N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase

Abstract

The present invention is directed to N-hydroxyamidino compounds which are modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof, wherein:
 W is O, S, or NR 1 ; 
 U is N or CR 3 ; 
 X is N or CR 4 ; 
 Q is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, pentahalosulfanyl, Cy 4 , —(C 1-4  alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4  alkyl)-OR a4 , SR a4 , —(C 1-4  alkyl)-SR a4 , C(O)R b4 , —(C 1-4  alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4  alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4  alkyl)-C(O)OR a4 , OC(O)R b4 , —(C 1-4  alkyl)-OC(O)R b4 , OC(O)NR c4 R d4 , —(C 1-4  alkyl)-OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , —(C 1-4  alkyl) NR c4 COR b4 , NR c4 C(O)NR c4 R d4 , —(C 1-4  alkyl)-NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , —(C 1-4  alkyl)-NR c4 C(O)OR a4 , C(═NR i4 )NR c4 R d4 , NR c4 C(═NR i4 )NR c4 R d4 , P(R f4 ) 2 , P(OR e4 ) 2 , P(O)R e4 R f4 , P(O)OR e4 OR f4 , S(O)R b4 , —(C 1-4  alkyl)-S(O)R b4 , S(O)NR c4 R d4 , —(C 1-4  alkyl)-S(O)NR c4 R d4 , S(O) 2 R b4 , —(C 1-4  alkyl)-S(O) 2 R b4 , NR c4 S(O) 2 R b4 , —(C 1-4  alkyl)-NR c4 S(O) 2 R b4 , S(O) 2 NR c4 R d4 , and —(C 1-4  alkyl)-S(O) 2 NR c4 R d4 ; 
 R 1  is H, C 1-10  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; 
 R 2  is halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, pentahalosulfanyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , P(R f3 ) 2 , P(OR e3 ) 2 , P(O)R e3 R f3 , P(O)OR e3 OR f3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , or S(O) 2 NR c3 R d3 ; wherein said C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-10  haloalkyl, C 1-10  hydroxyalkyl, C 1-10  cyanoalkyl, pentahalosulfanyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , P(R f3 ) 2 , P(OR e3 ) 2 , P(O)R e3 R f3 , P(O)OR e3 OR f3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ; 
 R 3  and R 4  are independently selected from H, halo, C 1-4  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 R 5  is H, C(O)R 6 , C(O)OR 7 , or C(O)NR 8 NR 9 ; 
 R 6  and R 7  are independently selected from H, C 1-8  alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4  alkoxy, C 1-4  haloalkoxy, amino, C 1-4  alkylamino, C 2-8  dialkylamino, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 R 8  and R 9  are independently selected from H, C 1-8  alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4  alkoxy, C 1-4  haloalkoxy, amino, C 1-4  alkylamino, C 2-8  dialkylamino, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 or R 1  and R 3  together with the atoms to which they are attached form a heteroaryl or a 4-20 membered heterocycloalkyl ring, wherein said heteroaryl or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy, CN, NO 2 , OR a3 , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d ; 
 or R 2  and R 3  together with the atoms to which they are attached form an aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring, wherein said aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 , wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; 
 or R 2  and R 4  together with the atoms to which they are attached form an aryl, cycloalkyl, heteroaryl or 4-20 membered heterocycloalkyl ring, wherein said aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; 
 R a3  and R a4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, Cy 5 , and Cy 5 —(C 1-6  alkyl)-, wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 R b3  and R b4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, Cy 5 , and Cy 5 —(C 1-6  alkyl)-, wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 P(O)OR e5 OR f5 , S(O) b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 R c3  and R c4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C(O)R b5 , C(O)NR c5 R d5 , C(═NR i5 )NR c5 R d5 , Cy 5 , and Cy 5 —(C 1-6  alkyl)-, wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 R d3  and R d4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C(O)R b5 , C(O)NR c5 R d5 , C(═NR i5 )NR c5 R d5 , Cy 5  and Cy 5 —(C 1-6  alkyl)-, wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 or R c3  and R d3  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 or R c4  and R d4  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 5 , CN, NO 2 , OR 35 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i5 )NR c5 R d5 , NR c5 C(═NR i5 )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R b5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; 
 Cy, Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5  are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents selected from halo, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, pentahalosulfanyl, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , C(═NR i6 )NR c6 R d6 , NR c6 C(═NR i6 )NR c6 R d6 , P(R f6 ) 2 , P(OR e6 ) 2 , P(O)R e6 R f6 , P(O)OR e6 OR f6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6  and S(O) 2 NR c6 R d6 ; 
 R a , R a1 , R a2 , R a5 , and R a6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 R b , R b1 , R b2 , R b5 , and R b6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 R c , R c1 , R c2 , R c5 , and R c6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 R d , R d1 , R d2 , R d5 , and R d6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 R e , R e1 , R e2 , R e5 , and R e6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 R f , R f1 , R f2 , R f3 , R f4 , R f5 , and R f6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and 
 R i , R i1 , R i2 , R i3 , R i4 , R i5 , and R i6  are independently selected from H, C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-10  haloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 with the proviso that when the ring containing U, W, and X is oxadiazole, then Q is other than C 1-6  alkyl substituted with NR c4 R d4 . 
 
