Patent EA-004205-B1 (EA)
Title: Alpha-methylbenzyl-containing thiourea inhibitors of herpes viruses containing a phenylenediamine group
Inventor: BLOOM JONATHAN DAVID
IPC: A61K31/472
Filed: 1999-12-06
Abstract: 1. 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; 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; "aryl" means an aromatic mono or bicyclic ring of 5 to 10 carbon atoms; "Heteroaryl" means an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S or O; "heterocycloalkyl" means saturated mono or bicyclic ring system of 3 to 10 members having 1 to 3 heteroatoms selected from N, S and O, and wherein alkyl, alkenyl, aryl, and heteroaryl groups in above mentioned values are optionally substituted; or a pharmaceutical salt thereof. 2. A compound of Claim 1 wherein R1-R5 are independently, alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR6 or N(R7R8). 3. A compound of Claim 1 wherein R4 is halogen, trifluoromethyl or cyano. 4. A compound of Claim 1 wherein G is substituted by one or more groups selected from 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. 5. A compound of Claim 1 wherein G is phenyl. 6. A compound of Claim 5 wherein G is substituted phenyl. 7. A compound of Claim 4 wherein G is substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, halogen, -SR6, -SOR6, N(R7R8) or -W-Y-(CH2)n-Z. 8. A compound of Claim 1 wherein G is 2-fluorophenyl. 9. A compound of Claim 1 wherein G is a fused bicyclic heteroaryl. 10. A compound of Claim 9 wherein G is quinoline, isoquinoline or benzofuran. 11. A compound of Claim 1 wherein X is a bond. 12. A compound of Claim 1 wherein X is straight chain alkyl. 13. A compound of Claim 1 wherein X is straight chain alkyl of 1 to 4 carbon atoms. 14. A compound of Claim 1 wherein X is CH(J). 15. A compound of Claim 1 wherein J is methyl. 16. A compound of Claim 1 selected from N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-trifluoromethyl-benzamide, N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide, Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-1-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide, Isoquinoline-1-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide, Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide, Benzofuran-2-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide, Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}phenyl)-amide, Isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide, Isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide, Quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Quinoline-6-carboxylic acid (4-{3-[1-{4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}phenyl)-amide, N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethyl-benzamide, 2-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide, N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide, 2-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide, N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide, 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide, 2-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide, N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide, N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide, N-{4-[3-{1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro-benzamide, 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide, (S)-N-(4-{3-[1-(4-Bromo-phenyl}-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, 2-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}phenyl)-benzamide, N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide, N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, 2-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide, N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide, 2-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide, 2-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide, 2-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide, N-(4-{3-[{1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, 2-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide, N-(4-{3-[1-{4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide, N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide, N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide, 3-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide, N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide, 4-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide, N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide, N-{4-{3-[(1S)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-4-fluoro-benzamide, N-(4-{3-[(1S)-1-(4-Bromo-phenyl}-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide, N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide, 2-fluoro-N-(4-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)benzamide, Isoquinoline-1-carboxylic acid (4-{3-[(1S)-1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-3-carboxylic acid (4-{3-[(1S)-1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-1-carboxylic acid (4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide, Isoquinoline-1-carboxylic acid (4-{3-[1-{4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide, and N-{4-[({[(1S)-1-(4-cyanophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1-nophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1-isoquinolinecarboxamide, and pharmaceutical salts thereof. 17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier or diluent. 18. A method of inhibiting the replication of a herpes virus comprising contacting a compound of claim 1 or a pharmaceutical salt thereof, with a herpes virus. 19. The method of Claim 18 wherein the herpes virus is human cytomegalovirus. 20. The method of Claim 18 wherein the herpes virus is varicella zoster virus. 21. The method of Claim 20 wherein the compound is substantially pure (S) optical isomer. 22. The method of Claim 18 wherein the herpes virus is herpes simplex virus. 23. A method of treating a patient suffering from a herpes virus infection comprising administering to the patient a therapeutically effective amount of a compound of formula 1 or a pharmaceutical salt thereof. 24. The method of Claim 23 wherein the herpes virus is human cytomegalovirus. 25. The method of Claim 23 wherein the herpes virus is varicella zoster virus. 26. The method of Claim 25 wherein the compound is substantially pure (S) isomer. 27. The method of Claim 23 wherein the herpes virus is herpes simplex virus.