Chemical compounds

Abstract

Compounds, specifically hepatitis B virus and/or hepatitis D virus inhibitors, more specifically compounds that inhibit HBe antigen and HBs antigen in a subject, for the treatment of viral infections, and methods of preparing and using such compounds.

What is claimed is: 
     
         1 . A compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 W is N: 
 Y is C; 
 
       wherein
 R 1  is absent; 
 R 2  and R 3  are independently selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 
 3- to 8-membered heterocycloalkyl or substituted 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, —C x H 2x -phenyl, —O—C x H 2x -phenyl, or —(C 1-6 alkyl)N—C x H 2x -phenyl wherein x is 0, 1, 2, 3, 4, 5, 6; or —OR 12 ; 
 R 5  is hydrogen; 
 R 8  is hydrogen; 
 R 6  and R 7  together form a 3- to 8-membered cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom or two or more heteroatoms, optionally substituted with R 15 , R 15′ , R 16  and/or R 16′ , wherein the one heteroatom in the heteroalkyl ring is NR 20  and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22  and SR 22 R 22 ′; 
 R 9  is hydrogen; 
 R 10  is —CO 2 H or a tautomer thereof; 
 R 11  is hydrogen; 
 R 12  is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; 
 R 15 , R 15′ , R 16  and R 16′  are independently hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, or C 1-6 alkoxy; or R 15  and R 15′  or R 16  and R 16′  together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl or C 1-6 alkoxy, wherein the heteroatom in the heterocycloalkyl ring is O, N, NR 22 , S, SR 22  or SR 22 R 22 ′; 
 R 19 , R 19′  and R 19″  are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 1-6 alkyl, phenyl, C 1-6 alkylimidizole, C 1-6 alkyltriazole, C 1-6 alkyltetrazole, C 1-6 alkylthiazole, C 1-6 alkyloxazole, C 1-6 alkyldioxazole; C 1-6 alkyloxazolidone; and 
 
       R 20  and R 21  are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkenyl, C 1-6 alkoxy, phenyl, C 1-6 alkylimidizole, C 1-6 alkyltriazole, C 1-6 alkyltetrazole, C 1-6 alkylthiazole, C 1-6 alkyloxazole, C 1-6 alkyldioxazole; C 1-6 alkyloxazolidone, or R 20  and R 21  together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; and
 R 22  and R 22′  are independently selected from hydrogen, oxygen, C 1-6 alkyl or substituted C 1-6 alkyl, C 1-6 alkoxy or substituted C 1-6 alkoxy, C 3-8 cycloalkyl or substituted C 3-8 cycloalkyl, C 2-6 alkenyl or substituted C 2-6 alkenyl, aryl or substituted aryl, including substituted or unsubstituted C 1-6 alkylimidizole, substituted or unsubstituted C 1-6 alkyltriazole, C 1-6 alkyltetrazole, C 1-6 alkylthiazole, substituted or unsubstituted C 1-6 alkyloxazole, C 1-6 alkyldioxazole; C 1-6 alkyloxazolidone; —COR 19 , —COOR 19′ , —CSOR 19″ , —CONR 20 R 21 , 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . (canceled) 
     
     
         3 . The compound of Formula I or pharmaceutically acceptable salt thereof according to  claim 1 , 
       wherein
 R 6  and R 7  together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R 15 , R 15′ , R 16  and/or R 16′ . 
 
     
     
         4 . (canceled) 
     
     
         5 . A compound of Formula IA or Formula IB: 
       
         
           
           
               
               
           
         
       
       wherein C* is a carbon atom stereocenter which has a configuration which is (R) or (S),
 w is N; 
 Y is C; 
 
       wherein
 R 1  is absent;
 R 2  and R 3  are independently selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 
 R 5  is hydrogen; 
 R 8  is hydrogen; 
 
 R 6  and R 7  together form a 3 to 8 membered cycloalkyl ring, optionally substituted with R 15 , R 15′ , R 16  and/or R 16′ ;
 R 9  is hydrogen; 
 
 R 10  is —CO 2 H or a tautomer thereof;
 R 11  is hydrogen; 
 R 12  is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; 
 R 15 , R 15′ , R 16  and R 16′  are independently hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, or C 1-6 alkoxy; 
 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . (canceled) 
     
