Substituted Indoles and Their Use as Integrin Antagonists

Abstract

The present invention relates to novel substituted indole compounds that are antagonists of alpha V (αv) integrins, for example α v β 3 and α v β 5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment of pathological conditions mediated by α v β 3 and α v β 5 integrins, including such conditions as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis. The compounds have the general formula: where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , D, X, W, a, m, n, i, j, k and v are defined herein.

1 - 65 . (canceled)  
     
     
         66 . A compound having the Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1 , R 2 , R 3 , R 4  and R 5  independently represent hydrogen, halogen, alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;  
 R 6 , R 7 , R 8  and R 9  independently represent hydrogen, alkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, aryl or aralkyl;  
 or R 6  and R 7  are taken together to form —(CH 2 ) p —, where p is 2-8, while R 8  and R 9  are defined as above; or R 8  and R 9  are taken together to form —(CH 2 ) q —, where q is 2-8, while R 6  and R 7  are defined as above; or R 6  and R 8  are taken together to form —(CH 2 ) r —, while r is zero (a bond), 1 or 2, while R 7  and R 9  are defined as above;  
 X represents oxygen, sulfur, —CH 2 —, —NH—, —(C═O)NH— or —NH(C═O)—;  
 n is from 0 to 4;  
 m is from 0 to 4;  
 a is 0 or 1;  
 D represents oxygen;  
 v is 0 or 1;  
 R 10 , R 11 , R 12  and R 13  independently represent: hydrogen; hydroxy; alkyl; alkoxy; cycloalkyl; aryl, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; monoalkylamino; dialkylamino; aminoalkyl; monoalkylaminoalkyl; dialkylaminoalkyl; alkanoyl; heteroaryl having 5-14 ring members, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; or  
                     
 wherein R 17  and R 18  together form —CH 2 CH 2 —O—, —O—CH 2 CH 2 —, —O—CH 2 —O— or —O—CH 2 CH 2 —O—; or  
 R 10  and R 12  are taken together to form —(CH 2 ) n —, wherein s is 0 (a bond) or 1 to 4, while R 11  and R 13  are as defined as above; or R 10  and R 12  are taken together to form a double bond when i is 0 and k is 1, while R 11  and R 13  are as defined above; or R 10  and R 11  are taken together to form —(CH 2 ) t —, wherein t is 2 to 8, while R 12  and R 13  are as defined as above, or R 12  and R 13  are taken together to form —(CH 2 ) n — wherein u is 2 to 8, while R 10  and R 11  are as defined as above;  
 i is from 0 to 4;  
 j is from 0 to 4;  
 k is 0 or 1;  
 R 14  is hydrogen or a functionality that acts as a prodrug (i.e., converts to the active species by an endogenous biological process such as an esterase, lipase, or other hydrolase), such as alkyl, aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl;  
 W is:  
                     
 wherein:  
 R 15  is hydrogen, halogen, alkyl, aryl or arylalkyl; and  
 R 16  is hydrogen, alkyl, haloalkyl or halogen.  
 
     
     
         67 . The compound of  claim 66 , wherein R 14  is a prodrug, selected from the group consisting of: alkyl, aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl.  
     
     
         68 . The compound of  claim 66 , wherein: 
 R 1 , R 2 , R 3 , R 4  and R 5  independently represent hydrogen, halogen, (C 1-8 )alkyl, (C 6-10 )aryl, (C 6-10 )ar(C 1-8 )alkyl, 5-14 member heteroaryl, or 5-14 member heteroaryl(C 1-8 )alkyl;    R 6 , R 7 , R 8  and R 9  independently represent hydrogen, (C 1-8 )alkyl, hydroxy(C 1-8 )alkyl, amino(C 1-8 )alkyl, mono(C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl, carboxy(C 1-8 )alkyl, (C 6-10 )aryl or (C 6-10 )ar(C 1-8 )alkyl;    or R 6  and R 7  are taken together to form —(CH 2 ) p —, where p is 2-8, while R 8  and R 9  are defined as above; or R 8  and R 9  are taken together to form —(CH 2 ) q —, where q is 2-8, while R 6  and R 7  are defined as above; or R 6  and R 3  are taken together to form —(CH 2 ) r —, while r is zero (a bond), 1 or 2, while R 7  and R 9  are defined as above;    X represents oxygen, sulfur, —CH 2 —, —NH—, —(C═O)NH— or —NH(C═O)—;    n is from 0 to 4;    m is from 0 to 4;    a is from 0 or 1;    D represents oxygen;    v is from 0 or 1;    R 10 , R 11 , R 12  and R 13  independently represent: hydrogen; hydroxy; (C 1-8 )alkyl; (C 1-8 )alkoxy; (C 3-8 )cycloalkyl; (C 6-10 )aryl, optionally substituted with one or more of halogen, hydroxy, cyano, (C 1-8 )alkyl, (C 6-10 )aryl, (C 1-8 )alkoxy, halo(C 1-8 )alkyl, (C 6-10 )aryl(C 1-8 )alkyl, (C 6-10 )aryl(C 1-8 )alkoxy, (C 6-10 )aryloxy, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkoxy(C 6-10 )aryl(C 1-8 )alkyl, mono(C 1-8 )alkylamino, di(C 1-8 )alkylamino, amino(C 1-8 )alkyl, mono(C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl, (C 1-8 )alkanoyl; mono(C 1-8 )alkylamino; di(C 1-8 )alkylamino; amino(C 1-8 )alkyl; mono(C 1-8 )alkylamino(C 1-8 )alkyl; di(C 1-8 )alkylamino(C 1-8 )alkyl; (C 1-8 )alkanoyl; heteroaryl having 5-14 ring members, optionally substituted with one or more of halogen, hydroxy, cyano, (C 1-8 )alkyl, (C 6-10 )aryl, (C 1-8 )alkoxy, halo(C 1-8 )alkyl, (C 6-10 )aryl(C 1-8 )alkyl, (C 6-10 )aryl(C 1-8 )alkoxy, (C 6-10 )aryloxy, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkoxy(C 6-10 )aryl(C 1-8 )alkyl, mono(C 1-8 )alkylamino, di(C 1-8 )alkylamino, amino(C 1-8 )alkyl, mono(C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl, (C 1-8 )alkanoyl; or                          wherein R 17  and R 18  together form —CH 2 CH 2 —O—, —O—CH 2 CH 2 —, —O—CH 2 —O— or —O—CH 2 CH 2 —O—; or    R 10  and R 12  are taken together to form —(CH 2 ) n —, wherein s is 0 (a bond) or 1 to 4, while R 11  and R 13  are as defined as above; or R 10  and R 12  are taken together to form a double bond when i is 0 and k is 1, while R 11  and R 13  are as defined above; or R 10  and R 11  are taken together to form —(CH 2 ) t —, wherein t is 2 to 8, while R 12  and R 13  are as defined as above, or R 12  and R 13  are taken together to form —(CH 2 ) n — wherein u is 2 to 8, while R 10  and R 11  are as defined as above; or    i is from 0 to 4;    j is from 0 to 4; and    k is 0 or 1; and    R 14  is hydrogen or a functionality that acts as a prodrug.    
     
