ZA200305623B - Aniline derivatives useful as phosphodiesterase 4 inhibitors - Google Patents

Aniline derivatives useful as phosphodiesterase 4 inhibitors Download PDF

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Publication number
ZA200305623B
ZA200305623B ZA2003/05623A ZA200305623A ZA200305623B ZA 200305623 B ZA200305623 B ZA 200305623B ZA 2003/05623 A ZA2003/05623 A ZA 2003/05623A ZA 200305623 A ZA200305623 A ZA 200305623A ZA 200305623 B ZA200305623 B ZA 200305623B
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Prior art keywords
pyridylmethyl
diphenylamine
methoxy
cyclopentyloxy
substituted
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ZA2003/05623A
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Hopper Allen
Tehim Ashok
Frederick Jr Brubaker William
Ernst Hess Hans-Jurgen
A Schumacher Richard
De Vivo Michael
Liu Ruiping
Unterbeck Axel
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Memory Pharm Corp
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Publication of ZA200305623B publication Critical patent/ZA200305623B/en

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Description

PHOSPHODIESTERASE 4 INHIBITORS
This application claims benefit of U.S. Provisional application Serial No. . 60/262,651, filed January 22, 2001, U.S. provisional application Serial No. 60/267,196, filed February 8, 2001, and U.S. Provisional application Serial No. 60/306,140, filed July 14, 2001.
FIELD OF THE INVENTION
The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically this invention relates to selective PDE4 inhibition by novel compounds, e.g., N-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various. cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role.
PDE enzymes can be grouped into eleven families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, ’ PDE 1 is stimulated by Ca*"/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart and adrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme creates positive inotropic activity. PDE 4 is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity. PDE 5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE 5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation.
PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B,
PDEA4C, 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, various splice variants of each
PDE4 isoform have been identified.
PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5’-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory.
Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are powerful antiinflammatory agents and therefore may be useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms. rd © 0) ~ of
N
0 0 0) | ~
N oO HA se rolipram piclamilast )
In addition to such compounds as rolipram, xanthine derivatives such as . pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received considerable attention of late for their cognition enhancing effects. cAMP and cGMP are ! second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body.
Rolipram, previously in development as an anti-depressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has subsequently been extended to include indications such as dementia. [see "The PDE IV
Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al., Drugs of the
Future 1992, 17(9):799-807 for a general review). 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, psychotrophic effects, increased gastric acid secretion and stomach erosion.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds, €.g., novel N-substituted aniline and diphenylamine compounds, that inhibit PDE4 enzymes, and especially have improved side effect profiles, e.g, are relatively non-emetic, (e.g., as compared to the previously discussed prior art compounds). Preferably, the compounds selectively inhibit
PDE4 enzymes. The compounds of this invention at the same time facilitate entry into } cells, especially cells of the nervous system. . Still further, the present invention provides methods for synthesizing compounds with such activity and selectivity as well as methods of (and corresponding pharmaceutical compositions for) treating a patient, e.g., mammals, including humans,
requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is due . in part to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where such memory impairment may be improved by effectively inhibiting PDE4 enzyme activity.
In a preferred aspect, the compounds of the invention improve such diseases by inhibiting PDE4 enzymes at doses which do not induce emesis.
The present invention includes compounds of Formula I: rR T ) 3 : R 9 \
R? R* wherein
R' is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and : which is unsubstituted or substituted one or more times by halogen (e.g.,
CH,, CHF,, CF, etc.);
R? is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-s-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH,CH»- groups is replaced in each case by -CH=CH- or -C=C- (e.g., CH3, CHF, CF3, methoxyethyl, etc.),
cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is ’ unsubstituted or substituted one or more times by halogen, hydroxy, oxo, . cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which 1s unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C;-4-alkyl,
C,-s-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF; OCF; alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.), arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which 1s branched or unbranched, has 1 to § carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF; OCFj3, alkyl, hydroxy, alkoxy, nitro, ) cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and ) wherein in the alkyl portion one or more -CH,CH,;- groups are each optionally replaced by -CH=CH- or -C=C-, and one or more -CH>- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations | . thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methox yphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, shenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, | hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.), a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ringatomisaN,OorS atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or oo a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at ’ least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or A unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion : ’ by halogen, OCF, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, . nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH,CH,- groups are each optionally replaced by -CH=CH- or -C=C-, and one or more -CH,- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);
R' isH, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C;-s-alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C,-4-alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.), ) arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF30, nitro,
amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), or . heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a
N, O or S atom, the alkyl portion, which 1s branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF30, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinyimethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);
R' isH, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,
OCF, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole- 5-yl (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, . alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- ‘ butyldimethylsilyloxy), R’-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl,
methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, . methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydrox ymethylphenyl, ‘ nitrophenyl, aminophenyl, etc.), or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl! (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, . alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R>-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinoliny}, pyrimidinyl, imidazolyl, thiazolyl, etc.);
R® isH, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C,-s-alkyl, C,-s-alkoxy, 0x0, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.) a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon . atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, 0xo, or combinations thereof (e.g., cyclohexenylmethyl, etc.),
cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, } cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy,
carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl,
: ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF30, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted . in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl,
phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, . methylenedioxobenzyl, etc.), . a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom isa N, OQ or S atom, which 1s unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pynmidinyl, imidazolyl, thiazolyl, etc.), or a heierocycie-alkyl group, wherein the heterocyclic portion is saturaied, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CFO, nitro, 0x0, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridyimethyl, etc.); Co
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms ~ wherein one or more -CH,- groups are each optionally replaced by -O-, , | -S-, -NR®-, -SO,NH-, -NHSO;-, -CO-, -NR®CO-, -CONR’-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-O-,
CH,-, -CO-, -CO-O-, -0-CO-, -CO-NH-, -NH-CO-, -CH,CH,CH,-NH-
CO-, -CH;-CH,-0-, -SO;-NH-CH,CH,-0O-, -O-CH,CH,-0O-, -CH,-NH-
CO-, -CO-NH-CH;-, -SO;-NH-, -CH,-NH-SO;-, -CH,CH,CH,-SO;-
NH-, etc.); and
R® is H, : alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or ’ unbranched and which is unsubstituted or substituted one or more times with halogen, C;-3-alkyl, C;-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.); wherein at least one of R® and R* is other than H; and pharmaceutically acceptable salts thereof.
