US2008287424A1PendingUtilityA1
AZOLYLACYLGUANIDINES AS beta-SECRETASE INHIBITORS
Est. expiryFeb 14, 2025(expired)· nominal 20-yr term from priority
Inventors:Derek Cecil ColeEric Steven ManasLee Dalton JenningsFrank Eldridge LoveringJoseph StockWilliam J. MooreJohn W. EllingboeJeffrey Scott CondonMohani Nirmala SukhdeoPing ZhouJunjun WuKoi Michele Morris
A61P 43/00C07D 401/10C07D 409/12C07D 207/327A61P 25/28C07D 207/337C07D 413/12C07D 417/12C07D 405/12C07D 207/333C07D 207/36C07D 417/10C07D 403/12C07D 405/06C07D 409/06C07D 413/04C07D 409/04C07D 405/04C07D 207/335C07D 207/33C07D 207/32
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Claims
Abstract
The present invention provides an azolylacylquanidine compound of formula I The present invention also provides methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.
Claims
exact text as granted — not AI-modified1 . A compound of formula I
wherein
X is N or CR 5 ;
Y is N or CR 6 ;
Z is CO or (CH 2 ) n ;
n is 0, 1, 2 or 3;
R is H, alkyl or aryl;
R 1 and R 2 are each independently cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;
R 3 and R 4 are each independently H, alkyl, alkoxy, alkanoyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl or R 3 and R 4 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and
R 5 and R 6 are each independently halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 wherein X is CR 5 ; Y is CR 6 ; and R is H.
3 . The compound according to claim 1 wherein R is H; R 1 is phenyl and R 2 is cycloalkyl.
4 . The compound according to claim 1 having the structure of formula Ia
wherein
X, Y, R 3 and R 4 are as defined for formula I hereinabove;
R 7 , R 8 , R 9 and R 10 are each independently H, halogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, OR 11 , COR 11 , CONR 12 R 13 , NR 12 R 13 , NR 14 COR 15 , NR 14 SO 2 R 15 or NR 14 CONR 16 R 17 ;
R 11 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;
R 12 , R 13 , R 16 and R 17 are each independently H, alkyl, alkoxy, alkenyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl or R 12 and R 13 or R 16 and R 17 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
R 14 is H, alkyl or cycloalkyl; and
R 15 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
5 . The compound according to claim 2 wherein Z is (CH 2 ) n ; n is 0; and R 2 is adamantyl.
6 . The compound according to claim 4 wherein X and Y are CH; and R 7 and R 9 are H.
7 . The compound according to claim 5 wherein X and Y are CH and R is H.
8 . The compound according to claim 6 wherein R 8 and R 10 are each independently H, halogen or OR 11 .
9 . The compound according to claim 1 selected from the group consisting of:
N-[amino(imino)methyl]-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2-chlorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-fluorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(3-fluorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2-methoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2-methoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-methoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(3-methoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(4-fluorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2,5-dimethoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2,5-dimethoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-2,4-dichlorobenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-4-bromobenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-methoxybenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-methylbenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-2-phenoxyacetamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-bromobenzamide;
2-{2-[4-(allyloxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(2-methylprop-2-enyl)oxy]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-[amino(imino)methyl]-2-{2-[4-(but-3-enyloxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(4-cyanobenzyl)oxy]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-[amino(imino)methyl]-2-[2-(4-ethoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-{2-[4-(3-cyanopropoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetamide;
N-[amino(imino)methyl]-2-[2-(4-{[(2S)-2-methylbutyl]oxy}phenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-hydroxypropyl)amino]methylene}-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
methyl (2R)-3-{[(Z)-amino({[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetyl}imino)methyl]amino}-2-methylpropanoate;
2-{[(Z)-amino({[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetyl}imino)methyl]amino}ethyl acetate;
2-{2-(2-chlorophenyl)-5-[4-(pent-4-enyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(4-cyanobutoxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(hex-5-enyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-(2-(2-chlorophenyl)-5-{4-[2-(1,3-dioxolan-2-yl)ethoxy]phenyl}-1H-pyrrol-1-yl)-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(pentyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyanophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-isopropylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-phenyl-5-(4-propylphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-isobutylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-pentylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(1,1′-biphenyl-4-yl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-bromophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyclohexylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyanophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}-2-[2-phenyl-5-(4-propylphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(4-cyclohexylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(ethylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(propylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-cyanopropyl)amino]methylene}acetamide;
