JP4223287B2 - Novel compounds and pharmaceutically acceptable salts thereof and pharmaceutical compositions using them - Google Patents

Description

  This application is filed with United States provisional application No. 10 filed Jan. 22, 2001. 60 / 262,651, United States provisional application No. 8 filed Feb. 8, 2001. 60/267, 196, United States provisional application no. Claim the benefit of 60 / 306,140.

This invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. In particular, the invention relates to selective PDE4 inhibition by novel compounds such as N-substituted anilines and diphenylamine analogs, methods for preparing such compounds, pharmaceutical compositions comprising such compounds, And how to use them.

Cyclic nucleotide specific phosphodiesterases (PDEs) represent a group of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as secondary messengers in the cell and carry stimuli from cell surface receptors to which various hormones and neurotransmitters are bound as messengers. PDEs regulate the level of intracellular cyclic nucleotides and maintain the homeostasis of cyclic nucleotides by degradation of the cyclic mononucleotides that will terminate the role of such cyclic mononucleotide messengers.

PDE enzymes can be classified into 11 groups according to their specificity for hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin, or cGMP, and their selective inhibition by various compounds. . For example, PDE1 is stimulated by Ca ²⁺ / calmodulin. PDE2 is dependent on cGMP and is present in the heart and adrenal glands. PDE3 is dependent on cGMP and inhibits this enzyme that produces positive inotropic activity. PDE4 is cAMP specific and its inhibition causes tracheal relaxation, anti-inflammatory and antidepressant activity. PDE5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE5 inhibitors will have cardiovascular activity. Because PDEs have distinct biochemical properties, they appear to be governed by a variety of different forms of regulation.

  PDE4 is distinguished by various kinetic properties including low Michaelis constants for cAMP and sensitivity to a given drug. A group of PDE4 enzymes consists of four genes that generate four isoforms of the PDE4 enzyme shown in PDE4A, PDE4B, PDE4C, and PDE4D [Wang et al., Expression, Purification, And characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D (Expression, Purification, and Characterization of human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D) Biochem. Biophys. See Reschem. Biochem. Biophys. Res. Comm, 234, 320-324 (1997)]. In addition, various splice variants of each PDE4 isoform have been identified.

  The PDE4 isoenzyme is localized in the cytoplasmic matrix of the cell and is not associated with any known membranous tissue. The PDE4 isoenzyme inactivates cAMP, specifically by catalyzing the hydrolysis of cAMP 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 anti-inflammatory agents, and therefore diseases in which inflammation is a problem, such as asthma and arthritis Would be effective in treating. In addition, rolipram improves the recognition of rats and mice in a learning paradigms.

  In addition to compounds such as rolipram, xanthine derivatives such as pentoxifylline, denbufylline and theophylline have recently received considerable attention for their ability to inhibit PDE4 and improve cognition. Yes. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, as a result of PDE inhibition, significant therapeutic effects can occur, resulting in an increase in intracellular cAMP and cGMP that are localized in the nervous system and elsewhere in the body.

Previously rolipram developed as an antidepressant, selectively inhibits the PDE4 enzyme and has become a standard reagent for classifying subtypes (subtypes) of PDE enzymes. PDE4 field Early studies of, focuses on depression and inflammation, then, [The · PDEIV · family-of-calcium are I Solstice in up to and including indications such as dementia - phosphodiesterase enzyme's (The PDE IV Family Of Calcium-Phosphodiesterases Enzymes), John A. Lowe, III, and others, Drugs of the Future 1992, 17 (9): See 799-807]. Further clinical development of rolipram and other first generation PDE4 inhibitors was terminated due to the side effects of these compounds. The primary side effect in primates is vomiting, and the primary side effect in rodents is testicular degranulation, weakening of vascular smooth muscle, psychotropic effects, increased gastric acid secretion, and It is a sore stomach.

Summary of the Invention

  The present invention relates to novel compounds, for example novel N-substituted aniline and diphenylamine compounds that inhibit the PDE4 enzyme, in particular, for example, which are relatively non-emetic (eg compared to the previously described prior art compounds). And a novel compound with improved side effects. Preferably, the compound selectively inhibits the PDE4 enzyme. At the same time, the compounds of the present invention are easy to enter into cells, particularly into cells of the nervous system.

Furthermore, the present invention requires PDE inhibition, in particular PDE4 inhibition, including conditions relating to neurological disease syndromes, in particular memory disorders, in particular long-term memory disorders, some of which are impaired intracellularly by PDE4 enzymes. In a disease state involving an increase in intracellular PDE4 levels or a decrease in cAMP levels, such as by catabolism of cAMP levels or such memory impairment is ameliorated by effectively inhibiting the activity of the PDE4 enzyme. In addition to providing pharmaceutical compositions for treating, for example, mammalian patients, including humans, methods of synthesizing compounds having such activity and selectivity are provided.

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

The present invention provides a compound of formula I
And pharmaceutically acceptable salts thereof,
: Wherein R ¹ has a 1 to 4 carbon atoms, not branched or branched, not substituted, or one or more alkyl substituted by halogen _(e.g., CH 3, _CHF 2, CF ₃ etc.);
R ² is 1 to 12, preferably with from 1 to 8 carbon atoms, not branched or branched, not substituted, or one or more halogen, hydroxy, _{cyano, C 1-4} - Substituted by alkoxy, oxo, or combinations thereof, in each case one or more —CH ₂ CH ₂ — groups are replaced by —CH═CH— groups or —C≡C— groups (eg, CH ₃ , Alkyl optionally substituted by CHF ₂ , CF ₃ , methoxyethyl, etc.),
3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, unsubstituted or substituted with one or more halogen, hydroxy, oxo, cyano, 1 to 4 carbon atoms, 1 to 4 carbon atoms Cyclo (cyclo) alkyl (eg, cyclopentyl) substituted by alkoxy having carbon atoms, or combinations thereof,
One or more halogen, oxo, cyano, hydroxy, C _1-4 -alkyl having 4 to 16, preferably 4 to 12 carbon atoms, unsubstituted or in the cycloalkyl and / or alkyl moiety , Cycloalkylalkyl substituted by C _1-4 -alkoxy, or combinations thereof (eg, cyclopentylmethyl, cyclopropylmethyl, etc.),
Having 6 to 14 carbon atoms, not substituted, or one or more _halogen, CF 3, OCF _3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy (methylenedioxy), ethylenedioxy (ethylenedioxy), cyano Or aryl substituted by a combination thereof (eg, methylphenyl, methoxyphenyl, chlorophenyl, etc.),
The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, and the arylalkyl radical is unsubstituted or said aryl moiety Wherein the one or more —CH ₂ in the alkyl moiety is substituted by one or more of halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof. Each CH ₂ — group is optionally substituted with —CH═CH— or —C≡C—, and one or more —CH ₂ — groups are each optionally substituted with —O— or —NH—, and / or Arylalkyl wherein the alkyl moiety is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof ( For example, phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl ( phenylethenyl), phenoxyethyl, phenoxybutyl, chlorophenylaminoethyl, etc.),
Partially unsaturated carbocycle having from 5 to 14 carbon atoms and unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof Groups (carbocyclic groups such as cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms in which at least one ring atom is an N, O, or S atom, not substituted, or one or more A heterocyclic group substituted by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, such as 3-thienyl, 3-tetrahydrofuran Nyl (3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or
The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and the alkyl moiety is branched or branched; Having 1 to 5 carbon atoms unbranched, and the heterocyclic-alkyl group is not substituted, or in said heterocyclic moiety one or more of halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, Substituted by trifluoromethyl, nitro, oxo, or combinations thereof, one or more —CH ₂ CH ₂ — groups in said alkyl moiety are each optionally substituted by —CH═CH— or —C≡C—, and one or more -CH ₂ - groups may be replaced by an appropriate -O-, or -NH- radical, respectively, and / or wherein the alkyl moiety is a halogen, oxo, hydroxy, cyano, Heterocycle is optionally substituted by these combinations are properly - alkyl group (heterocycle-alkyl group, for example, pyridylethyl (Pyridylethyl), pyridylpropyl (Pydridylpropyl), methylpiperazinyl ethyl (Methylpiperazinylethyl), etc.); and
R ³ has 5-10 ring atoms in which the heteroaryl moiety is partially or fully saturated and at least one ring atom is an N, O, or S atom, and is branched or branched. A non-branched alkyl moiety is a heteroarylalkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted in said heteroaryl moiety, one or more of halogen, alkyl, alkoxy, cyano, trifluoro Heteroaryl substituted by methyl, CF ₃ O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and / or substituted by halogen, cyano, or methyl, or combinations thereof in the alkyl moiety Alkyl groups such as pyridylmethyl, pyridylpropyl, Lupyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl (Piperidinylmethyl), furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);
R ⁴ will have from 6 to 14 carbon atoms, not substituted, or one or more halogen, alkyl, alkenyl (alkenyl), alkynyl (Alkynyl), hydroxy, alkoxy, alkoxyalkoxy (alkoxyalkoxy), nitro, methylene Dioxy, ethylenedioxy, trifluoromethyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl, eg, hydroxymethyl, hydroxamic acid, tetrazol-5-yl (tetrazole-5-yl), 2 (- heterocycle) tetrazole-5-yl (e.g., 2- (2-tetrahydropyranyl (-Tetrahydropyranyl)) tetrazol-5-yl), hydroxyalkoxy ( hydroxyalkoxy), carboxy, alkoxycarbonyl (alkox) ycarbonyl, for example, tertiary butyloxycarbonyl, ethoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsiloxy ( trialkylsilyloxy, for example, tert-butyldimethylsilyloxy, aryl substituted with R ⁵ -L-, or combinations thereof (eg, phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinyl) Phenyl (vinylphenyl), cyanophenyl (methylenedioxophenyl), ethylphenyl, dichlorophenyl (dichlorophenyl), carboxyphenyl (carboxyphenyl), ethoxycarbonyly (ethoxycarbony) lphenyl), dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, substituted or unsubstituted phenyl, naphthyl, and biphenyl), or
5-10 ring atoms, at least one ring atom being a heteroatom, unsubstituted or one or more halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, Trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (eg tertiary butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b alkoxy (e.g., tertiary-butyldimethylsilyloxy), R ⁵ - -Or a heteroaryl substituted by a combination thereof (for example pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, Thiazolyl);
R ⁵ is, H,
1 to 8, preferably 1 to 4 carbon atoms, unsubstituted or substituted by one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo, or combinations thereof Alkyl (eg, methyl, ethyl, propyl, etc.),
Each independently an alkyl moiety having 1 to 8, preferably 1 to 4 carbon atoms, or a dialkylamino (such as dimethylamino),
Carbocyclic moiety having 5 to 14 carbon atoms, the alkyl moiety has from 1 to 5 carbon atoms, not substituted, also one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, or A partially unsaturated carbocyclic-alkyl group (eg, cyclohexenylmethyl, etc.) substituted by any combination thereof,
3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, not substituted, or one or more halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or these Cycloalkyl substituted by a combination (eg, cyclopentyl),
One or more halogen, oxo, cyano, hydroxy, alkyl, alkoxy, or these having from 4 to 16, preferably from 4 to 12 carbon atoms, unsubstituted or in the cycloalkyl and / or alkyl moiety A cycloalkylalkyl substituted by a combination of (for example, cyclopentylmethyl, cyclopropylmethyl, etc.),
6 to 14 carbon atoms, unsubstituted or one or more, halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, amino Alkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (eg tertiary butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio Aryl substituted by alkylsulfinyl, alkylsulfonyl (for example, substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl) , Cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),
An arylalkyl group having 7 to 19 carbon atoms, an aryl moiety having 6 to 14 carbon atoms, and a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Or substituted in the aryl moiety by one or more of halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and / or halogen in the alkyl moiety, cyano, aryl alkyl substituted by methylation or combination thereof (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylene-dioxo benzyl, etc.),
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, alkyl , Hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg hydroxymethyl), hydroxamic acid, tetrazol-5- Multiples substituted by yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (eg, tertiary butyroxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof A cyclic group (eg, pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or
An alkyl having 5-10 ring atoms in which the heterocyclic moiety is saturated, partially saturated, or unsaturated, at least one ring atom is an N, O, or S atom, and is not branched or branched moiety has from 1 to 5 carbon atoms, a heterocyclic - alkyl group is not substituted, or in the heterocyclic moiety, one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heterocycle-alkyl group substituted one or more times by, oxo, amino, alkylamino, dialkylamino, or combinations thereof, and / or substituted at the alkyl moiety by halogen, cyano, methyl, or combinations thereof ( For example, pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.);
L has a single bond or 1 to 8 carbon atoms, and one or more —CH ₂ — groups are —O—, —S—, —NR ⁶ —, —SO ₂ NH—, —NHSO ₂ —. , —CO—, —NR ⁶ CO—, —CONR ⁶ —, —NHCONH—, —OCONH—, —NHCOO—, —SCON—, —SCSNH—, or —NHCSNH—, respectively. aliphatic group _{(e.g., -O-, CH 2 -, -} CO -, - CO-O -, - O-CO -, - CO-NH -, - NH-CO -, - CH 2 CH 2 CH 2 - NH—CO—, —CH ₂ CH ₂ —O—, —SO ₂ NH—CH ₂ CH ₂ —O—, —O—CH ₂ CH ₂ —O—, —CH ₂ —NH—CO—, —CO— _{NH-CH 2 -, - SO} 2 -NH -, - CH 2 -NH-SO 2 -, - CH Be CH ₂ CH ₂ -SO ₂ -NH-, etc.); and R ^6, H,
1 to 8, preferably 1 to 4, carbon atoms, branched or unbranched, unsubstituted or one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy , oxo, or alkyl (e.g., methyl, ethyl, propyl, etc.) to be replaced by a combination of these Ru der.

R ³ and R ⁴ are both other than H, are useful as intermediates for preparing compounds of Formula I of the present invention, the family of compounds represented by Formulas II and III (genus) are exemplified:
Here, R ¹ , R ² , R ³ and R ⁴ are defined as described above. The subgroup of formula I compounds of (subgenus), not only have PDE4 inhibitory activity, both R ³ and R ⁴ is other than H, as intermediates for preparing compounds of Formula I of the present invention Useful.

According to a further aspect of the invention, a preferred compound of formula I is subformula IV,
Here, R ¹ , R ² , and R ⁴ are defined as in Formula I, one of A, B, and D is N and the other is C. Preferably B is N. Further, R ⁴ is preferably Ri Pi lysyl or phenyl der, substituted or unsubstituted in any case.

The invention also includes compounds of formula I ′ and pharmaceutically acceptable salts thereof :
here,
R ^{1 'is} methoxy or CHF _2;
R ^{2 'is} alkyl having 1 to 12 carbon atoms,
Having 1 to 12 carbon atoms, 1 or more, halogen, oxo, cyano, or alkyl which is replacement by a combination thereof,
Alkenyl having 2 to 12 carbon atoms,
Having 2 to 12 carbon atoms, 1 or more, halogen, oxo, cyano, or alkenyl, which is replacement by a combination thereof,
Alkynyl having 2 to 12 carbon atoms,
Having 2 to 12 carbon atoms, 1 or more, halogen, oxo, cyano, or alkynyl is substitution by these combinations,
A cycloalkyl having 3 to 10 carbon atoms,
It has 3 to 10 carbon atoms, 1 or more, halogens, oxo alkyl, or cycloalkyl which are substitution by these combinations,
Cycloalkylalkyl having 4 to 12 carbon atoms,
Having 4 to 12 carbon atoms, 1 or more, halogen, oxo, alkyl, or cycloalkyl alkyl as substitution by these combinations,
A partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
Having 5 to 14 carbon atoms, 1 or more, halogens, alkyl, alkyloxy (alkyloxy), nitro, cyano, oxo, or are replacement by a combination thereof, partially carbocyclic group unsaturated ,
Arylalkyl having 7 to 26 carbon atoms,
Has 7 to 26 carbon atoms, 1 or more halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or arylalkyl which is replacement by a combination thereof,
A heteroarylalkyl having 5 to 10 ring atoms, at least one ring atom being a heteroatom, or
Having 5 to 10 ring atoms, at least one ring atom being a heteroatom, and in the heteroaryl moiety , one or more of halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, or by a combination thereof is substitution, and / or halogen in the alkyl moiety, oxo, cyano, or is replaced by a combination thereof, substituted heteroaryl alkyl;
X is O ;
R 3 ^'is heteroaryl having at least one ring atom is 5 to 10 ring atoms is a heteroatom, or,
5 to 10 ring atoms, at least one ring atom being a heteroatom, and 1 by halogen, aryl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof Substituted heteroaryl substituted more than once;
L ^{is, -NR 4 '-, - NR} 4' CH 2 -, or _-CH 2 NR ^{4 '-} a and; and R ^4' has from 6 to 14 carbon atoms, not substituted, or, One or more of halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or aryl as substitution by these combinations,
A heteroaryl having from 5 to 10 ring atoms, at least one ring atom being a heteroatom,
5 to 10 ring atoms in which at least one ring atom is a heteroatom, and one or more of halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or is substitution by these combinations, substituted heteroarylene Le.

  The compounds of the present invention are effective in inhibiting or modulating the activity of PDE4 in, for example, mammals, particularly human animals. These compounds exhibit neuronal activity, in particular such activity affects cognition including long-term memory. These compounds would also be effective in the treatment of diseases that include a decrease in cAMP levels. This includes, but is not limited to, inflammatory diseases. These compounds also have antidepressant activity and may be effective in treating cognitive and negative symptoms in schizophrenia.

As with selection of the selectivity and PDE isoenzymes inhibition of PDE inhibitory activity, assays for determining the PDE inhibition activity (assay) are known in the art. For example, see US 6,136,821 . This disclosure is incorporated herein by reference .

  According to a further aspect of the invention, compounds useful as intermediates for the preparation of PDE4 inhibitors described herein (eg, PDE4 inhibitors of formula I) and / or PDE4 inhibitors of this application Compounds useful for the synthesis of radio-labeled analogs are provided.

