IDO Inhibitors

Abstract

Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosuppression associated with an infectious disease.

1 . A compound of the formula, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         bond α is a single bond; 
         n is 0, 1, 2, 3, or 4; 
         each R 1  is independently halogen, cyano, nitro, C 1-6  alkyl, C 1-6 haloalkyl, —OR, —N(R) 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R) 2 ; 
         R 2  is —C 1-4  alkyl-R A  or —C 2-4 alkenyl-R 3  when bond α is a single bond; and 
         wherein
 R A  is —C(O)R 3 , —C(O)OR 3 , —C(O)N(R 3 )(R C ), —C(OR B )(R 3 )(R C ), —C(NHR B )(R 3 )(R C ), or —C(═N—OR C )R 3 , wherein
 R B  is hydrogen, C 1-6  alkyl, C 1-6 haloalkyl, —C 1-6  alkyl-R B1 , —C(O)R 3 , —C(O)N(H)R 3 , or —S(O) 2 R 3 , —C(O)(CH 2 ) 1-4 COOR, —C(O)(CH 2 ) 1-4 (NR)COOR, —C(O)CH(NH 2 )(R D ), —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , —CH 2 —OP(O) 2 (OR) 2 , or —P(O)(OR 3 ) 2 , wherein
 R B1  is cyano, nitro, C 1-6  alkyl, C 1-6 haloalkyl, —OR, —N(R) 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R) 2 ; 
 R D  is hydrogen, methyl, —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), benzyl, 4-hydroxybenzyl, —CH 2 (3-indolyl), —CH 2 SH, —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —N(H)C(═NH)NH 2 , —CH 2 (4-imidazolyl), —CH 2 COOH, —CH 2 CH 2 COOH, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 ; 
 
 each R 3  is independently aryl, heteroaryl, arylC 1-6  alkyl-, or heteroarylC 1-6  alkyl-, 
 wherein
 the aryl, heteroaryl, arylC 1-6  alkyl-, and heteroarylC 1-6  alkyl- groups, are each optionally substituted by one, two, three, or four R 31  groups; 
 wherein 
 each R 31  is independently halogen, cyano, nitro, C 1-6  alkyl, —C 1-6  alkyl-R 33 , C 1-6 haloalkyl, —OR, —N(R) 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)N(OH)R, —C(O)R, —C(NR 11 )R, —C(NR 11 )N(R 11 )R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , wherein 
  R 33  is cyano, —OR, —N(R) 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R) 2 ; 
 
 R C  is hydrogen or C 1-6  alkyl; 
 
 
         and 
         each R is independently hydrogen or R 10 , wherein
 R 10  is C 1-6  alkyl, C 1-6 haloalkyl, aryl, heteroaryl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-10 membered heterocyclyl, arylC 1-6  alkyl, heteroarylC 1-6  alkyl-, C 3-8  cycloalkylC 1-6  alkyl-, C 3-8  cycloalkenylC 1-6  alkyl-, or (3-10 membered heterocyclyl)C 1-6  alkyl-, each R 10  optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6  alkyl, C 1-6 haloalkyl, —OR 11 , —N(R 11 ) 2 , —SR 11 , —C(O)OR 11 , —C(O)N(R 11 ) 2 , —C(O)R 11 , —S(O)R 11 , —S(O)OR 11 , —S(O)N(R 11 ) 2 , —S(O) 2 R 11 , —S(O) 2 OR 11 , —S(O) 2 N(R 11 ) 2 , —OC(O)R 11 , —OC(O)OR 11 , —OC(O)N(R 11 ) 2 , —N(R 11 )C(O)R 11 , —N(R 11 )C(O)OR 11 , —N(R 11 )C(O)N(R 11 ) 2 , —N(R 11 )S(O) 2 R 11 , or —C(O)-(3-10 membered heterocyclyl),
 wherein each R 11  is independently hydrogen or C 1-6  alkyl. 
 
 
       
     
     
         2 . The compound according to  claim 1  wherein R 3  is phenyl or a five or six membered heteroaryl, each optionally substituted by one or two R 31  groups. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is —C 1-4  alkyl-R A . 
     
     
         4 . The compound of  claim 2 , wherein R 2  is —CH 2 —R A , —CH 2 CH 2 —R A , —C(H)(CH 3 )CH 2 —R A , or —C(H)═C(H)R 3 . 
     
     
         5 . The compound of  claim 3 , wherein R 2  is —CH 2 —R A . 
     
     
         6 . The compound of  claim 4 , wherein R A  is —C(O)R 3  or —C(OR B )(R 3 )(R C ). 
     
     
         7 . The compound of  claim 4 , wherein R A  is —C(NHR B )(R 3 )(R C ), or —C(═N—OR C )R 3 . 
     
     
         8 . The compound of  claim 4 , wherein R A  is —C(NHR B )(R 3 )(R C ), wherein R B  is hydrogen, C 1-6  alkyl, or —C(O)C 1-6  alkyl. 
     
     
         9 . The compound of  claim 4 , wherein R A  is —C(NH 2 )(R 3 )(R C ). 
     
     
         10 . The compound of  claim 4 , wherein R A  is —CH(OH)(R 3 ). 
     
     
         11 . The compound of  claim 1  of the formula, 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein
 R 3  is aryl, heteroaryl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, or 3-10 membered heterocyclyl, wherein
 the C 3-8  cycloalkyl, C 3-8  cycloalkenyl, and 3-10 membered heterocyclyl are each optionally substituted by one ═R 32  group and one, two, three, or four R 31  groups; and 
 the aryl and heteroaryl are each optionally substituted by one, two, three, or four R 31  groups. 
   
     
     
         13 . The compound of  claim 11  of the formula, 
       
         
           
           
               
               
           
         
       
       wherein the stereoisomeric configuration of carbon-1 (C-1) and carbon-3 (C-3) are respectively (R, R), (R, S), (S, R) or (S, S). 
     
     
         14 . The compound of  claim 11  of the formula, 
       
         
           
           
               
               
           
         
       
       wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R) or (S, S), and wherein R 3  is cyclohexyl and R 31  is OR 
     
     
         15 . The compound of  claim 11  of the formula, 
       
         
           
           
               
               
           
         
       
       wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R), or (S, S) and wherein R 3  is piperidine and R 31  is —C(O)R or —C(O)(NHR). 
     
     
         16 . A compound that is
 (E)-5-(2-bromostyryl)-5H-imidazo[5,1-a]isoindole;   tert-butyl (4-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate;   1-(4-aminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone;   tert-butyl (4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate;   1-(4-aminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-nitrophenyl)ethanone;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-nitrophenyl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-nitrophenyl)ethanone;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-nitrophenyl)ethanol;   tert-butyl (2-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate;   tert-butyl (2-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate;   1-(2-aminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone;   1-(2-aminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   1-(2-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone;   1-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-2-ol;   1-(2-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   1-(3-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-phenylethanone;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-phenylethanol;   1-(2,4-dimethylfuran-3-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   1-(3-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone;   tert-butyl (3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate;   1-(3-aminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(thiazol-4-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(thiazol-5-yl)ethanol;   2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(furan-2-yl)ethanol;   2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-3-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-4-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-2-yl)ethanol;   N-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethanol;   2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-4-yl)ethanol;   2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(thiazol-2-yl)ethanol;   or a pharmaceutically acceptable salt of one of the foregoing.   
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable diluent, excipient, or carrier. 
     
     
         18 . A method for treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound according to  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the immunosuppression is associated with an infectious disease or cancer. 
     
     
         20 . The method of  claim 19 , wherein the immunosuppression is associated with a cancer.