     
     
         2 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein W is O. 
     
     
         3 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein U is N. 
     
     
         4 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein X is CR 4 . 
     
     
         5 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein W is S. 
     
     
         6 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein U is CR 3 . 
     
     
         7 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein W is O and U is N. 
     
     
         8 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein W is S and U is CR 3 . 
     
     
         9 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein W is O and U is CR 3 . 
     
     
         10 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 4 , —(C 1-4  alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4  alkyl)-OR a4 , SR a4 , —(C 1-4  alkyl)-SR a4 , C(O)R b4 , —(C 1-4  alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4  alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4  alkyl)-C(O)OR a4 , OC(O)R b4 , —(C 1-4  alkyl)-OC(O)R b4 , OC(O)NR c4 R d4 , —(C 1-4  alkyl)-OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , —(C 1-4  alkyl)-NR c4 COR b4 , NR c4 C(O)NR c4 R d4 , —(C 1-4  alkyl)-NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , —(C 1-4  alkyl)-NR c4 C(O)OR a4 , C(═NR i4 )NR c4 R d4 , NR c4 C(═NR i4 )NR c4 R d4 , P(R f4 ) 2 , P(OR e4 ) 2 , P(O)R e4 R f4 , P(O)OR e4 R f4 , S(O)R b4 , —(C 1-4  alkyl)-S(O)R b4 , S(O)NR c4 R d4 , —(C 1-4  alkyl)-S(O)NR c4 R d4 , S(O) 2 R b4 , —(C 1-4  alkyl)-S(O) 2 R b4 , NR c4  S(O) 2 R b4 , —(C 1-4  alkyl)-NR c4 S(O) 2 R b4 , S(O) 2 NR c4 R d4 , and —(C 1-4  alkyl)-S(O) 2 NR c4 R d4 . 
     
     
         11 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 4 , —(C 1-4  alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4  alkyl)-OR a4 , SR a4 , —(C 1-4  alkyl)-SR a4 , C(O)R b4 , —(C 1-4  alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4  alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4  alkyl)-C(O)OR a4 , OC(O)R b4 , —(C 1-4  alkyl)-OC(O)R b4 , OC(O)NR c4 R d4 , —(C 1-4  alkyl)-OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , —(C 1-4  alkyl)-NR c4 COR b4 , NR c4 C(O)NR c4 R d4 , —(C 1-4  alkyl)-NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , —(C 1-4  alkyl)-NR c4 C(O)OR a4 , C(═NR i4 )NR c4 R d4 , NR c4 C(═NR i4 )NR c4 R d4 , P(R f4 ) 2 , P(OR e4 ) 2 , P(O)R e4 R f4 , P(O)OR e4 OR f4 , S(O)R b4 , —(C 1-4  alkyl)-S(O)R b4 , S(O)NR c4 R d4 , (C 1-4  alkyl)-S(O)NR c4 R d4 , S(O) 2 R b4 , —(C 1-4  alkyl)-S(O) 2 R b4 , NR c4 S(O) 2 R b4 , —(C 1-4  alkyl)-NR c4 S(O) 2 R b4 , S(O) 2 NR c4 R d4 , and —(C 1-4  alkyl)-S(O) 2 NR c4 R d4 . 
     
     
         12 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, CN, NO 2 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , and S(O) 2 NR c4 R d4 . 
     
     
         13 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 1-6  haloalkyl, and CN. 
     
     
         14 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo and CN. 
     
     
         15 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is C 1-6  alkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, pentahalosulfanyl, Cy 4 , —(C 1-4  alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4  alkyl)-OR a4 , SR a4 , —(C 1-4  alkyl)-SR a4 , C(O)R b4 , —(C 1-4  alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4  alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4  alkyl)-C(O)OR a4 , OC(O)R b4 , —(C 1-4  alkyl)-OC(O)R b4 , OC(O)NR c4 R d4 , —(C 1-4  alkyl)-OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , —(C 1-4  alkyl)-NR c4 COR b4 , NR c4 C(O)NR c4 R d4 , —(C 1-4  alkyl)-NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR b4 , —(C 1-4  alkyl)-NR c4 C(O)OR a4 , C(═NR i4 )NR c4 R d4 , NR c4 C(═NR i4 )NR c4 R d4 , P(R f4 ) 2 , P(OR e4 ) 2 , P(O)R e4 R f4 , P(O)OR f4 , S(O)R b4 , —(C 1-14  alkyl)-S(O)R b4 , S(O)NR c4 R d4 , —(C 1-14  alkyl)-S(O)NR c4 R d4 , S(O) 2 R e4 , —(C 1-4  alkyl)-S(O) 2 R b4 , NR c4 S(O) 2 R b4 , —(C 1-4  alkyl)-NR c4 S(O) 2 R b4 , S(O) 2 NR c4 R d4 , and —(C 1-4  alkyl)-S(O) 2 NR c4 R d4 . 
     
