Highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis B virus (HBV)

1. A compound of Formula I

in which

Z is H, D, O(R5), CH 3 , C≡N, Cl, C(═O)NH 2 , N(R5)(R6), N(R5)C(═O)(R6), NHC(═O)N(R5)(R6), N(R5)SO 2 (R6), NHC(═O)C(═O)O(R5), NHC(═O)C(═O)N(R5)(R6), NHC(═O)NHSO 2 R5, CH 2 —N(R5)(R6), or heteroaryl

R1 is H, D, F, Cl, Br, or NH 2

R2 is for each position independently selected from the group consisting of H, CF 2 H, CF 3 , CF 2 CH 3 , F, Cl, Br, CH 3 , Et, i-Pr, c-Pr, D, CH 2 OH, CH(CH 3 )OH, CH 2 F, C(F)CH 3 , I, C═C, C≡C, C≡N, C(CH 3 ) 2 OH, Si(CH 3 ) 3 , SMe, OH, and OCH 3

R3 and R4 are for each position independently selected from the group consisting of H, methyl and ethyl

R3 and R4 are optionally connected to form a C3-C5-cycloalkyl ring

R5 and R6 are independently selected from the group consisting of H, D, C1-C6-alkyl, C3-C6-cycloalkyl, C4-C7-heterocycloalkyl, C2-C6-aminoalkyl, and C2-C6-hydroxyalkyl, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, C≡N, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkyl substituted with acyl or carboxyl ester, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-alkyl-O-C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkylamino and C2-C6 -alkenyloxy

R5 and R6 are optionally connected to form a C4-C7-heterocyclic ring containing 1 or 2 nitrogen or oxygen atoms, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, and C2-C6 -alkenyloxy

n is 1 or 2

m is 0 or 1

with the proviso that

when Z is NHC(═O)N(R5)(R6), neither R5, nor R6 is cyclopentyl or isopropyl, and

when Z is N(R5)C(═O)(R6) and R5 is H, R6 is not unsubstituted cyclopropyl, unsubstituted cyclobutyl, CH 3 , or tetrahydrofuranyl,

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

2. The compound of Formula I according to claim 1 that is a compound of Formula II

in which

Y is N(R5)SO 2 (R6), N(R5)(R6), or N(R5)C(═O)(R6)

R1 is H

R2 is for each position independently selected from the group consisting of H, CF 2 H, CF 3 , CF 2 CH 3 , F, Cl, Br, CH 3 , Et, and i-Pr

R3 and R4 are for each position independently selected from the group consisting of H and methyl

R5 and R6 are independently selected from the group consisting of H, D, C1-C6-alkyl, C3-C6-cycloalkyl, C4-C7-heterocycloalkyl, C2-C6-aminoalkyl, and C2-C6-hydroxyalkyl, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkyl substituted with acyl or carboxyl ester, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-alkyl-O-C1-C6-alkyl, C1-C6-hydroxyalkyl, and C2-C6 -alkenyloxy

R5 and R6 are optionally connected to form a C4-C7-heterocyclic ring containing 1 or 2 nitrogen or oxygen atoms, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, and C2-C6 -alkenyloxy

n is 1 or 2

m is 0 or 1

with the proviso that

when Y is N(R5)C(═O)(R6) and R5 is H, R6 is not unsubstituted cyclopropyl, unsubstituted cyclobutyl, CH 3 , or tetrahydrofuranyl,

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The compound of Formula I according to claim 1 that is a compound of Formula III

in which

R2 is for each position independently selected from the group consisting of H, CF 2 H, CF 3 , CF 2 CH 3 , F, Cl, Br, CH 3 , Et, and i-Pr

R5 and R6 are independently selected from the group consisting of H, D, C1-C6-alkyl, C3-C6-cycloalkyl, C4-C7-heterocycloalkyl, C2-C6-aminoalkyl, and C2-C6-hydroxyalkyl, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkyl substituted with acyl or carboxyl ester, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-alkyl-O-C1-C6-alkyl, C1-C6-hydroxyalkyl, and C2-C6 -alkenyloxy

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

4. The compound of Formula I according to claim 1 that is a compound of Formula IVa or IVb

in which

R2 is for each position independently selected from the group consisting of H, CH 2 F, CF 2 H, CF 3 , C(F)CH 3 , CF 2 CH 3 , F, Cl, Br, CH 3 , and Et

R5 is selected from the group consisting of H, D, C1-C6-alkyl, C3-C6-cycloalkyl, C4-C7-heterocycloalkyl, C2-C6-aminoalkyl, and C2-C6-hydroxyalkyl, optionally substituted with 1, 2, or 3 groups each independently selected from the group consisting of OH, halo, acyl, SO 2 Me, carboxy, carboxyl ester, carbamoyl, substituted carbamoyl, C6-aryl, heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, and C2-C6 -alkenyloxy,

with the proviso that

when the said compound is a compound of Formula IVb, R5 is not unsubstituted cyclopropyl, unsubstituted cyclobutyl, CH 3 , or tetrahydrofuranyl,

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

5. A method for the treatment of an HBV infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof together with a pharmaceutically acceptable carrier.

7. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. A method for the preparation of a compound of Formula I according to claim 1

comprising reacting a compound of Formula V

in which R1 and R2 are as defined for the compound of formula I,

with a compound of Formula VI

in which n, m, Z, R3 and R4 are as defined for the compound of formula I.

9. The compound of Formula I according to claim 1 that is a compound of Formula IVa or IVb

in which

R2 is for each position independently selected from the group consisting of H, CH 2 F, CF 2 H, CF 3 , C(F)CH 3 , CF 2 CH 3 , F, Cl, Br, CH 3 , and Et

R5 is selected from the group consisting of C1-C6-alkyl, C3-C6-cycloalkyl, C4-C7-heterocycloalkyl and C2-C6-hydroxyalkyl optionally substituted with OH, C1-C6-alkoxy, C1-C6-hydroxylalkyl or C3-C7-heterocycloalkyl

with the proviso that

when the said compound is a compound of Formula IVb, R5 is not unsubstituted cyclopropyl, unsubstituted cyclobutyl, CH 3 , or tetrahydrofuranyl,

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

10. The compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The compound of Formula I according to claim 2 that is a compound of Formula II or a pharmaceutically acceptable salt thereof.

12. The compound of Formula I according to claim 3 that is a compound of Formula III or a pharmaceutically acceptable salt thereof.

13. The compound of Formula I according to claim 4 that is a compound of Formula IVa or a pharmaceutically acceptable salt thereof.

14. The compound of Formula I according to claim 4 that is a compound of Formula IVb or a pharmaceutically acceptable salt thereof.

15. The compound of Formula I according to claim 9 that is a compound of Formula IVa or a pharmaceutically acceptable salt thereof.

16. The compound of Formula I according to claim 9 that is a compound of Formula IVb or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

18. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.

19. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.

20. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.