IDO Inhibitors

Abstract

Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) 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 as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier and a compound of the formula (XL), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         ring A is benzothienyl, benzothiazolyl, or benzofuranyl, each optionally substituted with one or more R A  groups, wherein
 each R A  is independently halogen, cyano, nitro, —N(R A1 ) 2 , —OR A1 , —N(R A1 )N(R A1 ) 2 , —SR A1 , —C(O)R A1 , —C(O)OR A1 , —C(O)N(R A1 ) 2 , —S(O)R A1 , —S(O)OR A1 , —S(O)N(R A1 ) 2 , —S(O) 2 R A1 , —S(O) 2 O R A1 , —S(O) 2 N(R A1 ) 2 , —OC(O)R A1 , —OC(O)OR A1 , —OC(O)N(R A1 ) 2 , —N(R A1 )C(O)R A1 , —N(R A1 )S(O) 2 R A1 , —N(R A1 )C(O)OR A1 , —N(R A1 )C(O)N(R A1 ) 2 , —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl; —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, -heterocyclyl, —N(R A1 ) 2 , —OR A1 , —N(R A1 )N(R A1 ) 2 , —SR A1 , —C(O)R A1 , —C(O)OR A1 , —C(O)N(R A1 ) 2 , —S(O)R A1 , —S(O)OR A1 , —S(O)N(R A1 ) 2 , —S(O) 2 R A1 , —S(O) 2 OR A1 , —S(O) 2 N(R A1 ) 2 , —OC(O)R A1 , —OC(O)OR A1 , —OC(O)N(R A1 ) 2 , —N(R A1 )C(O)OR A1 , or —N(R A1 )C(O)N(R A1 ) 2 , wherein
 each R A1  is independently hydrogen, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, —N(R A2 ) 2 , —OR A2 , —N(R A2 )N(R A2 ) 2 , —SR A2 , —C(O)R A2 , —C(O)OR A2 , —C(O)N(R A2 ) 2 , —S(O)R A2 , —S(O)OR A2 , —S(O)N(R A2 ) 2 , —S(O) 2 R A2 , —S(O) 2 R A2 , —S(O) 2 N(R A2 ) 2 , —OC(O)R A2 , —OC(O)OR A2 , —OC(O)N(R A2 ) 2 , —N(R A2 )C(O)OR A2 , or —N(R A2 )C(O)N(R A2 ) 2 , wherein
 each R A2  is independently hydrogen, —C 1 -C 6  alkyl, aryl, or —C 1 -C 6  alkylaryl; and 
 
 
 
         L is a bond or —C(H)(R L )—, wherein
 R L  is hydrogen, halogen, cyano, nitro, —N(R L1 ) 2 , —OR L1 , —ON(R L1 ) 2 , —N(R L1 )N(R L1 ) 2 , —N(R L1 )C(O)R L1 , —N(R L1 )S(O) 2 R L1 , —SR L1 , —C(O)R L1 , —C(O)OR L1 , —C(O)N(R L1 ) 2 , —S(O)R L1 , —S(O)OR L1 , —S(O)N(R L1 ) 2 , —S(O) 2 R L1 , —S(O) 2 OR L1 , —S(O) 2 N(R L1 ) 2 , —OC(O)R L1 , —OC(O)OR L1 , —OC(O)N(R L1 ) 2 , —N(R L1 )C(O)OR L1 , —N(R L1 )C(O)N(R L1 ) 2 , —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, —C 1 -C 6  alkyl(C 3 -C 8 )cycloalkyl, -heterocyclyl, or —C 1 -C 6  alkylheterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl, and alkylheterocyclyl is optionally substituted with one halogen, cyano, nitro, —N(R L1 ) 2 , —N(R L1 )C(O)R L1 , —OR L1 , —N(R L1 )N(R L1 ) 2 , —SR L1 , —C(O)R L1 , —C(O)OR L1 , —C(O)N(R L1 ) 2 , —S(O)R L1 , —S(O)OR L1 , —S(O)N(R L1 ) 2 , —S(O) 2 R L1 , —S(O) 2 OR L1 , —S(O) 2 N(R L1 ) 2 , —OC(O)R L1 , —OC(O)OR L1 , —OC(O)N(R L1 ) 2 , —N(R L1 )C(O)OR L1 , or —N(R L1 )C(O)N(R L1 ) 2 , wherein
 each R L1  is independently hydrogen, —C 1 -C 6  alkyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, —C 1 -C 6  alkyl(C 3 -C 8 )cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, —N(R L11 ) 2 , —OR L11 , —ON(R L11 ) 2 , —N(R L11 )N(R L11 ) 2 , —SR L11 , —C(O)R L11 , —C(O)OR L11 , —C(O)N(R L11 ) 2 , —S(O)R L11 , —S(O)OR L11 —S(O)N(R L11 ) 2 , —S(O) 2 R L11 , —S(O) 2 OR L11 , —S(O) 2 N(R L11 ) 2 , —OC(O)R L11 , —OC(O)OR L11 —OC(O)N(R L11 ) 2 , —N(R L11 )C(O)OR L11 , or —N(R L11 )C(O)N(R L11 ) 2 , wherein each R L11  is independently hydrogen, —C 1 -C 6  alkyl, aryl, or —C 1 -C 6  alkylaryl. 
 