According to a further aspect of the invention there is provided a genus of novel compounds according to the formulas II and III: r'-° rR
Il . FR Ll} 6) NH
I, l, 2 H
R R R . wherein R', R?, rR’ , and R* are as defined above. The compounds of this subgenus of formula I not only have PDE4 inhibitory activity, but also are useful as intermediates for preparing compounds of Formula I in which R® and R* are both other than H.
In addition, preferred compounds of formula I are those of the subformula IV 0 .
Vv - oI
R? R* .D
} wherein R', R?, and R* are as defined in Formula I and one of A, Band Dis N and the others are C. Preferably, Bis N. Also, R* is preferably pyridyl or phenyl which - in each case is substituted or unsubstituted.
The present invention also includes compounds of Formula I’:
R" 3 I
PON R
I
R® wherein
RY 1s methoxy, F, Cl, CHF; or CFj;
RY 1S alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, alkenyl having 2 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms,
cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof, - cycloalkylalkyl having 4 to 12 carbon atoms, . . cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alky! or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, 0X0, or combinations thereof, arylalkyl having 7 to 26 carbon atoms arylalkyl having 7 to 26 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, : heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom isa heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; :
X 1sO or;
R® is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least | ring atom 1s a heteroatom, or substituted heteroaryl having 5 to 10 ring atoms in which at least | ring atom is a heteroatom which is substituted one or more times by haiogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof; *
L is-NH-, -NR*-, -NHCH,-, -NR*CH,-, or -CH,NR"-; and
RY is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, y heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, : substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom 1s a heteroatom, or : substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, 0x0, cyano, or combinations thereof; and : pharmaceutically acceptable salts thereof.
The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in animals, e.g., mammals, especially humans. These compounds exhibit neurological activity, especially where such activity affects cognition, including long term memory. These compounds will also be effective in treating diseases where decreased cAMP levels are involved. This includes but is not limited to inflammatory diseases. These compounds may also function as antidepressants, or be useful in treating } cognitive and negative symptoms of schizophrenia.
Assays for determining PDE inhibiting activity as well as selectivity of PDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known within the art. See, e.g., US 6,136,821, the disclosure of which is incorporated herein by reference.
According to a further aspect of the invention there are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g,
PDE4 inhibitors of Formula I) and/or useful for the synthesis of radio-labeled analogs of the PDE4 inhibitors with in this application.
Thus, there are provided intermediate compounds which correspond to compounds of Formula I, wherein rR? rR’? , and R* are as previously defined for Formuia i, but R' is H, tert-butyldimethylsilyl-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example; in Greene, T.W. and Wats,
P.G.M.,, Protective Groups in Organic Synthesis, 3" Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radio-labeled compounds, such as where R'is *H3C-, "CH;- or ''CHj;-, for example by removing the protecting group and reacting the resultant compound in which R' is H with suitable radio-labelled reagents. Such radio-labeled compounds are useful for determining compound tissue distribution in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies.
Also provided are intermediate compounds which correspond to compounds of
Formula I, wherein R', R?, and R* are as previously defined for Formula I, but R? is H, tert-butyldimethylsilyloxy-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example, in Greene, T.W. and Wuts, P.G.M,,
Protective Groups in Organic Synthesis, 3" Edition, John Wiley & Sons, 1999, pp. 246-

Claims (93)

What Is Claimed is:
1. A compound of Formula 1 RC | = 3 ~ = » AR nL, R® R* wherein: R' 1s alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen ; R? 1s alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C;-s-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH;CH,- groups is replaced in each case by —-CH=CH- or -C=C-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci-s-alkyl, Ci-s-alkoxy or combinations thereof, } aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF; OCF;, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF; OCF, alkyl, hydroxy, alkoxy, nitro, Cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH,CH,- groups are each optionally replaced by -CH=CH- or -C=C-, and one or more -CH,- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof , :
a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or a heterocyclicalkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH,CH,- groups are each optionally replaced by -CH=CH- or -C=C-, and one or more -CH;- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof; R’ isH, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C;-4-alkoxy, or combinations thereof ,
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, ) alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C,-s-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to S carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF;0, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3;O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R* isH, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, : alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF;, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl,
hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert-
. butyldimethytsilyloxy), R’-L-, or combinations thereof, or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which 1s unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl! hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, or combinations thereof; R® isH, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C,-4-alkyl, C;-4-alkoxy, oxo, or combinations thereof , alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, a partially unsaturated carbocycle-alkyl group wherein the portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy,
alkyl having 1 to 4 carbon atoms, or combinations thereof , cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy,
nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl,
: hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,
cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has
1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF30, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl,
a heterocyclic group, which is saturated, partially saturated or unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is aN, O or S atom, which is unsubstituted or substituted one or more times by halogen,
alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl,
hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof , or a heterocyclicalkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CFO, nitro, 0x0, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof} L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH»- groups are each optionally replaced by -O-, -S-, -NR’-, -SO;NH-, -NHSO;-, -CO-, -NR°CO-, -CONR®-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and RS is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C,- s-alkyl, C,-4-alkoxy, oxo, or combinations thereof ; wherein at least one of R® and R* is other than H; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R* is other than H.
3. A compound according to claim 1, wherein
R'is methyl or CHF,; R? is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle- alkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; rR? ; is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R* is aryl or heteroaryl, in each case substituted or unsubstituted.
4. A compound according to claim 1, wherein R? is heteroarylalkyl which is substituted or unsubstituted.
5. A compound according to claim 1, wherein R'is methyl or CHF,, and Ris cyclopentyl, CHF,, cyclopropylmethyl, pyridylethyl, or (3R)- tetrahydrofuranyl.
6. A compound according to claim 1, wherein R' is methyl or CHF; R? is cyclopentyl; R® is heteroarylalkyl, in each case substituted or unsubstituted; and R* is substituted or unsubstituted ary! or heteroaryl.
7. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; R® is arylalkyl or heteroarylalkyl, in each _ case substituted or unsubstituted; and R* is substituted or unsubstituted aryl.
8. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; and : R’ is heteroarylalkyl which is substituted or unsubstituted.
9. A compound according to claim 1, wherein R'is methyl; R? is cyclopentyl; R3is heteroarylalkyl which is substituted or unsubstituted; and R’ is phenyl which is substituted or unsubstituted.
10. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; R’ is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R* is phenyl! or phenyl substituted with 1 to 3 substituents.
11. A compound according to claim 1, wherein R'is methyl; Ris cyclopentyl; R’ is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R* is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
12. A compound according to claim 1, wherein R'is methyl or CHF; Ris cyclopentyl, CHF,, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, R’ is H; and R* is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
13. A compound according to claim 1, R' is methyl or CHF,; R? is cyclopentyl, CHF,, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R’is H; and R* is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
EEE ——————.
14. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; R? is H; and R* is phenyl, naphthyl, pyridyl, quinoliny}, or isoquinolinyl, which in each case Is . substituted or unsubstituted.
15. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; R3 is H; and R* is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, Cl, F, CF;, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3- pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
16. A compound according to claim 1, wherein R' is methyl or CHF,; R? is cyclopentyl, CHF, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R? is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted; and R* is H.
17. A compound according to claim 1, wherein R! is methyl or CHF,; R? is cyclopentyl, CHF, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R? is pyrazinylmethyl, pyrimidinylmethyl, or pyridylmethyl, which in each is unsubstituted or substituted; and R* is H.
18. A compound according to claim 1, wherein R' is methyl; R? is . cyclopentyl; R® is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted; and R* is H.
19. A compound according to claim 1, wherein R' is methyl; R? is cyclopentyl; R? is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted; and R* is H.
20. A compound according to claim 1, wherein said compound is of formula Iv R' TL 0 N Ag ™ 1, Lf R R -D wherein R' and R? are as defined, at least one of A, B, and D is N and the others are CH, and R* is pyridyl or phenyl which is each case is substituted or unsubstituted, and pharmaceutically acceptable salts thereof.
21. A compound according to claim 20, wherein R' is methyl or CHF,.
22. A compound according to claim 21, wherein B is N.
23 A compound according to claim 20, whereinR' is methyl or CHF,, and R? is cyclopentyl, CHF, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl.
24. A compound according to claim 23, wherein B is N.
25. A compound according to claim 19, wherein Ris methyl or CHF;, and R* ; 1s 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
26. A compound according to claim 25, wherein B is N.
27. A compound according to claim 20, wherein R' is methyl or CHF,, Ris cyclopentyl, CHF, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and R® is 3- pyridyl or phenyl, which in each case is substituted or unsubstituted.
28. A compound according to claim 27, wherein B is N.
29. | A compound according to claim 20, wherein R' is methyl or CHF,, and R* is phenyl which is substituted in the 3- or 4- position.
30. A compound according to claim 29, wherein B is N.
31. A compound according to claim 19, wherein R' is methyl or CHF,, R? is cyclopentyl, CHF, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R* is phenyl which is substituted in the 3- or 4- position.
32. A compound according to claim 31, wherein B is N.
33. A compound according to claim 20, wherein R'is methyl or CHF,, and R* is 3-pyndyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH- phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4- hydroxymethyl-phenyl. :
34. A compound according to claim 33, wherein B is N.
35. A compound according to claim 20, wherein R' is methyl or CHF,, R? is } cyclopentyl, CHF,, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R*is 3- pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3- tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH- phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4- hydroxymethyl-phenyl.
