Prodrugs of piperazine and substituted piperidine antiviral agents

A compound of Formula I,

• wherein:
• X is C;
• W is N with the proviso that when W is N, R2 does not exist;
• V is C;
• R1 is methoxy;
• E is hydrogen or a pharmaceutically acceptable mono or bis salt thereof;
• Y is
• R3 is triazolyl wherein said triazolyl may be independently optionally substituted with C1-6 alkyl;
• and
• R18 is quinazolinyl, and R10, R11, R12, R13, R14, R15, R16, R17, are each H.

A process for preparing Compound Iac having the structure

• comprising:
• (a) alkylating Compound IVa having the structure
• with about 1.2 molar equivalents of di-tert-butyl chioromethyl phosphate per mole of IVa, having the structure Z
• in the presence of about 2 molar equivalents of K2CO3 as a base, per mole of Compound IVa, and about 5-10 ml of N-methylpyrrolidinone as a solvent per gram of IVa, at a reaction temperature of about 30° C., to form Compound R having the structure
• (b) deprotecting at room temperature Compound R of both tert-butyl groups by adding to the resulting reaction mixture of step (a), about 10 ml of dichioromethane solvent per gram of IVa and about 15 molar equivalents of trifluoroacetic acid per mole of IVa;
• and
• (c) recovering Compound Iac.

A process for preparing Compound Ic having the structure

• comprising:
• (a) alkylating Compound IVc having the structure
• with about 2.5 molar equivalents of di-tert butyl chioromethyl phosphate per mole of IVc having the structure Z
• in the presence of about 2.5 molar equivalents of Cs2CO3 as a base per mole of IVc, about 2 molar equivalents of KI per mole of IVc, and about 5-10 ml of N-methyl-pyrrolidinone per gram of IVc, at a reaction temperature of about 25-30° C., to form a Compound IIc having the structure
• (b) deprotecting at a temperature of about 40° C. Compound IIc of both tert-butyl groups in an excess of acetone and water;
• and
• (c) recovering Compound Ic.

A process for preparing Compound Ibc having the structure

• comprising:
• (a) alkylating Compound IVb having the structure
• with about 2 molar equivalents of di-tert butyl chioromethyl phosphate per mole of IVb having the structure Z
• in the presence of about 2 molar equivalents of Cs2CO3 as a base per mole of IVb, about 2 molar equivalents of KI per mole of IVB, and about 2.5 ml of N-methyl-pyrroiidinone per gram of IVb, at a reaction temperature of about 30° C., to form a Compound IIb having the structure
• (b) deprotecting at a temperature of about 40° C. Compound IIb of both tert-butyl groups in an excess of acetone and water;
• and
• (c) recovering Compound Ibc.