provided, where R<2>, R<3> and R<4> are as previously defined for formula I, but R<1> is H, tert-butyldimethylsilyl- or a appropriate phenolic protecting group. Suitable phenolic protecting groups are described e.g. in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radioactively labeled compounds, such as those where R<1> is <3>H3C-, <14>CH3- or <11>CH3-, e.g. by removing the protecting group and reacting the resulting compound where R<1> is H with suitable radiolabelled reagents. Such radioactively labeled compounds can be used to determine the tissue distribution of compounds in animals, in PET imaging studies and for in vivo, ex vivo and in vitro binding studies.

Also provided are intermediate compounds corresponding to compounds of formula I, where R<1>, R<3> and R<4> are as previously defined for formula I, but R<2> is H, tert-butyl-dimethylsilyloxy group or a suitable phenolic protecting group. Suitable phenolic protecting groups are described e.g. in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999, pp. 246-293. Compounds where R<2> is H are useful as intermediates, e.g. as platforms for parallel or combinatorial chemistry applications. Furthermore, these compounds are useful for the introduction of radioactive markers, such as <3>H, <14>C or 11C.

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

Alkyl means as a group or substituent per se, or as part of a group or substituent (eg alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), a straight-chain or branched hydrocarbon radical of 1-12 carbon atoms, preferably 1-8 carbon atoms, in particular 1-4 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 alkyl groups as described above which are substituted in one or more positions with halogens, especially F and Cl.

Alkoxy means alkyl-O groups, and alkoxyalkyl means alkyl-O-alkyl-O groups where the alkyl parts are in accordance with the previous mention. Suitable alkoxy and alkoxyalkyloxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Alkoxycarbonyl likewise means alkyl-O-CG— where the alkyl part is in accordance with the previous mention. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

Cycloalkyl means a monocyclic, bicyclic or tricyclic, non-aromatic, saturated hydrocarbon radical of 3-10 carbon atoms, preferably 3-8 carbon atoms, especially 3-6 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 include 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. The cycloalkyl group may be substituted, e.g. substituted with halogen and/or alkyl groups.

Cycloalkylalkyl refers to cycloalkyl-alkyl radicals with 4-16 carbon atoms. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

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

In the compounds of formula I, R<1> is an alkyl group with 1-4 carbon atoms, which is optionally substituted with halogen, preferably fluorine or chlorine. R<1> is particularly preferably methyl or difluoromethyl.

R<2> is preferably cycloalkyl, especially cyclopentyl.

R<2> is also preferably an alkyl group with 1-8 carbon atoms, especially 1-4 carbon atoms, which is substituted or unsubstituted, e.g. methyl, difluoromethyl, trifluoromethyl and methoxyethyl.

R<3> is preferably pyridylmethyl.

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

In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by means of the subformulas Ia-Ih which correspond to formula I, but which have the following preferred groups:

Ia R<1> is methyl or CHF2,

Ib R<1> is methyl or CHF2, and

R<2> is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl).

Ic R<1> is methyl or CHF2, and

R<2> is cyclopentyl.

Id R<1> is methyl and

R<2> is cyclopentyl.

Ie R<1> is methyl,

R<2> is cyclopentyl and

R<4> is phenyl which is substituted or unsubstituted.

If R<1> is methyl,

R<2> is cyclopentyl,

R<3> is pyridylmethyl, phenethyl, benzyl, thienylmethyl or pyridylpropyl,

which is optionally substituted with methyl, ethyl or propyl, and

R<4> is phenyl or phenyl substituted with 1-3 substituents.

Ig R<1> is methyl,

R<2> is cyclopentyl,

R<3> is pyridylmethyl, benzyl, thienylmethyl, pyridylpropyl, which is optionally substituted with methyl, ethyl or propyl, and

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

In addition, preferred PDE4 inhibitors according to the invention are compounds described by means of the subformulas IVa-IVp, which correspond to formula IV, but which have the following preferred groups:

IVa R<1> is methyl or CHF2.

IVbR<1> is methyl or CHF2, and

B is N.

IVc R<1> is methyl or CHF2, and

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

IVd R1 is methyl or CHF2,

B is N, and

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

IVe R 1 is methyl or CHF 2 , and

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

IVf R1 is methyl or CHF2,

B is N, and

R 4 is 3-pyridyl or phenyl which in each case is substituted or substituted.

IVg R1 is methyl or CHF2,

R2 is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and

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

IVh R<1> is methyl or CHF2,

B is N,

R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl) or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and R 4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.

IVi R<1> is methyl or CHF2, and

R4 is phenyl which is substituted in the 3- or 4-position.

IVj R<1> is methyl or CHF2,

B is N, and

R4 is phenyl which is substituted in the 3- or 4-position.

IVk R1 is methyl or CHF2,

R2 is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and

R4 is phenyl which is substituted in the 3- or 4-position.

IVI R1 is methyl or CHF2,

B is N,

R2 is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and

R4 is phenyl which is substituted in the 3- or 4-position.

IVm R 1 is methyl or CHF 2 , 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.

IVn R<1> is methyl or CHF2,

B is N, 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.

IVo R<1> is methyl or CHF2,

R2 is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), 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.

IVp R<1> is methyl or CHF2,

B is N,

R2 is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and

R4 is 3-pyridyl, 3-C00H-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro- phenyl, 4-pyridyl, 4-COH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl.

Preferred aspects include pharmaceutical preparations comprising a compound of this invention and a pharmaceutically acceptable carrier, use of a compound of the invention for the manufacture of a medicament for the treatment of cognitive impairment or impairment, memory impairment, etc.

The compounds according to the present invention can be prepared in the usual way. Some of the methods that can be used are described below. All starting materials are known or can be produced in the usual way from known starting materials.

Reaction scheme 1

Starting nitrophenols of type 1 are either commercially available (e.g., RI = CH3) or prepared by published procedures (e.g., RI = CHF2 or both RI and R2 = CHF2, see Mueller, Klaus-Helmut. Eur. pat .app. (1994), 8 pp. CODEN: EPXXDW EP 626361A1; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN: JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew. ; Maiyorova, Helen; Chistokle-tov, Victor. Int. Symp. Wood. Pulping Chem., 1995, 8., 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 Al 19960808). Aniline intermediates 3 are prepared in two steps; first, an addition reaction gives intermediate 2, followed by reduction of the nitro group. Intermediate nitro compounds 2 are prepared by a large number of published methods, such as by Mitsunobu reactions or standard alkylation reactions. Compounds where R2 is aryl or heteroaryl can be prepared by copper-catalyzed reactions with aryl or heteroaryl iodides under Ullman conditions, or by coupling aryl, vinyl or heteroaryl boronic acids with phenol 2 in the presence of a copper catalyst (e.g. .Cu(OAc)2) and such base as TEA. Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using an azodicarboxylate (e.g. DEAD, DIAD) and a suitable phosphine (e.g. Ph3P, Bu3P) gives alkylated nitrophenols 2. Mitsunobu reactions are performed generally in aprotic solvents, such as dichloromethane or THF. Alternatively, alkylation can be achieved by the reaction between an appropriately substituted nitrophenol and an alkyl halide in the presence of a base (eg K2CO3 or NaH) in a polar aprotic solvent (eg DMF or CH3CN).

Nitrocatechols 2 are then reduced to the corresponding anilines 3 by methods standard in the art, such as by hydrogenation using a suitable catalyst (e.g. Pd-on-carbon) in a polar protic solvent (e.g. .MeOH or EtOH) under a hydrogen atmosphere. Alternatively, nitrocatechols 3 can be reduced by using a hydride source (e.g. NaBH4) and a transition metal catalyst (e.g. NiCl2, Pd-on-carbon) or by using metals (e.g. Zn, Sn, Fe) in mineral acid solutions (e.g. HC1), whereby the corresponding anilines are obtained. In general, polar, protic solvents, such as ethanol or methanol, are used in these reactions.

N-arylalkylanilines 4 are synthesized using standard procedures within the art, such as by reductive amination reaction, alkylation reaction or by reduction of corresponding amides. The reductive amination reaction of an aryl or arylalkylaldehyde with suitably substituted anilines in the presence of a borohydride reducing agent, such as NaBH4 or NaBH3CN, with an acid catalyst, such as acetic acid or pTsOH, gives e.g. desired N-arylalkylanilines. These reactions generally take place in polar, protic solvents, such as methanol, ethanol, isopropanol, n-propanol and the like.

N-Arylalkylanilines 4 readily undergo N-arylation by methods standard in the art, including Ullmann coupling reaction, metal-catalyzed coupling, or aromatic nucleophilic substitution reaction. For example, the metal-catalyzed reaction between an N-benzylaniline and an aryl halide using a palladium catalyst (e.g. Pd2dba3), a bulky, electron-rich phosphine ligand (e.g. tributylphosphine) and suitable base (e.g. NaOtBu) gives N-arylalkyl-diphenylamines. Nickel and copper catalysts have also been used. Solvents that can be used in this reaction include non-polar, aprotic solvents, such as toluene, benzene, xylenes, tetrahydrofuran and ether. When synthesizing compounds of type 5, where R4 is an alkoxycarbonyl-phenyl, it is advantageous that amine 4 is coupled with 1.1 equivalents of tert-butyl-3-iodobenzene, and that 22 mol% (tBu)3P , 5.5 mol% Pd2(dba)3 and 1.3 equivalents of tBuONa, are used.

Reaction scheme 2

Carboxylic acid intermediates 6 can be hydrolyzed under acidic or basic conditions, whereby the corresponding carboxylic acids 7 are obtained. For example, an ethyl ester (R5 = Et) can be hydrolyzed using a mixture of aqueous base (e.g. NaOH, KOH) and a water-miscible solvent (e.g. EtOH, THF). t-Butyl esters (R5 = t-butyl) can be hydrolyzed if necessary by using an aqueous acid (eg HCl, formic acid, TFA) in a water-miscible organic solvent.

Reaction form 3

Coupling of protected tetrazole bromo- or -iodobenzenes (e.g. 5-(3-iodophenyl)-2-(2-tetrahydropyran)tetrazole) with N-substituted aniline derivatives 4 gives THP-protected tetrazoles 8. Hydrolysis of THP-protected tetrazoles 8 can be carried out by using an aqueous acid, such as HC1 in water, and a miscible solvent, such as THF or EtOH, whereby tetrazoles 9 are obtained. Furthermore, THP tetrazoles 8 can also be cleaved oxidatively by using such reagents as CAN and DDQ , in halogenated hydrocarbon solvents, such as dichloromethane, chloroform, dichloroethane and the like, whereby tetrazoles 9 are obtained.

Alternatively, tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with azide ion (eg, KN3, NaN3, etc.) and a proton source (eg, NH4Cl) in a polar, aprotic solvent, such as DMF. They can also be prepared by treatment with an azide ion and a Lewis acid (eg ZnBr 2 ) in water, if necessary by using a water-miscible co-solvent such as isopropanol. Another production method is by treating a nitrile with tin or silicon azides (e.g. Me3SiN3, Bu3SnN3) in an aprotic, organic solvent, such as benzene, toluene, dichloromethane, dichloroethane, ether, THF and the like.

Reaction form 4

Diphenylamines 10 can be prepared by coupling appropriately substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyaniline, with aryl boronic acids in the presence of a base, such as triethylamine, and a copper catalyst, such as copper acetate (as described by Chan et al. , Tetrahedron Lett., 39, 2933-2936

(1998)). In general, halogenated solvents such as dichloromethane, chloroform, dichloroethane and the like are used, as well as non-polar, aprotic solvents, such as benzene, toluene or xylene. Such diphenylamines (e.g. 10) can more preferably be synthesized by means of metal-catalyzed amination reactions. Reaction of an appropriately substituted aniline 3 with an aryl halide in the presence of a base (eg K3PO4, CSCO3 or NaOtBu) and a palladium or nickel catalyst, e.g. Pd(dppf)Cl2, a ligand (e.g. dppf) and a base (e.g. NaOtBu) (JACS. 1996, 118, 7217) or with Pd2dba3, a bulky, electron-rich phosphine, such as P(tBu) 3, and a base (e.g. NaOtBu) (J. Org. Chem. 1999, 64, 5575), gives e.g. the desired diphenylamines 10. Solvents most commonly used in this type of reaction include non-polar, aprotic solvents, such as benzene, toluene, tetrahydrofuran, ether and the like.

Diphenylamines 10 can then be alkylated with various alkyl halides or arylalkyl halides, such as, but not limited to, iodomethane, ethyl bromide, benzyl chloride, 3-(chloromethyl)-pyridine, 4-(chloromethyl)-2,6-dichloropyridine and 4-(bromomethyl) benzoic acid, or salts thereof, in the presence of a non-nucleophilic base, such as sodium hydride, potassium hexamethyldisilazide or potassium di-isopropylamide, whereby N-substituted diphenylamines 5 are obtained. Solvents that can be used in this reaction include aprotic solvents, such as benzene, toluene, tetrahydrofuran, ether, DMF and the like.

Reaction form 5

Carboxylic acids 7 can be further manipulated so that carboxamides 11 are formed by using methods that are standard in the art. For example, a carboxylic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable coupling reagent, such as BOP, pyBOP or DCC, and a base, such as Et3N or DIEA, to give a carboxamide. These reactions generally take place in non-polar, aprotic solvents, such as dichloromethane, chloroform or dichloroethane.

Carboxylic acid esters 6 or carboxylic acids 7 can be reduced by using methods that are standard in the art, whereby the corresponding carboxaldehyde or hydroxymethyl analogues are obtained. For example, an aryl ethyl ester (eg formula 6, R5 = ethyl) can be treated with a suitable reducing agent (eg LAH, DIBAL, etc.) in an aprotic solvent, such as ether or THF, to give the corresponding carboxaldehydes or hydroxymethyl analogues. Such aldehydes and alcohols can be further derivatized using methods that are standard in the art.

Similar carboxamides (eg formula 11) and nitriles can be reduced using methods standard in the art, whereby the corresponding substituted amines or aminomethyl analogues are obtained. For example, an arylcarboxamide 11 can be reduced with a suitable reducing agent (e.g. LAH) in an aprotic solvent (e.g. benzene, toluene, ether, THF, etc.) to give the corresponding substituted aminomethyl analog. In contrast, reduction of an arylnitrile gives the corresponding primary aminomethyl analog.

Reaction form 6

Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by methods standard in the art, such as hydrogenation using a suitable catalyst (e.g. Pd-on-carbon) in a polar protic solvent (e.g. e.g. EtOH, MeOH, etc.)■ Nitrobenzenes 12 can also be reduced by using a hydride source (e.g. NaBH4) and a transition metal catalyst (e.g. NiCl2, Pd-on-carbon) in polar, protic solvents, such as EtOH, whereby the corresponding anilines 13 are prepared. These anilines can then be further substituted using methods which are standard in the art. For example, anilines of type 13 can be alkylated, acylated or sulfonylated, whereby the corresponding N-alkylamines, carboxamides (e.g. formula 15) or sulfonamides (e.g. formula 14) are obtained respectively. A sulfonamide can e.g. is prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (eg MeSO 2 Cl, EtSO 2 Cl, BnSO 2 Cl, PhSO 2 Cl, etc.) in the presence of a base (eg Et 3 N, pyridine, DIEA, etc.). Suitable solvents for this reaction include non-polar, aprotic solvents, such as dichloromethane, chloroform, ether and the like.

Reaction form 7

Trialkylsilyl ethers of type 16 are prepared as described in reaction scheme 1. The tert-butyldimethylsilyl protected catechol intermediates 16 are easily deprotected using a large number of literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, 1999, pp. 273-276) such as by using a fluoride ion source (eg, Bu4NF) in an aprotic solvent, such as ether or THF; or under acidic conditions (eg KF, 48% HBr, DMF). The resulting phenol 17, which is a very useful synthetic intermediate, can then be alkylated by methods standard in the art, and in a similar manner to that described for the alkylation of nitrophenol 2 in Scheme 1. For example, by means of the Mitsunobu reaction , by reaction with an alkyl halide in the presence of a base, or by means of Ullman-type aryl coupling or by reaction with vinyl, aryl or heteroaryl boronic acids in the presence of a copper catalyst.

Reaction form 8

Halogenalkoxy intermediates 18, prepared by alkylation of the corresponding phenol, can be alkylated by means of reactions with substituted amines, alcohols or thiols in the presence of a base, whereby such analogues as 19 are obtained. For example, an alkyl halide 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 synthetic methods are described more fully in the examples below.

Those skilled in the art will recognize that some of the compounds of formulas (I) and (I') may exist in different geometric isomeric forms. In addition, some of the compounds according to the present invention may have one or more asymmetric carbon atoms and are thus able to exist, among other things, in the form of optical isomers, as well as in the form of racemic or non-racemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures. All of these compounds, including cis-isomers, trans-isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers and substantially pure and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% by weight of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemic mixtures according to usual processes, e.g. by the formation of diastereomeric salts using an optically active acid or base, or formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, ditoluene tartaric acid and camphor sulphonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences, using methods known to those skilled in the art, e.g. by means of chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. Another method for the separation of optical isomers involves the use of chiral chromatography (eg chiral HPLC columns), with or without conventional derivatization, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g. Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds with formulas I and I' can likewise be obtained by means of chiral syntheses using optically active starting materials.

The present invention also relates to usable forms of the compounds as described here, such as pharmaceutically acceptable salts for all the compounds according to the present invention. Pharmaceutically acceptable salts include those obtained by reacting the parent compound, which acts as a base, with an inorganic or organic acid to form a salt, e.g. salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those where the main compound acts as an acid, and is reacted with a suitable base so that e.g. sodium, potassium, calcium, magnesium, ammonium and choline salts are formed. Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting the compounds according to the invention with the appropriate base via many different known methods.

The following are further examples of acid salts which can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzene sulphonates, bisulphates, butyrates, camphorates, digluconates, cyclopentane propionates, dodecyl sulphates, ethane sulphonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

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

The compound according to the invention can be administered alone or as an active ingredient in a formulation. The present invention thus also includes pharmaceutical preparations of compounds of formula I, which e.g. containing one or more pharmaceutically acceptable carriers.

A large number of standard references are available which describe methods for the preparation of various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations can be found, e.g. in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, eds.) (latest ed.), published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (Arthur Osol, ed.), 1553-1593 (latest ed.).

On the basis of their high degree of PDE4 inhibition, the compounds of the present invention can be administered to anyone who needs or wants PDE4 inhibition, and/or enhancement of cognition. Administration can be performed according to patient needs, e.g. oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and by infusion), by inhalation, rectal, vaginal, topical, local, transdermal and by ocular administration.

Various solid, oral dosage forms can be used for the administration of compounds according to the invention, including such solid forms as tablets, gel capsules, capsules, caplets, granules, lozenges and powder in loose weight. The compounds of the present invention may be administered alone or together with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose and starches) and excipients known in the art, including, but not limited to, suspending agents, solubilizing agents, buffering agents, binding agents, disintegrants, preservatives, colourings, flavorings, lubricants and the like. It is also advantageous to use capsules, tablets and gels with time-regulated release, when administering the compounds according to the present invention.

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

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

For topical administration, the pharmaceutical preparation may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via such means as transdermal patches.

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

The compounds according to the present invention can be used in methods of treatment involving inhibition of PDE4 enzymes, thus methods for selective inhibition of PDE4 enzymes in animals, e.g. mammals, especially humans, where such inhibition has a therapeutic effect, such as when such inhibition can alleviate conditions involving neurological syndromes, such as loss of memory, particularly long-term memory. Such methods comprise administering to an animal in need thereof, particularly a mammal, most particularly a human, an inhibitory amount of a compound, alone or as part of a formulation, as described herein.

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

Dementia are diseases that include memory loss and, in addition, intellectual disturbance separate from memory. The present invention comprises present methods for the treatment of patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementia (eg Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (eg infarcts, haemorrhage, cardiac disorders), mixed, vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jakob disease, multiple sclerosis, traumatic (eg subdural hematoma or traumatic brain injury), infectious (eg HIV), genetic (Down syndrome), toxic (eg heavy metals, alcohol, some medications), metabolic (eg vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (eg depression and schizophrenia) and hydrocephalus.

The compounds of the present invention can be used in methods of managing memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline. The compounds according to the present invention can further be used in methods for treating memory disorders as a result of disease. Another application includes methods for managing memory loss arising from the use of general anesthesia, chemotherapy, radiation therapy, post-surgical trauma and therapeutic intervention.

The compounds may be used to treat psychiatric conditions, including schizophrenia, bipolar or manic depression, major depression, and drug abuse and morphine addiction. These compounds can increase insomnia. PDE4 inhibitors can be used to increase cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of anti-apoptotic and anti-inflammatory properties makes these compounds useful in treating neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amyloid sclerosis (ALS) and multiple system atrophy (MSA). ).

In accordance with a preferred embodiment, the present invention thus comprises the use of the compounds for the preparation of a medicament for the treatment of patients suffering from memory disorders, e.g. due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, CNS hypoxia, cerebral senility, multi-infarct dementia and other neurological conditions, including acute neurological disorders, as well as HIV and cardiovascular diseases, comprising the administration of an effective amount of a compound of formula (I) or (I'), or pharmaceutically acceptable salts thereof.

The compounds according to the present invention can also be used in a method for the treatment of patients suffering from disease states characterized by reduced NMDA function, such as schizophrenia. The compounds can also be used to treat psychosis characterized by elevated levels of PDE4, e.g. different forms of depression, such as manic depression, major depression and depression associated with psychiatric and neurological disorders.

As mentioned, the compounds according to the invention also exhibit anti-inflammatory activity. As a result of this, the compounds according to the invention are useful in the treatment of many different allergic and inflammatory diseases, in particular disease states characterized by reduced levels of cyclic AMP and/or elevated levels of phosphodiesterase 4. In accordance with a further embodiment of the invention, it is thus provided a use of the compounds for the preparation of a medicament for the treatment of allergic and inflammatory disease states. Such disease states include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of heart muscle and brain, chronic glomerulonephritis, endotoxic shock, respiratory distress syndrome in adults, cystic fibrosis, arterial restenosis, arteriosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronic, obstructive respiratory disease, chronic, obstructive, pulmonary disease, toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and broad-area pyodermas, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpura nef rit, inflammatory bowel disease, leukaemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.

PDE4 inhibitors for the treatment of asthma, chronic bronchitis, psoriasis, allergic rhinitis and other inflammatory diseases, and for inhibition of tumor necrosis factor, are known in the art, see e.g. WO 98/58901, JP 11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 and US 5,935,9778. These references also describe assays for determining PDE4 inhibitory activity, and methods for synthesizing such compounds.

PDE4 inhibitors can be used to prevent or alleviate osteoporosis, as an antibiotic, to treat cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term inhibition is mesenchymal cell proliferation after transplantation, for the treatment of urinary tract obstruction due to benign prostatic hyperplasia, for the suppression of chemotaxis and reduction of invasion of cancer cells in the colon, for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), for the inhibition of uterine contractions, for the attenuation of pulmonary , vascular ischemia-reperfusion injury (IRI), to corneal hydration, to inhibit IL-2R expression and thereby disrupt HIV-1 DNA nuclear import in memory T cells, to increase glucose-induced insulin secretion, to both prevent and treatment of colitis, and to inhibit mast cell degranulation.

The compounds according to the present invention can be administered as the only active agent or in combination with other pharmaceutical agents, such as other agents used in the treatment of cognitive disorder and/or in the treatment of psychosis, e.g. other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakines-NMDA-R modulators, mGluR modulators and cholinesterase inhibitors (eg, donepezil, rivastigimine and glantanamine). In such combinations, each active ingredient may be administered either in accordance with their usual dosage range or at a dose below their usual dosage range.

The dosages of the compounds of the present invention depend on many different factors, including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosing interval, the particular compound used, the efficacy, the toxicological profile, the pharmacokinetic profile of the compound and the presence of any harmful side effects, among other considerations.

The compounds of the invention are usually administered at dosage levels and to a mammal that are customary for PDE4 inhibitors, such as the known compounds mentioned above. For example, the compounds can be administered in single or multiple doses by oral administration at a dosage level of e.g. 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can e.g. contain 0.1-50 mg of active compound. For intravenous administration, the compounds can be administered in single or multiple doses, at a dosage level of e.g. 0.001-

50 mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-

1 mg/kg/day. Unit dosage forms may contain e.g. 0.1-10 mg active compound.

In carrying out the methods of treatment, it should of course be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like is not intended to be limiting, but should be understood to include all related materials that those skilled in the art would recognize to be of interest or value in the particular context where the mention is presented. For example, it is often possible to replace one buffer system or culture medium with another and still achieve similar, if not identical, results. Those skilled in the art will have sufficient knowledge of such systems and methods to be able, without undue experimentation, to make such exploits as will optimally serve their purposes, using the methods and procedures described herein.

The present invention will now be further described by means of the following examples.

Above and in the following examples, all temperatures are stated uncorrected in degrees Celsius, and unless otherwise stated, all parts and percentages are based on weight.

Example IA

1- cyclopentyloxy- 2- methoxy- 5- nitrobenzene

To a suspension of 2-methoxy-5-nitrophenol (525 g, 3.104 mol) and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 L) under N2 protection was added cyclopentyl bromide (499, 2 mL, 4.66 mol). The suspension was heated to 100 °C for 6 hours. Potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100 °C for 4 hours. TLC indicated that the reaction was complete (9:1=DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3 L) and ether (3 L). The layers were separated and the aqueous layer was re-extracted with ether (2 L). The combined organic layers were washed with 1 N NaOH (2 L), water (2 L) and brine (2 L). The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting solid was azeotroped with toluene (2 x 300 mL) to give 736.7 g (99.6% yield) as a yellow solid.

Example IB

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

To a mixture of 2-methoxy-5-nitrophenol (1.69 g,

10 mmol), triphenylphosphine (5.24 g, 20 mmol) and 3-(R)-hydroxy-tetrahydrofuran (1.80 g, 20 mmol) in anhydrous tetrahydrofuran

(40 ml) was added dropwise with stirring diisopropylazo-dicarboxylate (4.0 ml, 20 mmol), and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ether (150 mL) and washed with 2 N NaOH (3 x 50 mL) and brine (50 mL), dried (MgSO 4 ) and concentrated in vacuo. The impure residue was purified by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes, whereby 1.05 g of product was obtained.

Example 1C

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

To a mixture of 2-methoxy-5-nitrophenol (1.53 g,

9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DMF (40 ml), tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) was added with stirring and the mixture was allowed to stir at room temperature

for 16 hours. The solvent was removed under vacuum and the residue was dissolved in 40 ml of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexanes, and the filtrates were combined and concentrated under vacuum to give 2.01 g of product as a tan crystalline solid. <X>H NMR (CDCl 3 ) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 ( d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Example 2

3- cyclopentyloxy- 4- methoxyaniline

To a suspension of 10% Pd-on-activated carbon (25 g) in ethanol (4 L) under N 2 protection was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250 g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4 hours, the reaction was complete by TLC (5:1=hex.:EA). The reaction mixture was filtered through a pad of celite, and the celite was rinsed with additional ethanol. The solvent was removed under vacuum to give 208.38 g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. <*>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).

Example 3

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

To a mixture of 3-pyridinecarboxaldehyde (106.55 g, 0.995 mol) in methanol (5 L) was added 3-cyclopentyloxy-4-methoxyaniline (208.38 g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg ). The reaction mixture was stirred for 4 hours. The flask was then cooled to 0 °C, and sodium borohydride (37.64 g,

2.3 mol) was added portionwise over 4 hours. reaction

the mixture was allowed to warm to room temperature over 16 hours with stirring. TLC indicated that the conversion was complete (1:3=hex.:EA). The solvent was evaporated until it returned to approx. 0.5 1 slurry. The slurry was diluted with water (1 L) and extracted with ethyl acetate (2x21). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate and concentrated to give 300 g (100% yield) of the desired product as a brown, viscous liquid. <1>H NMR (CDCl 3 ) δ 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6, 72 (d, 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).

Example 4

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

To a 100 ml oven-dried, argon-bubbled flask was added in the following order 0.59 g (6.10 mmol) NaOtBu,

360 mg Pd2dba3, 20 ml toluene, 0.14 ml P(tBu)3 and a 20 ml solution of 1.3 g (4.36 mmol) N-(3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline in toluene. With stirring, 3.1 g (15 mmol) of iodobenzene was added dropwise, and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with H 2 O and extracted with 3 x 15 mL 3 N HCl. The combined acid extracts were washed with 15 mL EtOAc and then carefully neutralized with 6 N NaOH until the pH was greater than 12. The basic solution was extracted with 2 x 15 mL EtOAc, and the combined organic fractions were then washed with 15 mL H 2 O and brine, dried (MgSO 4 ) and concd. The residue was purified by chromatography over silica gel (Biotage Flash 40M) eluting with 25% EtOAc in hexanes. The material was further purified by crystallization from hexanes, whereby 550 mg of a white solid was obtained. <1>H NMR (CDCl 3 ) δ 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7, 30-7.10 (m, 3H), 6.90-6.80 (m, 4H) , 6.80-6.60 (m, 2H) , 4.94 (s, 2H) , 4.64 ( p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

Example 5

N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-amino-benzoic 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 allowed to stand for 6 hours, concentrated and diluted with 50 ml of H 2 O. The aqueous mixture was extracted with 2 x 50 mL ether, acidified with AcOH to pH 3 and extracted with 2 x 50 mL 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 over SiO 2 (35 g RediSep column) using a linear gradient of EtOAc and hexanes as eluent (50% EtOAc to 70% EtOAc over 20 min) to give 4.8 g of a yellow solid product after drying under vacuum for 12 hours at 60 °C. <1>H NMR (CDCl3 ) 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).

Example 6

N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-amino-benzoic acid

Tert-butyl-N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL of 98% formic acid, and it was heated at 40 °C for 4 hours. The formic acid was removed under vacuum, and the residue was loaded onto a column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 minutes to give 16 mg of product as a brown solid. <X>H NMR (CDCl 3 ) δ 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7, 67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J= 8.7) , 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J = 4.3), 3 .77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).