36. A compound according to claim 35, wherein B is N.
37. A compound according to claim 1, wherein said compound is selected from: a) 3-Cyclopentyloxy-4’-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-3’,4-dimethoxy-N-(3-pyridylmethyl)diphenylamine ¢) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3’-trifluoromethyldiphenylamine d) 3-Cyclopentyloxy-3’-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-4’-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3’-phenyl-N-(3-pyridylmethyl)diphenylamine g) 4’-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-3’-nitro-N-(3-pyridylmethyl)diphenylamine 1) 4’-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3°- trifluoromethyldiphenylamine J) 4-Methoxy-3’-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine k) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine 1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl)amine n) 3’-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine 0) 3-[3-(4-Chlorophenyl)prop-1-yloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine p) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-1-ylJoxy-N-(3- pyridylmethyl)diphenylamine q) 4-Methoxy-3-[3-(2-pyridyl)prop-1-ylJoxy-N-(3-pyridylmethyl)diphenylamine I) 3-Cyclopentyloxy-4’-(2-methoxyethoxy)-4-methoxy-N-(3- pyridylmethyl)diphenylamine . ) s) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-[(3R)-tetrahydrofuranyloxy]- diphenylamine t) 3-Cyclopentyloxy-4-methoxy-4’-(1-methylpiperidin-4-yloxy)-N-(3- pyridylmethyl)diphenylamine u) 3-Cyclopentyloxy-4-methoxy-4’-(1-methylpyrrolidin-3-yloxy)-N-(3- pyridylmethyl)diphenylamine v) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-pyrrolidinylethoxy)-N-(3- pyridylmethyl)diphenylamine w) 3-Cyclopentyloxy-4-methoxy-4’-[2-(6-methylpyridyl)methoxy)-N-(3- pyridylmethyl)diphenylamine X) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-methylpiperidinylmethox y]-N-(3- pyridylmethyl)diphenylamine y) 3-Cyclopentyloxy-4-methoxy-3’-[2-(1-piperidinyl)ethoxy]-N-(3- pyridylmethyl)diphenylamine z) 3-Cyclopentyloxy-3’-[2-(1-imidazolyl)ethoxy]-4-methoxy-N-(3- pyridylmethyl)diphenylamine aa) 3-Cyclopentyloxy-4-methoxy-4’-[3-(2-methylpiperazin-4-yl)propoxy}-N-(3- pyridylmethyl)diphenylamine bb) 3-Cyclopentyloxy-4-methoxy-4’-[3-(2-morpholin-4-ylethylamino)propoxy]-N-(3- pyridylmethyl)diphenylamine cc) 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine dd) 3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine ee) 3-Cyclopentyloxy-4’-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine ff) 4’-[2-(1-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine gg) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine hh) 3-Cyclopentyloxy-4-methoxy-3’-methyl-N-(3-pyridylmethyl)diphenylamine if) 3-Cyclopentyloxy-4-methoxy-4’-methyl-N-(3-pyridylmethyl)diphenylamine 1) 3-Cyclopentyloxy-4-methoxy-4’-nitro-N-(3-pyridylmethyl)diphenylamine kk) 3-Cyclopentyloxy-3’,4’-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine 1) 3’-Chloro-3-cyclopentyloxy-4’-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine mm) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine nn) 4-Methoxy-4’-methyl-N-(3-pyridylmethy!)-3-(3-tetrahydrofuryloxy)diphenylamine 00) 4,4’-Dimethoxy-N-(3-pyridyimethyi)-3-(3-tetrahydrofuryloxy)diphenylamine pp) 3-Indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine qq) N-{4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid rr) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3- pyndylmethyl)amine ss) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5- pyrimidinyl)amine tt) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine uu) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxypheny!)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine vv) 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide ww) 3-Cyclopentyloxy-4-methoxy-3’-(4-methylpiperazin-1-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine xx) 3-Cyclopentyloxy-4-difluoromethoxy-4’-(4-methylpiperazin-1-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine yy) 4-Methoxy-4’-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3- tetrahydrofuryloxy)diphenylamine zz) 3’-(1-Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine aaa) 3’-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridytmethyl)diphenylamine bbb) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine ccc) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine ddd) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine eee) 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
££) 4-Methoxy-N-(3-pyridylmethyl)-3-[(35)-tetrahydrofuryloxy]diphenylamine BEE) 3’-Chloro-4-methoxy-3-| 2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine hhh) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine ui) 3-Cyclopentyloxy-3’-hydroxy-4-methoxy-N-{3-p yridylmethy!)diphenylamine , ji) 3-Cyclopentyloxy-4"-hydroxy-4-methoxy-NV-(3-pyridyimethyl)diphenylamine kkk) 4’-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3- pyrnidyluethyiydiphenyiamine 111) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-methylpyrrolidin-2-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine mmm) 3-Cyclopentyloxy-4-methoxy-4’-[3-(1-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine TnI) 3-Cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine coc) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine DDD) 3-Cyclopentyloxy-4-methoxy-4’-[2-(2-propanesulfonylamins Jothoxy]-N-(3- pyridylmethyldiphenylamine qqq) 3’-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine rT) 4’-Chloro-3-cyciopentyloxy-3°-f1 uoro-4-methoxy-~N-(3-pyridytmethyl)diphenylamine sss) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine ttt) 3-Cyclopentyloxy-4-methoxy-4’~(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-y1)-N-(3- } pyndylmethyl)diphenylamine uuu) 3-Cyclopentyloxy-4’-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyi}- diphenylamine vvv) 3-Cyclopentyloxy-4-methoxy-3’-hydroxymethyl-N-(3- pynidylmethyl)diphenylamine www) 3-Cyclopentyloxy-4-methoxy-4’-hydroxymethyl-N-(3- pyridylmethyl)diphenylamine xxx) 4-Methoxy-3-[3-(4-pyridyl)prop-1-yljoxy-N-(3-pyridylmethyl)diphenylamine yyy) 3’-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine zzz) 3-Cyclopropylmethoxy-4’-hydroxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine aaaa) 3-Cyclopentyloxy-4’-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3- pyndylmethyl)diphenylamine bbbb) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine ccee) 3’-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine dddd) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3- tetrahydrofuryloxy)diphenylamine eeee) 3’-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine fttt) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine geeg) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine hhhh) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine iif) 3’-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine 111)3’-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine kkkk) 4’-ters-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine HI N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid } mmmim) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4- aminobenzoic acid nnnn) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid 0000) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid pppp) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid qqqq) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl}-N-(3-pyridylmethyl)-3- aminobenzoic acid rrr) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4- aminobenzoic acid ssss) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid ttt) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid uuuu) N-[3-(4 Chlorophenyl)prop-1-yloxy-4-methoxyphenyi]-N-(3-pyridylmethyi)-3- aminobenzoic acid vvvv) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid
WWWW) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid
XXXX) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid yyyy) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid zzzz) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid aaaaa) 3-Cyclopropylmethyloxy-4-difiucromethoxy-N-(3-pyridylmethyl)-4-(2H- tetrazol-5-yl)diphenylamine bbbbb) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine cccee) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- yldiphenylamine ddddd) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4 -(2H-tetrazol-3- yl)diphenylamine eeeee) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine fffff) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H- tetrazol-5-yl)diphenylamine ggggg) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine hhhhh) 3-Cyclopropylmethyloxy-4-difluoromethox y-N-(3-pyridylmethyl)-3’-(2H- tetrazol-5-yl)diphenylamine iil) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5-
yhdiphenylamine Jijj)) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine kkkkk) N-(3-Cyclopentyloxy-4-difluoromethox yphenyl)-N-(3-pyridyl)-N-(3- pynidylmethyl)amine
Il) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyndyimethyl)amine mmmmm) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)- N-(3-pyridylmethyl)amine nnnnn) 3-Cyclopentyloxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine
00000) 3-Cyclopentyloxy-4-methoxy-3’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine ppppp) 3-Cyclopentyloxy-4’-ethanesulfonylamino-4-methoxy-N-(3- : pyndylmethyl)diphenylamine aaaqq) 3-Cyclopentyloxy-4-methoxy-4’-(1 -propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine rir) 3-Cyclopropylmethoxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine sssss) 4-Difluoromethoxy-3’-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy]diphenylamine ttt) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine uuuuu) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine vvvvv) 3’-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
WWWWW) 3’-Chloro-4-methox y-N-(3-pyridylmethyl)-3-[(3R)-
~ tetrahydrofuryloxy]diphenylamine xxxxx) 3-Cyclopentyloxy-4-methoxy-4’-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof,
38. A compound according to claim 1, wherein said compound is selected from:
a) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3’-methyl-N-(3-pyndylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4’-methyl-N-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4’-nitro-N-(3-pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-3’,4’-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 3’-Chloro-3-cyclopentyloxy-4’-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine h) 4-Methoxy-4’-methyl-N-(3-pynidylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine i) 4,4’-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
J) 3-Indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine k) N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid
1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3- pyridylmethyl)amine m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5- pyrimidinyl)amine n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine
0) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyndylmethyl)amine p) 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide q) 3-Cyclopentyloxy-4-methoxy-3’-(4-methylpiperazin-1-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine
1) 3-Cyclopentyloxy-4-difluoromethoxy-4’-(4-methylpiperazin-1-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine s) 4-Methoxy-4’-(4-methylpiperazin-i-yicarbonyl)-N-(3-pyridylmethyt)-(3-(3- tetrahydrofuryloxy)diphenylamine t) 3°-(1-Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine u) 3’-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine v) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine w) 4-Methoxy-3-[2-(4-pynidyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine X) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine y) 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine z) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuryloxy]diphenylamine aa) 3’-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine bb) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine cc) 3-Cyclopentyloxy-3’-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine dd) 3-Cyclopentyloxy-4’-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine ee) 4’-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3- pyndylmethyl)diphenylamine ff) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-methylpyrrolidin-2-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine gg) 3-Cyclopentyloxy-4-methoxy-4’-[3-(1-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine hh) 3-Cyclopentyloxy-4-methoxy-4’-[3-(1-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine il) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine iJ) 3-Cyclopentyloxy-4-methoxy-4’-[2-(2-propanesulfonylamino)ethoxy]-N-(3- } pyridylmethyl)diphenylamine kk) 3’-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine II) 4’-Chloro-3-cyclopentyloxy-3’-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine mm) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine nn) 3-Cyclopentyloxy-4-methoxy-4’-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-y1)-N-(3- pyridylmethyl)diphenylamine 00) 3-Cyclopentyloxy-4’-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)- diphenylamine pp) 3-Cyclopentyloxy-4-methoxy-3’-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine qq) 3-Cyclopentyloxy-4-methoxy-4’-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine rr) 4-Methoxy-3-[3-(4-pyridyl)prop-1-ylJoxy-N-(3-pyridylmethyl)diphenylamine
Ss) 3’-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine tt) 3-Cyclopropylmethoxy-4’-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine uu) 3-Cyclopentyloxy-4’-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine ww) 3’-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine xx) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine yy) 3’-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine zz) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine aaa) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine bbb) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ccc) 3’-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ddd) 3’-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine eee) 4 -tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine fff) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid .
ggg) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid hhh) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-
© aminobenzoic acid iii) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid jij) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid kkk) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid
111) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid mmm) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid nnn) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid 000) N-[3-(4-Chlorophenyl)prop-1-yloxy-4-methox yphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid PPP) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid qqq) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid rrr) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid SSS) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid ttt) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid uy) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridyimethyl)-4°-(2H- tetrazol-5-yl)diphenylamine vvv) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yhdiphenylamine www) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- ] yl)diphenylamine xxx) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H-tetrazol-5- yl)diphenylamine yyy) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4’~(2H-tetrazol-5- yl)diphenylamine 227) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H- tetrazol-5-yl)diphenylamine aaaa) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine bbbb) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3’-(2H- tetrazol-5-yl)diphenylamine ccee) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine dddd) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine eece) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine ffffy N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine gggg) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine hhhh) 3-Cyclopentyloxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine iiii) 3-Cyclopentyloxy-4-methoxy-3’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine
1331)3-Cyclopentyloxy-4’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine kkkk) 3-Cyclopentyloxy-4-methoxy-4’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine
111) 3-Cyclopropylmethoxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine
© mmmm) 4-Difluoromethoxy-3’-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-
tetrahydrofuryloxy]diphenylamine nnnn) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
0000) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine pPPPP) 3’-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine qqqq) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy]diphenylamine mr) 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 said compound is selected . from:
a) 3’-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 4’-Chloro-3-cyclopentyloxy-3’-fluoro-4-methoxy-N-(3-pyridylmethy!l)diphenylamine
¢) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4’-(2-(ietrahydropyran-2-yi)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-4’-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)- diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3’-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4’-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine h) 4-Methoxy-3-[3-(4-pyridyl)prop-1-yljoxy-N-(3-pyridylmethyl)diphenylamine
1) 3’-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine j) 3-Cyclopropylmethoxy-4’-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine :
k) 3-Cyclopentyloxy-4’-(2-ethanesulfonylamino)ethoxy-4-methox y-N-(3- pyridylmethyl)diphenylamine
1) 3-Cyclopentyloxy-4-methoxy-4’-[2-(1-propanesulfonylamino)ethoxy}-N-(3- pyridylmethyl)diphenylamine m) 3’-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine n) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
0) 3’-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine p) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine q) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine r) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine s) 3’-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine t) 3’-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine u) 4’-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine
CIEE SE mm————————————
v) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzojc acid Ww) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid X) N-(3-Cyclopentyloxy-4-diflucromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid y) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl)-N-(3-pyridylmethy1)-3-aminobenzoic acid z) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid aa) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid bb) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3 -pyridylmethyl)-4-aminobenzoic acid cc) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid dd) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid ee) N-[3-(4-Chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N-(3 -pyridylmethyl)-3- " aminobenzoic acid ff) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid 88) N-[3-(2-Indanyloxy)-4-methoxyphenyl] -N-(3-pyridylmethyl)-3-aminobenzoic acid hh) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic ] acid 1) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid ii) N-{3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid kk) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine 11) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yDdiphenylamine mm) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- yhdiphenylamine nn) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H-tetrazol-5- yl)diphenylamine 00) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pynidylmethyl)-4°-(2H-tetrazol-5- yl)diphenylamine pp) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H-tetrazol- 5-yl)diphenylamine qq) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4’ -(2H-tetrazol-5- yl)diphenylamine rr) 3-Cyclopropylmethyloxy-4-difluocromethoxy-N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- yl)diphenylamine ss) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5-yl)diphenylamine tt) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine uu) N-(3-Cyclopentylox y-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine vv) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine ww) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine xx) 3-Cyclopentyloxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyndylmethyl)diphenylamine | } yy) 3-Cyclopentyloxy-4-methoxy-3’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine zz) 3-Cyclopentyloxy-4’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine aaa) 3-Cyclopentyloxy-4-methoxy-4’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine bbb) 3-Cyclopropylmethoxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine ccc) 4-Difluoromethoxy-3’-ethanesulfonylamino-N-(3-pyridylmethy!)-3-[(3R)- tetrahydrofuryloxy)diphenylamine ddd) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine eee) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine fff) 3’-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy] -N-(3-pyridylmethyl)diphenylamine ggg) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy]diphenylamine hhh) 3-Cyclopentyloxy-4-methoxy-4’-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
40. A compound according to claim 1, wherein said compound is selected from: a) 3’-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine C) 3’-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine d) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine e) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine f) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine g) 3’-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ] h) 3’-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine 1) 4’-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine J) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid k) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid 1) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid m) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid n) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
0) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid p) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid q) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyt)-3- aminobenzoic acid 1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid s) N-[3-(4-Chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid t) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid u) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid v) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid w) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid X) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid y) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine z) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine aa) 3-Cyclopentyloxy-4-methoxy-/N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- yl)diphenylamine bb) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H-tetrazol-5- yl)diphenylamine cc) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yl)diphenylamine dd) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4’-(2H-tetrazol- 5-yl)diphenylamine ee) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5- yhdiphenylamine ff) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3’-(2H-tetrazol-5- yl)diphenylamine :
gg) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4’-(2H-tetrazol-5-yl)diphenylamine hh) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
11) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine
1) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine kk) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine
11) 3-Cyclopentyloxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridyimethyi)diphenyiamine mm) 3-Cyclopentyloxy-4-methoxy-3'-(1-propancsulfonylamme}-N-(3- pyridyimeihyijdiphenyiamine nn) 3-Cyclopentyloxy-4’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine
00) 3-Cyclopentyloxy-4-methoxy-4’-(1-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine }
pp) 3-Cyclopropylmethoxy-3’-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine qq) 4-Difluoromethoxy-3’-ethanesulfonylamino-N-(3-pvridvimethy!)-3-[(3R)- tetrahydrofuryloxy]diphenylamine tr) 4-Mcthoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine ss) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine tt) 3’-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine uu) 3’-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy}diphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4’-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
41. A compound according to formula I’: “1 3 R X L” u 4 wherein R" is methoxy, F, Cl, CHF; or CF3; R? 1s alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, alkenyl having 2 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof,
cycloalkylalkyl having 4 to 12 carbon atoms, cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or } more times by halogen, oxo, alkyl or combinations thereof,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, 0x0, or combinations thereof,
arylalkyl having 7 to 26 carbon atoms arylalkyl having 7 to 26 carbon atoms which 1s substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or } } substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; :
X isOorS; R* is aryl having 6 to 14 carbon atoms,
aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, aikyi or alkoxy, or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof} L is -NH-, -NR*-, -NHCH,-, -NR*CH,-, or -CH,NR*"-; and RY is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom,
: PCT/US02/01508 substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and pharmaceutically acceptable salts thereof.