Thus, R ² , R ³ , and R ⁴ are as previously defined for Formula I, but R ¹ is H or tertiary butyldimethylsilyl — Intermediate compounds corresponding to the compounds are provided . These intermediates are also useful for the synthesis of radiolabeled compounds where R ¹ is ³ H ₃ C—, ¹⁴ CH ₃ —, or ¹¹ CH ₃ —, eg, removing tertiary butyldimethylsilyl . The resulting R ¹ is synthesized by reacting a compound of H with an appropriate radiolabeled reagent. Such radiolabeled compounds are useful for determining the tissue distribution of compounds in animals by examination of PET images, and are also in vivo, ex vivo, and tested Useful for in vitro binding studies.

Further, R ^{1, R 3,} and although R ⁴ are as previously defined for Formula I, R ² is H, or a tertiary-butyldimethylsilyl Oki sheet, corresponding to the compound of Formula I intermediate Body compounds are provided . Compounds where R ² is H are useful as scaffolds for application to, for example, parallel or combinatorial chemistry. In addition, these compounds are useful for the introduction of radiolabels such as ³ H, ¹⁴ C, or ¹¹ C.

As previously mentioned, compounds according to Formula II where R ¹ , R ² , and R ⁴ are as previously described are useful as intermediates for the preparation of compounds according to Formula I where R ³ is other than H. is there.

Also, as previously mentioned, compounds according to Formula III where R ¹ , R ² , and R ³ are as previously described are useful as intermediates in the preparation of compounds according to Formula I where R ⁴ is other than H. is there.

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

  Alkyl as a group or as a substituent per se or as part of a group or substituent (eg alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), preferably 1-12, preferably It means a straight or branched chain aliphatic hydrocarbon group having 1 to 8, in particular 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups are 1-, 2-, or 3-methylbutyl, 1,1-, 1,2-, or 2,2-dimethylpropyl, 1-ethylpropyl ( ethylpropyl), 1-, 2-, 3-, or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-, or 3,3 Dimethylbuthyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethyl Contains methylmethylbutyl, dimethylbutyl, and the like.

A substituted alkyl group is an alkyl group as described above substituted at one or more positions with halogen, oxo, hydroxy, C _1-4 -alkoxy, and / or cyano. Halogen is a preferred substituent, especially F and Cl.

Alkoxy means an alkyl-O- group and alkoxyalkoxy means an alkyl-O-alkyl-O- group in which the alkyl moiety is in accordance with those previously described. Suitable alkoxy and alkoxyalkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy (Propoxymethoxy) and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl-O-CO- , where the alkyl moiety is as previously described . Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tertiary tert-butoxycarbonyl.

  Cycloalkyl is a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon group having 3 to 10, preferably 3 to 8, in particular 3 to 6 carbon atoms. Means. Suitable cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, 1-decalin, adamant -1 -yl (adamant-1-yl) and adamant-2-yl. Other suitable cycloalkyl groups are spiropentyl, bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl (bicyclo [3.1.0]). hexyl), spiro [2.4] heptyl (spiro [2.4] heptyl), spiro [2.5] octyl, bicyclo [5.1.0] octyl (bicyclo [5.1.0] octyl) ), Spiro [2.6] nonyl (spiro [2.6] nonyl), bicyclo [2.2.0] hexyl, spiro [3.3] heptyl (spiro [3.3] heptyl) , Bicyclo [4.2.0] octyl, and spiro [3.5] nonyl. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted, for example, with halogens and / or alkyl groups.

Cycloalkylalkyl refers to a cycloalkyl-alkyl group in which the cycloalkyl and alkyl moieties are as previously described . Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

As a group or as a substituent per se or as part of a group or substituent, aryl is an aromatic carbocyclic group having 6 to 14, preferably 6 to 12, in particular 6 to 10 carbon atoms. Point to. Suitable aryl groups include phenyl, naphthyl, and biphenyl. Substituted aryl groups are, for example , one or more of halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl includes alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and is substitution by phenoxy, an aryl group described above.

Arylalkyl, aryl and alkyl moieties are those previously mentioned, aryl - refers to an alkyl group. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthtylmethyl.

Heteroaryl refers to an aromatic heterocyclic group having a total of 5 to 10 ring atoms having 1 or 2 rings and at least one ring atom being a heteroatom. Preferably, the heteroaryl group contains 1 to 3, in particular 1 or 2, hetero-ring atoms selected from N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl (pyrazolyl), imidazolyl, triazolyl (triazolyl), tetrazolyl (tetrazolyl), dithia Li Le (dithialyl), Okisachiariru (oxathialyl), isoxazolyl (isoxazolyl), oxazolyl (Oxazolyl ), Thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinylpyridyl , Triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobazinyl Zofuraniru (isobenzofuranyl), thionaphthenyl (thionaphthenyl), isothiourea naphthenyl (thionaphthenyl), indolyl (indolyl), isoindolyl (isoindolyl), indazolyl (indazolyl), Ben's isoxazolyl (benzisoxazolyl), benzoxazolyl (benzoxazolyl), benzothiazolyl (Benzthiazolyl ), Ben Sui Sochiazoriru (Benzisothiazolyl) include purinyl (purinyl), benzopyranyl (benzopyranyl), quinolinyl, isoquinolinyl, cinnolinyl (cinnolinyl), quinazolinyl (quinazolinyl), naphthyridinyl (naphthyridinyl), and benzoxazinyl (benzoxazinyl), e.g. 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7-, or 8- Contains soquinolinyl.

Substituted heteroaryl is one or more of the above, substituted with , for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino Represents a heteroaryl group.

Heterocycles are preferably non-aromatic ring groups containing at least one heterocyclic atom selected from N, S and O, in addition to the heteroaryl groups mentioned above , such as tetrahydrofuranyl, piperidinyl, and a pyrrolidinyl (pyrrolidinyl).

  Heterocycle-alkyl refers to a heterocycle-alkyl group in which the heterocycle and alkyl moieties follow those previously described. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.

  A partially unsaturated carbocyclic structure is a non-aromatic monocyclic or bicyclic ring having 5-14, preferably 6-10 carbon atoms, the ring structure containing at least one C═C bond. The structure of the formula. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl, and indan-2-yl.

Alkenyl refers to a straight or branched chain aliphatic group having 2 to 12 carbon atoms in which one or more —CH ₂ —CH ₂ — structures are each substituted with —C═C—. Suitable alkenyl groups include ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and 2-pentenyl. It is.

Alkynyl refers to a straight or branched chain aliphatic group having 2 to 12 carbon atoms in which one or more —CH ₂ —CH ₂ — structures are each substituted with —C≡C—. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl and 2-butynyl.

  Acyl is an alkanoyl group having 1 to 13 carbon atoms in which the alkyl moiety can be substituted by halogen, alkyl, aryl, and / or alkoxy, or the aryl moiety is substituted by, for example, halogen, alkyl, and / or alkoxy Refers to an aroyl group having from 7 to 15 carbon atoms that can be made. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl, and benzoyl.

  The substituent preferably has 1 to 3 substituents, especially 1 to 2 substituents.

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

R ² is preferably cycloalkyl, especially cyclopentyl.

Further, R ² is preferably the aryl or arylalkyl, in particular, phenyl, methylphenyl (methylphenyl), methoxyphenyl (methoxyphenyl), chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl (Phenoxypropyl), phenoxybutyl, chlorophenylethyl, methoxyphenylethyl, chlorophenylethenyl, chlorophenoxyethyl, chlorophenylpropyl, methoxyphenpropyl, methoxyphenbutyl, chlorophenbutyl, nitrophenbutyl ), Chlorophenylaminoethyl, and the like, substituted or unsubstituted phenyl or phenylalkyl,
R ² is also preferably a partially unsaturated carbocyclic group which is unsubstituted or in particular substituted by cyclohexenyl, cyclohexadienyl, indan-2-yl.

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

R ² is preferably a heterocycle or heterocycle-alkyl in which the heterocyclic group has 5 to 6 ring atoms and 1 to 2 heteroatoms selected from N, O and S. Radicals such as tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl, and It is an equivalent group .

Preferred R ² is cyclopentyl, tetrahydrofuranyl, CHF ₂ , methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridyl Contains propyl.

R ³ is a hetero aryl group (e.g., substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents on the f heteroaryl portion of R ³ _{is, F, Cl, CH 3,} C 2 H 5, OCH 3, and is CN.

R ⁴ is aryl, heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl (furanyl), pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, and isoquinolinyl, which in any case is not substituted or is on one or more substituent The Preferred substituents are OH, F, Cl, CF ₃ , alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl group, CH ₂ OH, CONHOH, CONH ₂ , Methylenedioxy, COOH, and combinations thereof.

In addition, when R ⁴ is aryl, especially phenyl, preferred substituents are methyl, ethyl, Cl, F, CN, OCH ₃ , CF ₃ , amino, nitro, HOCH ₂ , and COOH, for example R ⁵ — ^{, R 5 -O-, R 5 -CO-} , R 5 -NH-CO-, R 5 -SO 2 -NH-, R 5 -SO 2 -NH- alkylene -O-, NH ₂ - alkyl -NH- CO-, ^{R 5} - containing alkylene -NH-CO-, the ^R 5-L-alkyl -CO-NH- alkyl.

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

When R ⁴ is aryl substituted by R ⁵ —SO ₂ —NH-alkylene-O—, it is preferably a substituted phenyl group. In such cases, R ⁵ is preferably methyl, ethyl, propyl, or phenyl, and alkylene is preferably —CH ₂ —, —CH ₂ CH ₂ —, or —CH ₂ CH ₂ CH ₂ —.

When R ⁴ is aryl substituted by R ⁵ -L-, it is preferably a substituted phenyl group. In such cases, preferred R ⁵ groups are tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperazinyl ( piperadinyl), or methylpiperadinyl, and L is preferably a single bond, —O—, —CO—, —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, _{-CH 2 -O -, - CH 2} CH 2 -O -, - CH 2 CH 2 CH 2 -O -, - CH 2 -NH-CH 2 CH 2 -O -, - CO-NH-, or -NH -CO-.

In addition, preferred PDE4 inhibitors definitive in this invention, Formula I listed are compounds described by the sub-formula Ia-Ih representing the following preferred groups:
Ia R ¹ is methyl or CHF ₂ ;
R ² is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocyclic alkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted ;
R ³ is a hetero aryl alkyl, in either case is substituted or unsubstituted;
R ⁴ is aryl or heteroaryl, and in each case is substituted or unsubstituted .
Ib R ³ is a substituted or unsubstituted heteroarylalkyl.

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

Id R ¹ is methyl or CHF ₂ ;
R ² is cyclopentyl;
R ³ is heteroarylalkyl, in each case substituted or unsubstituted ; and
R ⁴ is substituted or unsubstituted aryl or heteroaryl.

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

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

Ig R ¹ is methyl;
R ² is cyclopentyl;
R ³ is pyridylmethyl, Ji enylmethyl, pyridylpropyl, piperidinylmethyl, or a pyrazinylmethyl, in any case they are location 換若 properly is non substitution; and
R ⁴ is phenyl or phenyl substituted with 1 to 3 substituents.

Ih R ¹ is methyl;
R ² is cyclopentyl;
R ³ is pyridylmethyl, Ji enylmethyl, pyridylpropyl, piperidinylmethyl, a pyrazinylmethyl, in any case they are location 換若 properly is non substitution; and
R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, also location 換若 properly cases are non-substitution.

In addition, the intermediate used to prepare the compound of Formula I of the present invention, where R ³ and R ⁴ are both other than H, is a subchemical formula representing the following preferred groups described in Formula II: Compounds described by IIa-IId:
IIa R ¹ is methyl or CHF ₂ ;
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl); and
R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in any case is location 換若 properly is non substitution.

IIb R ¹ is methyl or CHF ₂ ;
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl); and
R ⁴ is unsubstituted or phenyl substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl group, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamide, or unsubstituted or carboxy or 3-pyridyl substituted by alkoxycarbonyl.

IIc R ¹ is methyl;
R ² is cyclopentyl; and
R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, also location 換若 properly cases are non-substitution.

IId R ¹ is methyl;
R ² is cyclopentyl; and
R ⁴ is unsubstituted or phenyl substituted by methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl group, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamide, or unsubstituted or carboxy or 3-pyridyl substituted by alkoxycarbonyl.

In addition, the intermediate used to prepare the compound of Formula I of the present invention, where R ³ and R ⁴ are both other than H, is a subchemical formula representing the following preferred groups described in Formula III: Compounds described by IIIa-IIId:
IIIa R ¹ is methyl or CHF ₂ ;
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl); and
R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl, or a pyrrolylmethyl, in any case they are location 換若 properly is non substitution .

IIIb R ¹ is methyl or CHF ₂ ;
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl);
R ³ is pyrazinylmethyl, pyrimidinyl methyl, or pyridylmethyl, which in any case is location 換若 properly is non substitution.

IIIc R ¹ is methyl;
R ² is cyclopentyl; and
R ³ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, isoimidazolyl, thiazolylmethyl, or pyrrolylmethyl, in any case the location 換若 properly is a non-substitution.

IIId R ¹ is methyl;
R ² is cyclopentyl; and
R ³ is pyrazinylmethyl or pyridylmethyl, in which case they are unsubstituted or substituted.

In addition, preferred PDE4 inhibitors according to this invention are the compounds described by the sub-formula IVa-IVp described in Formula IV, which represent the following preferred groups:
IVa R ¹ is methyl or CHF ₂ .

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

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

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

IVe R ¹ is methyl or CHF ₂ ; and
R ⁴ is 3-pyridyl, or phenyl, any case they location 換若 properly is non substitution.

IVf R ¹ is methyl or CHF ₂
B is N, and
R ⁴ is 3-pyridyl, or phenyl, any case they location 換若 properly is non substitution.

IVg R ¹ is methyl or CHF ₂ ,
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl), and
R ⁴ is 3-pyridyl, or phenyl, any case they location 換若 properly is non substitution.

IVh R ¹ is methyl or CHF ₂ ,
B is N,
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl), and
R ⁴ is 3-pyridyl, or phenyl, any case they location 換若 properly is non substitution.

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

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

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

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

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

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

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

IVp R ¹ is methyl or CHF ₂ ,
B is N,
R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R) -tetrahydrofuranyl), and
R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl @ - phenyl, 3-cyano - phenyl, 3-ethylsulfonamido - phenyl, 3-tetrazol-5-yl - phenyl, 3-hydroxymethyl - phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.

Preferred embodiment, compounds of the present invention, pharmaceutically acceptable base, and, optionally, includes a pharmaceutical composition comprising the active agent as described in detail below; for example in vitro (in vitro) or in vivo ( PDE4 enzyme determined by a general assay either in vivo, in an animal, eg, in an animal model, or in a mammal, or in the human body, or a test method described herein In particular methods of inhibiting isoenzymes; methods of treating neurological syndromes such as memory loss, cognitive impairment or cognitive decline, memory impairment, especially for long-term memory, such as mentioned here Methods of treating disease states modulated by PDE4 activity in mammals such as humans are included.

  The compounds of this invention may generally be prepared. Some processes that can be used are described below. All starting materials are known or can generally be prepared from known starting materials.

Scheme 1

Type 1 starting nitrophenols are commercially available (eg R1 = CH ₃ ) or published methods (eg R1 = CHF ₂ or R1 and R2 = CHF ₂ , Mueller Klaus-Helmut (Mueller Klaus-Helmut), European patent application, (1994), 8pp, code number: EPXXDW EP 626361A1;・ Platonov, Andrew, Seavakov, Andrew, Maiyorova, Helen, Chistokletov, Victor, “International Symposium Wood Palping Chem (Int. Symp. Wood) Pulping Chem.), 1995, 8th edition, 3, 295-299; Christensen Siegfried Ben See: Christensen, Siegfried Benjamin, Dabbs, Steven, Karpinski, Joseph M., PCT International Application (1996), 12pp, code number: PIXXD2 WO 9623754 A1 19960808 Prepared). Aniline intermediate 3 is produced in two steps; first the addition reaction yields intermediate 2 followed by reduction of the nitro group. The intermediate nitro compound 2 can be prepared by a number of published methods, such as by the Mitsunobu reaction or standard alkylation reaction. Compounds where R2 is aryl or heteroaryl are prepared by reactions catalyzed by aryl or heteroaryl iodides under copper conditions under the Ullman condition, or copper catalysts (eg, Cu (OAc) ₂ ) and TEA Prepared by coupling aryl-, vinyl-, or heteroaryl-boronic acid with phenol 2 in the presence of a base such as Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using azodicarboxylate (eg DEAD, DIAD) and an appropriate phosphine (eg Ph ₃ P) , Bu ₃ P) gives alkylated nitrophenol 2. The Mitsunobu reaction is generally performed in an aprotic solvent such as dichloromethane or THF. Other alkylations are the appropriate substituted nitrophenols and alkyl halides in the presence of a base (eg K ₂ CO ₃ or NaH) in a polar aprotic solvent such as DMF or CH ₃ CN. Can be carried out by reaction between

Nitrocatechols 2 is a standard in techniques such as hydrogenation using a suitable catalyst (eg Pd on the carbon surface) in a polar aprotic solvent such as MeOH or EtOH under a hydrogen atmosphere. The method is immediately reduced to the corresponding aniline 3. Alternatively, to produce the corresponding aniline, by using a hydride source (eg NaBH ₄ ) and a transition metal catalyst (eg NiCl ₂ , Pd on the carbon surface) or an inorganic acid solution (eg HCl ) Can be reduced by using a metal (eg Zn, Sn, Fe). In general, polar protic solvents such as ethanol and methanol are used in these reactions.

N-arylalkylanilines 4 are synthesized by standard methods in techniques such as by reductive amination reaction, alkylation reaction, or reduction of the corresponding amide. For example, an appropriate substitution with an aryl or arylalkyl aldehyde in the presence of a borohydride reducing agent such as NaBH ₄ or NaBH ₃ CN with an acid catalyst such as acetic acid or pTsOH. A reductive amination reaction with the resulting aniline yields the desired N-arylalkylanilines. These reactions generally occur in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol, and the like.