2-{[(Z)-({[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}imino)(amino)methyl]amino}ethyl acetate;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-hydroxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-hydroxyethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-cyanoethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1E)-amino{[2-(1,3-dioxolan-2-yl)ethyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(4-hydroxybutyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(tetrahydrofuran-2-ylmethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(2R)-2-hydroxypropyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(2S)-2-hydroxypropyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,3-dihydroxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(isobutylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,2,2-trifluoroethyl)amino]methylene}acetamide;
ethyl 4-{[(Z)-({[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}imino)(amino)methyl]amino}butanoate;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1E)-amino(cyclopropylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(cyclohexylmethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(trans-4-hydroxycyclohexyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1E)-amino{[3-(1H-imidazol-1-yl)propyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(3-methoxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(2-methoxyethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,2,3,3,3-pentafluoropropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1E)-amino(cycloheptylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-thien-2-ylethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-aminobenzyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-thien-3-ylethyl)amino]methylene}acetamide;
N-allyl-4-(1-{2-[((1Z)-amino{[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methylene)amino]-2-oxoethyl}-5-phenyl-1H-pyrrol-2-yl)benzamide;
N-allyl-4-(1-{2-[((1Z)-amino{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}methylene)amino]-2-oxoethyl}-5-phenyl-1H-pyrrol-2-yl)benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(2-thien-2-ylethyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-aminobenzyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(ethylsulfonyl)amino]methylene}acetamide;
N-(3-cyano-propyl)-N′-[2-(2-cyclohexyl-5-phenyl-pyrrol-1-yl)-acetyl]-guanidine;
N″-{[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}guanidine;
N″-{[2-(2,5-dimethylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}guanidine;
N″-({2-[3-(cyanomethyl)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetyl)guanidine;
N″-({2-[4-(2-cyanoethyl)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetyl)guanidine;
N″-[(2-cyclohexyl-5-phenyl-1H-pyrrol-1-yl)acetyl]guanidine;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-ethylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-cyclopropylbenzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-hydroxyethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-cyanoethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-propylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-methoxyethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(sec-butyl)benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-methylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2,2,3,3,3-pentafluoropropyl)benzamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-[2-phenyl-5-(trans-4-propylcyclohexyl)-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-(2-cyclohexyl-5-phenyl-1H-pyrrol-1-yl)acetamide;
a tautomer thereof;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.
10 . A method for the treatment of a disease or disorder associated with excessive BACE activity in a patient in need thereof which comprises providing to said patient an effective amount of a compound of claim 1 .
11 . The method according to claim 10 wherein said disease or disorder is selected from the group consisting of: Alzheimer's disease; cognitive impairment; Down's Syndrome; HCHWA-D; cognitive decline; senile dementia; cerebral amyloid angiopathy; and a neurodegenerative disorder.
12 . The method according to claim 10 wherein said disease or disorder is characterized by production of β-amyloid deposits or neurofibrillary tangles.
13 . A method for modulating the activity of BACE comprising contacting a receptor thereof with an effective amount of a compound of claim 1 .
14 . A method for the treatment of Alzheimer's disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of claim 4 .
15 . A method of inhibiting BACE comprising administering to a mammal an effective amount of a compound of claim 1 .
16 . A method of ameliorating β-amyloid deposits or neurofibrillary tangles in a mammal comprising administering to said mammal an effective amount of a compound of claim 1 .
17 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .
18 . The composition according to claim 17 wherein said compound has the structure of formula Ia
wherein
X, Y, R 3 and R 4 are as defined for formula I hereinabove;
R 7 , R 8 , R 9 and R 10 are each independently H, halogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, OR 11 , COR 11 , CONR 12 R 13 , NR 12 R 13 , NR 14 COR 15 , NR 14 SO 2 R 15 or NR 14 CONR 16 R 17 ;
R 11 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;
R 12 , R 13 , R 16 and R 17 are each independently H, alkyl, alkoxy, alkenyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl or R 12 and R 13 or R 16 and R 17 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
R 14 is H, alkyl or cycloalkyl; and
R 15 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
19 . The composition according to claim 17 having a formula I compound wherein X and Y are CH; Z is (CH 2 ) n ; n is 0; R is H; R 1 is phenyl and R 2 is adamantyl.
