Modified lysine-mimetic compounds

Abstract

Lysine mimetic compounds having useful pharmacological activity such as antiarrhythmic activity and desirable bioavailability properties are disclosed.

1 . A compound having the Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, 
         wherein:
 Y′ is OR 2 , or NR 2 R 3 ; 
 k is 0, 1, or 2; 
 Z′ is selected from the group consisting of H, (CH 2 ) m —C 6-20  aryl, (CH 2 ) m -5-20 membered heteroaryl, C(O)(CH 2 ) m —C 6-20  aryl, C(O)(CH 2 ) m -5-20 membered heteroaryl, (CH 2 ) m C(O)—C 6-20  aryl, (CH 2 ) m C(O)-5-20 membered heteroaryl, S(O) 2 (CH 2 ) m —C 6-20  aryl, and S(O) 2 (CH 2 ) m -5-20 membered heteroaryl, wherein each of the C 6-20  aryl and 5-20 membered heteroaryl is optionally substituted with 1-5 Q groups; 
 m is 0, 1, or 2; 
 Q, at each occurrence, independently is selected from the group consisting of an optionally substituted C 1-10  alkyl, an optionally substituted C 2-10  alkenyl, an optionally substituted C 2-10  alkynyl, an optionally substituted C 3-20  cycloalkyl, an optionally substituted C 6-20  aryl, an optionally substituted C 7-20  aralkyl, an optionally substituted 3-20 membered cycloheteroalkyl, an optionally substituted 5-20 membered heteroaryl, F, Cl, Br, I, CN, CF 3 , OCF 3 , NO 2 , OR 8 , SR 8 , S + R 8   2 , S(O)R 8 , S(O) 2 R 8 , S(O) 2 OH, S(O) 2 NR 8 R 9 , NR 8 S(O) 2 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , NR 8 R 9 , NR 8 C(O)R 9 , NR 8 C(O)OR 9 , NR 8 C(O)NR 8 R 9 , and N + R 8   3 ; 
 R 1  is selected from the group consisting of H, an optionally substituted C 1-10  alkyl, an optionally substituted C 6-20  aryl, an optionally substituted C 7-20  aralkyl, and an amino acid side chain; 
 R 2  and R 3  each independently is selected from the group consisting of H, an optionally substituted C 1-10  alkyl, an optionally substituted C 3-20  cycloalkyl, an optionally substituted C 7-20  aralkyl, an optionally substituted C 6-20  aryl, an optionally substituted 3-20 membered cycloheteroalkyl, an optionally substituted 5-20 membered heteroaryl, C(O)R 6 , C(O)OR 6 , C(O)NR 6 R 7 , SO 2 R 6 , and SO 2 NR 6 R 7 ; 
 alternatively, R 2  and R 3  together with the nitrogen atom to which they are bound form a 3-20 membered heterocycle optionally containing 1-4 ring heteroatoms independently selected from O, N, or S and optionally substituted with 1-5 Q groups; 
 R 4  is OR 6  or NR 6 R 7 ; 
 R 5  is H or optionally substituted C 1-10  alkyl; 
 R 6  and R 7  each independently is selected from the group consisting of H, an optionally substituted C 1-10  alkyl, an optionally substituted C 3-20  cycloalkyl, an optionally substituted C 2-10  alkenyl, an optionally substituted C 2-10  alkynyl, an optionally substituted C 6-20  aryl, an optionally substituted C 7-20  aralkyl, an optionally substituted 3-20 membered cycloheteroalkyl, an optionally substituted 5-20 membered heteroaryl, C(O)R 8 , C(O)OR 8 , and C(O)NR 8 R 9 ; 
 alternatively, R 6  and R 7  together with the nitrogen atom to which they are bound form a 3-20 membered heterocycle optionally containing 1-4 ring heteroatoms independently selected from O, N or S and optionally substituted with 1-5 Q groups; and 
 R 8  and R 9  each independently is selected from the group consisting of H, an optionally substituted C 1-10  alkyl, an optionally substituted C 3-20  cycloalkyl, an optionally substituted C 2-10  alkenyl, an optionally substituted C 2-10  alkynyl, an optionally substituted C 6-20  aryl, an optionally substituted C 7-20  aralkyl, an optionally substituted 3-20 membered cycloheteroalkyl, and an optionally substituted 5-20 membered heteroaryl, 
 provided that the compound is not 1-(2-aminopropanoyl)-4-benzamidopyrrolidine-2-carboxylic acid. 
 
       
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein k is 0 or 1. 
     
     
         3 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein:
 Y′ is NR 2 R 3 ;   R 2  is H; and   R 3  is selected from the group consisting of H, an optionally substituted C 1-10  alkyl, C(O)R 6 , and C(O)OR 6 .   
     