N-arylalkylanilines 4 can be readily synthesized by standard methods of technology including Ullman coupling reactions, metal-catalyzed couplings, or aromatic nucleophilic substitution reactions. -Undergoes N-arylation. For example, using a palladium catalyst (eg, Pd ₂ dba ₃ ), a bulky electron rich phosphine ligand (eg, tributylphosphine), and a suitable base (eg, NaOtBu), N-benzylaniline The metal catalyzed reaction between (benzylaniline) and aryl halides yields N-arylalkyldiphenylamines. Nickel and copper catalysts are used as well. Useful solvents for this reaction include nonpolar aprotic solvents such as toluene, benzene, xylene, tetrahydrofuran, and ether. When synthesizing a compound of type 5 where R4 is alkoxycarbonylphenyl, it is advantageous to couple 1.1 equivalents of tertiary butyl 3-iodobenzene with amine 4. 22 mol% (tBu) ₃ P, 5.5 mol% Pd ₂ (dba) ₃ , and 1.3 equivalents of tBuONa are used.

Scheme 2

  The carboxylic ester intermediate 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acid 7. For example, the ether ester (R5 = Et) can be hydrolyzed using a mixture of an aqueous base (eg, NaOH, KOH) and a solvent that can be mixed with water (eg, EtOH, THF). On the other hand, tertiary butyl ester (R5 = tertiary butyl) is an aqueous acid (eg, HCl, formic acid, TFA) in an organic solvent that can be mixed with water if necessary. Can be hydrolyzed.

Scheme 3

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

On the other hand, tetrazole analog 9 can be treated by treatment with azide ions (eg KN ₃ , NaN ₃ etc.) and hydrogen source (eg NH ₄ Cl) in a polar aprotic solvent such as DMF. Can be prepared from nitriles. They can also be prepared by treatment with azide ions and a Lewis acid (eg, ZnBr ₂ ) in water, using a cosolvent miscible with water, such as isopropanol, if necessary. Other preparation methods include nitrile and tin or silicon azides (eg, Me ₃ SiN ₃ , Bu in aprotic organic solvents such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like. ₃ SnN ₃ ).

Scheme 4

Diphenylamine 10 is based on a base such as triethylamine and a copper catalyst such as copper acetate (described in Chan et al., Tetrahedron Lett., 39, 2933-2936 (1998)). In the presence, it can be prepared by coupling an appropriately substituted aniline 3 such as 3-cyclopentyloxy-4-methoxyaniline with an arylboronic acid. Generally, halogenated solvents such as dichloromethane, chloroform, dichloroethane and the like are used as well as nonpolar aprotic solvents such as benzene, toluene or xylene. Such diphenylamine (eg, 10) is more preferably synthesized by a metal catalyzed amination reaction. For example, Pd (dppf) Cl ₂ , a ligand (eg, dppf), a base (eg, NaOtBu) (JACS., 1996, 118, 7217), or P (tBu with Pd ₂ dba ₃ Bulky electron rich phosphines and bases (e.g. NaOtBu) (J. Org. Chem, 1996, 64, 5575), e.g. bases (e.g. K ₃ PO ₄ , CsCO ₃ , or NaOtBu) and reaction of an appropriately substituted aniline 3 with an aryl halide in the presence of a palladium or nickel catalyst yields the preferred diphenylamine 10. The most commonly used solvents for this type of reaction include nonpolar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.

  In order to produce N-substituted diphenylamine 5, diphenylamine 10 is then present in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide, or potassium diisopropylamide. Under, but not limited to, iodomethane, ethyl bromide, benzyl chloride, 3- (chloromethyl) pyridine, 4- (chloromethyl) -2,6-dichloropyridine, and 4- (bromomethyl) -benzoic acid, or It can be alkylated with various alkyl halides or arylalkyl halides, such as these salts. Solvents used for this reaction include aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like.

Scheme 5

Carboxylic acid 7 can be further processed using standard methods in the art to produce carboxamides 11. For example, carboxylic acids are suitable primary or secondary to obtain carboxamides in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC and a base such as Et ₃ N or DIEA. Can be treated with amines. These reactions generally occur in nonpolar aprotic solvents such as dichloromethane, chloroform, or dichloroethane.

  Carboxylic acid ester 6 or acid 7 can be reduced using standard methods in the art to yield the corresponding carboxaldehyde or hydroxymethyl analog. For example, to produce the corresponding carboxaldehyde or hydroxymethyl analog, an aryl ethyl ester (eg, chemical structure 6, R5 = ethyl) is suitable in an aprotic solvent such as ether or THF. Can be treated with various reducing reagents (eg, LAH, DIBAL, etc.). Such aldehydes and alcohols can be further derivatized using standard methods in the art.

  Similarly, carboxamides (eg, chemical structure 11) and nitriles can be reduced using standard methods in the art to obtain the corresponding substituted amine or aminomethyl analog. For example, arylcarboxamide 11 can be reduced with a suitable reducing reagent (eg, LAH) in an aprotic solvent (eg, benzene, toluene, ether, THF, etc.) to obtain the corresponding substituted aminomethyl analog. In contrast, reduction of an aryl nitrile yields the corresponding primary aminomethyl analog.

Scheme 6

The nitrobenzene compound 12 is reduced to the corresponding aniline 13 by standard methods in techniques such as hydrogenation using a suitable catalyst (eg Pd on the carbon surface) in a polar protic solvent (eg EtOH, MeOH, etc.). Can be done. Also, a hydride source (eg, NaBH ₄ ) and a transition metal catalyst (eg, NiCl ₂ , Pd on the carbon surface) are used in a polar protic solvent such as EtOH to produce the corresponding aniline 13. Nitrobenzene 12 can be reduced. These anilines can be further replaced by standard methods in the art. For example, type 13 anilines are alkylated, acylated, or sulfonated to yield the corresponding N-alkylamines, carboxamides (eg, chemical structure 15), or sulfonamides (eg, chemical structure 14), respectively. can do. For example, aniline and an appropriate sulfonyl halide or anhydrous sulfone (eg, MeSO ₂ Cl, EtSO ₂ Cl, BnSO ₂ Cl, PhSO ₂ Cl, etc.) in the presence of a base (eg, Et ₃ N, pyridine, DIEA, etc.) Sulfonamides can be prepared from Suitable solvents for this reaction include nonpolar aprotic solvents such as dichloromethane, chloroform, ether, and the like.

Scheme 7

Type 16 Trialkylsilylethers are prepared as described in Scheme 1. Numerous literature methods such as using a fluoride ion source (eg Bu ₄ NF) in an aprotic solvent such as ether, THF; or under acidic conditions (eg KF, 48% HBr, DMF) ( Tertiary butyl by Green Tea W, Utz PGM, Protective Groups in Organic Synthesis, 3rd Edition, see John Willie and Sons, 1999, pp 273-276) The catechol intermediate 16 protected with butyldimethylsilyl is easily deprotected. The resulting phenol 17 is a very useful synthetic intermediate that is subsequently alkylated by standard methods in this technology and by methods similar to those described for alkylation of nitrophenol 2 in Scheme 1. can do. For example, by a Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by Ullmann-type aryl coupling, or in the presence of a copper catalyst, a vinyl group-, aryl-, or heteroaryl -By reaction with boronic acid.

Scheme 8

The Haloalkoxy intermediate 18 is prepared by alkylation of the corresponding phenol to obtain an analog such as 19, which is alkylated by reaction with a substituted amine, alcohol, or thiol in the presence of a base. be able to. For example, amination of an alkyl halide with a suitable primary or secondary amine and a base such as K ₂ CO ₃ in a polar aprotic solvent such as THF, DMF, or CH ₃ CN. Can do.

  Many of these synthetic procedures are fully described by the following examples.

  One skilled in the art will recognize that some of the compounds of formula (I) and (I ') may exist in different geometric isomer forms. In addition, some of the compounds of the present invention have one or more asymmetric carbon atoms, so they can exist in the form of optical isomers as well as their racemic or non-racemic mixtures, In particular, they can exist in the form of diastereomers and diastereomeric mixtures. All these compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemic acids (rcemate), non-racemic mixtures of enantiomers, and substantially pure enantiomers are included within the scope of the present invention. Substantially pure enantiomers include corresponding opposite enantiomers of 5% w / w or less, preferably 2% w / w or less, most preferably 1% w / w or less.

  Optical isomers can be obtained, for example, by general methods by the production of diastereoisomeric salts using optically active acids or bases, or by the production of covalent diastereomers. Can be obtained by resolution of the racemic mixture according to a typical method. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomeric isomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. . The optically active base or acid is then liberated from the separated diastereomeric salt. Other methods for separating optical isomers use chiral chromatography (eg, chiral HPLC columns) with or without a general derivation optimally chosen to maximize separation of enantiomers. Including doing. Suitable chiral HPLC columns are produced, for example, by diacel, which are inter alia Chiracel OD and Chiracel OJ, which can be chosen normally. Enzymatic separation with or without derivatization is also useful. In addition, optically active compounds of formulas I and I 'can be obtained by chiral synthesis utilizing optically active starting materials.

  The invention also relates to useful forms of the compounds disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all compounds of the invention. Pharmaceutically acceptable salts can be used as bases to form salts such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, and citric acid salts. Including those obtained by reacting major functional compounds with inorganic or organic acids. Also, pharmaceutically acceptable salts include, for example, those in which the main compound that functions as an acid is reacted with a suitable base to produce sodium, potassium, calcium, magnesium, ammonium, and choline salts. One skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reaction of the compound with a suitable inorganic or organic acid by any number of known methods.

  The following are further examples of acidic salts obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonates , Bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate , Hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfone Acid salt, oxalate, palmate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propion Acid salt, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.

  Preferably, the salt produced is pharmaceutically acceptable for administration to a mammal. However, salts of pharmaceutically unacceptable compounds are suitable as intermediates for converting the salt to the free basic compound, for example, by separating the compound as a salt and then treating with an alkaline reagent. If desired, the free base can then be converted to a pharmaceutically acceptable acid addition salt.

The compounds of the present invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of formula I or I ′ that include, for example, one or more pharmaceutically acceptable bases.

  Many standard references are available that describe methods for preparing various formulations suitable for administering the compounds according to the invention. Examples of possible formulations and preparations are similar to, for example, Remington's Pharmaceutical Sciences (Arthur Osol, Editor), 1553-1593 (latest edition), Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition); Pharmaceutical Dosage Forms: Tablets ) Lieberman, Lachman and Schwartz, editor), latest edition, published by Marcel Dekker, Inc.

Considering the height of PDE4 inhibition degree, the compounds of the present invention can be administered to anyone of or desired require PDE4 inhibition and / or improvement of cognitive (enhancement of cognition). Administration is according to the needs of the patient, for example, oral, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally ), Vaginally, topically, locally, transdermally and by ocular administration.

  Various solid oral drug forms for administration of the compounds of the present invention include solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders. Can be used. The compounds of the present invention may be used alone or in various pharmaceutically acceptable bases, diluents (such as sucrose, mannitol, lactose, starch) and, but not limited to, suspending agents, solubilizing It can be administered with excipients known in the art, including agents, buffers, binders, disintegrants, preservatives, colorants, flavorants, lubricants, and the like. Time-released capsules, tablets, and gels are also advantageous for administering the compounds of the present invention.

  Various liquid oral drug forms, including water-soluble and water-insoluble solutions, emulsions, suspensions, syrups, and elixirs can also be used to administer the compounds of the present invention. Such dosage forms may also be suitable excipients known in the art such as water and preservatives, wetting agents, sweeteners, fragrances as well as emulsifiers and / or suspensions of the compounds of the present invention. Any suitable diluent known in the art can be included. The compounds of the invention can be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

  Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compounds with excipients such as cocoa butter, salicylates, polyethylene glycols. Dosage forms for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms, as well as active ingredients such as bases known in the art.

For topical dosing, the pharmaceutical composition is suitable for dosing to the skin, eyes, ears or nose, cream, ointment, paste, lotion, emulsion, suspension, gel, aqueous solution, paste, It can take the form of powders, sprays, and drops. Topical dosing also includes transdermal dosing via means such as a transdermal patch.

  Aerosol dosage forms suitable for administration by inhalation can also be produced. For example, for the treatment of airway disorders, the compounds according to the invention may be administered by inhalation in powder (eg finely divided) form or by inhalation in the form of an atomized aqueous solution or suspension. The aerosol dosage form can be placed in a pressurized acceptable propellant.

  The compounds may be used alone or as other PDE4 inhibitors, calcium channel blockers, choloinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modifiers, for example. Together with other medications such as substances and other drugs used to treat cognitive and / or psychiatric disorders, such as cholinesterase inhibitors (eg, donepezil, rivastigimine, and glanthanamine) Dosed. In such combinations, the individual active ingredients can be dosed at dosages consistent with or below their normal dosage range.

  The invention further encompasses therapeutic methods involving inhibition of the PDE4 enzyme. That is, the present invention encompasses a method for the selective inhibition of the PDE4 enzyme in an animal, particularly a human being, eg a mammal, such that such inhibition has a therapeutic effect, , Especially to alleviate conditions involving neurological syndromes such as long-term memory loss of memory. Such methods include dosing to an animal in need thereof, particularly a mammal, especially a human, and include an inhibitory amount of the compound, as disclosed herein, alone or as part of a formulation.

The state of memory impairment is manifested by impaired learning ability of new information and / or inability to recall previously learned information. Memory impairment is an early symptom of dementia, as well as age-related cognitive decline , Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob (Creutzfeld- Jakob) may be symptoms associated with diseases such as disease, HIV, cardiovascular disease, and head trauma.

  Dementia is a disease that includes memory loss and additional intelligence impairment that is decoupled from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementia is classified according to their cause, as well as neurodegenerative dementia (eg Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (eg infarct, bleeding, heart disease), vascular and Alzheimer's. Mixed, bacterial meningitis, Creutzfeldt-Jakob disease, multiple sclerosis, traumatic (eg, subdural hematoma or traumatic brain injury), infectious (eg, HIV), genetic (Down syndrome), toxic (eg heavy metals, alcohol, some drugs), metabolic (eg vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (eg depression) And schizophrenia), and hydrocephalus.

The present invention encompasses methods for treating memory loss as distinguished from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline . The present invention includes a method for treating memory impairment resulting from a disease. In other applications, the invention includes methods of treating memory impairment resulting from the use of common anesthetics, chemotherapy, radiation therapy, post-surgical trauma, and therapeutic treatments.

  The compounds are used for the treatment of psychiatric conditions including schizophrenia, bipolar or manic depression, severe depression, and drug addiction and morphine dependence. These compounds enhance wakefulness. PDE4 inhibitors can be used to raise cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to have anti-inflammatory properties. The combination of anti-apoptotic and anti-inflammatory properties makes these compounds useful for stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (amylolaterosclerosis ( ALS)), and multiple systems atrophy (MSA), making it useful for treating neurodegeneration resulting from any disease or injury.

  Thus, according to a preferred embodiment, the present invention relates to acute neurological diseases as well as HIV and cardiovascular diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick disease, Creutzfeld Of patients suffering from memory impairment due to Jacob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiple infarct dementia, and other neurological conditions Including therapeutic methods, administration of an effective amount of the compound according to formula (I) or (I ′) or a pharmaceutically acceptable salt thereof.

  The compounds of the invention can also be used in the treatment of patients suffering from disease states characterized by reduced NMDA function, such as schizophrenia. The compound may also be a psychosis characterized by elevated levels of PDE4, for example, various forms of depression such as manic depression, severe depression, and depression associated with psychiatric and psychiatric disorders. Can be used in the treatment of

  As mentioned above, the compounds of the present invention also exhibit anti-inflammatory activity. Consequently, the compounds of the invention are effective in the treatment of various allergic and inflammatory diseases, particularly in the treatment of disease states characterized by decreased cyclic AMP levels and / or increased phosphodiesterase 4 levels. . Thus, according to a further embodiment of the invention, allergic and inflammatory comprising the administration of an effective amount of a compound according to formula (I) or (I ′) or a pharmaceutically acceptable salt thereof. A method of treating a disease state is provided. Such disease states include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic (esoniophilic ) Granulomas, psoriasis, inflammatory arthritis, rheumatoid arthritis, infectious shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, cystic fiber Disease, arterial restenosis, atherosclerosis, keratosis, rheumatic myelitis, osteoarthritis, pyresis, diabetes, pneumoconiosis, chronic obstructive airway disease, chronic obstructive pulmonary disease, toxic and allergic contact Dermatitis, atopic dermatitis, seborrheic dermatitis, simple lichen, sunburn, pruritus of anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus , Systemic lupus erythematosus, follicular and widespread pus, endogenous and exogenous acne, rosacea acne, Beghet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple Sclerosis, gastrointestinal tract disease, autoimmune disease, and the like.

  PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factors are known to those skilled in the art. Reference is made, for example, to WO 98/58901, JP 11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 and US 5,935,9778. These references also describe test methods for determining PDE4 inhibitory activity and methods for the synthesis of such compounds. The complete disclosure of these documents is included in the references here.

  PDE4 inhibitors are used as antibiotics to prevent or ameliorate osteoporosis, are used to treat cardiovascular disease by isolating cholesterol from atherosclerotic lesions, and are used to treat rheumatoid arthritis (RA). Used for long-term suppression of mesenchymal cell proliferation after transplantation, used to treat urinary obstruction following prostate enlargement, to suppress chemotaxis and to reduce colon cancer cell wetting Used to treat B-cell chronic lymphocytic leukemia (B-CLL), used to suppress uterine contractions, used to attenuate pulmonary vascular ischemia-reperfusion injury (IRI), corneal water Used for corneal hydration, used to suppress IL-2R expression and thereby disrupt nuclear translocation of HIV-1 DNA into memory T cells, used to enhance glucose-induced insulin secretion It is used in the prevention and treatment of colitis, and will be used to inhibit mast cell degranulation.

  The compounds of the present invention may be used alone or as other PDE4 inhibitors, calcium channel blockers, cholinergic agents, adenosine receptor modifiers, amfakines NMDA-R modifiers, mGluR modifiers, and cholinesterase inhibitors, for example. Dosage with other medications such as other medications used to treat cognitive and / or psychiatric disorders, such as donepezil, rivastidimine, and grantanamine. In such combinations, the individual active ingredients can be dosed at dosages consistent with or below their normal dosage range.

