CHEMICAL COMPOUNDS
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.
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)