42. A method for enhancing cognition in a subject in whom such enhancement is desired comprising administering to said subject an effective amount of a compound according to claim 1. 43, A method according to claim 42, wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day. AMENDED SHEET
’ PCT/US02/01508
44. A method according to claim 42, wherein said subject is a human.
45. Use of a compound according to claim 1 in the manufacture of a preparation for treating a patient suffering from cognition impairment or decline.
46. Use according to claim 45, wherein said patient is a human.
47. Use according to claim 46, wherein said patient is suffering from memory impairment.
48. Use according to claim 45, wherein said preparation is administrable in an amount of 0.01-100 mg/kg of body weight/day.
49. Use according to claim 47, wherein said patient is suffering from memory impairment due to Alzheimer’s disease, schizophrenia, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease.
50. Use of a compound according to claim 1 in the manufacture of a preparation for treating a patient having a disease involving decreased cAMP levels.
51. A method of inhibiting PDE4 enzyme activity in a subject comprising administering to said subject an effective amount of a compound according to claim
1.
52. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. AMENDED SHEET
PCT/US02/01508
53. A composition according to claim 51, wherein said composition contains
0.1-50 mg of said compound.
54. Use of a compound according to claim 1 in the manufacture of a preparation for treating a patient suffering from memory impairment due to a neurodegenerative disease.
55. Use of a compound according to claim 1 in the manufacture of a preparation for treating a patient suffering from memory impairment due to an acute neurodegenerative disorder.
56. Use of a compound according to claim | in the manufacture of a preparation for treating a patient suffering from an allergic or inflammatory disease.
57. A compound of the Formula
0
1. SOW R 0
\2. r* R wherein: R! is H, tert-butydimethylsilyl, >H;C-, '4CH;-, !!CH;- or a phenolic protective group; R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, C;-4-alkoxy, oxo or combinations thereof, and wherein AMENDED SHEET optionally one or more -CH,CH,- groups is replaced in each case by
. ~CH=CH- or -C=C-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo. cvano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C;-s-alkyl, Cj-4-alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms, which 1s unsubstituted or substituted one or more times by halogen, CFs; OCFs, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF; OCF;, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH,CH,- groups are each optionally replaced by -CH=CH- or -C=C-, and one or more -CH,- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is . optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, 0x0, or combinations thereof , a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH,CH,- groups are each optionally replaced by -CH=CH- or
-C=C-, and one or more -CH;- groups are each optionally replaced by -O-
) or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof;
rR’ 1s H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, C;-s-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl! portion is optionally substituted by halogen, C;-s-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF;0, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or § atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy,
cyano, trifluoromethyl, CFO, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R* isH,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF;, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, tnalkylsilyloxy (eg. tert- butyldimethylsilyloxy), R’-L-, or combinations thereof, or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, - aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, phenoxy, tralkylsilyloxy R3-L-, dialkylamino-L-, or combinations thereof;
R* isH, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C;-s-alkyl, C,-;-alkoxy, oxo, or combinations ’ thereof,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
. a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, 0xo, of combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyane, hydroxy, alkyl, alkoxy or combinations thereof, . aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted - one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, co : arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to S carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF,0, nitro,
amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, a heterocyclic group, which is saturated, partially saturated or unsaturated, . having 5 to 10 ring atoms in which at least 1 ring atom isa N, O or S * atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or - a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ning atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF;0, nitro,. oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH,- groups are each optionally replaced by -O-, S-, -NR®-, -SO;NH-, -NHSO,-, -CO-, -NR®CO-, -CONR®-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and R® isH,or 124 _
alkyl having 1 to 8 carbon atoms, which is branched or unbranched and X which is unsubstituted or substituted one or more times with halogen, Ci- s-alkyl, Cy-4-alkoxy, oxo, or combinations thereof ; wherein at least one of R® and R* is other than H; and pharmaceutically acceptable salts thereof.
58. A compound of the Formula 0 rR” TL 3 R 0 N” R2 ie wherein: : R! is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen ; R? is H, tert-butyldimethylsilyloxy- or a phenolic protectibe group; R® isH, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times : with halogen, cyano, C,-s-alkoxy, or combinations thereof, : a partially unsaturated carbocycle-alkyl group wherein the carbocyclic : portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which 1s unsubstituted or : substituted in the carbocyclic portion one or more times by halogen, alkyl, 125 alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci-s-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which 1s branched or unbranched, has oo 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF-0, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ning atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalky! group is unsubstituted or substituted one or more times in the ‘heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CFO, nitro, oxo, amino, alkylamino, : dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
R* is H, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF,, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic = acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R>-L-, or combinations thereof, or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by
‘ halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, tnalkylsilyloxy R-L-, dialkylamino-L-, or combinations thereof;
R® isH, alkyl having 1 to 8 carbon atoms, which 1s unsubstituted or substituted one or more times with halogen, C;-4-alkyl, C,-s-alkoxy, oxo, or combinations thereof , alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, ' a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or . substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted . one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, ‘hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, : ~ arylalkyl having 7 to 19 carbon atoms, wherein the aryl'portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF;0, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, :
a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, = aminoalkyl,
aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, atkylsulfonyl, phenoxy, or combinations thereof , or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom isa N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF;O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
L . is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms - wherein one or more -CH,- groups are each optionally replaced by -O-, -S-, -NR®-, -SO,NH-, -NHSO;-, -CO-, -NR°CO-, -CONR’-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and RC i 1s H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C;- 4-alkyl, C-s-alkoxy, oxo, or combinations thereof; wherein at least one of R? and R* is other than H; and pharmaceutically acceptable salts thereof.
59, A compound slected from: a) 3-Cyclopentyl-4-methoxy-N-(3-pyridylmethyl)aniline; - - b) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)aniline; c¢) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine; d) 3-tert-Butyldimethylsilyloxy-3’-chloro-4-methoxy-N-(3- pyridylmethyl)diphenylamine e) Ethyl N-(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-N-(3- oo pyridylmethyl)-3-aminobenzoate; : } f) 3-Cyclopentyloxy-4-methoxydiphenylamine; g) 3-Hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine; oo h) 3’_Chloro-3-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine;
PCT/US02/01508 i) Ethyl N-(3-hydroxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate; 1 3'-(2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine; k) 4'-[1-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine; and 1) 4-hydroxy-3-cyclopenthloxy-N-(3-pyridylmethyl)diphenlamine.
60. Use of a compound according to claim 1 in the manufacture of a preparation for enhancing cognition in a subject in whom such enhancement is desired.
61. Use according to claim 60, wherein said preparation is administrable in an amount of 0.01-100 mg/kg of body weight/day.
62. Use according to claim 61, wherein said subject is 2 human.
63. Use of a compound according to claim 1 in the manufacture of a preparation for inhibiting PDE4 enzyme activity in a subject.
64. A substance or composition for use in a method for enhancing cognition in a subject in whom such enhancement is desired, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said subject an effective amount of said substance or composition.
65. A substance or composition for use in a method of treatment or prevention according to claim 64, wherein said substance or composition is administered in an amount of 0.01-100 mg/kg of body weight/day.
66. A substance or composition for use in a method of treatment or prevention according to claim 64, wherein said subject 1s a human.
67. A substance or composition for use in a method of treating a patient suffering from cognition impairment or decline, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said patient an effective amount of said substance or composition. AMENDED SHEET
PCT/US02/01508
68. A substance or composition for use in a method of treatment or prevention according to claim 67, wherein said patient is a human.
69. A substance or composition for use in a method of treatment or prevention according to claim 68, wherein said patient is suffering from memory impairment.
70. A substance or composition for use in a method of treatment according to claim 67, wherein said substance or composition is administered in an amount of
0.01-100 mg/kg of body weight/day.
71. A substance or composition for use in a method of treatment or prevention according to claim 69, wherein said patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease.
72. A substance or composition for use in a method for treating a patient having a disease involving decreased cAMP levels, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said patient an effective amount of said substance or composition.
73. A substance or composition for use in a method of inhibiting PDE4 enzyme activity in a subject, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said subject an effective amount of said substance or composition.
74. A substance or composition for use in a method of treating a patient suffering from memory impairment due to a neurodegenerative disease, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said patient an effective amount of said substance or composition.
75. A substance or composition for use in a method of treating a patient suffering from memory impairment due to an acute neurodegenerative disorder, said substance or composition comprising a compound according to claim 1, and said AMENDED SHEET
PCT/US02/01508 method comprising administering to said patient an effective amount of said substance or composition.
76. A substance or composition for use in a method of treating a patient suffering from an allergic or inflammatory disease, said substance or composition comprising a compound according to claim 1, and said method comprising administering to said patient an effective amount of said substance or composition.
77. A compound according to claim 1, wherein said compound is N-3,4- bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic ~~ acid or a pharmaceutically acceptable salt thereof.
78. A compound according to claim 1, wherein said compound 1s N-(3- cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.
79. A method according to claim 44, or use according to claim 62, wherein said compound 1s N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3- aminobenzoic acid or a pharmaceutically acceptable salt thereof.
80. Use according to claim 50, wherein said compound 1s N-3,4 bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic ~~ acid or a pharmaceutically acceptable salt thereof.
81. Use according to claim 63, wherein said disease is depression.
82. A method according to claim 44, or use according to claim 62, wherein said compound is N-3,4-bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3- aminobenzoic acid or a pharmaceutically acceptable salt thereof. AMENDED SHEET
PCT/US02/01508
83. A composition according to claim 52, wherein said compound N-3,4- bis(difluoromethoxy)phenyl-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.
84. A composition according to claim 52, wherein said compound is N-(3- cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.
85. A composition according to claim 52, wherein said composition further comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, cholinesterase inhibitors, or any combination thereof.
86. A composition according to claim 83, wherein said composition further comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, cholmesterase inhibitors, or any combination thereof.
87. A composition according to claim 84, wherein said composition further comprises an additional pharmaceutical agent selected from calcium channel blockers, cholinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, cholinesterase inhibitors, or any combination thereof.
88. A compound according to any one of claims 1 to 4, 57 to 59, 77 or 78, substantially as herein described and illustrated.
89. A method according to claim 42, claim 51, claim 79 or claim 82, substantially as herein described and illustrated. AMENDED SHEET
. PCT/US02/01508
90. Use according to any one of claims 45 to 50, 55, 56, 60 to 63 or 79 to 82, substantially as herein described and illustrated.
91. A composition according to claim 52, or any one of claims 83 to 87, substantially as herein described and illustrated.
92. A substance or composition or use in a method of treatment or prevention according to any one of claims 64 to 76, substantially as herein described and illustrated.
93. A new compound, a new non-therapeutic method of treatment, a new use of a compound as claimed in claim 1, a new composition, or a substance or composition for a new use in a method of treatment or prevention, substantially as herein described. AMENDED SHEET
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