  The dosage of the compound of the present invention depends on various factors including the particular syndrome being treated, severity of symptoms, route of administration, frequency of dosing interval, specific compound used, efficacy, toxicity, compound drug Depends on kinetic properties and the presence of harmful side effects.

The compounds of the invention are typically dosed at the usual mammalian dosage levels for PDE4 inhibitors such as the known compounds described above. For example, the compound is a single or multiple dosages, for example 0.01-100 mg / kg / day, preferably 0.1-70mg / kg / day, especially at a dosage level of 0.5-10 mg / kg / day by oral administration Can be dosed. One unit of dosage form contains, for example, 0.1-50 mg of active agent. For intravenous administration, the compound is administered in single or multiple doses, for example at a dosage level of 0.001-50 mg / kg / day, preferably 0.001-10 mg / kg / day, especially 0.01-1 mg / kg / day. Can be dosed. One unit of dosage form contains, for example, 0.1-10 mg of active agent.

In practicing the method of the present invention, it should be understood that references to specific buffers, media, reagents, cells, culture conditions, and the like are not limiting , and those skilled in the art will be able to discuss Oite a particular context (context) but present, recognize as there is benefit or value, Ru is interpreted to include all related materials. For example, it is often possible to replace one buffer system or medium with another and achieve similar, if not identical, results. Those skilled in the art are familiar with such systems and use the methods and procedures disclosed herein to enable such alternatives that are most useful for their purposes without undue experimentation. have.

The present invention, Ru further described by the following real施例but the present invention is not limited thereto. When applying the disclosure of these examples, the embodiments and different embodiments other than the disclosed method according to the invention, it will no doubt suggest themselves should clearly borne in mind to those skilled in the art is there.

In the examples described above and in the examples below, all temperatures are not corrected for degrees Celsius; and unless otherwise indicated, all parts and percentages are by weight.

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

Example 1 (Method A)
1-Cyclopentyloxy-2-methoxy-5-nitrobenzene Under N ₂ protection, 2-methoxy-5-nitrophenol (525 g, 3.104 mol) and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 L) To the suspension was added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100 ° C. for 6 hours. Potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100 ° C. for 4 hours. TLC showed that the reaction had gone completely (9: 1 DCM: MeOH). The reaction mixture was cooled to room temperature and diluted with water (3 L) and ether (3 L). The layers were separated and the aqueous layer was re-extracted with ether (2 L). The combined oil layer was washed with 1N NaOH (2 L), water (2 L), and brine (2 L). The organic layer was dried over sodium sulfate, filtered and further evaporated. The resulting solid was azeotroped with toluene (2 × 300 mL) to give 736.7 g (99.6% yield) of a yellow solid.

The following compounds were prepared in a similar manner as above:
a) 1-cyclopropylmethoxy-2-methoxy-5-nitrobenzene b) 1-cyclopentoxy-2-difluoromethoxy-5-nitrobenzene c) 1-cyclopropylmethoxy-2-difluoromethoxy-5-nitrobenzene

(Method B)
2-Methoxy-5-nitro-1-((3R) -tetrahydrofuryloxy) benzene In anhydrous tetrahydrofuran (40 mL), 2-methoxy-5-nitrophenol (1.69 g, 10 mmol), triphenylphosphine (5.24 g, 20 mmol). ) And 3- (R) -hydroxytetrahydrofuran (1.80 g, 20 mmol) was added dropwise with stirring, diisopropyl azodicarboxylic acid (4.0 mL, 20 mmol), and the mixture was stirred at room temperature for 16 hours. . The mixture was diluted with ether (150 mL), washed with 2N NaOH (3 × 50 mL) and brine (50 mL), and concentrated in vacuo (MgSO ₄ ). The crude residue was purified by flash column chromatography on silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product.

The following compounds were prepared in a similar manner as above:
a) 2-methoxy-5-nitro-1- (3-tetrahydrofuryloxy) benzene b) 2-methoxy-5-nitro-1-((3S) -tetrahydrofuryloxy) benzene c) 2-difluoromethoxy-5 -Nitro-1- (3-tetrahydrofuryloxy) benzene d) 2-difluoromethoxy-5-nitro-1-((3R) -tetrahydrofuryloxy) benzene e) 2-difluoromethoxy-5-nitro-1- ( (3S) -tetrahydrofuryloxy) benzene f) 2-methoxy-5-nitro-1- (3-phenpropyloxy) benzene g) 1- (2-indanyloxy) -4-methoxy-5-nitrobenzene

(Method C)
1- (tert-Butyldimethylsilyl) oxy-2-methoxy-5-nitrobenzene In anhydrous DMF (40 mL), 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol). To the mixture was added tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) with stirring and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexane and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexane and the filtrates were mixed and concentrated in vacuo to give 2.01 g of product as tan solid crystals. ¹ H NMR (CDCl ₃ ) δ 7.89 (dd, 1H, J = 9.0Hz, 2.8Hz), 7.69 (d, 1H, J = 2.8Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

3-Cyclopentyloxy-4-methoxyaniline Under N ₂ protection, a suspension of 10% Pd on activated carbon (25 g) in ethanol (4 L) was added to 1-cyclopentyloxy 2-methoxy-5-nitrobenzene (250 g, 1.054). mol) was added. The reaction mixture was degassed under vacuum for 3 hours. The reaction mixture was stirred vigorously while flowing hydrogen gas over the reaction mixture. After 4 hours, the reaction was completed by TLC (5: 1 hexane: ethyl acetate (EA)). The reaction mixture was filtered through a pad of celite and the celite was washed away with additional ethanol. The solvent was removed in vacuo to give 208.38 g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. ¹ H NMR (CDCl ₃ ) δ 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8,8.4,1H), 4.69 (p, J = 4.4Hz, 1H ), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m, 6H), 1.61-1.55 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy 4-difluoromethoxyaniline b) 3-cyclopropylmethoxy-2-methoxyaniline c) 3-cyclopropylmethoxy-4-difluoromethoxyaniline d) 4-methoxy-3-((3R) -tetrahydro Furyloxy) aniline e) 4-methoxy-3- (tetrahydrofuryloxy) aniline f) 4-methoxy-3-((3S) -tetrahydrofuryloxy) aniline g) 4-difluoromethoxy-3- (3-tetrahydrofuryl) Oxy) aniline h) 4-difluoromethoxy-3-((3R) -tetrahydrofuryloxy) aniline i) 4-difluoromethoxy-3-((3S) -tetrahydrofuryloxy) aniline j) 3- (tert-butyldimethyl) Silyl) oxy-4-methoxyaniline 4-methoxy-3- (3-phen propyloxy) aniline l) 3- (2-indanyloxy) 4-methoxy aniline

3-Cyclopentyl-4-methoxy-N- (3-pyridylmethyl) aniline In a mixture of 3-pyridinecarboxaldehyde (106.55 g, 0.995 mol) in methanol (5 L), 3-cyclopentyloxy-4-methoxyaniline ( 208.38 g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg) were added. The reaction mixture was stirred for 4 hours. The flask was then cooled to 0 ° C. and sodium borohydride (37.64 g, 2.3 mol) was added portionwise over 4 hours. The reaction mixture was allowed to warm to room temperature with stirring for 16 hours. TLC showed the reaction was complete (1: 3 hexane: ethyl acetate). The solvent was evaporated until approximately 0.5 L of slurry remained. The slurry was diluted with water (1 L) and extracted with ethyl acetate (2 × 2 L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate and further concentrated to give 300 g (100% yield) of the desired product as a brown viscous liquid. ¹ H NMR (CDCl ₃ ) δ 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4Hz, 1H), 6.23 (s , 1H), 6.13 (dd, J = 2.6,8.6,1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 (m , 6H), 1. 65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) aniline b) 3-cyclopentyloxy-4-methoxy-N- (4-pyridylmethyl) aniline c) 3-cyclopentyloxy-N- ( 2,6-dichloro-4-pyridylmethyl) -4-methoxyaniline d) 3-cyclopentyloxy-4-methoxy-N- (2-quinolinylmethyl) aniline e) 3-cyclopentyloxy-4-methoxy-N- (3 -Quinolinylmethyl) aniline f) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) aniline g) 3-cyclopentyloxy-4-methoxy-N- (2-pyrazinylmethyl) aniline h) 4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) anily i) 4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) aniline j) 4-methoxy-N- (3-pyridylmethyl) -3-((3S) -tetrahydro Furyloxy) aniline k) 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) aniline l) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) aniline m) 4 -Difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) aniline n) 4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) Aniline o) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) aniline p) 3-tert -Butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) aniline q) 3-cyclopentyloxy-4-methoxy-N- (2-pyridylmethyl) aniline r) 3-cyclopentyloxy-4-methoxy- N- [1- (2-phenethyl)] aniline s) N-benzyl-3-cyclopentyloxy-4-methoxyaniline t) N-[(cyclohex-1-en-1-yl) methyl] -3-cyclopentyloxy -4-methoxyaniline u) 3-cyclopentyloxy-4-methoxy-N- (3,4,5-trimethoxybenzyl) aniline v) N-[(cyclohex-3-en-1-yl) methyl] -3 -Cyclopentyloxy-4-methoxyaniline w) 3-cyclopentyloxy-4-methoxy-N- (2,4,6-trimethyl) Nyl) aniline x) 3-cyclopentyloxy-4-methoxy-N- (2-methylbenzyl) aniline y) 3-cyclopentyloxy-4-methoxy-N- (2-trifluoromethylbenzyl) aniline z) 3-cyclopentyl Oxy-4-methoxy-N-((3,4-methylenedioxy) benzyl) aniline aa) 3-cyclopentyloxy-N- (2-hydroxy-3-methoxylbenzyl) -4-methoxyaniline bb) 3-cyclopentyl Oxy-N- (3-furylmethyl) -4-methoxyaniline cc) 3-cyclopentyloxy-4-methoxy-N- (3-methylbenzyl) aniline dd) 3-cyclopentyloxy-4-methoxy-N- (2 -Methoxybenzyl) aniline ee) 3-cyclopentyloxy-4-meth Cis-N- (3-chlorobenzyl) aniline ff) 3-cyclopentyloxy-4-methoxy-N- (3-methoxybenzyl) aniline gg) 3-cyclopentyloxy-4-methoxy-N- (2-chlorobenzyl) Aniline hh) 3-cyclopentyloxy-4-methoxy-N- (3-methylbenzyl) aniline ii) 4-methoxy-3- (3-phenpropyloxy) -N- (4-pyridylmethyl) aniline jj) N- (2,6-dichloro-4-pyridylmethyl) -3- (2-indanyloxy) -4-methoxyaniline kk) 4-methoxy-3- (3-phenpropyloxy) -N- (2-pyridylmethyl) Aniline ll) N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3- (3-phenpropyloxy) ani Mm) 4-methoxy-3- (3-phenpropyloxy) -N- (3-pyridylmethyl) aniline nn) 3-cyclopentyloxy-4-methoxy-N- (2-thienylmethyl) aniline oo) 3- (2-Indanyloxy) -4-methoxy-N- (3-thienylmethyl) aniline pp) 4-methoxy-3- (3-phenpropyloxy) -N- (3-thienylmethyl) aniline qq) 3- (2-Indanyloxy) -4-methoxy-N- (2-pyridylmethyl) aniline rr) 3- (2-Indanyloxy) -4-methoxy-N- (3-pyridylmethyl) aniline ss) 3- (2-Indanyloxy) -4-methoxy-N- (4-pyridylmethyl) aniline tt) 3-cyclopentyloxy-4-methoxy-N- (3-piperidine Methyl) aniline uu) 3-cyclopentyloxy-4-methoxy-N- (3- (1-tert-butyloxycarbonyl) piperidinemethyl) aniline vv) 3-cyclopentyloxy-4-methoxy-N- (6-methyl- 2-pyridylmethyl) aniline ww) N- (2-chloro-3-pyridylmethyl) 3-cyclopentyloxy-4-methoxyaniline xx) N- (2-chloro-5-pyridylmethyl) 3-cyclopentyloxy-4- Methoxyaniline yy) 3-cyclopentyloxy-4-methoxy-N- (2-thiazolylmethyl) aniline

3-Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine In a 100 mL flask dried in an oven and flushed with argon, 0.59 g (6.10 mmol) NaOtBu, 360 mg Pd ₂ dba ₃ in the following order: 20 mL of toluene, 0.14 mL of P (tBu) ₃ , and 1.3 g (4.36 mmol) of N- (3-pyridylmethyl) -3-cyclopentyloxy-4-methoxyaniline in 20 mL of toluene were added. While stirring, 3.1 g (15 mmol) iodobenzene was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc, washed twice with H ₂ O and extracted with 3 × 15 mL of 3N HCl. The combined acid extract was washed with 15 mL of EtOAc and then carefully neutralized with 6N NaOH to pH 12 or higher. The basic solution was extracted with 2 × 15 mL EtOAc and the combined organic fractions were subsequently washed with 15 mL H ₂ O and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by chromatography through silica gel (Biotage Flash 40M) eluting with 25% EtOAc in hexane. The material was further purified by crystallization from hexane to give 550 mg of a white solid. ¹ H NMR (CDCl ₃ ) δ 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2Hz), 7.67 (d, 1H, 7.9Hz), 7.30-7.10 (m, 3H), 6.90-6.80 ( m, 4H), 6.80-6.60 (m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J = 4.1Hz), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65 -1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-4-methoxy-2'-methyl-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-3'-methyl-N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-4′-methyl-N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4′-ethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine e) 3'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine f) 4'-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine g) 3-Cyclopentyloxy-2 ′, 4-dimethoxy-N- (3-pyridyl Til) diphenylamine h) 3-cyclopentyloxy-3 ′, 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine i) 3-cyclopentyloxy-4 ′, 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine j ) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3'-trifluoromethyldiphenylamine k) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4'-tri Fluoromethyldiphenylamine l) 3-cyclopentyloxy-3′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine m) 3-cyclopentyloxy-4′-fluoro-4-methoxy-N- (3-pyridyl Methyl) diphenylamine n) 3-cyclopentyloxy- -Methoxy-3'-phenyl-N- (3-pyridylmethyl) diphenylamine o) 3-cyclopentyloxy-4-methoxy-4'-phenyl-N- (3-pyridylmethyl) diphenylamine p) 3'-cyano-3 -Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine q) 4'-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine r) ethyl N- (3- Cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid s) ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4 -Aminobenzoic acid t) 3-cyclopentyloxy-4-methoxy-3'-nitro-N- (3-pyri Rumethyl) diphenylamine u) 3-cyclopentyloxy-4-methoxy-4′-nitro-N- (3-pyridylmethyl) diphenylamine v) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) Methyl) -1-naphthylamine w) 3-cyclopentyloxy-2 ′, 3′-dimethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine x) 3-cyclopentyloxy-2 ′, 4′-dimethyl-4 -Methoxy-N- (3-pyridylmethyl) diphenylamine y) 3-cyclopentyloxy-2 ', 5'-dimethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine z) 3-cyclopentyloxy-3', 4′-dimethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine aa) 3 Cyclopentyloxy-2 ′, 3′-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine bb) 3-cyclopentyloxy-3 ′, 4′-dichloro-4-methoxy-N- (3-pyridylmethyl) ) Diphenylamine cc) 3-cyclopentyloxy-3 ′, 5′-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine dd) 3′-chloro-3-cyclopentyloxy-4′-fluoro-4-methoxy -N- (3-pyridylmethyl) diphenylamine ee) 4'-chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine ff) 4'-chloro-3-cyclopentyl Oxy-4-methoxy-N- (3-pyridylmethyl) -3'-trifluoromethyldiphenyl Amine gg) 3-cyclopentyloxy-4-methoxy-N- (3-thienylmethyl) diphenylamine hh) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-thienylmethyl) -1-naphthylamine ii ) 3-cyclopentyloxy-2 ′, 3′-dichloro-4-methoxy-N- (3-thienylmethyl) diphenylamine jj) 3-cyclopentyloxy-4-methoxy-4′-methyl-N- (4-pyridylmethyl) ) Diphenylamine kk) 3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxy-3'-methyldiphenylamine ll) 2'-chloro-3-cyclopentyloxy-N- (2, 6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine mm) 3-cycl Pentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine nn) 3-cyclopentyloxy-4-methoxy-N- (6-methyl-2-pyridylmethyl) diphenylamine oo) 3- Cyclopentyloxy-4-methoxy-N- (3-quinolinylmethyl) diphenylamine pp) 3-cyclopentyloxy-4-methoxy-N- (4-quinolinylmethyl) diphenylamine qq) 3-cyclopentyloxy-4-methoxy-N- (2- Pyrazinylmethyl) diphenylamine rr) 4-methoxy-3'-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine ss) 4-methoxy-4'-methyl-N- (3-pyridyl) Methyl) -3- (3-tetrahydrofuryl) Oxy) diphenylamine tt) 4,4′-dimethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine uu) 3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine vv) 4-methoxy-4 '-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) Diphenylamine ww) 3'-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine xx) 3'-cyano-4-methoxy-N- (3-pyridyl Methyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine yy) 3-cyclopropylmethoxy -4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine zz) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine aaa) 4-difluoromethoxy-N- (3-pyridylmethyl ) -3- (3-tetrahydrofuryloxy) diphenylamine bbb) 3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine ccc) 4-difluoromethoxy-N- (3-pyridylmethyl) -3 -((3R) -tetrahydrofuryloxy) diphenylamine ddd) 3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine ee) 3'-chloro -4-difluoromethoxy-N- 3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine fff) ethyl N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid Acid ggg) 3-cyclopentyloxy-4-methoxy-3 '-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine hh) 3-cyclopentyloxy-4-methoxy-4'- (4-Methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine iii) 3'-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) Diphenylamine jjj) 4'-tert-butyldimethylsilyloxy-3 Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine kkk) tert-butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid ) Ethyl N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid mmm) Ethyl N- (4-difluoromethoxy-3- (3-tetrahydrofuryloxy) ) Phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid nnn) ethyl N- (3,4-bis (difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid oo) ethyl N- (4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl)- -(3-pyridylmethyl) -3-aminobenzoic acid ppp) ethyl N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid qqq) 3-cyclopentyl Oxy-4-methoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine rrr) 3-cyclopentyloxy-4-methoxy- 3 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine sss) 4-methoxy-4 ′-(2- (tetrahydropyran-2 -Yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy Diphenylamine ttt) 3-cyclopropylmethoxy-4-methoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine uuu) 4- Difluoromethoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine vvv) 3-cyclopropylmethoxy-4-difluoromethoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine www) 3-cyclopentyloxy -4-difluoromethoxy-4 '-(2- (tetrahydropyran-2-yl) -2 H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine xxx) 3-cyclopropylmethoxy-4-difluoromethoxy-3 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazole- 5-yl) -N- (3-pyridylmethyl) diphenylamine yyy) bis- (3,4-difluoromethoxy) -3 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine zzz) 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine aaa) 3-tert-butyldimethylsilyloxy-3'-chloro- 4-methoxy-N- (3-pyridylmethyl) diphenylamine bbbb) ethyl N- (3-tert- Tildimethylsilyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid cccc) 3-cyclopentyloxy-2′-chloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine dddd) 3- (2-indanyloxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 2
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid
A solution of 6.5 g ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid in 50 mL EtOH was treated with 10 mL 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated and diluted with 50 mL H ₂ O. The aqueous mixture was extracted with 2 × 50 mL of ether, acidified with AcOH until pH 3 and extracted with 2 × 50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL H ₂ O and 25 mL brine, dried (MgSO ₄ ) and concentrated. The residue was chromatographed through SiO ₂ (35 g RediSep® column) with a linear gradient of EtOAc and hexane (50% EtOAc to 70% EtOAc over 20 min) as eluent. And purified to obtain 4.8 g of a yellow solid product after drying in vacuo at 60 ° C. for 12 hours. ¹ H NMR (CDCl ₃ ) δ 11.15 (bs, 1H), 8.70-8.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8Hz, 1H ), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid b) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- ( 3-pyridylmethyl) -3-aminobenzoic acid c) N- [4-difluoromethoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid d) N -3,4-bis ((difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid e) N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid f) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl 4-aminobenzoic acid g) N-(3- cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N-(3- pyridylmethyl) -3-aminobenzoic acid
h ) N- [3- (4-Chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid
i ) N- (3-Cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid
j ) N- [3- (2-Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid
k ) N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid
l ) N- [4-Methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid
m ) N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid
n ) N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid

Example 3
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoic acid
tert-Butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -2-aminobenzoic acid (60 mg, 0.13 mmol) was placed in 2 mL 98% formic acid at 40 ° C. Heated for 4 hours. Formic acid was removed in vacuo and the residue was placed in a column of silica gel (Readycept, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 minutes to give 16 mg of a brown solid product. ¹ H NMR (CDCl ₃ ) δ 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H) , 4.54 (p, 1H, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid b) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3 -Pyridylmethyl) -6-aminonicotinic acid

Example 4
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3- Pyridylmethyl) -4 ′-[2- (2-tetrahydropyranyl) -2H-tetrazol-5-yl] diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF (5 mL) and 3 mL of 1N HCl was added. It was. After 6 hours at room temperature, the mixture was neutralized with saturated aqueous sodium bicarbonate until pH = 5 and extracted with EtOAc (3 × 50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was placed in a readycept column (10 g, silica gel) and the product was 0.96 g product as a white powder with a linear gradient over 20 minutes from 0% MeOH in EtOAc to 50% MeOH in EtOAc. Was eluted to obtain ¹ H NMR (CD ₃ OD) δ 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H, 8.0 Hz), 7.21 (dd, 1H, J = 4.9 HZ, 8.0 Hz), 7.18 (d, 1H, J = 8.9 HZ), 7.10-6.90 (m, 3H), 6.87 (dd, 1H, J = 8.6 Hz, 2.5 HZ), 6.75 (t, 1H, J = 75.5 Hz) , 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-N- (3-pyridyl) Methyl) -3 '-(2H-tetrazol-5-yl) diphenylamine c) 4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4'-(2H-tetrazole -5-yl) diphenylamine d) 3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine e) 4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(2H-tetrazol-5-yl) diph Enylamine f) 3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine g) 3-cyclopropylmethyloxy-4-difluoromethoxy-N -(3-pyridylmethyl) -3 '-(2H-tetrazol-5-yl) diphenylamine h) bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4'-(2H-tetrazole-5 -Yl) diphenylamine

Example 5 (Method A)
3-Cyclopentyloxy-4-methoxydiphenylamine Method A (reference, Chan, DMT; Monaco, KL; Wang, W., Wang, RP); Winters, MP (Winters, MP), Tetrahedron Lett., 1998, 39, 2933-2936.). 207mg of 4-methoxy-3-cyclopentyloxy-aniline, phenyl boronic acid of 280 mg, 182 mg of _{Cu (OAc) 2, Et 3} N and 4.0 mL of of _CH 2 Cl ₂ slurry 280μL was stirred at room temperature for 20 hours. The black mixture is filtered through silica, eluting with CH ₂ Cl ₂ , concentrated, and further chromatographed through SiO ₂ using EtOAc / hexane (15/85) as eluent to give 75 mg of desired product. Was purified to obtain ¹ H NMR (CDCl ₃ ) δ 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-3 ′, 4-dimethoxydiphenylamine b) 3′-chloro-3-cyclopentyloxy-4-methoxydiphenylamine c) 3-cyclopentyloxy-4-methoxy-3′methyldiphenylamine d) 3-cyclopentyl Oxy-4′-fluoro-4-methoxydiphenylamine e) 3-cyclopentyloxy-4-methoxy-4′-vinyldiphenylamine f) 3′-cyano-3-cyclopentyloxy-4-methoxydiphenylamine g) 4′-chloro- 3-cyclopentyloxy-4-methoxydiphenylamine h) 3-cyclopentyloxy-4,4′-dimethoxydiphenylamine i) 3-cyclopentyloxy-4-methoxy-2′-methyldiphenylamine j) 3-cyclopentyloxy-4-me Toxi-4′-methyldiphenylamine k) 2′-chloro-3-cyclopentyloxy-4-methoxydiphenylamine l) 3-cyclopentyloxy-2 ′, 4-dimethoxydiphenylamine m) 3-cyclopentyloxy-4-methoxy-3 ′ -Trifluoromethyldiphenylamine n) 3-cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine o) 3-cyclopentyloxy-2 ', 5'-dimethyl-4-methoxydiphenylamine

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

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-4-methoxy-2 ′, 4′-dimethyldiphenylamine b) 3-cyclopentyloxy-2 ′, 5′-dimethyl-4-methoxydiphenylamine c) 3-cyclopentyloxy-2 ′, 3 ′ -Dimethyl-4-methoxydiphenylamine d) 3-cyclopentyloxy-3 ', 4'-dimethyl-4-methoxydiphenylamine e) 3-cyclopentyloxy-3', 4'-methylenedioxydiphenylamine f) 4'-tert- Butyl-3-cyclopentyloxy-4-methoxydiphenylamine g) 3-cyclopentyloxy-3 ′, 4′-dichloro-4-methoxydiphenylamine h) 3-cyclopentyloxy-2 ′, 3′-dichloro-4-methoxydiphenylamine

( Method C)
3-Cyclopentyloxy-2 ′, 4,5′-trimethoxydiphenylamine Method C. To a mixture of Pd (dppf) Cl ₂ (0.025 mmol, 5 mol%), dppf (0.075 mmol, 3dppf / Pd) and NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 mL THF was added 1-bromo-2,5-dimethoxy. Benzene (0.55 mmol, 1.1 eq) was added followed by 1.0 mL of a 0.5 M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated to 60 ° C. for 3 hours, diluted with ether, further washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by chromatography through silica gel (Biotage Flash 12) eluting with 15% EtOAc in hexane.

The following compounds were prepared in a similar manner as above:
a) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-pyridylamine b) 3-cyclopentyloxy-2 ', 4', 4-trimethoxydiphenylamine c) N- (3-cyclopentyloxy-4- Methoxyphenyl) -2-pyridylamine d) N- (3-cyclopentyloxy-4-methoxyphenyl) -8-quinolinylamine e) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-naphthylamine f) N- (3-cyclopentyloxy-4-methoxyphenyl) -1-naphthylamine g) 3-cyclopentyloxy-4′-ethyl-4-methoxydiphenylamine h) 3-cyclopentyloxy-2′-fluoro-4-methoxy-5′- Methyldiphenylamine i) 3-cyclopentyloxy-3′-fluor -4-methoxy-4'-methyldiphenylamine j) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrimidinylamine k) 3-cyclopentyloxy-3 ', 5'-dichloro-4-methoxydiphenylamine ) 3-cyclopentyloxy-2′-ethyl-4-methoxydiphenylamine m) 4′-chloro-3-cyclopentyloxy-3′-fluoro-4-methoxydiphenylamine n) N- (3-cyclopentyloxy-4-methoxyphenyl) ) -4-isoquinolinylamine o) N- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrazinylamine p) N- (3-cyclopentyloxy-4-methoxyphenyl) -5-pyrimidinylamine q) N -(3-cyclopentyloxy-4-methoxyphenyl ) -1-Isoquinolinylamine r) N- (3-cyclopentyloxy-4-methoxyphenyl) -3-quinolinylamine s) N- (3-cyclopentyloxy-4-methoxyphenyl) -4-pyridylamine t) N -(3-Cyclopentyloxy-4-difluoromethoxyphenyl) -3-pyridylamine u) N- (3-cyclopropylmethyloxy-4-methoxyphenyl) -3-pyridylamine v) N- (3-cyclopropylmethyl Oxy-4-difluoromethoxyphenyl) -3-pyridylamine w) N- (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -3-pyridylamine x) N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -3-pyridylamine y) ethyl N- 3-cyclopentyloxy-4-methoxyphenyl) -3-aminobenzoic acid z) 3-cyclopentyloxy-4 ′-(N, N-dimethylamino) -4-methoxydiphenylamine aa) N- (3-cyclopentyloxy-4 -Methoxyphenyl) -3- (6-methoxypyridyl) amine bb) methyl N- (3-cyclopentyloxy-4-methoxyphenyl) -2-aminonicotinic acid cc) tert-butyl N- (3-cyclopentyloxy-4 -Methoxyphenyl) -6-aminonicotinic acid dd) 2'-amino-3-cyclopentyloxy-4-methoxydiphenylamine ee) 3-cyclopentyloxy-4-methoxy-3 '-(1-phthalimido) diphenylamine ff) 3- Cyclopentyloxy-4-methoxy-3 '-[2- (2-teto Hidoropiraniru) -2H- tetrazol-5-yl] diphenylamine

( Method D )
3-cyclopentyloxy-4-methoxy-N-methyldiphenylamine To a solution of 0.5M KN (TMS) _{2 in} toluene in a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 mL of THF at 0 ° C. 0.55 mL was added. The solution was stirred for 0.5 h at 0 ° C., 2.0 equivalents of iodomethane were added, and the reaction mixture was allowed to warm to room temperature. Completion of the reaction was indicated by TLC, 10 mL EtOAc was added and the mixture was washed with 3 mL H ₂ O, 3 mL brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by column chromatography (Biotage Flash 12) using 5% EtOAc in hexane as the eluent.

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-N-ethyl-4-methoxydiphenylamine b) 3-cyclopentyloxy-4-methoxy-N- (1-propyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-N- [1 -(3-phenpropyl)] diphenylamine d) N-benzyl-3-cyclopentyloxy-4-methoxydiphenylamine e) 3-cyclopentyloxy-4-methoxy-N- (4-pyridylmethyl) diphenylamine f) 3-cyclopentyloxy -4-methoxy-N- (2-pyridylmethyl) diphenylamine g) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine h) 3-cyclopentyloxy-4-methoxy-N- [3- (3-pyridyl) -1-propyl Diphenylamine i) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-ethyl-4-isoquinolinylamine j) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-benzyl-4-iso Quinolinylamine k) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-methyl-4-isoquinolinylamine l) N- (3-cyclopentyloxy-4-methoxyphenyl) -N-propyl-4 -Isoquinolinylamine m) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N- (4-pyridylmethyl) amine n) N- (3-cyclopentyloxy-4- Methoxyphenyl) -N- (4-isoquinolinyl) -N- (3-pyridylmethyl) amine o) N- (3- Lopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -N- (5-pyrimidinyl) amine p) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyrazinyl) -N- (3-pyridylmethyl) amine q) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine r) N- (3- Cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine s) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-pyridyl)- N- (3-pyridylmethyl) amine t) tert-butyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-a Nonicotinic acid u) N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine v) N- (4-methoxy-3- (3R) -Tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine w) N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N -(3-pyridylmethyl) amine x) N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine y) N- (4- Difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine z) N- (4-chloro (Ro-3-pyridylmethyl) -N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) amine aa) N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4 -Methyl-3-pyridylmethyl) -N- (2-pyridyl) amine bb) 3-cyclopentyloxy-4-methoxy-N- (2-thiazolylmethyl) diphenylamine cc) N- (2-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxydiphenylamine dd) N- (6-chloro-3-pyridylmethyl) -3-cyclopentyloxy-4-methoxydiphenylamine

( Method E )
N-4-chloro-3-pyridylmethyl) -N- (3-cyclopentyl-4-methoxyphenyl) -N- (2-pyridyl) amine (3-cyclopentyloxy-4-methoxyphenyl) -2-pyridylamine ( 30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol) are dissolved in DMF (1 mL) and 50 mg of sodium hydride (60% mineral oil dispersion), 1.3 mmol) was added in small portions. After stirring for 1 hour at room temperature, the mixture was poured into 25 mL of ice water. The mixture was extracted with EtOAc (2 × 15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was applied to a readycept column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of a yellow crystalline solid. ¹ H NMR (CDCl ₃ ) δ8.61 (d, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33 (m, 1H), 7.25 (m, 1H ), 6.83 (d, 1H, J = 8.5), 6.75 (d, 1H, J = 8.5), 6.71 (s, 1H), 6.62 (m, 1H), 6.42 (d, 1H, J = 8.6), 5.31 (s, 2H), 4.63 (P, 1H, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3,4-bis (difluoromethoxy) -N- (4-chloro-3-pyridylmethyl) -3 '-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) diphenylamine b ) 3,4-Bis (difluoromethoxy) -N- (4-methyl-3-pyridylmethyl) -3 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) diphenylamine

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

The following compounds were prepared in a similar manner as above:
a) 3- (3-Cyclopentyloxy-4-methoxyanilino) -N- (3-pyridylmethyl) -N-3- [3- (N, N-dimethylamino) prop-1-yl] benzamide b) 3-cyclopentyloxy-4-methoxy-3 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-difluoromethoxy-4 ′-(4 -Methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4 '-(4-methylpiperazin-1-ylcarbonyl) -N- (3- Pyridylmethyl) -3- (3-tetrahydrofuranyloxy) -diphenylamine

Example 7
The following compounds were prepared in a manner similar to the method for preparing 3-cyclopentyloxy-4-methoxyaniline described in Example 1 :
a) 4'-amino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3'-amino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine c) 3'-amino-3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine d) 3'-amino-4-methoxy-N- (3-pyridylmethyl) -3-[( 3R) -Tetrahydrofuryloxy] diphenylamine

Example 8
3-cyclopentyloxy-4′-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) -diphenylamine 4′-amino-3-cyclopentyloxy-4-in CH ₂ Cl ₂ (2 mL) at room temperature To a solution of methoxy-N- (3-pyridylmethyl) diphenylamine (47 mg, 0.12 mmol) is added pyridine (20 μL, 0.24 mmol), followed by methanesulfonyl chloride (15 μL, 0.18 mmol), and the mixture Was allowed to stand at room temperature for 16 hours. The mixture was diluted with ether (50 mL), washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated. The crude residue was eluted by flash column chromatography (4.2 g readycept column, silica gel) with a linear gradient from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 minutes to give 41 mg of product, Purified. ¹ H NMR (CDCl ₃ ) δ 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 HZ), 6.80-6.60 (m, 6H), 4.82 (s, 2H), 4.56 (p, 1H, J = 4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86- 1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-Cyclopentyloxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-3 ′-(1-propanesulfonylamino) -N -(3-pyridylmethyl) diphenylamine c) 3 '-(1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine d) 3'-benzylsulfonylamino-3- Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine e) 3'-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine f) 3-cyclopentyloxy-4 ' -Ethanesulfonylamino-4-methoxy-N- ( -Pyridylmethyl) diphenylamine g) 3-cyclopentyloxy-4-methoxy-4 '-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine h) 3-cyclopropylmethoxy-3'-ethanesulfonylamino -4-methoxy-N- (3-pyridylmethyl) diphenylamine i) 4-difluoromethoxy-3'-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine

Example 9
3-Cyclopentyloxy-4-methoxy-3′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine Ethyl N- (3-cyclopentyloxy-4-methoxyphenyl) -N—in THF (5 mL) at 0 ° C. (3-pyridylmethyl) -3-aminobenzoic acid (50 mg, 0.11 mmol) to a solution of dropwise with stirring, diisobutylaluminum hydride (0.4 mL, 1.00 mmol) in toluene 2.5M was while handling. The mixture was stirred for 1 hour at 0 ° C., by adding EtOAc5 drops to the mixture to inactivate the diisobutylaluminum hydride over over -. The mixture was concentrated and partitioned between a residue CH ₂ C l ₂ (50mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgSO ₄ ) and concentrated. The crude residue by flash column chromatography (4.2 g ready sepsis column, silica gel), 300mL50% in hexanes EtOAc, and then, extracted with 100% EtOAc, to give the product 15 mg. ¹ H NMR (CDCl ₃ ) δ 8.51 (s, 1H), 8.40 (br, 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6. 60 (m, 5H ), 4.85 (s, 2H), 4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine

Example 10
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-(2H-tetrazol-5-yl) diphenylamine N- (3-cyclopentyloxy-4-methoxyphenyl) in DMF (3 mL) -N-(3- pyridylmethyl) -3-aminobenzonitrile (100 mg, 0.25 mmol) in a solution _{of, NaN 3 (163 mg, 2.5} mmol) and _{NH 4 C1 (135 mg, 2.5} mmol) was added, The mixture was stirred at 120 ° C. for 6 hours. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 × 25 mL). The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was placed on a readycept column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes to give 12 mg of product. ¹ H NMR (CDCl ₃ ) δ 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz) , 7.36 (m, 1H), 6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H ), 1.65-1.45 (m, 2H).

Example 11
3-cyclopentyloxy-4-methoxy-4 '-(4-methyl-1-piperazinylmethyl) -N- (3-pyridylmethyl) diphenylamine 3-cyclopentyloxy-4-methoxy-4 in THF (5 mL) '- (4-methylpiperazin-1-ylcarbonyl) diphenylamine (100 mg, 0.20 mmol) to a solution of stirring lithium aluminum hydride (50 mg, 1.3 mmol) was carefully pressure to give a. The mixture was stirred for 15 minutes, to inactivate the excess hydride was e carefully pressing a few drops EtOAc. Water (50 mL) and CH ₂ Cl ₂ (50 mL) were added and the mixture was filtered through celite. Separating CH ₂ C l ₂ layer, brine (25 mL) at washing, dried (MgSO _4), and a vacuum (in vacuo) and concentrated. Give a crude residue ISCO ready sepsis column (4.2 g, silica) on at, by linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc, eluted as a pale yellow oil, the product purified by 60mg It was. ¹ H NMR (CDCl ₃ ) δ 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz ), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 HZ) , 3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-Cyclopentyloxy-4-methoxy-3 ′-(4-methyl-1-piperazinylmethyl) N- (3-pyridylmethyl) diphenylamine

Example 12
3′-Aminomethyl-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) in THF (5 mL) methyl) -3-aminobenzonitrile (50 mg, to a solution of 0.12 mmol), with stirring lithium aluminum hydride (20 mg, was carefully pressurized to give a 0.52 mmol). The mixture was stirred for 4 hours, to deactivate the excess hydride was carefully pressurized to give a few drops of water. Water (50 mL) and CH ₂ Cl ₂ (50 mL) were added and the mixture was filtered through celite. Separating CH ₂ C l ₂ layer, brine (25 mL) at washing, dried (MgSO _4), and a vacuum (in vacuo) and concentrated. The crude residue ISCO ready sepsis column (4.2 g, silica) on at elution Ri by the 10% MeOH in EtOAc, and give the product of 20mg was purified. ¹ H NMR (CDCl ₃ ) δ 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, 1H, J =, 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).

Example 13
3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine 3- (tert-butyldimethylsiloxy) -N- (3-pyridylmethyl) -4-methoxydiphenylamine in THF (40 mL) at 0 ° C To a solution of (1.20 g, 2.85 mmol) was added 1.0 M tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred at 0 ° C. for 30 minutes. Water (50 mL) was added and the mixture was extracted with ether (3 × 25 mL). The ether extracts were combined, washed with water (3 × 25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with hexane and collected by vacuum filtration to obtain 0.85 g of product. ¹ H NMR (CDCl ₃ ) δ 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-6.65 (m, 5H), 6.64 (dd, 1H, J = 8.6 HZ, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s, 3H).

The following compounds were prepared in a similar manner as above:
a) 3'-chloro-3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) ethyl N- (3-hydroxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3 -Aminobenzoic acid

Example 14 (Method B)
The following compounds were prepared in a manner similar to that described in Example 1 (Method B) :
a) 3- [3- (4-Chlorophenyl) prop-1-yloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3- [2- (4-chlorophenyl) ethoxy] -4-methoxy -N- (3-pyridylmethyl) diphenylamine c) 4-methoxy-3- (4-phenoxybut-1-yl) oxy-N- (3-pyridylmethyl) diphenylamine d) 4-methoxy-N- (3- Pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine e) 4-methoxy-3- [3- (4-methoxyphenyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine f) 4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine g) 4 -Methoxy-3- [2- (4-methoxyphenyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine h) 4-methoxy-3- (4-phenylbut-1-yl) oxy-N- (3 -Pyridylmethyl) diphenylamine i) 4-methoxy-3- [4- (4-methoxyphenyl) but-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine j) 4-methoxy-3- [4- (4-Nitrophenyl) but-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine k) 4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) Diphenylamine l) 4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine m) 4-methoxy-3- [3- ( -Pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine n) 4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine o) 3-cyclopropyl Methoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine p) 4-methoxy-3- (1-methylpyrrolidin-3-yl) oxy-N- (3-pyridylmethyl) diphenylamine q) 4-methoxy- 3- (1-methylpiperidin-4-yl) oxy-N- (3-pyridylmethyl) diphenylamine r) 4-methoxy-N- (3-pyridylmethyl) -3-[(3S) -tetrahydrofuryloxy] diphenylamine s) 4-Methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy Diphenylamine t) 3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine u) 3'-chloro-4-methoxy-3- [2- (4-Pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine v) 3′-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine w) 3 ′ -Chloro-4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine x) 3-cyclohexyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine y) 3-cycloheptyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine z) 3- (2-cyclopropyleth C) -4-methoxy-N- (3-pyridylmethyl) diphenylamine aa) 3-cyclopentylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine bb) ethyl N- [3- (4-chlorophenyl) propa -1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid cc) ethyl N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) ) -3-Aminobenzoic acid dd) Ethyl N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid ee) Ethyl N- [3- (2 -Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid ff) Eth N- [4-Methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid gg) Ethyl N- [4-methoxy-3-((3R)- Tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid hh) ethyl N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-Aminobenzoic acid ii) Ethyl N- [4-methoxy- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid

Example 14 (Method C)
The following compounds were prepared in a manner similar to that described in Example 5 (Method A) by coupling phenol with boronic acid instead of coupling aniline with boronic acid:
a) 4-methoxy-3- (4-methoxyphenoxy) -N- (3-pyridylmethyl) diphenylamine b) 4-methoxy-3-phenoxy-N- (3-pyridylmethyl) diphenylamine c) 4-methoxy-3 -(4-methylphenoxy) -N- (3-pyridylmethyl) diphenylamine d) 3- (4-chlorophenoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine e) 3- [2- (4 -Chlorophenyl) ethenyloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 15
The following compounds were prepared in a similar manner as described in Example 13 :
a) 3-cyclopentyloxy-3′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine c) 3-Cyclopropylmethoxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 16 (Method A)
The following compounds were prepared in a manner similar to that described in Example 1 (Method A) :
a) 3 '-(2-Bromoethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine

Example 16 (Method B)
The following compounds were prepared in a manner similar to that described in Example 1 (Method B) :
a) 3-cyclopentyloxy-4 ′-(2-methoxyethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4 ′-(3-methyl-1-butoxy)- 4-methoxy-N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-[(3S) -tetrahydrofuranyloxy] -diphenylamine d) 3 -Cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 '-[(3R) -tetrahydrofuranyloxy] -diphenylamine e) 3-cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-N -(3-pyridylmethyl) diphenylamine f) 4'-cyclohexylethoxy-3-cycl Pentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine g) 4'-cyclopentylethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine h) 3-cyclopentyloxy-4 -Methoxy-4 '-(1-methylpiperidin-4-yloxy) -N- (3-pyridylmethyl) diphenylamine i) 3-cyclopentyloxy-4-methoxy-4'-(1-methylpyrrolidin-3-yloxy) -N- (3-pyridylmethyl) diphenylamine j) 3-cyclopentyloxy-4-methoxy-4 '-[2- (1-methylpyrrolidin-2-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine k ) 3-Cyclopentyloxy-4-methoxy-4 '-[2- (1-pyrrole) Nylethoxy) -N- (3-pyridylmethyl) diphenylamine l) 3-cyclopentyloxy-4-methoxy-4 ′-[2- (6-methylpyridyl) methoxy] -N- (3-pyridylmethyl) diphenylamine m) 3 -Cyclopentyloxy-4-methoxy-4 '-[3- (1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine n) 3-cyclopentyloxy-4-methoxy-4'-[2 -(1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine o) 3-cyclopentyloxy-4-methoxy-4 '-[2- (5-oxopyrrolidinyl) methoxy] -N -(3-pyridylmethyl) diphenylamine p) 4 '-[1- (3-bromopropyl) oxy] -3-cyclopentyloxy -4-methoxy-N-(3- pyridylmethyl) diphenylamine q) 3- cyclopentyloxy-4-methoxy -4 '- [2- (N- phthalimido) ethoxy]-N-(3- pyridylmethyl) diphenylamine

Example 17
3-cyclopentyloxy-4-methoxy-3 ′-[2- (1-piperidinyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine in acetonitrile (1 mL) 3 ′-(2-bromoethoxy) -3- To a solution of cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine (17 mg, 0.03 mmol) was added potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 μL, 0.05 mmol) and the mixture Was stirred at 60 ° C. for 4 hours. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was loaded onto an ISCO readycept column (4.2 g, silica) and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg of product. ¹ H NMR (CDCl ₃ ) δ 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7.20 (m, 1H), 7.06 (t, 1H , J = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.75-6.68 (m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70 (m, 6H), 1.86-1.70 (m, 6H), 1.65- 1.45 (m, 2H).

The following compounds were prepared in a similar manner as above:
a) 3-cyclopentyloxy-3 ′-[2- (1-imidazolyl) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4-methoxy-3 ′-[2 -(1-methylpiperazin-4-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-4 '-[3- (2-methylpiperazin-4-yl) Propoxy] -N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4 '-[3- (1-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) Diphenylamine e) 3-cyclopentyloxy-4-methoxy-4 '-[3- (2-morpholin-4-ylethylamino) propoxy C] -N- (3-pyridylmethyl) diphenylamine f) 4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine g) 3- [2- (4-chlorophenoxy) ethoxy ] -4-methoxy-N- (3-pyridylmethyl) diphenylamine h) 4-methoxy-3- (2-pyrrolidin-1-yl) ethoxy) -N- (3-pyridylmethyl) diphenylamine i) 4-methoxy- 3- (2- (4-Methylpiperazin-1-yl) ethoxy) -N- (3-pyridylmethyl) diphenylamine j) 3- [2- (4-Chlorophenylamino) ethoxy] -4-methoxy-N- ( 3-pyridylmethyl) diphenylamine

Example 18
4'-aminoethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine in MeOH (5 mL) N- (3-pyridylmethyl) -3 '-[2- (2-phthalimide) Hydrazine hydrate (1.0 mL, 20 mmol) was added to a solution of ethoxy] -3-cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol). After 6 hours at room temperature, EtOAc (50 mL) was added and the precipitate was filtered off. The filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was placed in an ISCO ready sep column (10 g, silica). The column was washed with 10% MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH in EtOAc to give 0.21 g. ¹ H NMR (CDCl ₃ ) δ 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10 (m, 1H), 6.91 (d, 2H, J = 9.0 HZ), 6.78 (d, 2H, J = 9.0 HZ), 6.70 (d, 1H, J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 ( p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m , 2H).

Example 19
The following compounds were prepared in a similar manner as described in Example 8 :
a) 3-cyclopentyloxy-4 ′-(2-methanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine b) 3-cyclopentyloxy-4 ′-(2-ethanesulfonylamino) ethoxy -4-methoxy-N- (3-pyridylmethyl) diphenylamine c) 3-cyclopentyloxy-4-methoxy-4 '-[2- (2-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine d) 3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine e) 4 ′-[2- (1-butanesulfonylamino) ) Ethoxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) ) Diphenylamine

Example 20
In vitro measurement of type 4 phosphodiesterase inhibitory activity Human PDE4 was obtained from Sf9 cells infected with baculovirus and expressing recombinant enzyme. cDNA encoding hPDE-4D6 was subcloned into baculovirus. Insect cells (Sf9) were infected with baculovirus and the cells were cultured until protein was expressed. Cells infected with baculovirus were lysed and lysate was used as the source of hPDE-4D6 enzyme. The enzyme was partially purified using DEAE ion exchange chromatography. This procedure can be repeated with cDNA encoding other PDE-4 enzymes.

Test method:
Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. Thus, the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. With the neutral alumina column, adenosine is easily separated from cAMP. Phosphodiesterase inhibition blocks the conversion of cAMP to adenosine in this assay; as a result, PDE4 inhibitors cause adenosine reduction.

Cell lysates (40 μl) expressing hPDE-4D6 were mixed with 50 μl assay mix and 10 μl inhibitor and incubated for 12 minutes at room temperature. The final concentration of assay components is: 0.4 μg enzyme, 10 mM tris-HCl (pH 7.5), 10 mM MgCl ₂ , 3 μM cAMP, 0.002 U5′-nucleotidase, and 3 × 10 ⁴ counts per minute (cpm ) [3H] cAMP. The reaction was stopped by adding 100 μl of boiling 5 mN HCl. 75 μl aliquots of the reaction mixture were transferred from individual wells to an alumina column (Multiplate; Millipore). Labeled adenosine was eluted into the OptiPlate by spinning at 2000 rpm for 2 minutes; 150 μl per well of scintillation fluid was added to the Optiplate. Plates were sealed, shaken for 30 minutes, and [ ³ H] adenosine counts per minute were determined using Wallac Triflux®.

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

A decrease in adenosine concentration indicates inhibition of PDE activity. pIC ₅₀ values are determined by screening 6 to 12 concentrations of compounds ranging from 0.1 nM to 10,000 nM and then plotting the drug concentration against ³ H adenosine concentration. It was. Nonlinear regression software (Assay Explorer®) was used to assess pIC ₅₀ values.

Example 21 (Method A)
In vivo tests on passive avoidance, learning and memory in rats The tests were performed as previously described (Zhang, H.-T., Chrisman, AM) (Crissman, AM), Dryraja, Dorairaj, NR, Chandler, LJ and O'Donnell, JM, Neuropsychopharmacolo (Neuropsychopharmacology), 2000, 23, 198-204.). The instrument (E10-16SC, Coulbourn Instruments, Allentown, PA) has two separate rooms with one illuminated room connected to one dark room by a guillotine door Consisted of. Floor darkroom consists rods stainless steel, Ru can flow shock to electric foot through rods of stainless steel from the constant current source. All experimental groups were first accustomed to the equipment one day before the start of the experiment. During training, for 1 minute before the door is raised, the rat (Spraque-Dawley (Harlan) 250-350 g weight) faces the opposite side of the guillotine door and enters the illuminated room. Was placed. The waiting time for entering the darkroom was recorded. When the rat entered the dark room, the door was closed and a 0.5 mA electric shock was applied for 3 seconds. After 24 h, (2.5 mg / kg 0.1, dosage of ip) injections memory power test 30 minutes before the beginning saline or test compound 30 minutes before prior to, rats 0.1 mg / kg MK-801 or Saline was administered. Rats again, with the guillotine door opened, placed in the illuminated chamber. The waiting time to enter the dark room was recorded up to 180 seconds when the test was completed.
All data were analyzed by analysis of variance (ANOVA); individual comparisons were made using the Kewman-Keuls test. On average, it took 30 seconds or less for rats that had not been tested to cross from the illuminated room to the dark room. However, 24 hours after exposure to electric shock, most rats pretreated with vehicle did not attempt to re-enter the darkroom; the average waiting time increased to 175 seconds (p <0.001). Pretreatment with MK-801 (0.1 mg / kg) significantly reduced this waiting time compared to vehicle (p <0.001). This amnestic effect of MK-801 is dose-dependent (eg, 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, effective dosage range = 0.5 to 2.5 mg / kg, ip And N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid, effective dosage range = 0.1 to 2.5 mg / kg, ip) There is a statistically significant reversal with the compounds.

Example 21 (Method B)
In-vivo tests on radial arm maze work, learning and memory in rats Tests were performed as previously described (Zhang, H.-T., Chrisman, A.). M. (Crissman, AM), Dry Raja, Dorairaj, NR, Chandler, L. J. and O'Donnell, JM, Neuropsychopharma Collology (Neuropsychopharmacology), 2000, 23, 198-204.). Five days after initial containment, rats (male sprack-dawley (Harlan) 250-350 g weight) are accommodated in an eight-arm radial maze (each arm is 60 x 10 x 12 cm high; the maze is the floor) From 70 cm above) for 2 days. Rats were then individually placed in the center of the maze where the bait was placed near the bait hole and then placed in the hole at the end of the arm the next day; Was done. Next, one food grain was placed on each of the 4 randomly chosen arms. Rats were tied to a central platform (26 cm diameter) for 15 seconds and then allowed to move freely through the maze until either all the bait grains were collected or until 10 minutes had passed first. . Four factors: 1) Work memory error, ie, intrusion into fed arm already visited in the same test; 2) Collation memory error, ie, intrusion into arm without feed 3) penetration into all arms; and 4) test duration (seconds), ie the time spent collecting all the grains in the maze. Memory errors work is 0, the five consecutive average rat stored error less than one matching was in the test began drug testing. MK-801 or saline was injected 15 minutes prior to the vehicle or test drug given 45 minutes before the test. The experiment was conducted in a lighted room containing visual cues for several additional mazes.
All data were analyzed by analysis of variance (ANOVA); individual comparisons were made using the Kewman-Coils test. Compared to controls, MK-801 (0.1 mg / kg, ip) increased the frequency of working and collation memory errors (p <0.001). With respect to working memory, this amnestic effect of MK-801 is dose-dependent (eg, 3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, effective dose range = 2.5 mg / A statistically significant reversal is achieved by administration of the actual test compound (kg, ip; p <0.01).

  By replacing the reactants and / or operating conditions used in the previous examples with the reactants and / or operating conditions generally or specifically described in the present invention, the previous examples achieve similar results. Can be repeated with it.

Although the invention has been described with reference to preparation and specific compounds, it will be apparent that variations and modifications of the invention are possible without departing from the spirit or scope of the invention.