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]diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF (5 mL), and 3 mL of 1 N HCl was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude residue was loaded onto a RediSep column (10 g, silica gel) and the product was eluted using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc over 20 min to give 0.96 g product as a white powder. <X>H NMR (CD3OD) 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).

Example 8 (method A)

3- cyclopentyloxy- 4- methoxydiphenylamine

Method A. (Ref. Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P., Tetrahedron Lett., 1998, 39, 2933-2936). A slurry of 207 mg 4-methoxy-3-cyclopentyloxyvaniline, 280 mg phenylboric acid, 182 mg Cu(OAc) 2 , 280 µl Et 3 N and 4.0 mL CH 2 Cl 2 was stirred for 20 hours at room temperature. The black mixture was filtered through silica eluting with CH 2 Cl 2 , concentrated and purified by chromatography over SiO 2 using EtOAc/hexanes (15/85) as eluent to give 75 mg of the desired product. <1>H NMR (CDCl3 ) δ 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8H).

Example 8 (method B)

3- cyclopentyloxy- 4- methoxydiphenylamine

Method B (Angerw Chem. Int. Ed., 1995, 34(17), 1348-1351). A mixture of 207 mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of NaOtBu, 9 mg of Pd2(dba)3, 12 mg of P(o-tol)3 and 7 ml of toluene was combined and heated with stirring to 100 °C for 4 hours. The mixture was cooled to room temperature, diluted with 25 mL EtOAc and washed with 10 mL H 2 O, 10 mL brine, dried (MgSO 4 ) and concentrated. The residue was purified by chromatography over SiO 2 using EtOAc/hexanes (5/95) as eluent to give 84 mg of the desired product.

Example 8 (method C)

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

Method C. To a mixture of Pd(dppf)Cl2 (0.025 mmol,

5 mol%), dppf (0.075 mmol, 3 dppf/Pd) and NaOtBu (0.70 mmol,

1.4 equivalents) and 1.0 mL of THF was added 1-bromo-2,5-dimethoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a 0.5 M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated to 60 °C for 3 h and diluted with ether and washed with H 2 O and brine, dried (MgSO 4 ) and concentrated. The crude residue was purified by chromatography over silica gel (Biotage Flash 12) eluting with 15% EtOAc in hexanes.

Example 9 (method A)

3-cyclopentyloxy-4-methoxy-N-methyldiphenylamine

To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 mL of 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, and 2.0 equivalents of iodomethane were added, and the reaction mixture was warmed to room temperature. After reaction completion as indicated by TLC, 10 mL EtOAc was added and the mixture was washed with 3 mL H 2 O, 3 mL brine, dried (MgSO 4 ) and concentrated. The crude residue was purified by column chromatography (Biotage Flash 12) using 5% EtOAc in hexanes as eluent.

Example 9 (method B)

N- 4- chloro- 3- pyridylmethyl)- N-( 3- cyclopentyl- 4- methoxyphenyl)- N-( 2-pyridyl) amine

To a solution of (3-cyclopentyloxy-4-methoxy-phenyl)-2-pyridylamine (30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol), dissolved in DMF (1 mL ), sodium hydride (50 mg of a 60% mineral oil dispersion,

1.3 mmol) in small portions. After stirring for 1 hour at room temperature, the mixture was poured into 25 ml of ice water. The mixture was extracted with EtOAc (2 x 15 mL), and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSO 4 ), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline substance. <1>H NMR (CDCl 3 ) δ 8.61 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7, 33 (m, 1H), 7.25 (m, 1H), 6.83 (d, 1H, 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).

Example 10

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

To a solution of N-(3-cyclopentyloxy-4-methoxy-phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg, 0.08 mmol) in CH 2 Cl 2 (2 mL) at room temperature was added diisopropylethylamine (20 µl, 0.11 mmol). After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added and the mixture was allowed to stir for 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2 x 15 mL) and brine (15 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to give 22 mg product. 1 H NMR (CDCl 3 ) δ 8.70-8.40 (m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 ( m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, 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, 6H), 1.65-1.45 (m, 2H).

Example 11

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

To a solution of 4'-amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine (47 mg, 0.12 mmol) in CH 2 Cl 2

(2 mL) at room temperature was added pyridine (20 microliters, 0.24 mmol) followed by methanesulfonyl chloride (15 microliters, 0.18 mmol), and the mixture was allowed to stand at room temperature for 16 hours. The mixture was diluted with ether (50 mL) and washed with water

(25 mL) and brine (25 mL), dried (MgSO 4 ) and concd. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with a linear gradient from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 min to give 41 mg of product . <1>H NMR (CDCl3) 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, 6H), 1.65-1.45 ( m, 2H).

Example 12

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

To a solution of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate (50 mg,

0.11 mmol) in THF (5 ml) at 0 °C was added dropwise with stirring 2.5 M diisobutylaluminum hydride in toluene (0.4 ml,

1.00 mmol). The mixture was stirred at 0 °C for 1 h, and the excess diisobutylaluminum hydride was neutralized by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between CH 2 Cl 2 (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 10 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgSO 4 ) and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with 300 mL of 50% EtOAc in hexanes, then 100% EtOAc, yielding 15 mg of product. <X>H NMR (CDCl 3 ) δ 8.51 (s, 1H), 8.40 (br, 1H), 7.58 (d, 1H,

7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5H), 4.85 (s, 2H), 4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H) .

Example 13

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

To a solution of N-(3-cyclopentyloxy-4-methoxy-phenyl)-N-(3-pyridylmethyl)-3-aminobenzonitrile (100 mg, 0.25 mmol) in DMF (3 mL) was added NaN3 (163 mg, 2.5 mmol) and NH 4 Cl (135 mg, 2.5 mmol) and the mixture was stirred at 120 °C for 6 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was loaded onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes, yielding 12 mg of product. <1>H NMR (CDCl3 ) 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, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).

Example 14

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

To a solution of 3-cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)diphenylamine (100 mg, 0.20 mmol) in THF (5 mL) was carefully added with stirring lithium aluminum hydride ( 50 mg, 1.3 mmol). The mixture was stirred for 15 min, and a few drops of EtOAc were carefully added to neutralize the excess hydride. Water (50 mL) and CH 2 Cl 2 (50 mL) were added and the mixtures were filtered through Celite. The CH 2 Cl 2 layer was separated, washed with brine (25 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 60 mg of product as a pale yellow oil. <X>H NMR (CDCl 3 ) δ 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7, 21 (dd, 1H, J =

4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J= 4.12 Hz), 3.82 (s, 3H), 3.41 (s, 2H), 2.75- 2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

Example 15

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

To a solution of N-(3-cyclopentyloxy-4-methoxy-phenyl)-N-(3-pyridylmethyl)-3-aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added with stirring lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 hours, and a few drops of water were carefully added to neutralize the excess hydride. Water (50 mL) and CH 2 Cl 2 (50 mL) were added and the mixtures were filtered through Celite. The CH 2 Cl 2 layer was separated, washed with brine (25 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with 10% MeOH in EtOAc to give 20 mg of product. <X>H NMR (CDCl 3 ) δ 8, 60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m , 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, 1H, J = 4.1 Hz), 3.83 (s, 3H) , 3.75 (m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

Example 16

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

To a solution of 3-(tert-butyldimethylsiloxy)-N-(3-pyridylmethyl)-4-methoxydiphenylamine (1.20 g, 2.85 mmol) in THF (40 mL) at 0 °C was added 1, 0 M tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred at 0 °C for 30 minutes. Water (50 mL) was added and the mixture was extracted with ether (3 x 25 mL). The ether extracts were combined and washed with water (3 x 25 mL) and brine (25 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was triturated with hexanes and collected by vacuum filtration, whereby 0.85 g of product was obtained. <X>H NMR (CDCl 3 ) δ 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m , 3H), 6.90-6.65 (m, 5H), 6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H) , 3.86 (s, 3H) .

Example 17

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

To a solution of 3'-(2-bromomethoxy)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine (17 mg, 0.03 mmol) in

acetonitrile (1 ml) was added potassium carbonate (25 mg,

0.18 mmol) and piperidine (5 µl, 0.05 mmol) and the mixture was stirred at 60 °C for 4 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was loaded onto an ISCO RediSep column (4.2 g, silica), and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc, yielding 11 mg of product. <X>H NMR (CDCl 3 ) δ 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26 -7.20 (m, 1H), 7.06 (t, 1H, J = 8.6 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).

Example 18

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

To a solution of N-(3-pyridylmethyl)-3'-[2-(2-phthalimido)ethoxy]-3-cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol) in MeOH (5 ml) was added hydrazine hydrate (1.0 ml, 20 mmol). After 6 h at room temperature, EtOAc was added

(50 ml), and the precipitate was filtered off. The filtrate was washed with water (25 ml) and brine (25 ml), dried (MgSO 4 ) and concentrated under vacuum. The residue was loaded onto an ISCO RediSep column (10 g, silica). The column was washed with 10% MeOH in EtOAc (200 mL) and the product eluted with 50% MeOH in EtOAc to give 0.21 g. <X>H NMR (CDCl 3 ) 6 8, 55 (s, 1H) , 8 .42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10 (m, 1H), 6.91 (d, 2H, J =

9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 6.70 (d, 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 19

In vitro measurement of phosphodiesterase type 4 inhibitory activity

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

Analysis:

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5<1->adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. The combined activity of PDE and nucleotidase therefore converts cAMP to adenosine. Adenosine is easily separated from cAMP using neutral alumina columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine. Cell lysates (40 µl) expressing hPDE-4D6 were combined with 50 µl assay mixture and 10 µl inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0.4 µg enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl 2 , 3 µM cAMP, 0.002 U 5'-nucleotidase and 3 x 10<4> cpm [3H]cAMP. The reaction was stopped by adding 100 µl of boiling 5 mN HCl. A 75 µl aliquot of reaction mixture was transferred from each well to alumina columns (Multiplate, Millipore). Labeled adenosine was eluted into an OptiPlate by centrifugation at 2000 rpm for 2 min; 150 ul per well of scintillation fluid was added to the aforementioned OptiPlate. The plate was closed, shaken for approx. 30 minutes, and the cpm for [<3>H]adenosine was determined using a Wallac Triflux.

All test compounds are dissolved in 100% DMSO and diluted in the assay so that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration.

A reduction in adenosine concentration is indicative of inhibition of PDE activity. pIC 50 values were determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then by plotting drug concentration versus <3>H-adenosine concentration. Non-linear regression software (Assay Explorer) was used to calculate pIC50 values.

Example 20 (method A)

Passive avoidance in rats, an in vivo test of learning and memory

The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J. and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204). The apparatus (model E10-16SC, Coulbourn Instruments, Allentown, PA) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by means of a guillotine door. The floor in the darkened room consisted of stainless steel rods from which an electric foot shock could be given from a constant current source. All experimental groups were first introduced to the apparatus the day before the start of the experiment. During training, the rat (male Sprague-Dawley (Harlan) weighing 250-350 g) was placed in the lighted room facing away from the closed guillotine door for 1 minute before the door was opened. The latency before entering the darkened room was measured. After the rat entered the darkened room, the door was closed and a 0.5 mA electric shock was administered for 3 seconds. 24 h later, the rat was administered 0.1 mg/kg MK-801 or saline, 30 min before the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 min before retention- the test started. The rat was again placed in the lighted room with the guillotine door open. The latency before entering the darkened room was measured for up to 180 seconds, at which time the experiment was terminated.

All data were analyzed using analyzes of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Natural rats needed less than 30 seconds on average to move from the lighted room to the darkened room. However, 24 hours after exposure to the electric shock, most of the vehicle-pretreated rats did not re-enter the darkened room; the average latency was increased up to 175 seconds (p < 0.001). Pretreatment with MK-801 (0.1 mg/kg) significantly reduced this latency compared to vehicle (p < 0.001). This amnesic effect of MK-801 is reversed in a statistically significant manner by real test compounds in a dose-dependent manner (eg, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, effective dose range = 0.5 to 2.5 mg/kg, i.p.; and N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, effective dose range = 0.1 to 2.5 mg/kg, i.p.).

Example 20 (method B)

Rat radial branch maze task, an in vivo test of learning and memory

The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J. and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204). 5 days after initial housing, rats (male Sprague-Dawley (Harlan) weighing 250 to 350 g) were placed in the eight-branch radial maze (each branch was 60 x 10 x 12 cm high; the maze was raised 70 cm above the floor) for acclimatization for 2 days. Rats were then placed individually in the center of the maze i

5 minutes with prepellets placed near the front walls, and then the next day in the wells at the end of the branches; 2 sessions were performed each day. Then four arbitrarily chosen branches were then provided with bait consisting of one pellet in each. The rat was confined to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely through the maze until it collected all pellets by or 10 minutes had passed, whichever occurred first. Four parameters were measured: 1) working memory errors, i.e. entries into branches with bait that had already been visited during the same trial; 2) reference memory errors, i.e. entries into unbaited branches; 3) total branch entries; and 4) the test duration (seconds), i.e. the time spent collecting all the pellets in the maze. If the working memory error was zero and the mean reference memory error was less than one on five consecutive trials, the rats began the drug tests. MK-801 or saline was injected 15 min before vehicle or test agent, which was given 45 min before the test. Experiments were conducted in a lighted room containing several visible extra-maze cues.

All data were analyzed using analyzes of variance (ANOVA); individual comparisons were made by applying

Kewman-Keuls tests. Compared to control, MK-801 increased

(0.1 mg/kg, i.p.) the frequencies of both working and reference memory errors (p<0.01). This amnesic effect of MK-801 on working memory is reversed in a statistically significant manner by the administration of relevant test compounds in a dose-dependent manner (e.g. 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, effective dose =2 .5 mg/kg, i.p.; p<0.01).

Claims (58)