 
       
     
     
         2 - 11 . (canceled) 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein R L  is hydrogen. 
     
     
         13 - 19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier and a compound selected from
 O-((5-chlorobenzo[b]thiophen-3-yl)methyl)hydroxylamine,   O-(benzo[d]thiazol-2-ylmethyl)hydroxylamine,   O-(benzofuran-2-ylmethyl)hydroxylamine,   and a pharmaceutically acceptable salt thereof   
     
     
         21 . 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 pharmaceutical composition of any one of  claims 1 ,  12 , and  20 . 
     
     
         22 - 26 . (canceled) 
     
     
         27 . 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 of formula (XXI), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein ring A is benzothienyl, benzothiazolyl, or benzodioxanyl, each optionally substituted with one or more R A  groups, wherein
 each R A  is independently halogen, cyano, nitro, —N(R A1 ) 2 , —OR A1 , —ON(R A1 ) 2 , —N(R A1 )N(R A1 ) 2 , —SR A1 , —C(O)R A1 , —C(O)OR A1 , —C(O)N(R A1 ) 2 , —S(O)R A1 , —S(O)OR A1 , —S(O)N(R A1 ) 2 , —S(O) 2 R A1 , —S(O) 2 OR A1 , —S(O) 2 N(R A1 ) 2 , —OC(O)R A1 , —OC(O)OR A1 , —OC(O)N(R A1 ) 2 , —N(R A1 )C(O)OR A1 , —N(R A1 )C(O)N(R A1 ) 2 , —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl; —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, -heterocyclyl, —N(R A1 ) 2 , —OR A1 , —ON(R A1 ) 2 , —N(R A1 )N(R A1 ) 2 , —SR A1 , —C(O)R A1 , —C(O)OR A1 , —C(O)N(R A1 ) 2 , —S(O)R A1 , —S(O)OR A1 , —S(O)N(R A1 ) 2 , —S(O) 2 R A1 , —S(O) 2 OR A1 , —S(O) 2 N(R A1 ) 2 , —OC(O)R A1 , —OC(O)OR A1 , —OC(O)N(R A1 ) 2 , —N(R A1 )C(O)OR A1 , or —N(R A1 )C(O)N(R A1 ) 2 , wherein
 each R A1  is independently hydrogen, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl; —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, —N(R A2 ) 2 , —OR A2 , —ON(R A2 ) 2 , —N(R A2 )N(R A2 ) 2 , —SR A2 , —C(O)R A2 , —C(O)OR A2 , —C(O)N(R A2 ) 2 , —S(O)R A2 , —S(O)OR A2 , —S(O)N(R A2 ) 2 , —S(O) 2 R A2 , —S(O) 2 R A2 , —S(O) 2 N(R A2 ) 2 , —OC(O)R A2 , —OC(O)OR A2 , —OC(O)N(R A2 ) 2 , —N(R A2 )C(O)OR A2 , or —N(R A2 )C(O)N(R A2 ) 2 , wherein
 each R A2  is independently hydrogen, —C 1 -C 6  alkyl, aryl, or —C 1 -C 6  alkylaryl; and 
 
 
 L is a bond or —X-L 1 -, wherein
 X is bonded to A, and is a bond, —O—, —S—, —N(R X )—, —C(Y)—, —S(O)—, —S(O) 2 —, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(R X )—, —N(R X )C(O)O—, —C(O)N(R X )—, —N(R x )C(O)—, —N(R x )C(O)N(R x )—, —S(O)O—, —OS(O)—, —S(O)N(R x )—, —N(R x)S (O)—, —S(O) 2 O—, —OS(O) 2 —, —S(O) 2 N(R X )—, —N(R X )S(O) 2 —, —C 1 -C 3 alkylO-, —C 1 -C 3 alkylS-, —C 1 -C 3 alkylN(R X )—, —C 1 -C 3 alkylC(Y)—, —C 1 -C 3 alkylS(O)—, —C 1 -C 3 alkylS(O) 2 —, —C 1 -C 3 alkylC(O)O—, —C 1 -C 3 alkylOC(O)—, —C 1 -C 3 alkylOC(O)O—, —C 1 -C 3 alkylN(R X )—C(O)O—, —C 1 -C 3 alkylC(O)—(R X )—, —C 1 -C 3 alkylC(O)N(R X )—, —C 1 -C 3 alkylN(R X )C(O)—, —C 1 -C 3 alkylN(R X )C(O)N(R X )—, —C 1 -C 3 alkylS(O)O—, —C 1 -C 3 alkylOS(O)—, —C 1 -C 3 alkylS(O)—N(R X )—, —C 1 -C 3 alkylN(R X )S(O)—, —C 1 -C 3 alkylS(O) 2 O—, —C 1 -C 3 alkylOS(O) 2 —, —C 1 -C 3 alkyl—S(O) 2 N(R X )—, or —C 1 -C 3 alkylN(Rx) S(O) 2 —, wherein
 each Rx is independently hydrogen or —C 1 -C 6  alkyl; 
 Y is ═O, ═S, or ═NH; and 
 