     
         4 . The compound according to  claim 3 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein R 3  is H. 
     
     
         5 . The compound according to  claim 3 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein R 3  is C(O)R 6  and R 6  is H or an optionally substituted C 1-10  alkyl. 
     
     
         6 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein Y′ is OR 2 . 
     
     
         7 . The compound according to  claim 6 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein R 2  is H or an optionally substituted C 1-10  alkyl. 
     
     
         8 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein R 1  is H. 
     
     
         9 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein:
 R 1  is an amino acid side chain selected from the group consisting of valine, norvaline, leucine, norleucine, isoleucine, methionine, alanine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, ornithine, 2,4-diaminobutyric acid, and 2,6-diaminopimelic acid.   
     
     
         10 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein R 4  is OH or NH 2 . 
     
     
         11 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate or prodrug thereof, wherein:
 R 6  is H; and   R 7  is selected from the group consisting of an optionally substituted C 1-10  alkyl, an optionally substituted C 3-20  cycloalkyl, an optionally substituted 3-20 membered cycloheteroalkyl, and an optionally substituted C 6-20  aryl.   
     
     
         12 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein:
 R 6  and R 7  together with the nitrogen atom to which they are bound form a 3-20 membered heterocycle optionally containing 1-4 ring heteroatoms independently selected from O, N, or S and optionally substituted with 1-5 Q groups; and   the 3-20 membered heterocycle is selected from the group consisting of piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, oxazolidine, thiazolidine, and imidazolidine.   
     
     
         13 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein:
 Z′ is C(O)(CH 2 ) m —C 6-20  aryl optionally substituted with 1-5 Q groups; and   m is 0.   
     
     
         14 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, wherein Z′ is benzoyl. 
     
     
         15 . The compound according to  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof. 
       
     
     
         16 . The compound according to  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof. 
       
     
     
         17 . The compound according to  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof. 
       
     
     
         18 . The compound according to  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof. 
       
     
     
         19 . The compound according to  claim 1 , selected from the group consisting of:
 1-(2-Amino-acetyl)-4-(4-nitro-benzoylamino)-pyrrolidine-2-carboxylic acid;   1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid;   1-(2-Amino-acetyl)-4-(4-methyl-benzoylamino)-pyrrolidine-2-carboxylic acid;   1-(2-Amino-acetyl)-4-(4-methoxy-benzoylamino)-pyrrolidine-2-carboxylic acid;   1-(2-Amino-acetyl)-4-(4-hydroxy-benzoylamino)-pyrrolidine-2-carboxylic acid;   1-(3-Amino-propionyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; and   4-Benzoylamino-1-(2-hydroxy-acetyl)-pyrrolidine-2-carboxylic acid,   and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof.   
     
     
         20 . The compound according to  claim 19  selected from the group consisting of:
 (2S,4R)1-(2-Amino-acetyl)-4-(4-nitro-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(2-Amino-acetyl)-4-(4-methyl-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(2-Amino-acetyl)-4-(4-methoxy-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(3-Amino-propionyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(2-Amino-acetyl)-4-(4-hydroxy-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4S)1-(2-Amino-acetyl)-4-(4-methoxy-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4S)1-(2-Amino-acetyl)-4-(4-methyl-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4S)1-(2-Amino-acetyl)-4-(4-nitro-benzoylamino)-pyrrolidine-2-carboxylic acid; 
 (2S,4S)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; and 
 (2S,4R)4-Benzoylamino-1-(2-hydroxy-acetyl)-pyrrolidine-2-carboxylic acid, 
 and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof. 
 
     
     
         21 . The compound according to  claim 1 , selected from the group consisting of:
 1-(2-Amino-4-carboxy-butyryl)-4-benzoylamino-pyrrolidine-2-carboxylic acid;   1-[2-Amino-3-(1H-indol-3-yl)-propionyl]-4-benzoylamino-pyrrolidine-2-carboxylic acid;   1-(2-Amino-4-methyl-pentanoyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; and   1-(2-Amino-3-phenyl-propionyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid;   and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof.   
     
     
         22 . The compound according to  claim 21  selected from the group consisting of:
 (2S,4R)1-(2-Amino-4-carboxy-butyryl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-[2-Amino-3-(1H-indol-3-yl)-propionyl]-4-benzoylamino-pyrrolidine-2-carboxylic acid; 
 (2S,4R)1-(2-Amino-4-methyl-pentanoyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid; and 
 (2S,4R)1-(2-Amino-3-phenyl-propionyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid, 
 and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof. 
 
     
     
         23 . The compound according to  claim 1 , selected from the group consisting of:
 1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-methylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-ethylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-isopropylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-cyclopropylpyrrolidine-2-carboxamide;   4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-(pentan-3-yl)pyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-cyclopentylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-isobutylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-cyclobutylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-tert-butylpyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-(3-methylbutan-2-yl)pyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-(3,3-dimethylbutan-2-yl)pyrrolidine-2-carboxamide;   1-(2-aminoacetyl)-4-benzamido-N-phenylpyrrolidine-2-carboxamide; and   1-(2-aminoacetyl)-4-benzamido-N-(tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide,   and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof.   
     
     
         24 . The compound according to  claim 23  selected from the group consisting of:
 (2S,4R)1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-methylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-ethylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-isopropylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-cyclopropylpyrrolidine-2-carboxamide; 
 (2S,4R)4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-(pentan-3-yl)pyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-cyclopentylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-isobutylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-cyclobutylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-tert-butylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N—((R)-3-methylbutan-2-yl)pyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N—((R)-3,3-dimethylbutan-2-yl)pyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N-phenylpyrrolidine-2-carboxamide; 
 (2S,4R)1-(2-aminoacetyl)-4-benzamido-N—((R)-tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide, 
 and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof. 
 
     
     
         25 . The compound according to  claim 1 , selected from the group consisting of:
 1-(2-acetamidoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid;   4-benzamido-1-(2-(methylamino)acetyl)-pyrrolidine-2-carboxylic acid;   4-benzamido-1-(2-(2,2,2-trifluoroacetamido)acetyl)pyrrolidine-2-carboxylic acid;   4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid;   4-benzamido-1-(2-(dimethylamino)acetyl)pyrrolidine-2-carboxylic acid; and   4-benzamido-1-(2-formamidoacetyl)pyrrolidine-2-carboxylic acid,   and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof.   
     
     
         26 . The compound according to  claim 25  selected from the group consisting of:
 (2S,4R)1-(2-acetamidoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; 
 (2S,4R)4-benzamido-1-(2-(methylamino)acetyl)-pyrrolidine-2-carboxylic acid; 
 (2S,4R)4-benzamido-1-(2-(2,2,2-trifluoroacetamido)acetyl)pyrrolidine-2-carboxylic acid; 
 (2S,4R)4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid; 
 (2S,4R)4-benzamido-1-(2-(dimethylamino)acetyl)pyrrolidine-2-carboxylic acid; and 
 (2S,4R)4-benzamido-1-(2-formamidoacetyl)pyrrolidine-2-carboxylic acid, 
 and pharmaceutically acceptable salts, esters, hydrates, and prodrugs thereof. 
 
     
     
         27 . A prodrug of a compound according to  claim 1 , wherein the prodrug is an oxazolidinone or imidazolidinone prodrug. 
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt, ester, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of treating or preventing a pathological condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition according to  claim 1 . 
     
     
         30 . The method according to  claim 29 , wherein the subject is a human being. 
     
     
         31 . The method according to  claim 29 , wherein the pathological condition is selected from the group consisting of cardiovascular disease; osteoporosis; inflammation of airway epithelium; disorders of alveolar tissue; bladder incontinence; impaired hearing; endothelial lesions; Type I or Type II diabetes; diabetic retinopathy; diabetic neuropathy; atherosclerosis; CNS related conditions; seizures; ischemia; dental tissue disorders; kidney diseases; anaemia; leukopenia; thrombocytopenia; pancytopenia; superficial wounds; deep wounds resulting from trauma; bone fractures; erectile dysfunction; urinary bladder incontinence; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow; stem cell transplantation; conditions arising during transplantation of cells and tissues; conditions arising during medical procedures; conditions caused by an excess of reactive oxygen species, free radicals or nitric oxide; diseases or disorders of pregnancy; female infertility; and stroke. 
     
     
         32 . The method according to  claim 29 , wherein the pathological condition is cardiovascular disease. 
     
     
         33 . The method according to  claim 32 , wherein the cardiovascular disease is selected from atrial fibrillation, atrial flutter, ventricular tachycardia and ventricular fibrillation. 
     
     
         34 . The method according to  claim 29 , wherein the compound is formulated for parenteral or oral administration. 
     
     
         35 . A method of treating ischemia, or ischemic injury in the organs of a mammal, comprising administering to a subject a therapeutically effective amount of a compound or pharmaceutical composition according to  claim 1 . 
     
     
         36 . The method according to  claim 35 , for treating acute ischemic heart disease, stable or unstable angina pectoris, or acute myocardial infarction. 
     
     
         37 . The method according to  claim 35 , for treating ischemic injury in the gastrointestinal tract, the heart, the kidney, the liver, the lungs, the central nervous system, or the limbs. 
     
     
         38 . The method according to  claim 35 , wherein the subject is a human being. 
     
     
         39 . The method according to  claim 35 , wherein the compound is formulated for parenteral or oral administration.