     
         16 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is C 1-6  alkyl substituted by Cy 4 . 
     
     
         17 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein Q is C 1-6  alkyl substituted by phenyl, wherein said phenyl is substituted by 1, 2, or 3 substituents independently selected from halo and C 1-4  alkyl. 
     
     
         18 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , or S(O) 2 NR c3 R d3 ; wherein said C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-10  haloalkyl, C 1-10  hydroxyalkyl, C 1-10  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR c3 C(O)R b3 , C(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , P(R f3 ) 2 , P(OR e3 ) 2 , P(O)R e3 R f3 , P(O)OR e3 OR f3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 . 
     
     
         19 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 ; wherein said C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-10  haloalkyl, C 1-10  hydroxyalkyl, C 1-10  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , P(R f3 ) 2 , P(OR e3 ) 2 , P(O)R e3 R f3 , P(O)OR e3 OR f3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 . 
     
     
         20 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 ; wherein said C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-10  haloalkyl, C 1-10  hydroxyalkyl, C 1-10  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)NR b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 . 
     
     
         21 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo, C 1-10  alkyl, Cy 3 , OR a3 , wherein said C 1-10  alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-10  haloalkyl, C 1-10  hydroxyalkyl, C 1-10  cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR i3 )NR c3 R d3 , NR c3 C(═NR i3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 . 
     
     
         22 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo, C 1-10  alkyl, OR a3 , aryl, heteroaryl, or heterocycloalkyl, wherein said C 1-10  alkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10  alkyl, C 1-6  haloalkyl, OR a3 , and NR c3 R d3 . 
     
     
         23 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is halo. 
     
     
         24 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is C 1-10  alkyl. 
     
     
         25 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is NR c3 R d3 . 
     
     
         26 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  is NH 2 . 
     
     
         27 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl, heteroaryl, or 4-20 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         28 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         29 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         30 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         31 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         32 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, CN, NO 2 , OR a1 , and SR a1 . 
     
     
         33 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 3  together with the atoms to which they are attached form a phenyl group. 
     
     
         34 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl, heteroaryl or 4-20 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR 2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ), P(OR e1 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 . 
     
     
         35 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 . 
     
     
         36 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 . 
     
     
         37 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2  and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR 2 , C(O)R b2 , C(O)NR c2 R d2 C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR i2 )NR c2 R d2 , NR c2 C(═NR i2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 . 
     
     
         38 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 . 
     
     
         39 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR i1 )NR c1 R d1 , NR c1 C(═NR i1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 . 
     
     
         40 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form an aryl optionally substituted 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  cyanoalkyl, CN, NO 2 , OR a1 , and SR a1 . 
     
     
         41 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2  and R 4  together with the atoms to which they are attached form a phenyl group. 
     
     
         42 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5  is H. 
     
     
         43 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, having Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, having Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, having Formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, having Formula V: 
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound of  claim 1  selected from: 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-(3-morpholin-1-ylpropoxy)isoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-(3-(pyrrolidin-1-yl)propoxy)isoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-morpholin-1-ylisoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-phenylisoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-(4-methoxyphenyl)isoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-methoxyisoxazole-5-carboximidamide; 
       3-bromo-N-(3-bromophenyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       3-bromo-N-(3-chloro-4-fluorophenyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-(3-(4-methylpiperazin-1-yl)propoxy)isoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-methylisoxazole-5-carboximidamide; 
       4-chloro-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-3-methylisoxazole-5-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4,5-dimethylfuran-2-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-2,1-benzisoxazole-3-carboximidamide; 
       N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1-benzothiophene-2-carboximidamide; 
       3-bromo-N-(3-chlorobenzyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       3-bromo-N-(3-chloro-2-methylbenzyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       3-bromo-N-(5-chloro-2-methylbenzyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       3-bromo-N′-hydroxy-N-(2-methylbenzyl)isoxazole-5-carboximidamide; 
       N′-hydroxy-3-methyl-N-(2-methylbenzyl)isoxazole-5-carboximidamide; 
       N′-hydroxy-N-(2-methylbenzyl)-2,1-benzisoxazole-3-carboximidamide; 
       3-Amino-N-(5-chloro-2-methylbenzyl)-N′-hydroxyisoxazole-5-carboximidamide; 
       N-[5-[(5-chloro-2-methylbenzyl)amino](hydroxyimino)methyl]isoxazol-3-ylacetamide; 
       N-(5-chloro-2-methylbenzyl)-N′-hydroxy-3-[(2-methoxyethyl)amino] isoxazole-5-carboximidamide; and 
       3-amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxyisoxazole-5-carboximidamide, 
       or pharmaceutically acceptable salt thereof. 
     
     
         48 . A composition comprising a compound of  claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         49 . A method of modulating activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound of  claim 1 , or pharmaceutically acceptable salt thereof. 
     
     
         50 . The method of  claim 49  wherein said modulating is inhibiting. 
     
     
         51 . A method of inhibiting immunosuppression in a patient comprising administering to said patient an effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof. 
     
     
         52 . A method of treating cancer, viral infections, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 52  further comprising administering an anti-viral agent, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor.