Methods for the preparation of hcv polymerase inhibitors   

This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Nos. 60/711,042, filed Aug. 24, 2005, 60/744,273, filed Apr. 4, 2006, and 60/804,644, filed Jun. 13, 2006, all of which are hereby incorporated by reference in their entirety.

The present invention relates to methods for the preparation of compounds useful as inhibitors of the Hepatitis C virus (HCV) polymerase enzyme, and intermediate compounds useful in their preparation.

Hepatitis C virus (HCV) is a member of the hepacivirus genus in the family Flaviviridae. It is the major causative agent of non-A, non-B viral hepatitis and is the major cause of transfusion-associated hepatitis and accounts for a significant proportion of hepatitis cases worldwide. Although acute HCV infection is often asymptomatic, nearly 80% of cases resolve to chronic hepatitis. The persistent property of the HCV infection has been explained by its ability to escape from the host immune surveillance through hypermutability of the exposed regions in the envelope protein E2 (Weiner, et al., Virology, 180:842-848 (1991); Weiner, et al., Proc. Natl. Acad. Sci. USA, 89:3468-3472 (1992).

Since persistent infection of HCV is related to chronic hepatitis and eventually to hepatocarcinogenesis, HCV replication is one of the targets to eliminate HCV reproduction and to prevent hepatocellular carcinoma. Unfortunately, present treatment approaches for HCV infection are characterized by relatively poor efficacy and an unfavorable side-effect profile. Therefore, intensive effort is directed at the discovery of molecules to treat this disease, including the discovery of drugs designed to inhibit HC replication, as there is a persistent need for non-peptide, small-molecule compounds that are HCV RdRp inhibitors having desirable or improved physical and chemical properties appropriate for pharmaceutical applications.

Compounds useful as inhibitors of the HCV polymerase enzyme are disclosed in U.S. patent application Ser. Nos. 10/718,337, filed Nov. 19, 2003, and 11/204,269, Aug. 15, 2005, both of which are hereby incorporated by reference in their entirety. The present invention provides improved methods and intermediate compounds useful in the preparation of compounds useful as inhibitors of the HCV polymerase enzyme.

SUMMARY

The present invention provides methods of preparing compounds of formula (Ia):

wherein:

R1 is C1-C6 alkyl or C3-C6 cycloalkyl;

R2a, R2b, and R2c are each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, —OR12a, —CF3, —CN, and —NR12aR12b;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR9R10;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5; said method comprising:

a) treating a compound of formula (V), wherein R1 is defined above, with an anion of a compound of formula (X), wherein R13 is hydrogen, C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2, to afford a compound of formula (IV);

b) hydrolyzing the compound of formula (IV) to afford a compound of formula (IV) wherein R13 is hydrogen;

c) treating the compound of formula (IV) with a combination of reagents to afford a compound of formula (III), wherein P1 is hydrogen or a suitable protecting group and R14 is C1-C6 alkyl or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2;

d) treating the compound of formula (III) with an acid or base to afford a compound of formula (II); and

e) treating the compound of formula (II) with a compound of formula (IXa), to afford the compound of formula (Ia)

Further provided herein are such methods, wherein in the compound of formula (Ia):

R1 is C3-C6 cycloalkyl;

R2a, R2b, and R2c are each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, —OR12a, —CF3, —CN, and —NR12aR12b;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR12aR12b;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5.

Also provided herein are such methods, wherein in the compound formula (Ia):

R1 is cyclopentyl;

R2a, R2b, and R2c are each independently selected from hydrogen, halogen, and C1-C6 alkyl;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR12aR12b;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5.

Further included are such methods, wherein in the compound formula (Ia):

R1 is cyclopentyl;

R2a is C1-C6 alkyl;

R2b is hydrogen;

R2c is C1-C6 alkyl;

R4 is hydrogen;

R5 is C1-C6 alkyl;

R6 is hydrogen; and

R7 is C1-C6 alkyl.

In another aspect are afforded such methods, wherein in the compound formula (Ia):

R1 is cyclopentyl;

R2a is —CH3;

R2b is hydrogen;

R2c is —CH3;

R4 is hydrogen;

R5 is —CH2CH3;

R6 is hydrogen; and

R7 is —CH2CH3.

