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US 2004/0171848 A1Published application
Fluoropyrrolidines as dipeptidyl peptidase inhibitors
AssigneeSmithKlineBeecham Corporation
InventorsCurt Dale Haffner, Darryl Lynn McDougald, Amarjit Sab Randhawa, Steven Michael Reister, James Martin Lenhard
Life of this patent
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Abstract
The present invention relates to novel compounds, their use for inhibiting serine proteases, such as dipeptidyl peptidases, such as dipeptidyl peptidase IV (DPP-IV) and to methods for their production and their therapeutic utility.
Claims51
A compound of formula (I):
- 62
- including salts, solvates, and pharmaceutically functional derivatives thereof, wherein
- X is For H;
- R1 and R2 each are either
- (i) H;
- (ii) alkyl;
- (iii) optionally substituted aryl or heteroaryl;
- or
- (iv) combine to form a 3 to 14 membered ring sytem, optionally containing one or more heteroatoms, and optionally containing one or more degrees of unsaturation;
- when R1 and R2 are (iii), then R3 is H or alkyl;
- when R1 and R2 are (i), (ii), or (iv), then R3 is
- 63
- where n is 0-5;
- m is 0-12;
- Y is S(O)p, O, alkylene, alkenylene, alkynylene, or a bond;
- p is 0-2;
- R4 is R5 when Y is S, O, alkylene, alkenylene, alkynylene, or a bond, where R5 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;
- R4 is R6 when Y is S(O) or S(O)2, where R6 is optionally substituted alkyl, aryl, cycloalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino, or hydroxy.
15 more elements
A compound of formula (I):
- 65
- including salts, solvates, and pharmaceutically functional derivatives thereof, wherein
- X is F or H;
- R1 and R2 each are optionally substituted aryl or heteroaryl;
- and
- R3 is H or alkyl.
3 more elements
A compound of formula (I):
- 66
- including salts, solvates, and pharmaceutically functional derivatives thereof, wherein
- X is F or H;
- R1 and R2 each are either
- (iii) alkyl;
- or
- (iv) combine to form a 3 to 14 membered ring sytem, optionally containing one or more heteroatoms, and optionally containing one or more degrees of unsaturation;
- R3 is
- 67
- where n is 0-5;
- m is 0-12;
- Y is S(O)p, O, alkylene, alkenylene, or alkynylene;
- p is 0-2;
- R4 is R5 when Y is S, O, alkylene, alkenylene, or alkynylene, where R5 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;
- R4 is R6 when Y is S(O) or S(O)2, where R5 is optionally substituted alkyl, aryl, cycloalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino, or hydroxy.
12 more elements
A compound selected from:
- 68
A compound selected from:
- 69
A compound selected from:
- (2S,4S)-1-[(2S)-2-Amino-3,3-diphenyl propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-5-(4-fluorophenyl)-3,3-dimethyl pentanoyl]-4-fluoro-2-pyrrolidinecarbonitrile hydrochloride;
- (2S,4R)-1-[(2S)-2-Amino-4-(4-fluorophenyl)-3,3-dimethylbutanoyl]-4-fluoropyrrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(4-methoxybenzyl)thio]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(3-phenylpropyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(2-phenylethyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-((2R)-2-Amino-3-{[3-(4-fluorophenyl)propyl]thio}-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(4-methoxybenzyl)sulfonyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(4-methoxybenzyl)sulfinyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-((2R)-2-Amino-3-methyl-3-{[4-(trifluoromethyl)benzyl]thio}butanoyl)-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-2-(1-vinylcyclopentyl)ethanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-5-(4-methoxyphenyl)-3,3-dimethylpentanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(3-phenylpropyl)sulfonyl]butanoyl}-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(4-methylbenzyl)sulfonyl]butanoyl}-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-((2R)-2-amino-3-{[4-(benzyloxy)benzyl]sulfonyl}-3-methyl butanoyl)-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-{(2R)-2-amino-3-[(4-cyanobenzyl)sulfonyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-((2R)-2-amino-3-methyl-3-{[4-(methylsulfonyl)benzyl]sulfonyl}butanoyl)-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-{(2S)-2-Amino-2-[1-(4-fluorobenzyl)cyclopentyl]ethanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-((2S)-2-Amino-2-{1-[4-(trifluoromethyl)phenyl]cyclopentyl}ethanoyl)-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2S)-2-Amino-2-[1-(4-fluorobenzyl)cyclopropyl]ethanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2R)-2-Amino-3-(benzylsulfonyl)-3-methylbutanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-amino-3-[(3-methoxybenzyl)sulfonyl]-3-methylbutanoyl}-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(1,1′-biphenyl-4-ylmethyl)sulfonyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(2-methoxybenzyl)sulfonyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(pyridin-3-yl methyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(pyridin-2-ylmethyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-amino-3-methyl-3-[(pyridin-4-ylmethyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-amino-3-[(4-fluorobenzyl)sulfonyl]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-amino-3-methyl-3-[(3-phenoxybenzyl)sulfonyl]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-amino-3-methyl-3-[(3-phenoxybenzyl)thio]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-((2R)-2-Amino-3-{[(5-chloro-1,1-dioxido-1-benzothien-3-yl)methyl]sulfonyl}-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-[(2,1,3-benzoxadiazol-5-ylmethyl)thio]-3-methylbutanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2R)-2-Amino-3-methyl-3-[(pyridin-4-ylmethyl)sulfonyl]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-pyridin-4-ylpropanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-pyridin-3-ylpropanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-piperidin-4-yl propanoyl]-4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-piperidin-3-ylpropanoyl]-4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-piperidin-2-ylpropanoyl]-4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
- (2S,4S)-1-{(25)-2-Amino-3-[1-(isopropylsulfonyl)piperidin-4-yl]propanoyl}-4-fluoropyrrolidine-2-carbonitrilehydrochloride;
- (2S,4S)-1-{(2S)-2-Amino-3-[1-(4-methylphenylsulfonyl)piperidin-4-yl]propanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2S)-2-Amino-3-[1-(isopropylsulfonyl)piperidin-3-yl]propanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2S)-2-Amino-3-[1-(4-methylphenylsulfonyl)piperidin-3-yl]propanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-[(2S)-2-Amino-3-(1-benzothien-3-yl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- (2S,4S)-1-{(2S)-2-Amino-3-methyl-3-[4-(trifluoromethyl)phenyl]butanoyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride;
- and
- (3R)-3-Amino-4-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]-2-methyl-4-oxobutane-2-sulfonic acid.
44 more elements
Dependencies are inferred from the claim text.