Viral inhibitors
Pyrrolo[2,3-c]pyridine or pyrrolo[3,2-c]pyridine compounds having the general formula (A), wherein the dashed lines, X, Y and R 1 through R 5 are as defined in the specification. The compounds are useful in the prophylaxis or treatment of viral infections.
1. A method of treating viral infections with a compound of Formula (A):
wherein:
the dotted lines represent at least 3, optionally 4 double bonds, provided that no two double bonds are adjacent to one another;
each A is —N═ or CR 26 , but at least one A is CR 26 ;
R 1 is selected from hydrogen, aryl, heterocycle, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, C 1 -C 10 alkyl-amino, C 1 -C 10 dialkyl-amino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each is optionally substituted with 1 or more R 6 ;
Y is a single bond;
provided that YR 1 is not hydrogen;
R 2 and R 4 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 3-10 cycloalkynyl, and heterocycle;
X is absent or is selected from hydrogen, C 1 -C 10 alkylene, C 2-10 alkenylene and C 2-10 alkynylene, wherein 1 to 3 —C(H)=, —C(≡) or —CH 2 — groups of each alkylene, alkenylene or alkynylene optionally are independently replaced with a heteroatom or heteroatom group selected from —O—, ═O, —OR 27 , —S—, ═S, —SR 27 , —NR 27 , and —N(R 27 ) 2 where R 27 independently is hydrogen, C 1-18 alkyl, C 2-18 alkenyl, or C 2-18 alkynyl;
m is any integer from 0 to 2;
R 3 is an aromatic heterocycle, where said aromatic heterocycle is optionally substituted with 1 or more R 17 ;
R 5 is selected from hydrogen; C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═O)OR 9 , —C(═S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, and heterocycle;
R 6 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO 2 R 18 , NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, C(═O)R 18 , C(═S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C 1-18 )alkyl, aryl(C 1-18 )alkyloxy, aryl(C 1-18 )alkylthio, heterocycle and C 1-18 hydroxyalkyl, where each is optionally substituted with 1 to 3 R 19 ;
R 7 and R 8 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocycle, —C(═O)R 12 ; —C(═S)R 12 , and an amino acid residue linked through a carboxyl group thereof, or R 7 and R 8 are taken together with the nitrogen to form a heterocycle;
R 9 and R 18 are independently selected from hydrogen, OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —NR 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, CH 2 OCH(═O)R 9a , and CH 2 OC(═O)OR 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;
R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C(═O)R 12 , heterocycle, and an amino acid residue;
R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;
R 15 and R 16 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;
R 17 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halogenated alkyl, C 2-18 halogenated alkenyl, C 2-18 halogenated alkynyl, C 1-18 halogenated alkoxy, C 1-18 halogenated alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, CO 2 H, CO 2 R 18 , NO 2 , NR 7 R 8 , haloalkyl, C(═O)R 18 , C(═S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, and C 1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, or C 1-18 hydroxyalkyl is optionally substituted with 1 or more R 19 ;
R 19 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C(═O)R 18 , —C(═O)OR 18 , —OalkenylC(═O)OR 18 , —OalkylC(═O)NR 20 R 21 , —OalkylOC(═O)R 18 , —C(═S)R 18 , SH, —C(═O)N(C 1-6 alkyl), —N(H)S(O)(O)(C 1-6 alkyl), aryl, heterocycle, C 1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C 1-18 )alkyloxy, aryloxy, aryl(C 1-18 alkyl)oxy, arylthio, aryl(C 1-18 )alkylthio and aryl(C 1-18 )alkyl, where each is optionally substituted with 1 to 3 of ═O, NR 20 R 21 , CN, C 1-18 alkoxy, heterocycle, C 1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R 17 by alkyl, alkoxyalkoxy or halogen;
R 20 and R 21 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C(═O)R 12 , and —C(═S)R 12 ;
R 26 is independently selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, aryl, and heterocycle, where each is optionally independently substituted with 1 to 3 of C 1-6 alkyl, C 1-6 alkoxy, halo, CH 2 OH, benzyloxy, or OH; or
a salt, tautomer, stereoisomer, or solvate thereof.
2. The method of claim 1 , wherein said viral infection is an infection of a virus belonging to the family of the Flaviviridae.
3. The method of claim 1 , wherein said viral infection is an infection of a hepatitis-C virus.
4. The method of claim 1 , wherein R 26 is hydrogen.
5. The method of claim 1 , wherein R 1 is phenyl substituted with 1 to 3 R 6 .
6. The method of claim 1 , wherein X is C1-C3 alkyl and R 3 is aromatic heterocycle independently substituted with 1 or 2 R 17 .
7. The method of claim 1 wherein R 17 independently is substituted with 1 or 2 R 19 .
8. The method of claim 7 wherein R 1 is aryl independently substituted with 1 or 2 R 6 .
9. The method of claim 7 wherein R 2 , R 4 and R 5 are hydrogen.
10. The method of claim 7 wherein X is methylene.
11. The method of claim 7 wherein R 3 is a five membered heteroaryl containing 1 to 3 N, O and/or S ring atoms.
12. The method of claim 7 wherein R 3 is isoxazolyl or pyridizinyl.
13. The method of claim 7 wherein R 19 independently is aryl.
14. The method of claim 13 wherein aryl is phenyl.
15. The method of claim 7 wherein R 6 is independently substituted with 1 or 2 R 19 .
16. The method of claim 15 wherein R 19 is independently halo or C1-C6 haloalkyl.
17. The method of claim 15 wherein R 6 is substituted with 2 R 19 .
18. The method of claim 1 wherein X is methylene and R 3 is isoxazolyl substituted with 1 R 17 .
19. The method of claim 18 wherein R 17 is substituted with 1 R 19 .
20. The method of claim 19 wherein R 6 is substituted with 1 or 2 R 19 .
21. The method of claim 1 wherein R 26 is C3-C6 cycloalkyl.