In still another aspect are afforded such methods, wherein the compound of formula (Ia) is (Iaa),

Furthermore, included herein are such methods, wherein the compound of formula (Ia) is (Iab),

Further provided herein are methods of preparing a compound of formula (Ia):

wherein:

R1 is C1-C6 alkyl or C3-C6 cycloalkyl;

R2a, R2b, and R2c are each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, —OR12a, —CF3, —CN, and —NR12aR12b;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR12aR12b;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5; said method comprising:

a) treating a compound of formula (IV), wherein R1, R4, R5, R6, and R7 are as defined herein, P1 is hydrogen or a suitable protecting group, and R13 is hydrogen, C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2, with a combination of reagents to afford a compound of formula (III), wherein R14 is C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2;

b) treating the compound of formula (III) with an acid or base to afford a compound of formula (II); and

e) treating the compound of formula (II) with a compound of formula (IXa), to afford the compound of formula (Ia)

In still another aspect are provided methods of preparing a compound of formula (II),

wherein:

R1 is C1-C6 alkyl or C3-C6 cycloalkyl;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b:

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR9R10;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5; said method comprising:

a) treating a compound of formula (V), wherein R1 is defined above, with an anion of a compound of formula (X), wherein R13 is hydrogen, C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2, to afford a compound of formula (IV);

b) hydrolyzing the compound of formula (IV) to afford a compound of formula (IV) wherein R13 is hydrogen;

c) treating the compound of formula (IV) with a combination of reagents to afford a compound of formula (III), wherein P1 is hydrogen or a suitable protecting group, and R14 is C1-C6 alkyl or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2;

d) treating the compound of formula (III) with an acid or base to afford the compound of formula (II),

Further provided herein are such methods, wherein the compound of formula (II) is (IIa)

or wherein the compound of formula (II) is (IIb):

Also included herein are any of the above-described methods, wherein in the compound of formula (II):

R1 is C3-C6 cycloalkyl;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR12aR12b;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5.

Furthermore, the present invention includes such above-described methods, wherein in the compound of formula (II):

R1 is C3-C6 cycloalkyl;

R4 is hydrogen;

R5 is C1-C6 alkyl;

R6 is hydrogen;

R7 is C1-C6 alkyl;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR9R10;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5.

Also included are any of the above-described methods, wherein in the compound of formula (II):

R1 is cyclopentyl;

R4 is hydrogen;

R5 is —CH2CH3;

R6 is hydrogen;

R7 is —CH2CH3;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR12aR12b; and

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl.

In still another aspect of the present invention are provided methods of preparing a stereoisomerically enriched compound of formula (Ia),

wherein:

R1 is C1-C6 alkyl or C3-C6 cycloalkyl;

R2a, R2b, and R2c are each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, —OR12a, —CF3, —CN, and —NR12aR12b;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;

each R11 is independently selected from hydrogen, C1-C6 alkyl, halogen, —OR12a, —CN, —CF3, and —NR9R10;

each R12a and R12b is independently selected from hydrogen and C1-C6 alkyl; and

each n is independently chosen and is an integer from 0 to 5; said method comprising:

a) treating a compound of formula (IV), wherein R1, R4, R5, R6, and R7 are as hereinbefore defined and P1 is hydrogen or a suitable protecting group, with a chiral, non-racemic base to afford a mixture of diastereomeric salts;

b) separating said diastereomeric salts from each other;

c) converting said separated diastereomeric salts to a stereoisomerically enriched compound of formula (IV);

d) treating the stereoisomerically enriched compound of formula (IV), wherein R13 is hydrogen, C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2, with a combination of reagents to afford a stereoisomerically enriched compound of formula (III), wherein R14 is hydrogen, C1-C6 alkyl, —Si(C1-C6 alkyl)3, or —CH2(C6-C10 aryl), wherein said C6-C10 aryl group is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, —OH, —OCH3, and —N(C1-C6 alkyl)2;

e) treating the stereoisomerically enriched compound of formula (III), wherein P1 is hydrogen, with an acid or base to afford the stereoisomerically enriched compound of formula (II); and

f) treating the stereoisomerically enriched compound of formula (II) with a compound of formula (IXa), to afford the stereoisomerically enriched compound of formula (Ia)

A further aspect of the present invention affords methods of preparing a stereoisomerically enriched compound of formula (II),

wherein:

R1 is C1-C6 alkyl or C3-C6 cycloalkyl;

R4 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R5 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R6 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

R7 is selected from hydrogen, C1-C6 alkyl, —(CR9R10)nR11, —CF3, halogen, —OR12a, —CN, and —NR12aR12b;

each R9 and R10 is independently selected from hydrogen and C1-C6 alkyl, or R9 and R10, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group;