 L 1  is -linear C 1 -C 6 alkyl- or -linear C 2 -C 6 alkenyl-, wherein the alkyl and alkenyl are each optionally substituted with one or two R L  groups, wherein
 each R L  is independently halogen, cyano, nitro, —N(R L1 ) 2 , —OR L1 , —ON(R L1 ) 2 , —N(R L1 )N(R L1 ) 2 , —N(R L1 )C(O)R L1 , —SR L1 , —C(O)R L1 , —C(O)OR L1 , —C(O)N(R L1 ) 2 , —S(O)R L1 , —S(O)OR L1 , —S(O)N(R L1 ) 2 , —S(O) 2 R L1 , —S(O) 2 OR L1 , —S(O) 2 N(R L1 ) 2 , —OC(O)R L1 , —OC(O)OR L1 , —OC(O)N(R L1 ) 2 , —N(R L1 )C(O)OR L1 , —N(R L1 )C(O)N(R L1 ) 2 , —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, —C 1 -C 6  alkylC 3 -C 8  cycloalkyl, -heterocyclyl, or —C 1 -C 6  alkylheterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or two halogen, cyano, nitro, —N(R L1 ) 2 , —OR L1 , —ON(R L1 ) 2 , —N(R L1 )N(R L1 ) 2 , —SR L1 , —C(O)R L1 , —C(O)OR L1 , —C(O)N(R L1 ) 2 , —S(O)R L1 , —S(O)OR L1 , —S(O)N(R L1 ) 2 , —S(O) 2 R L1 , —S(O) 2 OR L1 , —S(O) 2 N(R L1 ) 2 , —OC(O)R L1 , —OC(O)OR L1 , —OC(O)N(R L1 ) 2 , —N(R L1 )C(O)R L1 , —N(R L1 )C(O)OR L1 , or —N(R L1 )C(O)N(R L1 ) 2 , 
 wherein
 each R L1  is independently hydrogen, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl; —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, -aryl, —C 1 -C 6  alkylaryl, -heteroaryl, —C 1 -C 6  alkylheteroaryl, —C 3 -C 8  cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, —N(R L2 ) 2 , —OR L2 , —ON(R L2 ) 2 , —N(R L2 )N(R L2 ) 2 , —SR L2 , —C(O)R L2 , —C(O)OR L2 , —C(O)N(R L2 ) 2 , —S(O)R L2 , —S(O)OR L2 , —S(O)—N(R L2 ) 2 , —S(O) 2 R L2 , —S(O) 2 OR L2 , —S(O) 2 N(R L2 ) 2 , —OC(O)R L2 , —OC(O)—OR L2 , —OC(O)N(R L2 ) 2 , —N(R L2 )C(O)OR L2 , or —N(R L2 )C(O)N(R L2 ) 2 , wherein 
  each R L2  is independently hydrogen, —C 1 -C 6  alkyl, aryl, or —C 1 -C 6  alkylaryl. 
 
 
 
 
     
     
         28 - 34 . (canceled) 
     
     
         35 . The method of  claim 27 , wherein L 1  is —CH 2 —. 
     
     
         36 . The method of  claim 35 , wherein L is —X-L 1 -, wherein X is a bond. 
     
     
         37 - 43 . (canceled) 
     
     
         44 . The method of  claim 27 , wherein ring A is substituted with one or two R A . 
     
     
         45 . The method of  claim 36 , wherein ring A is substituted with one R A . 
     
     
         46 - 48 . (canceled) 
     
     
         49 . The method of claim  26 , wherein the compound is
 O-(( 5 -chlorobenzo[b]thiophen-3-yl)methyl)hydroxylamine;   O-(benzo[d]thiazol-2-ylmethyl)hydroxylamine;   O-(benzofuran-2-ylmethyl)hydroxylamine; or   a pharmaceutically acceptable salt thereof.   
     
     
         50 - 179 . (canceled)