Compounds and methods for the treatment or prevention of Flavivirus infections

A compound having the formula Ia:

• or pharmaceutically acceptable salts thereof;
• wherein,
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7,
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-14 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR10R11, CON(R9)—SO2—R5, CONR9OH or halogen, wherein R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• provided that R16 is other than methyl or ethyl;
• R1 is chosen from C2-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• R2 is chosen from C2-12 alkyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl;
• with the proviso that:
• i) when X is 4-Chloro-2,6-dimethyl-benzenesulfonamide and, R1 is phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2;
• compound #580
• ii) when X is Toluene-4-sulfonamide and R1 is 4-chloro-phenyl, and R3 is H, and Y, is a bond, then Y is other than CONH2;
• compound #563
• iii) when X is Toluene-4-sulfonamide and R1 is 4-fluoro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2;
• compound #564
• iv) when X is Toluene-4-sulfonamide and R1 is 4-methoxy-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2;
• compound #565
• v) when X is Benzamide and R1 is phenyl Y1 is a bond and Y is COOH then R3 is other than hydrogen.

A method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound having the formula III:

• or pharmaceutically acceptable salts thereof;
• wherein,
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is chosen from H or C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7;
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-12 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR1OR1, CON(R9)—SO2—R5, CONR9OH or halogen, wherein;
• R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl.

A pharmaceutical composition comprising at least one compound having the formula III:

• or pharmaceutically acceptable salts thereof;
• wherein,
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is chosen from H or C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7;
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-12 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR10R1, CON(R9)—SO2—R5, CONR9OH or halogen, wherein;
• R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl;
• at least one pharmaceutically acceptable carrier or excipient.

A method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound having the formula III:

• or pharmaceutically acceptable salts thereof,
• wherein
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is chosen from H or C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7,
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-12 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C 2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR10R11, CON(R9)—SO2—R5, CONR9OH or halogen, wherein
• R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• Or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl.

A method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula III:

• or pharmaceutically acceptable salts thereof;
• wherein,
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is chosen from H or C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7;
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-12 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR1OR1, CON(R9)—SO2—R5, CONR9OH or halogen, wherein;
• R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl.

A combination comprising a compound having the formula III:

• or pharmaceutically acceptable salts thereof;
• X is chosen from:
• wherein,
• M is chosen from:
• wherein,
• R4 is chosen from H or C1-6 alkyl;
• R8 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and
• R15 is chosen from H or C1-6 alkyl;
• J is chosen from:
• wherein, W is chosen from O, S or NR7,
• wherein R7 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, C3-12 heterocycle, C3-12 heteroaralkyl, C6-16 aralkyl;
• and R6 is chosen from H, C1-12 alkyl, C6-12 aryl or C6-16 aralkyl;
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR10R11, CON(R9)—SO2—R5, CONR9OH or halogen, wherein;
• R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• or R10 and R1 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl;
• and
• one or more additional agent chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.

A process for preparing a compound of formula A:

• said process comprising the steps of adding:
• an enol ether;
• an hydride donating agent;
• and
• an organic carboxylic acid;
• to a compound of formula B:
• wherein,
• Y1 is chosen from a bond, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
• Y is chosen from COOR16, COCOOR5, P(O)ORaORb, S(O)OR5, S(O)2OR5, tetrazole, CON(R9)CH(R5)COOR5, CONR10R1, CON(R9)—SO2—R5, CONR9OH or halogen, wherein R9, R5, R10 and R11 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl;
• or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
• Ra and Rb are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• or Ra and Rb are taken together with the oxygens to form a 5 to 10 membered heterocycle;
• R16 is chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl and C6-18 aralkyl;
• R1 is chosen from C1-2 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3 18 heteroaralkyl, C6-18 aralkyl or halogen;
• R2 is chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 heterocycle, C3-18 heteroaralkyl, or C6-18 aralkyl;
• R3 is chosen from H, C1-12 alkyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl or C6-18 aralkyl;
• Z is chosen from H, halogen, C1-6 alkyl.