Hsp90 inhibitors

Abstract

The invention relates to HSP90 inhibiting compounds consisting of the formula: wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein
 X is O; 
 R 1  is -L-R 45 ; 
 R 2  is selected from the group consisting of hydrogen and methyl; 
 R 3  is of the formula 
 
       
         
           
           
               
               
           
         
         wherein 
         Ring C is selected from the group consisting of (C 4-6 )aryl or (C 1-5 )heteroaryl, each unsubstituted or substituted with said 1-3 substituents selected from the group consisting halo, (C 1-10 )alkoxy, (C 1-10 )alkyl, amino, (C 1-10 )alkylamino, halo(C 1-10 )alkyl, and halo(C 1-10 )alkoxy; 
         R 12  is selected from the group consisting of (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, (C 3-12 )cycloalkyl, and hetero(C 2-11 )cycloalkyl, each unsubstituted or substituted with 1-3 substituents selected from Group A; 
         R 4  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, C 4-12 )aryl, hetero(C 1-10 )alkyl, (C 3-7 )cycloalkyl, (C 5-7 )cycloalkenyl, and hetero(C 3-12 )cycloalkyl, each unsubstituted or substituted with 1-3 substituents selected from Group A; 
         R 6  and R 6′  are each independently selected from the group consisting of hydrogen, halogen, and (C 1-6 )alkyl; 
         R 45  is selected from the group consisting of hydrogen, hydroxyl, halo, (C 1-3 )alkyl, hydroxy(C 1-3 )alkyl, (C 1-3 )alkoxy, amino, carbonylamino, aminocarbonyl, carbonyl, (C 4-6 )aryl, hetero(C 1-5 )aryl, (C 3-8 )cycloalkyl, and hetero(C 3-5 )cycloalkyl, each unsubstituted or substituted with 1-3 substituents selected from Group A; 
         L is (—CR 46 R 47 —) n ; 
         n is 1, 2, 3, 4, or 5; 
         R 46  and R 47  are each independently selected from the group consisting of hydrogen, hydroxyl, oxo, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy, amino and aminocarbonyl, each substituted or unsubstituted with 1-3 substituents selected from Group A; 
         Group A consists of (C 1-10 )alkyl, (C 1-10 )alkoxy, amino, aminoalkyl, (C 4-12 )aryl, (C 3-12 )cycloalkyl, halo, (C 1-10 )heteroaryl, hetero(C 3-12 )cycloalkyl, and hydroxy, each unsubstituted or substituted by a further substituent selected from Group B; and 
         Group B consists of halo, nitro, cyano, hydroxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, amino, (C 1-10 )alkylamino, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 4-12 )aryl, and hetero(C 1-10 )aryl. 
       
     
     
         2 .- 5 . (canceled) 
     
     
         6 . The compound according to  claim 1  consisting of the formula 
       
         
           
           
               
               
           
         
       
     
     
         7 .- 18 . (canceled) 
     
     
         19 . The compound according to any one of  claim 1  or  6 , wherein L is (—CR 46 R 47 —) 5 . 
     
     
         20 . The compound according to any one of  claim 1  or  6 , wherein L is (—CR 46 R 47 —) 4 . 
     
     
         21 . The compound according to any one of  claim 1  or  6 , wherein L is (—CR 46 R 47 —) 3 . 
     
     
         22 . The compound according to any one of  claim 1  or  6 , wherein L is (—CR 46 R 47 —) 2 . 
     
     
         23 . The compound according to any one of  claim 1  or  6 , wherein L is —CR 46 R 47 —. 
     
     
         24 .- 37 . (canceled) 
     
     
         38 . The compound according to  claim 1 , wherein —X—R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 .- 49 . (canceled) 
     
     
         50 . The compound according to claim  30 , wherein R 2  is hydrogen. 
     
     
         51 . The compound according to claim  30 , wherein R 2  is methyl. 
     
     
         52 .- 53 . (canceled) 
     
     
         54 . The compound according to  claim 51 , wherein R 4  is hydrogen. 
     
     
         55 .- 60 . (canceled) 
     
     
         61 . The compound according to  claim 54 , wherein R 6  and R 6′  are both hydrogen. 
     
     
         62 .- 75 . (canceled) 
     
     
         76 . The compound according to  claim 61 , wherein at least one of the 1-3 substituents on Ring C is selected from the group consisting of fluoro, methyl, and methoxy. 
     
     
         77 .- 86 . (canceled) 
     
     
         87 . The compound according to  claim 76 , wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         88 .- 100 . (canceled) 
     
     
         101 . The compound according to  claim 1 , where-in R 12  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         102 .- 113 . (canceled) 
     
     
         114 . A compound of  claim 1  selected from the group consisting of:
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3-hydroxy-2-(hydroxymethyl)propyl oxime; 
 (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)amino)butane-1,2-diol; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(S)-morpholin-2-ylmethyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2R,3S,4R,5R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2S,4R)-4-hydroxypyrrolidin-2-yl)methyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((3R,4S)-3,4-dihydroxycyclopentyl)methyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3,4-dihydroxy-4-methylpentyl oxime; 
 (R)-4-(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-c]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-c]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(tetrahydro-2H-pyran-4-yl)methyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((1s,4S)-4-hydroxycyclohexyl)methyl oxime; 
 (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-(morpholin-2-yl)ethyl oxime; 
 (S)-4-(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-3-benzyloxazolidin-2-one; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(R)-2-amino-3-hydroxypropyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(1-methyl-1H-imidazol-4-yl)methyl oxime; 
 (R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(S)-3,4-dihydroxybutyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(S)-3,4-dihydroxybutyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(2-methoxythiazol-4-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(S)-3,4-dihydroxybutyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyridol[4,3-d]pyrimidin-5(6H)-one O—(S)-4,5-dihydroxypentyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(S)-3-amino-2-hydroxypropyl oxime; 
 (S)-5-(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3-hydroxypropyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-4-hydroxybutyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3-hydroxy-2-methoxypropyl oxime; 
 (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(R)-4,5-dihydroxypentyl oxime; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypyrrolidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-fluoropyrrolidin-1-yl)ethanone; 
 (S,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—(R)-3,4-dihydroxybutyl oxime; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-bis(2-hydroxyethyl)acetamide; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-N,N-bis(2-hydroxypropyl)acetamide; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(azetidin-1-yl)ethanone; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrrolidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-hydroxypiperidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydroxypyrrolidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydroxypiperidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypyrrolidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypiperidin-1-yl)ethanone; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3-hydroxyazetidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-fluoropyrrolidin-1-yl)ethanone; 
 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-fluoropyrrolidin-1-yl)ethanone; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-methoxypiperidin-1-yl)ethanone; 
 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrazin-2-yl)ethanone; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-c]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-c]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxime; 
 (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; 
 (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3-amino-4-hydroxybutyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-4-amino-3-hydroxybutyl oxime; 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-amino-3-hydroxypropyl oxime; and 
 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-3-amino-2-hydroxypropyl oxime; or a pharmaceutically acceptable salt of each of the above-mentioned compounds. 
 
     
     
         115 . The compound according to any one of  claim 1  or  114 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         116 . The compound according to any one of  claim 1  or  114 , wherein the compound is present as a mixture of stereoisomers. 
     
     
         117 . The compound according to any one of  claim 1  or  114 , wherein the compound is present as a single stereoisomer. 
     
     
         118 . A pharmaceutical composition comprising as an active ingredient a compound according to any one of  claim 1  or  114  and a pharmaceutical excipient. 
     
     
         119 .- 187 . (canceled)