     
         7 . The compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 2  and R 3  are independently selected from hydrogen, hydroxy, halogen, cyano, amino, thio, C 1-6 alkyl or substituted C 1-6 alkyl, C 1-6 alkoxy or substituted C 1-6 alkoxy; C 3-8  cycloalkyl or substituted C 3-8 cycloalkyl; C 2-8 alkenyl or substituted C 2-8 alkenyl, or 
 —OR 12 ; 
 R 6  and R 7  together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R 15 , R 15′ , R 16  and/or R 16′ 
 R 12  is hydrogen; C 1-6 alkyl or substituted C 1-6 alkyl, C 1-6 alkoxy or substituted C 1-6 alkoxy, C 3-8 cycloalkyl or substituted C 3-8 cycloalkyl, C 3-8 heterocycloalkyl or substituted C 3-8 heterocycloalkyl; and 
 R 22  and R 22′  are independently selected from hydrogen, oxygen, C 1-6 alkyl or substituted C 1-6 alkyl, C 1-6 alkoxy or substituted C 1-6 alkoxy, C 3-8 cycloalkyl or substituted C 3-8 cycloalkyl, C 2-6 alkenyl or substituted C 2-6 alkenyl. 
 
 
     
     
         8 . The compound of Formula I pharmaceutically acceptable salt thereof according to  claim 1 , 
       wherein:
 R 15 , R 15′ , R 16  and/or R 16′  are independently hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, or C 1-6 alkoxy. 
 
     
     
         9 . The compound of Formula I a pharmaceutically acceptable salt thereof according to  claim 8 , 
       wherein:
 R 2  is halogen; and 
 R 3  is OR 12 . 
 
     
     
         10 . The compound of Formula I pharmaceutically acceptable salt thereof according to  claim 9 , 
       wherein:
 R 15 , R 15′ , R 16  and/or R 16′  are independently C 1-6 alkyl. 
 
     
     
         11 . The compound of Formula I pharmaceutically acceptable salt thereof according to  claim 1 , 
       wherein:
 R 6  and R 7  together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R 15 , R 15′ , R 16  and/or R 16′ . 
 
     
     
         12 . (canceled) 
     
     
         13 . A compound selected from the group:
 (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   (4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-1-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   (2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;   2′-Chloro-3′-(cyclopropylmethoxy)-10′-oxo-5′,10′-dihydrospiro[cyclobutane-1,6′-pyrido[1,2-h][1,7]naphthyridine]-9′-carboxylic acid;   2′,3′-Dimethoxy-10′-oxo-5′,10′-dihydrospiro[cyclobutane-1,6′-pyrido[1,2-h][1,7]naphthyridine]-9′-carboxylic acid;   6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid;   2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;   3′-(cyclopropylmethoxy)-2′-(difluoromethyl)-11′-fluoro-10′-oxo-5′,10′-dihydrospiro[cyclobutane-1,6′-pyrido[1,2-h][1,7]naphthyridine]-9′-carboxylic acid;   2′-(difluoromethyl)-11′-fluoro-10′-oxo-3′-((tetrahydrofuran-3-yl)methoxy)-5′,10′-dihydrospiro[cyclobutane-1,6′-pyrido[1,2-h][1,7]naphthyridine]-9′-carboxylic acid;   (S)-3-(cyclopropylmethoxy)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; and   (6S)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-3-((tetrahydrofuran-3-yl)methoxy)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; or a pharmaceutically acceptable salt or tautomer thereof.   
     
     
         14 . The compound according to  claim 1  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 - 30 . (canceled) 
     
     
         31 . A method of treating or preventing a virus infection in a subject susceptible to or suffering from the virus infection comprising administering to the subject an inhibitor of a HBe or HBs antigen wherein the inhibitor is a compound of Formula I according to  claim 1 . 
     
     
         32 . The method of treating or preventing a virus infection in a subject according to  claim 31 , wherein the virus infection is a hepatitis B virus infection. 
     
     
         33 . (canceled) 
     
     
         34 . A method of inhibiting the level of HBe or HBs antigen in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         35 . The method according to  claim 34 , wherein the mammal is a human. 
     
     
         36 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I according to  claim 1 . 
     
     
         37 - 43 . (canceled)