Claims (59)

Formula I
And pharmaceutically acceptable salts thereof,
here:
R ¹ is alkyl having ¹ to 4 carbon atoms, branched or unbranched, unsubstituted, or substituted with one or more halogens;
R ² has 1 to 12 carbon atoms, is branched or unbranched, is not substituted, or is one or more of halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo, or these Alkyl substituted by a combination, in each case one or more —CH ₂ CH ₂ — groups are optionally substituted by a —CH═CH— group or a —C≡C— group,
Having 3 to 10 carbon atoms, unsubstituted or one or more halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or Cycloalkyl substituted by these combinations,
One or more of halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy having 4 to 16 carbon atoms, unsubstituted or in the cycloalkyl and / or alkyl moiety Or a cycloalkylalkyl substituted by a combination thereof,
Having 6 to 14 carbon atoms, not substituted, or one or more _halogen, CF 3, OCF _3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or a combination thereof Substituted aryl,
The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the arylalkyl group is unsubstituted or has one or more in the aryl moiety, One or more —CH ₂ CH ₂ — groups in the alkyl moiety, substituted by halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, Each optionally substituted by —CH═CH— or —C≡C—, wherein one or more —CH ₂ — groups are each optionally substituted by —O— or —NH—, and / or the alkyl moiety is halogen, Arylalkyl optionally substituted by oxo, hydroxy, cyano, or combinations thereof,
Partially unsaturated carbocycle having from 5 to 14 carbon atoms and unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof Group,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, hydroxy A heterocyclic group substituted by aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and the alkyl moiety is branched or branched; Having 1 to 5 carbon atoms unbranched, and the heterocyclic-alkyl group is not substituted, or in said heterocyclic moiety one or more of halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, Substituted by trifluoromethyl, nitro, oxo, or combinations thereof, one or more —CH ₂ CH ₂ — groups in said alkyl moiety are each optionally substituted by —CH═CH— or —C≡C—, and one or more -CH ₂ - groups may be replaced by an appropriate -O-, or -NH- radical, respectively, and / or wherein the alkyl moiety is a halogen, oxo, hydroxy, cyano, It is properly a heterocyclic alkyl group optionally substituted by these combinations;
R ³ is an alkyl that is partially or fully saturated with a heteroaryl moiety, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and is not branched or branched. moiety is a heteroarylalkyl group having 1 to 5 carbon atoms, in substituted without or said heteroaryl moiety with one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heteroarylalkyl group substituted by, oxo, amino, alkylamino, dialkylamino, or combinations thereof, and / or substituted at the alkyl moiety by halogen, cyano, or methyl, or combinations thereof;
R ⁴ has 6 to 14 carbon atoms and is unsubstituted or substituted with one or more of halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoro Methyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (-heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl , alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b alkoxy, R ^5-L-, or aryl substituted by these combinations, or,
5-10 ring atoms, at least one ring atom being a heteroatom, unsubstituted or one or more halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, Trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, A heteroaryl substituted by trialkylsilyloxy, or a combination thereof;
R ⁵ is H,
Alkyl having 1-8 carbon atoms, unsubstituted or substituted by one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo, or combinations thereof;
Alkylamino or dialkylamino, each alkyl moiety independently having 1 to 8 carbon atoms,
The carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms and is unsubstituted or substituted with one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, or these A partially unsaturated carbocyclic-alkyl group substituted by a combination of
Cycloalkyl having 3 to 10 carbon atoms and unsubstituted or substituted by one or more halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof ,
A cyclohexane having 4 to 16 carbon atoms that is unsubstituted or substituted in the cycloalkyl and / or alkyl moiety by one or more of halogen, oxo, cyano, hydroxy, alkyl, alkoxy, or combinations thereof Alkylalkyl,
6 to 14 carbon atoms, unsubstituted or one or more, halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, amino Aryl substituted by alkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
An arylalkyl group having 7 to 19 carbon atoms, an aryl moiety having 6 to 14 carbon atoms, and a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Or substituted in the aryl moiety by one or more of halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and / or Arylalkyl substituted in the alkyl moiety by halogen, cyano, methyl or combinations thereof,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, alkyl Hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, A heterocyclic group substituted by carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or
An alkyl having 5-10 ring atoms in which the heterocyclic moiety is saturated, partially saturated, or unsaturated, at least one ring atom is an N, O, or S atom, and is not branched or branched moiety has from 1 to 5 carbon atoms, a heterocyclic - alkyl group is not substituted, or in the heterocyclic moiety, one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heterocyclic alkyl group substituted by, oxo, amino, alkylamino, dialkylamino, or combinations thereof, and / or substituted at the alkyl moiety by halogen, cyano, methyl, or combinations thereof;
L has a single bond or 1 to 8 carbon atoms, and one or more —CH ₂ — groups are —O—, —S—, —NR ⁶ —, —SO ₂ NH—, —NHSO ₂ —. , —CO—, —NR ⁶ CO—, —CONR ⁶ —, —NHCONH—, —OCONH—, —NHCOO—, —SCON—, —SCSNH—, or —NHCSNH—, respectively. And R ⁶ is H, or has 1 to 8 carbon atoms, is branched or unbranched, is not substituted, or is one or more halogen, C _1-4 -alkyl. , C _1-4 -alkoxy, oxo, or alkyl substituted by combinations thereof. R ¹ is methyl or CHF ₂ ; and R ² is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocycle, in each case substituted or non-substituted The compound of claim 1 which is a substitution. A compound according to claim 1 wherein R ¹ is methyl or CHF ₂ and R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or (3R) -tetrahydrofuranyl. The compound of claim 1 wherein R ¹ is methyl or CHF ₂ ; and R ² is cyclopentyl. The compound of claim 1 wherein R ¹ is methyl; and R ² is cyclopentyl. The compound of claim 1, wherein R ¹ is methyl; R ² is cyclopentyl; and R ⁴ is substituted or unsubstituted phenyl. R ¹ is methyl; R ² is cyclopentyl; R ³ is pyridylmethyl, pyrimidinylmethyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, in each case they are substituted or unsubstituted There; and R ⁴ is phenyl, or 1-3 of a compound of claim 1, wherein a phenyl substituted with a substituent. R ¹ is methyl; R ² is cyclopentyl; R ³ is pyridylmethyl, pyrimidinylmethyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, in each case they are substituted or unsubstituted And R ⁴ is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, each of which is substituted or unsubstituted. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, and 2. The compound according to claim 1, wherein they are also substituted or unsubstituted. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is unsubstituted or methyl, ethyl, methoxy, Cl, F, CF ₃ , phenyl substituted by vinyl, cyano, amino, carboxy, hydroxymethyl, ethylsulfonamide, or combinations thereof, or 3-pyridyl unsubstituted or substituted by carboxy, alkoxycarbonyl, or combinations thereof A compound according to claim 1. A compound according to claim ^{1 wherein} R ¹ is methyl; R ² is cyclopentyl; and R ⁴ is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, in each case they are substituted or unsubstituted. R ¹ is methyl; R ² is cyclopentyl; and R ⁴ is unsubstituted or methyl, ethyl, methoxy, Cl, F, CF ₃ , vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamide 2. A compound according to claim 1 which is phenyl substituted by or 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ³ is furanylmethyl, thienylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl 2. A compound according to claim 1, wherein: thiazolylmethyl, or pyrrolylmethyl, which in each case are substituted or unsubstituted. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ³ is pyrazinylmethyl, pyrimidinylmethyl, or pyridylmethyl, in each case 2. A compound according to claim 1 which is substituted or unsubstituted. R ¹ is methyl; R ² is cyclopentyl; and R ³ is furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, in each case 2. A compound according to claim 1 which is substituted or unsubstituted. A compound according to claim ^{1 wherein} R ¹ is methyl; R ² is cyclopentyl; and R ³ is pyrazinylmethyl or pyridylmethyl, in each case they are substituted or unsubstituted. Formula IV
And a pharmaceutically acceptable salt thereof according to claim 1, represented by
Here, at least one of A, B, and D is N, the other is CH, and R ⁴ is pyridyl or phenyl, and in each case, they are substituted or unsubstituted. R ¹ is The compound of claim 17 wherein is methyl or CHF _2.   19. A compound according to claim 18 wherein B is N. R ¹ is methyl or CHF _2; ^{R 2} is cyclopentyl, CHF _2, cyclopropylmethyl, pyridylethyl, or claim 17 A compound according tetrahydrofuranyl.   21. A compound according to claim 20, wherein B is N. R ¹ is methyl or CHF _2; and R ⁴ is 3-pyridyl or phenyl, claim 17 A compound according any case they are substituted or unsubstituted.   23. A compound according to claim 22 wherein B is N. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is 3-pyridyl or phenyl, in each case they are substituted Or a compound according to claim 17 which is unsubstituted.   25. A compound according to claim 24, wherein B is N. R ¹ is methyl or be CHF _2; and ^{R 4} is 3- or 4-position according to claim 17 A compound according phenyl which is substituted.   27. The compound of claim 26, wherein B is N. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is phenyl substituted in the 3- or 4-position. 17. The compound according to 17.   29. A compound according to claim 28, wherein B is N. R ¹ is methyl or CHF ₂ ; and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5 -Yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl The compound according to claim 17, which is -phenyl or 4-hydroxymethyl-phenyl.   The compound according to claim 30, wherein B is N. R ¹ is methyl or CHF ₂ ; R ² is cyclopentyl, CHF ₂ , cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; and R ⁴ is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4 18. A compound according to claim 17, which is -cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.   33. The compound of claim 32, wherein B is N. The compound is:
3-cyclopentyloxy-4′-ethyl-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3 ′, 4-dimethoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3′-trifluoromethyldiphenylamine,
3-cyclopentyloxy-3′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-phenyl-N- (3-pyridylmethyl) diphenylamine,
4′-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-nitro-N- (3-pyridylmethyl) diphenylamine,
4′-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3′-trifluoromethyldiphenylamine,
4-methoxy-3′-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -6-aminonicotinic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyrazinyl) -N- (3-pyridylmethyl) amine,
3′-benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3- [3- (4-chlorophenyl) prop-1-yloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- [3- (4-methoxyphenyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- [3- (2-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4 ′-(2-methoxyethoxy) -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-[(3R) -tetrahydrofuranyloxy] diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-methylpiperidin-4-yloxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-methylpyrrolidin-3-yloxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-pyrrolidinylethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (6-methylpyridyl) methoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3 ′-[2- (1-piperidinyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3 ′-[2- (1-imidazolyl) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (2-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (2-morpholin-4-ylethylamino) propoxy] -N- (3-pyridylmethyl) diphenylamine,
3- [2- (4-chlorophenoxy) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3- [2- (4-chlorophenylamino) ethoxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4 ′-(2-methanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4 ′-[2- (1-butanesulfonylamino) ethoxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-methyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-methyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-nitro-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3 ′, 4′-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-cyclopentyloxy-4′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine,
4-methoxy-4′-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
4,4′-dimethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3-Indanyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -N- (5-pyrimidinyl) amine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-4-methoxyanilino-N- (3-pyridylmethyl) -N-3- (4-pyridyl) benzamide,
3-cyclopentyloxy-4-methoxy-3 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-4 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-4 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl)-(3- (3-tetrahydrofuryloxy) diphenylamine,
3 ′-(1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3S) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3- [2- (4-chlorophenyl) ethenyloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4′-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-methylpyrrolidin-2-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (1-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (2-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4′-chloro-3-cyclopentyloxy-3′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) -diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine,
3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4 ′-(2-ethanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3′-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3′-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4′-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N-3,4-bis ((difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
Bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-3′-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (5-oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine,
A compound according to claim 1 selected from: and pharmaceutically acceptable salts thereof. The compound is:
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-methyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-methyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-nitro-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3 ′, 4′-dichloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-cyclopentyloxy-4′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-N- (2,6-dichloro-4-pyridylmethyl) -4-methoxydiphenylamine,
4-methoxy-4′-methyl-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
4,4′-dimethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3-Indanyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine N- [4-methoxy-3- (2- (2-pyridyl) ethyl) oxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (4-isoquinolinyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -N- (5-pyrimidinyl) amine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (2-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-methoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-4-methoxyanilino-N- (3-pyridylmethyl) -N- (4-pyridyl) benzamide,
3-cyclopentyloxy-4-methoxy-3 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-4 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-4 ′-(4-methylpiperazin-1-ylcarbonyl) -N- (3-pyridylmethyl)-(3- (3-tetrahydrofuryloxy) diphenylamine,
3 ′-(1-butanesulfonylamino) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-acetamido-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3S) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (4-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3- [2- (4-chlorophenyl) ethenyloxy] -4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-3′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4′-cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-methylpyrrolidin-2-yl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (1-methylpiperidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[3- (1-methylpiperazin-4-yl) propoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- (2-phenoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (2-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4′-chloro-3-cyclopentyloxy-3′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) -diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine,
3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4 ′-(2-ethanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3′-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3′-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4′-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N-3,4-bis ((difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
Bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-3′-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
A compound according to claim 1 selected from 3-cyclopentyloxy-4-methoxy-4 '-[2- (5-oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable Can salt them. The compound is:
3′-cyano-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4′-chloro-3-cyclopentyloxy-3′-fluoro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4-difluoromethoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(2- (tetrahydropyran-2-yl) -2H-tetrazol-5-yl) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-methanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) -diphenylamine,
3-cyclopentyloxy-4-methoxy-3′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4′-hydroxymethyl-N- (3-pyridylmethyl) diphenylamine,
4-methoxy-3- [3- (4-pyridyl) prop-1-yl] oxy-N- (3-pyridylmethyl) diphenylamine,
3'-chloro-4-methoxy-3- (2-methoxyethoxy) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-4′-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4 ′-(2-ethanesulfonylamino) ethoxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-[2- (1-propanesulfonylamino) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3′-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine 4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3′-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4′-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N-3,4-bis (difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
Bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-3′-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
A compound according to claim 1 selected from 3-cyclopentyloxy-4-methoxy-4 '-[2- (5-oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable Can salt them. The compound is:
3′-chloro-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3′-cyano-4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3- (3-tetrahydrofuryloxy) diphenylamine,
3,4-bis (difluoromethoxy) -N- (3-pyridylmethyl) diphenylamine 4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuroxy) diphenylamine,
3'-cyano-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
3′-chloro-4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) diphenylamine,
4′-tert-butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N-3,4-bis ((difluoromethoxy) phenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -4-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (4-chlorophenyl) prop-1-yloxy-4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- (3-cyclopropylmethoxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-Indanyloxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3- (3-tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [4-methoxy-3-((3R) -tetrahydrofuryloxy) phenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
N- [3- (2-methoxyethoxy) -4-methoxyphenyl] -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 '-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-methoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
4-difluoromethoxy-N- (3-pyridylmethyl) -3-((3R) -tetrahydrofuryloxy) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopentyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
3-cyclopropylmethyloxy-4-difluoromethoxy-N- (3-pyridylmethyl) -3 ′-(2H-tetrazol-5-yl) diphenylamine,
Bis-3,4-difluoromethoxy-N- (3-pyridylmethyl) -4 ′-(2H-tetrazol-5-yl) diphenylamine,
N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
N- (4-difluoromethoxy-3- (3R) -tetrahydrofuryloxyphenyl) -N- (3-pyridyl) -N- (3-pyridylmethyl) amine,
3-cyclopentyloxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-3 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-cyclopentyloxy-4-methoxy-4 ′-(1-propanesulfonylamino) -N- (3-pyridylmethyl) diphenylamine,
3-cyclopropylmethoxy-3′-ethanesulfonylamino-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4-difluoromethoxy-3′-ethanesulfonylamino-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
3'-chloro-4-methoxy-3- [2- (2-pyridyl) ethoxy] -N- (3-pyridylmethyl) diphenylamine,
3′-chloro-4-methoxy-N- (3-pyridylmethyl) -3-[(3R) -tetrahydrofuryloxy] diphenylamine,
A compound according to claim 1 selected from 3-cyclopentyloxy-4-methoxy-4 '-[2- (5-oxopyrrolidinyl) methoxy] -N- (3-pyridylmethyl) diphenylamine; and pharmaceutically acceptable Can salt them. Formula I '
And pharmaceutically acceptable salts thereof,
here:
R ^{1 ′} is methoxy or CHF ₂ ;
R ^{2 ′} is alkyl having 1 to 12 carbon atoms,
Alkyl having 1 to 12 carbon atoms and substituted by one or more halogen, oxo, cyano, or combinations thereof;
Alkenyl having 2 to 12 carbon atoms,
Alkenyl having 2 to 12 carbon atoms and substituted by one or more halogen, oxo, cyano, or combinations thereof,
Alkynyl having 2 to 12 carbon atoms,
Alkynyl having 2 to 12 carbon atoms and substituted by one or more halogen, oxo, cyano, or combinations thereof;
A cycloalkyl having 3 to 10 carbon atoms,
A cycloalkyl having 3-10 carbon atoms, substituted by one or more halogen, oxo, alkyl, or combinations thereof;
Cycloalkylalkyl having 4 to 12 carbon atoms,
A cycloalkylalkyl having 4-12 carbon atoms, substituted by one or more halogen, oxo, alkyl, or combinations thereof;
A partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
A partially unsaturated carbocyclic group having from 5 to 14 carbon atoms and substituted by one or more halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof;
Arylalkyl having 7 to 26 carbon atoms,
Arylalkyl having 7 to 26 carbon atoms and substituted by one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof;
A heteroarylalkyl having 5 to 10 ring atoms, at least one ring atom being a heteroatom, or
Having 5-10 ring atoms, at least one ring atom being a heteroatom, and in the heteroaryl moiety one or more halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkyl A substituted heteroarylalkyl substituted by amino, or a combination thereof, and / or substituted at the alkyl moiety by halogen, oxo, cyano, or a combination thereof;
X is O;
R ^{3 ′} is a heteroaryl having 5 to 10 ring atoms in which at least one ring atom is a heteroatom, or
5 to 10 ring atoms, at least one ring atom being a heteroatom, and one or more halogen, aryl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or these Substituted heteroaryl substituted by a combination;
L is —NR ^{4 ′} —, —NR ^{4 ′} CH ₂ —, or —CH ₂ NR ^{4 ′} —; and R ^{4 ′} has 6 to 14 carbon atoms and is unsubstituted or 1 Halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl Aryl substituted by phenoxy, or combinations thereof,
A heteroaryl having from 5 to 10 ring atoms, at least one ring atom being a heteroatom,
5 to 10 ring atoms, at least one ring atom being a heteroatom, and one or more halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or Substituted heteroaryl substituted by these combinations.   A pharmaceutical composition for enhancing a patient's cognitive ability, comprising an effective amount of the compound of claim 1.   A pharmaceutical composition for treating a patient suffering from cognitive impairment or cognitive decline, comprising an effective amount of the compound of claim 1.   41. The pharmaceutical composition of claim 40, wherein the patient is a patient suffering from memory impairment.   The patient has Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral aging, cerebrovascular 42. The pharmaceutical composition according to claim 41, which is a patient suffering from dementia, HIV or cardiovascular disease.   A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.   44. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition comprises 0.1-50 mg of the compound.   A pharmaceutical composition for treating a patient suffering from memory impairment due to a neurodegenerative disease, the pharmaceutical composition comprising an effective amount of the compound of claim 1.   A pharmaceutical composition for treating a patient suffering from memory impairment due to an acute neurodegenerative disease, comprising an effective amount of the compound according to claim 1. Chemical formula
Intermediate compounds for producing the compounds according to claim 1 and their salts, and their salts,
here:
R ¹ is H or tert-butyldimethylsilyl;
R ² has 1 to 12 carbon atoms, is branched or unbranched, is not substituted, or is one or more of halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo, or these Alkyl substituted by a combination, in each case one or more —CH ₂ CH ₂ — groups are optionally substituted by —CH═CH— or —C≡C—,
Having 3 to 10 carbon atoms, unsubstituted or one or more halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or Cycloalkyl substituted by these combinations,
One or more of halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy having 4 to 16 carbon atoms, unsubstituted or in the cycloalkyl and / or alkyl moiety Or a cycloalkylalkyl substituted by a combination thereof,
Having 6 to 14 carbon atoms, not substituted, or one or more _halogen, CF 3, OCF _3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or a combination thereof Substituted aryl,
The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the arylalkyl group is not substituted, or in the aryl moiety one or more , Halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, wherein one or more —CH ₂ CH ₂ — groups in the alkyl moiety are Each optionally substituted with —CH═CH— or —C≡C—, wherein one or more —CH ₂ — groups are each optionally substituted with —O— or —NH—, and / or the alkyl moiety is halogenated. Arylalkyl optionally substituted by oxo, hydroxy, cyano, or combinations thereof,
Partially unsaturated carbocycle having from 5 to 14 carbon atoms and unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof Group,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, hydroxy A heterocyclic group substituted by aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and the alkyl moiety is branched or branched; Having 1 to 5 carbon atoms unbranched, and the heterocyclic-alkyl group is not substituted, or in said heterocyclic moiety one or more of halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, Substituted by trifluoromethyl, nitro, oxo, or combinations thereof, one or more —CH ₂ CH ₂ — groups in said alkyl moiety are each optionally substituted by —CH═CH— or —C≡C—, and one or more -CH ₂ - groups may be replaced by an appropriate -O- or -NH- respectively, and / or wherein the alkyl moiety is a halogen, oxo, hydroxy, cyano, young Ku heterocyclic is optionally substituted by a combination of these - an alkyl group;
R ³ is an alkyl that is partially or fully saturated with a heteroaryl moiety, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and is not branched or branched. moiety is a heteroarylalkyl group having 1 to 5 carbon atoms, not substituted, or in the heteroaryl moiety with one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, A heteroarylalkyl group substituted by nitro, oxo, amino, alkylamino, dialkylamino, or a combination thereof, and / or substituted at the alkyl moiety by halogen, cyano, or methyl, or a combination thereof;
R ⁴ has 6 to 14 carbon atoms and is unsubstituted or substituted with one or more of halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoro Methyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (-heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl , alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b alkoxy, R ^5-L-, or aryl substituted by these combinations, or,
5-10 ring atoms, at least one ring atom being a heteroatom, unsubstituted or one or more halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, Trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b ^alkoxy, R 5 ^-L-, dialkylamino-L-, or heteroaryl substituted by combinations thereof;
R ⁵ is H,
Alkyl having 1-8 carbon atoms, unsubstituted or substituted by one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo, or combinations thereof;
Alkylamino or dialkylamino, each alkyl moiety independently having 1 to 8 carbon atoms,
The carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms and is unsubstituted or substituted with one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, or these A partially unsaturated carbocyclic-alkyl group substituted by a combination of
Cycloalkyl having 3 to 10 carbon atoms and unsubstituted or substituted by one or more halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof ,
A cyclohexane having 4 to 16 carbon atoms that is unsubstituted or substituted in the cycloalkyl and / or alkyl moiety by one or more of halogen, oxo, cyano, hydroxy, alkyl, alkoxy, or combinations thereof Alkylalkyl,
6 to 14 carbon atoms, unsubstituted or one or more, halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, amino Aryl substituted by alkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
An arylalkyl group having 7 to 19 carbon atoms, an aryl moiety having 6 to 14 carbon atoms, and a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Or substituted in the aryl moiety by one or more of halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and / or Arylalkyl substituted in the alkyl moiety by halogen, cyano, methyl or combinations thereof,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, alkyl Hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, A heterocyclic group substituted by carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or
An alkyl having 5-10 ring atoms in which the heterocyclic moiety is saturated, partially saturated, or unsaturated, at least one ring atom is an N, O, or S atom, and is not branched or branched moiety has from 1 to 5 carbon atoms, a heterocyclic - alkyl group is not substituted, or in the heterocyclic moiety, one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heterocyclic-alkyl group substituted by, oxo, amino, alkylamino, dialkylamino, or combinations thereof and / or substituted at the alkyl moiety by halogen, cyano, methyl, or combinations thereof;
L has a single bond or 1 to 8 carbon atoms, and one or more —CH ₂ — groups are —O—, —S—, —NR ⁶ —, —SO ₂ NH—, —NHSO ₂ —. , —CO—, —NR ⁶ CO—, —CONR ⁶ —, —NHCONH—, —OCONH—, —NHCOO—, —SCON—, —SCSNH—, or —NHCSNH—, respectively. And R ⁶ is H, or has 1 to 8 carbon atoms, is branched or unbranched, is not substituted, or is one or more halogen, C _1-4 -alkyl. , C _1-4 -alkoxy, oxo, or alkyl substituted by combinations thereof. Chemical formula
Intermediate compounds for producing the compounds according to claim 1 and their salts, and their salts,
here:
R ¹ is alkyl having ¹ to 4 carbon atoms, branched or unbranched, unsubstituted, or substituted with one or more halogens;
R ² is H or tert-butyldimethylsilyloxy-;
R ³ is an alkyl that is partially or fully saturated with a heteroaryl moiety, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and is not branched or branched. moiety is a heteroarylalkyl group having 1 to 5 carbon atoms, not substituted, or in the heteroaryl moiety with one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, A heteroarylalkyl group substituted by nitro, oxo, amino, alkylamino, dialkylamino, or a combination thereof, and / or substituted at the alkyl moiety by halogen, cyano, or methyl, or a combination thereof;
R ⁴ has 6 to 14 carbon atoms and is unsubstituted or substituted with one or more of halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoro Methyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (-heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl , alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b alkoxy, R ^5-L-, or aryl substituted by these combinations, or,
5-10 ring atoms, at least one ring atom being a heteroatom, unsubstituted or one or more halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, Trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b ^alkoxy, R 5 ^-L-, dialkylamino-L-, or heteroaryl substituted by combinations thereof;
R ⁵ is H,
Alkyl having 1-8 carbon atoms, unsubstituted or substituted by one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo, or combinations thereof;
Alkylamino or dialkylamino, each alkyl moiety independently having 1 to 8 carbon atoms,
The carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms and is unsubstituted or substituted with one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, or these A partially unsaturated carbocyclic-alkyl group substituted by a combination of
Cycloalkyl having 3 to 10 carbon atoms and unsubstituted or substituted by one or more halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof ,
A cyclohexane having 4 to 16 carbon atoms that is unsubstituted or substituted in the cycloalkyl and / or alkyl moiety by one or more of halogen, oxo, cyano, hydroxy, alkyl, alkoxy, or combinations thereof Alkylalkyl,
6 to 14 carbon atoms, unsubstituted or one or more, halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, amino Aryl substituted by alkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
An arylalkyl group having 7 to 19 carbon atoms, an aryl moiety having 6 to 14 carbon atoms, and a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Or substituted in the aryl moiety by one or more of halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and / or Arylalkyl substituted in the alkyl moiety by halogen, cyano, methyl or combinations thereof,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, alkyl Hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, A heterocyclic group substituted by carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or
An alkyl having 5-10 ring atoms in which the heterocyclic moiety is saturated, partially saturated, or unsaturated, at least one ring atom is an N, O, or S atom, and is not branched or branched moiety has from 1 to 5 carbon atoms, a heterocyclic - alkyl group is not substituted, or in the heterocyclic moiety, one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heterocyclic-alkyl group substituted by, oxo, amino, alkylamino, dialkylamino, or combinations thereof and / or substituted at the alkyl moiety by halogen, cyano, methyl, or combinations thereof;
L has a single bond or 1 to 8 carbon atoms, and one or more —CH ₂ — groups are —O—, —S—, —NR ⁶ —, —SO ₂ NH—, —NHSO ₂ —. , —CO—, —NR ⁶ CO—, —CONR ⁶ —, —NHCONH—, —OCONH—, —NHCOO—, —SCON—, —SCSNH—, or —NHCSNH—, respectively. And R ⁶ is H, or has 1 to 8 carbon atoms, is branched or unbranched, is not substituted, or is one or more halogen, C _1-4 -alkyl. , C _1-4 -alkoxy, oxo, or alkyl substituted by combinations thereof. 3-tert-butyldimethylsilyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3-tert-butyldimethylsilyloxy-3′-chloro-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
Ethyl N- (3-tert-butyldimethylsilyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
3′-chloro-3-hydroxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
Ethyl N- (3-hydroxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid,
3 ′-(2-bromoethoxy) -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine,
4 ′-[1- (3-bromopropyl) oxy] -3-cyclopentyloxy-4-methoxy-N- (3-pyridylmethyl) diphenylamine, and 4-hydroxy-3-cyclopentyloxy-N- (3-pyridyl Methyl) diphenylamine:
49. An intermediate compound according to claim 48 selected from.   The compound according to claim 1, wherein the compound is N-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof.   The compound according to claim 1, wherein the compound is N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. .   40. The pharmaceutical composition of claim 39, wherein the compound is N-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. object.   40. The agent of claim 39, wherein the compound is N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. Composition.   44. The pharmaceutical composition of claim 43, wherein the compound is N-3,4-bis (difluoromethoxy) phenyl-N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. object.   44. The agent of claim 43, wherein the compound is N- (3-cyclopentyloxy-4-methoxyphenyl) -N- (3-pyridylmethyl) -3-aminobenzoic acid or a pharmaceutically acceptable salt thereof. Composition.   The pharmaceutical composition further comprises a drug selected from a calcium antagonist, a cholinergic agent, an adenosine receptor modulator, an NMDA-receptor modulator, a metapotropic glutamate receptor modulator, a cholinesterase inhibitor, or a combination thereof. 44. The pharmaceutical composition according to claim 43, further comprising:   The pharmaceutical composition further comprises a drug selected from a calcium antagonist, a cholinergic agent, an adenosine receptor modulator, an NMDA-receptor modulator, a metapotropic glutamate receptor modulator, a cholinesterase inhibitor, or a combination thereof. 55. The pharmaceutical composition according to claim 54, further comprising:   The pharmaceutical composition further comprises a drug selected from a calcium antagonist, a cholinergic agent, an adenosine receptor modulator, an NMDA-receptor modulator, a metapotropic glutamate receptor modulator, a cholinesterase inhibitor, or a combination thereof. 56. The pharmaceutical composition according to claim 55, further comprising: Chemical formula
Radiolabeled compounds of the compounds according to claim 1 and their salts, and salts thereof, represented by
here:
R ¹ is ³ H ₃ C—, ¹⁴ CH ₃ — or ¹¹ CH ₃ —;
R ² has 1 to 12 carbon atoms, is branched or unbranched, is not substituted, or is one or more of halogen, hydroxy, cyano, C _1-4 -alkoxy, oxo, or these Alkyl substituted by a combination, in each case one or more —CH ₂ CH ₂ — groups are optionally substituted by —CH═CH— or —C≡C—,
Having 3 to 10 carbon atoms, unsubstituted or one or more halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or Cycloalkyl substituted by these combinations,
One or more of halogen, oxo, cyano, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy having 4 to 16 carbon atoms, unsubstituted or in the cycloalkyl and / or alkyl moiety Or a cycloalkylalkyl substituted by a combination thereof,
Having 6 to 14 carbon atoms, not substituted, or one or more _halogen, CF 3, OCF _3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or a combination thereof Substituted aryl,
The aryl moiety has 6 to 14 carbon atoms, the branched or unbranched alkyl moiety has 1 to 5 carbon atoms, the arylalkyl group is not substituted, or in the aryl moiety one or more , Halogen, CF ₃ , OCF ₃ , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, wherein one or more —CH ₂ CH ₂ — groups in the alkyl moiety are Each optionally substituted with —CH═CH— or —C≡C—, wherein one or more —CH ₂ — groups are each optionally substituted with —O— or —NH—, and / or the alkyl moiety is halogenated. Arylalkyl optionally substituted by oxo, hydroxy, cyano, or combinations thereof,
Partially unsaturated carbocycle having from 5 to 14 carbon atoms and unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof Group,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, hydroxy A heterocyclic group substituted by aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
The heterocyclic moiety is saturated, partially saturated or unsaturated, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and the alkyl moiety is branched or branched; Having 1 to 5 carbon atoms unbranched, and the heterocyclic-alkyl group is not substituted, or in said heterocyclic moiety one or more of halogen, OCF ₃ , hydroxy, aryl, alkyl, alkoxy, cyano, Substituted by trifluoromethyl, nitro, oxo, or combinations thereof, one or more —CH ₂ CH ₂ — groups in said alkyl moiety are each optionally substituted by —CH═CH— or —C≡C—, and one or more -CH ₂ - groups may be replaced by an appropriate -O- or -NH- respectively, and / or wherein the alkyl moiety is a halogen, oxo, hydroxy, cyano, young Ku heterocyclic is optionally substituted by a combination of these - an alkyl group;
R ³ is an alkyl that is partially or fully saturated with a heteroaryl moiety, has 5 to 10 ring atoms in which at least one ring atom is an N, O, or S atom, and is not branched or branched. moiety is a heteroarylalkyl group having 1 to 5 carbon atoms, not substituted, or in the heteroaryl moiety with one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, A heteroarylalkyl group substituted by nitro, oxo, amino, alkylamino, dialkylamino, or a combination thereof, and / or substituted at the alkyl moiety by halogen, cyano, or methyl, or a combination thereof;
R ⁴ has 6 to 14 carbon atoms and is unsubstituted or substituted with one or more of halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoro Methyl, OCF ₃ , amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, 2 (-heterocyclic) tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl , alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b alkoxy, R ^5-L-, or aryl substituted by these combinations, or,
5-10 ring atoms, at least one ring atom being a heteroatom, unsubstituted or one or more halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, Trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyl b ^alkoxy, R 5 ^-L-, dialkylamino-L-, or heteroaryl substituted by combinations thereof;
R ⁵ is H,
Alkyl having 1-8 carbon atoms, unsubstituted or substituted by one or more halogen, C _1-4 -alkyl, C _1-4 -alkoxy, oxo, or combinations thereof;
Alkylamino or dialkylamino, each alkyl moiety independently having 1 to 8 carbon atoms,
The carbocyclic moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms and is unsubstituted or substituted with one or more halogen, alkyl, alkoxy, nitro, cyano, oxo, or these A partially unsaturated carbocyclic-alkyl group substituted by a combination of
Cycloalkyl having 3 to 10 carbon atoms and unsubstituted or substituted by one or more halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof ,
A cyclohexane having 4 to 16 carbon atoms that is unsubstituted or substituted in the cycloalkyl and / or alkyl moiety by one or more of halogen, oxo, cyano, hydroxy, alkyl, alkoxy, or combinations thereof Alkylalkyl,
6 to 14 carbon atoms, unsubstituted or one or more, halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, amino Aryl substituted by alkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
An arylalkyl group having 7 to 19 carbon atoms, an aryl moiety having 6 to 14 carbon atoms, and a branched or unbranched alkyl moiety having 1 to 5 carbon atoms, Or substituted in the aryl moiety by one or more of halogen, trifluoromethyl, CF ₃ O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and / or Arylalkyl substituted in the alkyl moiety by halogen, cyano, methyl or combinations thereof,
Saturated, partially saturated, or unsaturated, having 5-10 ring atoms, at least one ring atom being an N, O, or S atom, unsubstituted, or one or more halogen, alkyl Hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, A heterocyclic group substituted by carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or
An alkyl having 5-10 ring atoms in which the heterocyclic moiety is saturated, partially saturated, or unsaturated, at least one ring atom is an N, O, or S atom, and is not branched or branched moiety has from 1 to 5 carbon atoms, a heterocyclic - alkyl group is not substituted, or in the heterocyclic moiety, one or more halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 _O, nitro A heterocyclic-alkyl group substituted by, oxo, amino, alkylamino, dialkylamino, or combinations thereof and / or substituted at the alkyl moiety by halogen, cyano, methyl, or combinations thereof;
L has a single bond or 1 to 8 carbon atoms, and one or more —CH ₂ — groups are —O—, —S—, —NR ⁶ —, —SO ₂ NH—, —NHSO ₂ —. , —CO—, —NR ⁶ CO—, —CONR ⁶ —, —NHCONH—, —OCONH—, —NHCOO—, —SCON—, —SCSNH—, or —NHCSNH—, respectively. And R ⁶ is H, or has 1 to 8 carbon atoms, is branched or unbranched, is not substituted, or is one or more halogen, C _1-4 -alkyl. , C _1-4 -alkoxy, oxo, or alkyl substituted by combinations thereof.