1. Compound of formula I where R<1> is alkyl with 1-4 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen; R<2> is alkyl with 1-12 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen, cycloalkyl with 3-10 carbon atoms, cycloalkylalkyl with 4-16 carbon atoms, or methoxyethoxy, tetrahydrofuranyl or indanyl; R<3> is benzyl, quinolinylmethyl, thienylmethyl or pyridyl-Ci-C6-alkyl which is optionally substituted by halogen or C1-C6-alkyl; R<4> is naphthyl or phenyl which is unsubstituted or substituted one or more times by halogen, C1-C6-alkyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, nitro, trifluoromethyl, hydroxy-Ci-C6-alkyl, tetrazol-5-yl, 2-(tetrahydropyranyl)-tetrazol-5-yl, hydroxy-Ci-C6-alkyl, carboxy, Ci-C6-alkyl-OOC-, cyan, acetamido, Ci -C6-alkyl-sulfonylamino-, benzyl-sulfonyl-amino-, C1-C6-alkyl-sulfonylamino-C1-C6-alkoxy, pyrrolidinyl-oxy-, pyrrolidinyl-C1-C6-alkoxy which is optionally substituted with oxo or Ci- C6-alkyl, C1-C6-alkyl-carbonylamino-, piperazinyl-oxy-, piperazinyl-carbonyl which is optionally substituted with C1-C6-alkyl, piperazinyl-C1-C6-alkyl which is optionally substituted with -C1-C6-alkyl . C6-alkyl, piperidinyl-C1-C6-alkoxy which is optionally substituted with C1-C6-alkyl, imidazolyl-C1-C6- alkoxy, morpholinyl-C 1 -C 6 -alkyl-amino-C 1 -C 6 -alkoxy, phenyl, tetrahydrofuranyl, tri-C 1 -C 6 -alkylsilyloxy or combinations thereof, or isoquinolinyl, pyrimidinyl, pyrazinyl or pyridyl which is unsubstituted or substituted by carboxy; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, where R<1> is methyl or CHF2; and R<2> is alkyl, cycloalkyl or cycloalkylalkyl. 3. Compound according to claim 1, where R<3> is quinolinylmethyl or thienylmethyl, or is pyridylmethyl. 4. Compound according to claim 1, where R<1> is methyl or CHF2, and R<2> is cyclopentyl, CHF2 or cyclopropylmethyl. 5. Compound according to claim 1, where R<1> is methyl or CHF2; R 2 is cyclopentyl; R 3 is quinolinylmethyl or thienylmethyl, or is pyridylmethyl which is substituted or unsubstituted. 6. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; and R<4> is substituted or unsubstituted phenyl. 7. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; and R<3> is is quinolinylmethyl or thienylmethyl, or is pyridylmethyl which is substituted or unsubstituted. 8. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; R 3 is is quinolinylmethyl or thienylmethyl, or is pyridylmethyl which is substituted or unsubstituted; and R<4> is phenyl which is substituted or unsubstituted. 9. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; R 3 is benzyl, thienylmethyl or pyridylpropyl, or is pyridylmethyl which is substituted or unsubstituted; and R<4> is phenyl or phenyl substituted with 1-3 substituents. 10. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; R 3 is benzyl, thienylmethyl or pyridylpropyl, or is pyridylmethyl which is substituted or unsubstituted; and R<4> is naphthyl, pyridyl, pyrimidinyl, pyrazinyl or isoquinolinyl, or is phenyl which is substituted or unsubstituted. 11. Compound according to claim 1, where R<1> is methyl or CHF2; R<2> is cyclopentyl, CHF2 or cyclopropylmethyl; and R 4 is naphthyl, pyridyl or isoquinolinyl, or is phenyl which is substituted or unsubstituted. 12. Compound according to claim 1, where R<1> is methyl or CHF2; R<2> is cyclopentyl, CHF2 or cyclopropylmethyl; and R 4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF 3 , cyan, carboxy, hydroxymethyl, ethylsulfonamino or combinations thereof, or is 3-pyridyl which is unsubstituted or substituted by carboxy. 13. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; and R<4> is naphthyl, pyridyl or isoquinolinyl, or is phenyl which is substituted or unsubstituted. 14. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; and R<4> is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF3, cyan, carboxy, hydroxymethyl, ethylsulfonamino or combinations thereof, or is 3-pyridyl which is unsubstituted or substituted by carboxy. 15. Compound according to claim 1, where R<1> is methyl or CHF2; R<2> is cyclopentyl, CHF2 or cyclopropylmethyl; and R 3 is benzyl, thienylmethyl or quinolinylmethyl, or is pyridylmethyl optionally substituted with halogen or C 1 -C 6 alkyl. 16. Compound according to claim 1, where R<1> is methyl or CHF2; R<2> is cyclopentyl, CHF2 or cyclopropylmethyl; and R 3 is pyridylmethyl which is optionally substituted with halogen or C 1 -C 6 alkyl. 17. Compound according to claim 1, where R<1> is methyl; R<2> is cyclopentyl; and R<3> is benzyl, thienylmethyl, quinolinylmethyl, or is pyridylmethyl optionally substituted with halogen or C 1 -C 6 alkyl. 18. A compound according to claim 1, wherein R<1> is methyl; R<2> is cyclopentyl; and R<3> is pyridylmethyl which is optionally substituted with halogen or C1-C6 alkyl. 19. A compound according to claim 1, wherein the compound has formula IV where at least one of A, B and D is N and the others are CH, and R<4> is pyridyl or phenyl which in each case is substituted or unsubstituted, or a pharmaceutically acceptable salt thereof. 20. Compound according to claim 19, where R<1> is methyl or CHF2. 21. Compound according to claim 20, where B is N. 22. Compound according to claim 19, where R<1> is methyl or CHF2, and R2 is cyclopentyl, CHF2 or cyclopropylmethyl. 23. Compound according to claim 22, where B is N. 24. Compound according to claim 19, where R<1> is methyl or CHF2, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. 25. A compound according to claim 24, wherein B is N. 26. Compound according to claim 19, where R<1> is methyl or CHF2, R<2> is cyclopentyl, CHF2 or cyclopropylmethyl, and R<4> is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. 27. Compound according to claim 26, wherein B is N. 28. Compound according to claim 19, where R<1> is methyl or CHF2, and R<4> is phenyl which is substituted in the 3- or 4-position. 29. A compound according to claim 28, wherein B is N. 30. Compound according to claim 19, where R<1> is methyl or CHF2, R<2> is cyclopentyl, CHF2, cyclopropylmethyl or tetrahydrofuranyl, and R<4> is phenyl which is substituted in the 3- or 4-position. 31. Compound according to claim 30, where B is N. 32. Compound according to claim 19, where R<1> is methyl or CHF2, and R<4> is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamino-phenyl , 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamino-phenyl, 4-tetrazol-5 -yl-phenyl or 4-hydroxymethyl-phenyl. 33. Compound according to claim 32, where B is N. 34. Compound according to claim 19, where R<1> is methyl or CHF2, R<2> is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and R<4> is 3-pyridyl, 3-COOH-phenyl, 3- Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamino-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4- cyano-phenyl, 4-ethylsulfonamino-phenyl, 4-tetrazol-5-yl-phenyl or 4-hydroxymethyl-phenyl. 35. A compound according to claim 34, wherein B is N. 36. A compound according to claim 1, wherein the compound is selected from: 3-cyclopentyloxy-4<1->ethyl-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 3-cyclopentyloxy-3',4-dimethoxy-N -(3-pyridylmethyl)-diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine, 3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4<1->fluoro-4-methoxy-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl) diphenylamine, 4< 1->cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 3-cyclopentyloxy-4-methoxy-3<1->nitro-N-(3-pyridylmethyl)diphenylamine, 4'- chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-diphenylamine, N-(3-cyclopentyloxy-4- methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl)amine, 3'-benzylsulfonylamino-3 -cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)di phenylamine, 3-cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-[(3R )-tetrahydrofuranyloxy]diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(1-methylpiperidin-4-yloxy)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(l- methylpyrrolidin-3-yloxy)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(1-pyrrolidinyl-ethoxy)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy -4-methoxy-4'-[2-(6-methylpyridyl)-methoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41 -[2-(1-methylpiperidinyl)-methoxy] -N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-31 -[2-(1-piperidinyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-3'-[2 -(1-imidazolyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[3-(2-methylpiperazin-4-yl)propoxy]-N- (3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41-[3-(2-morpholin-4-ylethyl-amino)propoxy]-N-(3-pyridylme tyl)diphenylamine, 3-cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4'-[2-(1-butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4 -methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3<1->methyl-N-(3-pyridylmethyl) ) diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy -3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3 -cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine, 3-indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)- N-(4-isoquinolinyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidinyl)amine, N-(3 -cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy-4- methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide, 3-cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine , 3-cyclopentyloxy-4-difluoromethoxy-41 -(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine, 3'-(1-butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N -(3-pyridylmethyl)diphenylamine, 3'-acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)- diphenylamine, 3-cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4'-hydroxy -4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4'-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41 -[2-( 1-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperidinyl)methoxy]-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[3-(1-methylpi perazin-4-yl)propoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonyl-amino)ethoxy]-N-(3-pyridylmethyl)diphenylamine , 3'-cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 4<1->chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl )diphenylamine, 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl) -N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4<1->methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3<1->hydroxymethyl-N -(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-4-methoxy-3-(2-methoxyethoxy)-N-( 3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(1-propanesulfonyl-ami no) ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 3,4-bis(difluoromethoxy)-N-(3 -pyridylmethyl)diphenylamine, 4<1->tert.-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl) ) -3-aminobenzoic acid, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)- 3-aminobenzoic acid, N-3,4-bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4 -aminobenzoic acid, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid , N-[3-(2-indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3-(2-methoxyethoxy)-4-methoxyphenyl]-N-(3- pyridylmethyl) -3-aminobenzoic acid, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyr dylmethyl) -41 -(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy- 4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol- 5-yl)diphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-41-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl) -3'-(2H-tetrazol-5-yl)diphenylamine, bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, N-(3- cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) )amine, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4<1->ethanesulfonylamine o-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41 -(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-3<1->ethanesulfonylamino -4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41-[2-(5-oxopyrrolidinyl)-methoxy]-N-(3-pyridylmethyl)diphenylamine, and pharmaceutically acceptable salts thereof. 37. A compound according to claim 1, wherein the compound is selected from: 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy- 3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3- cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine, 3-indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N -(4-isoquinolinyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidinyl)amine, N-(3- cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide , 3-cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)d iphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine, 3'-(1-butanesulfonylamino)-3-cyclopentyloxy-4-methoxy -N-(3-pyridylmethyl)diphenylamine, 3'-acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl) )-diphenylamine, 3-cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 3-cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl) diphenylamine, 3-cyclopentyloxy-4< 1->hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4<1->cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy- 41 -[2-(1-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperidinyl)-methoxy]-N -(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperazin-4-yl)propoxy]-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy -41 -[2-(2-propanesulfonyl-amino)ethoxy]-N-(3-pyridylm ethyl)diphenylamine, 3<1->cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-( 3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-41 -(2-(tetrahydropyran-2-yl)-2H-tetrazol-5- yl)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-( 3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3- pyridylmethyl) diphenylamine, 3-cyclopropylmethoxy-4<1->hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(1-propanesulfonyl-amino)ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-3-cyclopentyloxy-4-methoxy -N-(3-pyridylmethyl)-diphenylamine, 3,4-bis(difluoromethoxy)- N-(3-pyridylmethyl)diphenylamine, 4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine, 3'-cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3 -((3R)-tetrahydrofuryloxy)diphenylamine, 3<1->chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine, 4<1->tert-butyldimethylsilyloxy- 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopentyloxy-4- methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-3,4-bis(difluoromethoxy)phenyl )-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3-(2-indanyloxy)-4-methoxyphenyl ]-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3-(2-metho oxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-41-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H -tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-41 - (2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-N-(3 -pyridylmethyl)-41 - (2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-31 -(2H-tetrazol-5-yl)diphenylamine, bis-3, 4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3 -pyridylmethyl)amine, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3 -pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy-3*-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclo opentyloxy-4-methoxy-31 -(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4<1->ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy -4-methoxy-4'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4 -methoxy-4'-[2-(5-oxopyrrolidinyl)-methoxy]-N-(3-pyridylmethyl)diphenylamine, and pharmaceutically acceptable salts thereof. 38. A compound according to claim 1, wherein the compound is selected from: 3'-cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine, 4'-chloro-3-cyclopentyloxy-3'-fluoro- 4-Methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl )-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy- 3'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-4-methoxy-3-(2- methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-41-(2-ethanesulfonylamino)ethoxy-4-methoxy -N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(1-propanesulfonyl-amino)ethoxy]-N-(3-pyridylmethyl)diphenylamine, 3'-chloro-3- cyclopentyloxy-4-methoxy-N-(3-pyridyl). tyl)-diphenylamine, 3,4-bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine, 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N- (3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3 -cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-3,4-bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3- cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy- 4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3-(2-indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3- (2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl )diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'- (2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-31 -(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-31-(2H-tetrazol-5-yl)diphenylamine, bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H -tetrazol-5-yl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)- N-(3-pyridyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy- 3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4' -ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(1-propanesulfonylamino )-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-[2-(5- oxopyrrolidinyl)-methoxy]-N-(3-pyridylmethyl)diphenylamine, and pharmaceutically acceptable salts thereof. 39. A compound according to claim 1, wherein the compound is selected from: 3<1->chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3,4-bis(difluoromethoxy)-N-(3 -pyridylmethyl)diphenylamine, 4'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl) - 3-aminobenzoic acid, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid, N-3,4-bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid , N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, N -[3-(2-indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid, N-[3-(2-methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl) -3-aminobenzoic acid, 3-cyclopropylmethyloxy-4-diflu ormethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-41 -(2H-tetrazol-5-yl )diphenylamine, 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4 '-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine, 3-cyclopropylmethyloxy-4-difluoromethoxy -N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine, bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl) )diphenylamine, N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl ) -N-(3-pyridylmethyl)amine, N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine, 3-cyclopentyloxy-3'-ethanesulfonylamino-4 -methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-3'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4' -ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine, 3-cyclopentyloxy-4-methoxy-4'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine, 3-cyclopropylmethoxy-3'-ethanesulfonylamino -4-methoxy-N-(3-pyridylmethyl)diphenylamine, 4-difluoromethoxy-31-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine, 3-cyclopentyloxy-4-methoxy-41 -[2-(5-oxopyrrolidinyl)-methoxy]-N-(3-pyridylmethyl)diphenylamine, and pharmaceutically acceptable salts thereof. 40. A compound according to claim 1, wherein the compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 41. A compound according to claim 1, wherein the compound is N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. 42. Compound according to claim 1, where R<1> is <3>H3C-, <14>CH3- or <n>CH3-. 43. A pharmaceutical preparation comprising a compound according to any one of claims 1-42 and a pharmaceutically acceptable carrier. 44. Preparation according to claim 43, where a unit dosage form of the preparation contains 0.1-50 mg of the compound. 45. Use of a compound according to any one of claims 1-42 for the preparation of a drug for improving cognition in a patient in whom such an improvement is desired. 46. Use according to claim 45, where the drug is in a dosage form suitable for administering the compound in an amount of 0.01-100 mg/kg body weight/day. 47. Use according to claim 45 or 46, where the drug is in a dosage form suitable for administration to a human. 48. Use of a compound according to any one of claims 1-42 for the preparation of a medicament for the treatment of a patient suffering from cognitive impairment or reduction. 49. Use according to claim 48, where the drug is in a dosage form suitable for administration to a human. 50. Use according to claim 49, where the drug is for the treatment of memory disorder. 51. Use according to claim 47, where the drug is in a dosage form suitable for administering the compound in an amount of 0.01-100 mg/kg body weight/day. 52. Use according to claim 50, where the drug is for the treatment of memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarct dementia, HIV or cardiovascular disease. 53. Use of a compound according to any one of claims 1-42 for the manufacture of a medicament for the treatment of a patient suffering from depression. 54. Use of a compound according to any one of claims 1-42 for the preparation of a medicament for the treatment of a patient suffering from memory impairment due to a neurodegenerative disease. 55. Use of a compound according to any one of claims 1-42 for the manufacture of a medicament for the treatment of a patient suffering from memory impairment due to an acute neurodegenerative disorder. 56. Use of a compound according to any one of claims 1-42 for the preparation of a medicament for the treatment of a patient suffering from an allergic or inflammatory disease. 57. Use according to claim 56, where the drug is for the treatment of asthma. 58. Use according to claim 56, where the drug is for the treatment of chronic obstructive pulmonary disease (COPD).