     
         69 . The compound of  claim 66 , wherein R 1  and R 2  independently represent hydrogen, halogen, (C 1-6 )alkyl, (C 6-10 )aryl, (C 6-10 )ar(C 1-6 )alkyl, 5-14 member heteroaryl, or 5-14 member heteroaryl(C 1-8 )alkyl.  
     
     
         70 . The compound of  claim 69 , wherein R 1  and R 2  independently represent hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl or phenylethyl.  
     
     
         71 . The compound of  claim 70 , wherein R 1  and R 2  independently represent hydrogen, methyl, ethyl or propyl.  
     
     
         72 . The compound of  claim 66 , wherein R 3 , R 4  and R 5  independently represent hydrogen, (C 1-6 )alkyl, (C 6-10 )aryl, or (C 6-10 )ar(C 1-6 )alkyl.  
     
     
         73 . The compound of  claim 72 , wherein R 3 , R 4  and R 5  are hydrogen or (C 1-4 )alkyl.  
     
     
         74 . The compound of  claim 66 , wherein R 6 , R 7 , R 8  and R 9  independently represent hydrogen, halogen or (C 1-6 )alkyl.  
     
     
         75 . The compound of  claim 66 , wherein X is oxygen, —CH 2 — or —(C═O)NH—.  
     
     
         76 . The compound of  claim 75 , wherein X is oxygen or —CH 2 —.  
     
     
         77 . The compound of  claim 66 , wherein: 
 X is —(C═O)NH—;    n, m, a and v are each 0; and    R 6 , R 7 , R 12  and R 13  are hydrogen.    
     
     
         78 . The compound of  claim 66 , wherein: 
 X is oxygen;    n and m are each 0;    a and v are each 1;    D is oxygen;    R 6 , R 7 , R 8  and R 9  are hydrogen.    
     
     
         79 . The compound of  claim 66 , wherein: 
 X is oxygen;    n, m and v are each 0;    a is 1; and    R 6 , R 7 , R 12  and R 13  are hydrogen.    
     
     
         80 . The compound of  claim 66 , wherein: 
 X is —CH 2 —;    n, m and v are each 0;    a is 1; and    R 6 , R 7 , R 12  and R 13  are hydrogen.    
     
     
         81 . The compound of  claim 66 , wherein v is 0.  
     
     
         82 . The compound of  claim 66 , wherein: 
 R 1  is hydrogen or —CH 3 ;    R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are hydrogen;    X is oxygen or —CH 2 —;    n is 0 or 1;    m is 0 or 1;    R 10 , R 11 , R 12  and R 13  independently represent hydrogen, (C 1 -C 6 )alkyl or (C 6-10 )ar(C 1-6 )alkyl; or    one of the combination R 10  and R 11 , R 12  and R 13  or R 10  and R 12  are taken together to form —(CH 2 ) n —, wherein s is 1 while the remaining of R 10 —R 13  are defined above;    i is 0 or 1;    j is 0 or 1;    k is 0 or 1;    R 14  is hydrogen or alkyl;    W is:                          wherein:    R 15  is hydrogen, halogen, (C 1-8 )alkyl, (C 6-10 )aryl or (C 6-10 )aryl(C 1-8 )alkyl; and    R 16  is hydrogen, (C 1-8 )alkyl, halo(C 1-8 )alkyl or halogen.    
     
     
         83 . The compound of  claim 66 , which is one of: 
 3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;    3-{5-[3-(2-pyridylamino)propoxy]indolyl}acetic acid;    3-{2-methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;    2-(trans-2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropyl)acetic acid;    3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoic acid;    2-benzyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;    2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;    2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)pentanoic acid;    2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoic acid;    3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionic acid;    3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionic acid;    3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionic acid;    3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic acid;    or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.    
     
     
         84 . A pharmaceutical composition comprising a compound of  claim 66  and a pharmaceutically acceptable carrier or diluent.  
     
     
         85 . The compound according to  claim 66 , wherein R 12  and R 13  are independently selected from: