Pyrido[2,3-d]pyrimidines useful as HCV inhibitors, and methods for the preparation thereof

• US 8,022,077 B2
• Filed: 05/12/2006
• Issued: 09/20/2011
• Est. Priority Date: 05/12/2005
• Status: Expired due to Fees

• Current Assignee: Janssen Sciences Ireland UC (Johnson & Johnson)
• Original Assignee: Tibotec Pharmaceuticals Limited (Johnson & Johnson)
• Inventors: Surleraux, Dominique Louis Nestor Ghislain, Lin, Tse-I, Raboisson, Pierre Jean-Marie Bernard, Lenz, Oliver, Simmen, Kenneth Alan
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): Jaisle; Cecilia M
• Application Number:
  US11/914,044
• Publication Number:
  US 20090131460A1
• Time in Patent Office: 1,957 Days
• Field of Search: 544/279, 514/264.1, 514/264.11
• US Class Current: 514/264.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to the use of pyrido[2,3-d]pyrimidines of formula (I)

wherein L, R¹, R² and R³ have specific meaning. The present invention also relates to the use of the compounds of formula (I) as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds of formula (I) per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.

Claims

1. A method of inhibiting HCV replication in a mammal infected with HCV, wherein said method comprises the administration of an effective amount of a HCV inhibitory compound, said compound having the formula (I)

2. The method of inhibiting HCV replication according to claim 1, wherein the compound has the formula (II)

3. The method of inhibiting HCV replication of claim 1, wherein the compound has the formula (III)

4. The method of inhibiting HCV replication according to claim 3, wherein the compound has the formula (IV)

5. The method of inhibiting HCV replication according to claim 1, wherein the compound has the formula (V)

6. The method of inhibiting HCV replication according to claim 5, wherein

R¹ is hydrogen, amino, mono- or disubstituted amino, wherein the substituents of the amino may be selected from C_1-6alkyl, C_1-4alkyloxyC_1-4alkyl, diC_1-4alkylaminoC_1-4alkyl, piperidin-1-yl-C_1-4alkyl, phenylC_1-6alkyl, wherein the phenyl group may be further substituted with C_1-4alkyl, or C_1-4alkoxy;

each R^4a and R^4b is independently hydrogen, or C_1-4alkyl;

each R⁵ is independently hydrogen, or C_1-4alkyl;

each R⁶ is independently hydrogen, or C_1-4alkyl;

each R⁷ is independently hydrogen, or C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl which may be further substituted with —

COOR⁷, polyhaloC_1-4alkyl, halo, —

COR⁶, —

COOR⁷, —

OR⁷, —

NR^4aR^4b, —

NR^4aSO₂R⁵, —

SR⁵, —

SO₂R⁵, or —

SO₂NR^4aR^4b;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

7. The method of inhibiting HCV replication according to claim 5, wherein

R¹ is hydrogen, amino, mono- or disubstituted amino, wherein the substituents of the amino may be selected from C_1-6alkyl, C_1-4alkyloxyC_1-4alkyl, diC_1-4alkylaminoC_1-4alkyl, piperidin-1-yl-C_1-4alkyl, phenylC_1-6alkyl, wherein the phenyl group may be further substituted with C_1-4alkyl, or C_1-4alkoxy;

each R⁵ is independently hydrogen, or C_1-4alkyl;

each R⁶ is independently hydrogen, or C_1-4alkyl;

each R⁷ is independently hydrogen, or C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl which may be further substituted with —

COOR⁷, polyhaloC_1-4alkyl, halo, —

COR⁶, —

COOR⁷,

—

OR⁷, —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

8. The method of inhibiting HCV replication according to claim 5, wherein

R¹ is hydrogen, amino, monosubstituted amino, wherein the substituents of the amino may be selected from C_1-4alkyloxyC_1-4alkyl, diC_1-4alkylaminoC_1-4alkyl, piperidin-1-yl-C_1-4alkyl, phenylC_1-6alkyl, wherein the phenyl group may be further substituted with C_1-4alkoxy;

each R⁵ is C_1-4alkyl;

each R⁷ is C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl which may be further substituted with —

COOR⁷, polyhaloC_1-4alkyl, halo, —

COOR⁷, —

OR⁷, —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

9. The method of inhibiting HCV replication according to claim 5, wherein

R¹ is hydrogen, amino, monosubstituted amino, wherein the substituents of the amino may be selected from C_1-4alkyloxyC_1-4alkyl, piperidin-1-yl-C_1-4alkyl, phenylC_1-6alkyl, wherein the phenyl group may be further substituted with C_1-4alkoxy;

each R⁵ is C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl which may be further substituted with —

COOR⁷, halo, —

OR⁷, or —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

10. The method of inhibiting HCV replication according to claim 1, wherein

R¹ is hydrogen, or amino;

each R⁵ is C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl, —

OR⁷, or —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

11. The method of inhibiting HCV replication according to claim 1, wherein the nitrogen-protecting group is C_1-6alkyloxycarbonyl, arylmethoxycarbonyl, trifluoroacetyl, or arylmethyl.

12. The method of inhibiting HCV replication according to claim 1, wherein the nitrogen-protecting group is t-butoxycarbonyl, benzyloxycarbonyl, benzyl, or trifluoromethyl.

13. A compound of the formula (V)

14. A compound according to claim 13, wherein

R¹ is amino, or mono- or disubstituted amino, wherein the substituents of the amino may be selected from C_1-6alkyl, C_1-4alkyloxyC_1-4alkyl, diC_1-4alkylaminoC_1-4alkyl, piperidin-1-yl-C_1-4alkyl, phenylC_1-6alkyl, wherein the phenyl group may be further substituted with C_1-4alkyl, or C_1-4alkoxy;

each R^4a, R^4b, R⁵, R⁷, independently, is hydrogen, or C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl, halo, —

OR⁷, or —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

15. A compound according to claim 13, wherein

R¹ is amino;

each R^4a, R^4b, R⁵, R⁷, independently, is hydrogen, or C_1-4alkyl;

R⁸ is hydrogen, or a nitrogen-protecting group;

each R¹¹ and R¹² represent, independently, hydrogen, C_1-4alkyl, halo, —

OR⁷, or —

SR⁵;

R¹³ represents hydrogen, or halo; and

R¹⁴ represents halo.

16. A compound according to claim 13, wherein

R¹¹ is hydrogen;

and

R¹² is C_1-4alkyl, halo, C_1-4alkoxy, C_1-4alkylthio, or trifluoromethyl.

17. A compound according to claim 13, wherein

R¹³ and R¹⁴ represent halo.

18. A compound according to claim 13, wherein the nitrogen-protecting group is C_1-6alkyloxycarbonyl, arylmethoxycarbonyl, trifluoroacetyl, or arylmethyl.

19. A compound according to claim 13, wherein the nitrogen-protecting group is t-butoxycarbonyl, benzyloxycarbonyl, benzyl, or trifluoromethyl.

20. A pharmaceutical composition comprising a compound of formula (V)

21. A pharmaceutical composition comprising a compound of formula (V)

22. A method of treating a mammal infected with HCV, wherein said method comprises the administration of an effective amount of a HCV inhibitory compound, said compound having the formula (I)