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1. (WO2008019303) PYRIDAZINONYL MACROCYCLIC HEPATITIS C SERINE PROTEASE INHIBITORS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED:

1. A compound of Formula I :



or pharmaceutically acceptable salts, esters, or prodrugs thereof, wherein

A is selected from the group consisting Of-(C=O)-O-R1, -(C=O)-R2,
-Q=O)-NR1R2, or -S(O)2-R1, -S(O)2-N R1R2;

Wherein, R1 is independently selected at each occurrence from the following groups:

(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl; and
(vii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-Cg alkyl,
substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; -C3-C12 cycloalkyl, or
substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3- Ci2 cycloalkenyl;

Wherein, R2 is independently selected at each occurrence from the following groups:

(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl; and
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing 0, 1, 2, or 3
heteroatoms selected from O, S, or N; substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl containing 0, 1, 2, or 3
heteroatoms selected from O, S or N; -C3-C12 cycloalkyl, or substituted - C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2
cycloalkenyl;

G is selected from the group consisting of -NHS(O)2-R3 and -NH(SO2)NR4R5;

wherein, R is independently selected at each occurrence from the following groups:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl; and
(vii) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or

3 heteroatoms selected from O, S or N, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C3-Ci2 cycloalkyl, or substituted - C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2
cycloalkenyl;

provided that R3 is not -CH2Ph or -CH2CH2Ph;

Wherein, R4 and R5 are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ϋ) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl; and
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-Cg alkyl,
substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C3-C12 cycloalkyl, or
substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3- Ci2 cycloalkenyl;

L is selected from the group consisting Of -CH2-, -O-, -S-, and -S(O)2-;

X, Y, and Z are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ϋ) -CN;
(iii) -N3;
(iv) halogen;
(v) OR6;
(vi) NR7R8;
(vii) aryl;
(vϋi) substituted aryl;
(ix) heteroaryl;
(x) substituted heteroaryl;

(xi) -C3-C12 cycloalkyl, substituted -C3-C12 cycloalkyl, heterocycloalkyl,
substituted heterocycloalkyl;
(xii) -Ci-C6 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(xiii) -C2-C6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or

N, optionally substituted with one or more substituent selected from
halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and
(xiv) -C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from
halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form a cyclic moiety, which is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

wherein, R6 is independently selected at each occurrence from the following groups:
(i) hydrogen
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl; and
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C3-Ci2 cycloalkyl, or substituted - C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2
cycloalkenyl;

wherein, R7 and R8 are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl; and
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or

3 heteroatoms selected from O, S, or N; substituted -Ci-Cg alkyl,
substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C3-C12 cycloalkyl, or
substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3- Ci2 cycloalkenyl;

denotes a carbon-carbon single or double bond.

J = O, 1, 2, 3, or 4;
k=l, 2, or 3;
m = 0, 1, or 2;
n = 1, 2, or 3.

2. The compound of claim 1, wherein the compound is of Formula II:



( H )
Wherein A, G, X, Y, and Z are as previously defined in claim 1.

3. A compound according to claim 1, which is selected from compounds of Formula III, table 1.



( III )
Table 1











4. A compound having a formula selected from formulae I, II or III, as described in the specification, or a pharmaceutically acceptable salt, ester or prodrug thereof.

5. A pharmaceutical composition comprising a compound of claim 1, or a
pharmaceutically acceptable salt, ester or prodrug of said compound.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.

7. A method of treating a hepatitis C viral infection in a subject, comprising
administering to the subject an inhibitory amount of a pharmaceutical composition according to claim 6.

8. A method of inhibiting the replication of hepatitis C virus, the method comprising supplying a hepatitis C viral NS3 protease inhibitory amount of the pharmaceutical composition of claim 6.

9. The method of claim 7 further comprising administering concurrently an additional anti-hepatitis C virus agent.

10. The method of claim 7, wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.

11. The method of claim 7, wherein said additional anti-hepatitis C virus agent is an inhibitor of hepatitis C virus helicase, polymerase, metalloprotease, or IRES.

12. A process of making a compound having a formula selected from formulae I, II or III, as described in the specification, according to the schemes and examples described therein.

13. The pharmaceutical composition of claim 5, further comprising another anti-HCV agent.

14. The pharmaceutical composition of claim 5, further comprising an agent selected from interferon, ribavirin, amantadine, another HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal ribosome entry site inhibitor.

15. The pharmaceutical composition of claim 5, further comprising pegylated interferon.

16. The pharmaceutical composition of claim 5, further comprising another anti-viral, antibacterial, anti-fungal or anti-cancer agent, or an immune modulator.