Alpha-methylbenzyl-containing thiourea inhibitors of herpes viruses containing a substituted phenylene-diamine group

A pharmaceutical composition comprising a compound of the formula:

• wherein
• R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, —CN, —NO2, —CO2R6, —COR6, —OR6, —SR6, —SOR6, —SO2R6, —CONR7R8, —NR6N(R7R8), —N(R7R8) or W—Y—(CH2)n—Z provided that at least one of R1-R5 is not hydrogen;
• or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
• R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
• R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or
• R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
• R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms;
• provided that at least one of R9-12 is not hydrogen;
• W is O, NR6, or is absent;
• Y is —(CO)— or —(CO2)—, or is absent;
• Z is alkyl of 1 to 4 carbon atoms, —CN, —CO2R6, COR6, —CONR7R8, —OCOR6, —NR6COR7, —OCONR6, —OR6, —SR6, —SOR6, —SO2R6, SR6N(R7R8), —N(R7R8) or phenyl;
• G is aryl or fused bicyclic heteroaryl,
• X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
• J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl;
• and
• n is an integer from 1 to 6;
• or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier or diluent.

A method of inhibiting the replication of a herpes virus comprising contacting a compound of the formula:

• wherein
• R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, —CN, —NO2, —CO2R6, —COR6, —OR6, —SR6, —SOR6, —SO2R6, —CONR7R8, —NR6N(R7R8), —N(R7R8) or W—Y—(CH2)n—Z provided that at least one of R1-R5 is not hydrogen;
• or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
• R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
• R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or
• R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
• R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to;
• form aryl of 5 to 7 carbon atoms;
• provided that at least one of R9-12 is not hydrogen;
• W is O, NR6, or is absent;
• Y is —(CO)— or —(CO2)—, or is absent;
• Z is alkyl of 1 to 4 carbon atoms, —CN, —CO2R6, COR6, —CONR7R8, —OCOR6, —NR6COR7, —OCONR6, —OR6, —SR6, —SOR6, —SO2R6, SR6N(R7R8), —N(R7R8) or phenyl;
• G is aryl or fused bicyclic heteroaryl;
• X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
• J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl;
• and
• n is an integer from 1 to 6;
• or a pharmaceutically acceptable salt thereof;
• with a herpes virus.

A method of treating a patient suffering from a herpes virus infection comprising administering to the patient a therapeutically effective amount of a compound having the formula:

• wherein
• R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, —CN, —NO2, —CO2R6, —COR6, —OR6, —SR6, —SOR6, —SO2R6, —CONR7R8, —NR6N(R7R8), —N(R7R8) or W—Y—(CH2)n—Z provided that at least one of R1-R5 is not hydrogen;
• or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
• R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
• R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or
• R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
• R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms;
• provided that at least one of R9-12 is not hydrogen;
• W is O, NR6, or is absent;
• Y is —(CO)— or —(CO2)—, or is absent;
• Z is alkyl of 1 to 4 carbon atoms, —CN, —CO2R6, COR6, —CONR7R8, —OCOR6, —NR6COR7, —OCONR6, —OR6, —SR6, —SOR6, —SO2R6, SR6N(R7R8), —N(R7R8) or phenyl;
• G is aryl or fused bicyclic heteroaryl;
• and
• X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
• J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl;
• and
• n is an integer from 1 to 6;
• or a pharmaceutical salt thereof.