20 . The composition according to claim 17 having a formula I compound selected from the group consisting of:
N-[amino(imino)methyl]-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2-chlorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-fluorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(3-fluorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2-methoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2-methoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(3-methoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(3-methoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(4-fluorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-[2-(2,5-dimethoxyphenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-[4-(4-acetylphenoxy)phenyl]-5-(2,5-dimethoxyphenyl)-1H-pyrrol-1-yl]-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-2,4-dichlorobenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-4-bromobenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-methoxybenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-methylbenzamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-2-phenoxyacetamide;
N-{4-[1-(2-{[amino(imino)methyl]amino}-2-oxoethyl)-5-phenyl-1H-pyrrol-2-yl]phenyl}-3-bromobenzamide;
2-{2-[4-(allyloxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[amino(imino)methyl]acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(2-methylprop-2-enyl)oxy]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-[amino(imino)methyl]-2-{2-[4-(but-3-enyloxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetamide;
N-[amino(imino)methyl]-2-(2-{4-[(4-cyanobenzyl)oxy]phenyl}-5-phenyl-1H-pyrrol-1-yl)acetamide;
N-[amino(imino)methyl]-2-[2-(4-ethoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[amino(imino)methyl]-2-{2-[4-(3-cyanopropoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetamide;
N-[amino(imino)methyl]-2-[2-(4-{[(2S)-2-methylbutyl]oxy}phenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-hydroxypropyl)amino]methylene}-2-[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetamide;
methyl (2R)-3-{[(Z)-amino({[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetyl}imino)methyl]amino}-2-methylpropanoate;
2-{[(Z)-amino({[2-(2-chlorophenyl)-5-(4-phenoxyphenyl)-1H-pyrrol-1-yl]acetyl}imino)methyl]amino}ethyl acetate;
2-{2-(2-chlorophenyl)-5-[4-(pent-4-enyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(4-cyanobutoxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(hex-5-enyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-(2-(2-chlorophenyl)-5-{4-[2-(1,3-dioxolan-2-yl)ethoxy]phenyl}-1H-pyrrol-1-yl)-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-{2-(2-chlorophenyl)-5-[4-(pentyloxy)phenyl]-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyanophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-isopropylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-phenyl-5-(4-propylphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-isobutylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-pentylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(1,1′-biphenyl-4-yl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-bromophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyclohexylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
N-[[(3-hydroxypropyl)amino](imino)methyl]-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;
2-[2-(4-cyanophenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}-2-[2-phenyl-5-(4-propylphenyl)-1H-pyrrol-1-yl]acetamide;
2-[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(4-butoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(4-cyclohexylphenyl)-5-phenyl-1H-pyrrol-1-yl]-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}-2-[2-(4-phenoxyphenyl)-5-phenyl-1H-pyrrol-1-yl]acetamide;
2-{2-[4-(4-acetylphenoxy)phenyl]-5-phenyl-1H-pyrrol-1-yl}-N-{imino[(2,3,4-trifluorobenzyl)amino]methyl}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(ethylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(propylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-cyanopropyl)amino]methylene}acetamide;
2-{[(Z)-({[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}imino)(amino)methyl]amino}ethyl acetate;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-hydroxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-hydroxyethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-cyanoethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1E)-amino{[2-(1,3-dioxolan-2-yl)ethyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(4-hydroxybutyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(tetrahydrofuran-2-ylmethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(2R)-2-hydroxypropyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(2S)-2-hydroxypropyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,3-dihydroxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1Z)-amino(isobutylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,2,2-trifluoroethyl)amino]methylene}acetamide;
ethyl 4-{[(Z)-({[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}imino)(amino)methyl]amino}butanoate;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1E)-amino(cyclopropylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(cyclohexylmethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(trans-4-hydroxycyclohexyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1E)-amino{[3-(1H-imidazol-1-yl)propyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(3-methoxypropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(2-methoxyethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2,2,3,3,3-pentafluoropropyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-[(1E)-amino(cycloheptylamino)methylene]acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-((1Z)-amino{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}methylene)acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-thien-2-ylethyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(3-aminobenzyl)amino]methylene}acetamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1E)-amino[(2-thien-3-ylethyl)amino]methylene}acetamide;
N-allyl-4-(1-{2-[((1Z)-amino{[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methylene)amino]-2-oxoethyl}-5-phenyl-1H-pyrrol-2-yl)benzamide;
N-allyl-4-(1-{2-[((1Z)-amino{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}methylene)amino]-2-oxoethyl}-5-phenyl-1H-pyrrol-2-yl)benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(2-thien-2-ylethyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-aminobenzyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
2-[2-(1-adamantyl)-5-phenyl-1H-pyrrol-1-yl]-N-{(1Z)-amino[(ethylsulfonyl)amino]methylene}acetamide;
N-(3-cyano-propyl)-N′-[2-(2-cyclohexyl-5-phenyl-pyrrol-1-yl)-acetyl]-guanidine;
N″-{[2-(4-butylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}guanidine;
N″-{[2-(2,5-dimethylphenyl)-5-phenyl-1H-pyrrol-1-yl]acetyl}guanidine;
N″-({2-[3-(cyanomethyl)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetyl)guanidine;
N″-({2-[4-(2-cyanoethyl)phenyl]-5-phenyl-1H-pyrrol-1-yl}acetyl)guanidine;
N″-[(2-cyclohexyl-5-phenyl-1H-pyrrol-1-yl)acetyl]guanidine;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-ethylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-cyclopropylbenzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-hydroxyethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-cyanoethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-propylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2-methoxyethyl)benzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(sec-butyl)benzamide;
N-allyl-4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-methylbenzamide;
4-{1-[2-({(1E)-amino[(3-hydroxypropyl)amino]methylene}amino)-2-oxoethyl]-5-phenyl-1H-pyrrol-2-yl}-N-(2,2,3,3,3-pentafluoropropyl)benzamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-[2-phenyl-5-(trans-4-propylcyclohexyl)-1H-pyrrol-1-yl]acetamide;
N-{(1E)-amino[(3-cyanopropyl)amino]methylene}-2-(2-cyclohexyl-5-phenyl-1H-pyrrol-1-yl)acetamide;
a tautomer thereof;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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