Patent EA-001915-B1 (EA)
Title: Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease
Inventor: TUNG ROGER D
IPC: A61K38/08
Filed: 1997-10-17
Abstract: 1. A compound of the formula (II):   wherein W is:   m is 0 or 1; each R<2> is independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, or two R<2> groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a 5-7 membered monocyclic heterocyclic ring system; wherein any R<2> carbon atom is optionally substituted with J; J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, keto-, hydroxy-, amino-, alkylamino, alkanoylamino-, aroylamino-, aralkanoylamino-, carboxy-, carboxyalkyl-, carboxamidoalkyl-, halo, cyano-, nitro-, formyl, acyl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J<1> groups; J<1> is alkyl, aryl, aralkyl, alkoxy-, aryloxy-, heterocyclyl, heterocyclyloxy-, keto-, hydroxy-, amino-, alkanoylamino-, aroylamino-, carboxy-, carboxyalkyl, carboxamidoalkyl, halo, cyano-, nitro-, formyl, sulfonyl, or sulfonamido; L is alkyl, alkenyl, or alkynyl, wherein any hydrogen is optionally substituted with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy; A<1> is a bond,   R<4> is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups; R<5> and R<6> are independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionally substituted with 1-3 J groups; X is a bond, -C(H)(R<7>)-, -O-, -S-, or -N(R<8>)-; R<7> is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionally substititued with 1-3 J groups; R<8> is hydrogen, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl, heterocyclanoyl, heteroaralkanoyl, -C(O)R<14>, -SO2R<14>, or carboxamido, and is optionally substititued with 1-3 J groups; or R<8> and Z, together with the atoms to which they are bound, form a nitrogen containing mono- or bicyclic ring system optionally substituted with 1-3 J groups; R<14> is alkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, or heteroaralkyl; Y is a bond, -CH2-, C(O)-, C(O)C(O)-, -S(O)-, -S(O)2-, or -S(O)(NR<7>)-, wherein R<7> is as defined above; Z is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -OR<2>, or -N(R<2>)2, wherein any carbon atom is optionally substituted with J, wherein R<2> is as defined above; A<2> is a bond or   R<9> is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups; M is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, optionally substituted by 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom; V is a bond, -CH2-, -C(H)(R<11>)-, -O-, -S-, or -N(R<11>)-; R<11> is hydrogen or C1-3 alkyl; K is a bond, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, or -S(O)(NR<11>)-, wherein R<11> is as defined above; T is -R<12>, -alkyl-R<12>, -alkenyl-R<12>, -alkynyl-R<12>, -OR<12>, -N(R<12>)2, C(O)R<12>, -C(=NOalkyl)R<12>, or   R<12> is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylidenyl, or heterocycloalkylidenyl, and is optionally substituted with 1-3 J groups, or a first R<12> and a second R<12>, together with the nitrogen to which they are bound, form a mono- or bicyclic ring system optionally substituted by 1-3 J groups; R<10> is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups; R<15> is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups; and R<16> is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl with proviso than when L is alkyl and W is   wherein R<2> is hydrogen, methyl or ethyl,   wherein one R<2> is hydrogen, and the other R<2> is hydrogen, alkyl, phenyl, cyclohexyl, cyclohexylmethyl or benzyl; or   wherein R<2> is alkyl, A<1> must be   wherein alkyl separately or in combination with any other alkyl from definition of other radicals is linear or branched saturated aliphatic hydrocarbon, preferably having 1-10 carbon atoms; alkenyl separately or in combination with any other alkenyl from definition of other radicals is mono- or poly- unsaturated aliphatic hydrocarbon, with straight or branched chain preferably having 2-10 carbon atoms; alkynyl separately or in combination with any other alkynyl from definition of other radicals is mono- or poly- unsaturated aliphatic hydrocarbon, with straight or branched chain preferably having 2-10 carbon atoms, wherein at least one unsaturated aliphatic hydrocarbon comprises triple bond; cycloalkyl separately or in combination with any other cycloalkyl from definition of other radicals is saturated cyclic aliphatic hydrocarbon, having 3-8 carbon atoms; heterocyclyl separately or in combination with any other heterocycle from definition of other radicals is stable 5-15-membered mono-, bi- or tricyclic heterocyclic ring, which is either saturated or partly unsaturated but not aromatic and which is optionally condensed; aryl separately or in combination with any other aryl from definition of other radicals is carbocyclic aromatic ring, preferably having 6-14 carbon atoms which is optionally condensed with other ring system; heteroaryl separately or in combination with any other heteroaryl from definition of other radicals is monocyclic ring, preferably having 3-7 members which is aromatic and which can be condensed with other ring, heteroaryl ring can contain 1-4 heteroatoms, selected from N, O and S; aralkyl is alkyl substituted with aryl; and aralkenyl is alkenyl substituted with aryl; and 2. The compound according to Claim 1, wherein A<1> is:   3. The compound according to Claim 2, wherein R<5> and R<6> are hydrogen. 4. The compound according to Claim 3, wherein A<2> is:   and R<9> is alkyl. 5. The compound according to Claim 4, wherein R<9> is isopropyl. 6. The compound according to Claim 5, wherein L is alkyl, alkenyl, or alkynyl, wherein any hydrogen is optionally substituted with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom is optionally substituted with sulfhydryl or hydroxyl. 7. The compound according to Claim 6, wherein L is trihalomethyl, sulfhydryl, or alkyl substituted with trihalomethyl, sulfhydryl, or hydroxyl. 8. The compound according to Claim 7, wherein: X is -O- or -N(H)-; and Y is -CH2-, -C(O)-, or -S(O)2-. 9. The compound according to Claim 8, wherein V is -N(H)- and K is -C(O)- or -S(O)2-. 10. The compound according to Claim 1, wherein A<1> is   and R<5> and R<6> are hydrogen; A<2> is:   and R<9> is isopropyl; L is ethyl; X is -O- or -N(H)-; Y is -CH2-, -C(O)-, or -S(O)2-; V is -N(H)-; and K is -C(O)-. 11. The compound according to Claim 10, wherein M is isopropyl. 12. The compound according to Claim 11, wherein Z is aryl or heteroaryl. 13. The compound according to Claim 12, wherein T is aryl or heteroaryl. 14. The compound according to Claim 13, wherein T is pyrazine. 15. The compound according to Claim 10, wherein X is -O- and Y is -CH2-. 16. The compound according to Claim 15, wherein Z is aryl or heteroaryl. 17. The compound according to Claim 16, wherein Z is aryl. 18. The compound according to Claim 17, wherein M is isopropyl. 19. The compound according to Claim 18, wherein T is -R<12>, -OR<12>, -N(R<12>)2, or   20. The compound according to Claim 10, wherein M is alkyl, heteroaralkyl, aryl, cycloalkylalkyl, aralkyl, or aralkyl, wherein one of the alkyl carbon atoms is replaced by O or S. 21. The compound according to Claim 20, wherein M is propyl, methyl, pyridilmethyl, benzyl, naphthylmethyl, phenyl, imidazolylmethyl, thiophenylmethyl, cyclohexylmethyl, phenetyl, benzylthiomethyl, or benzyloxyethyl. 22. The compound according to Claim 21, wherein T is aryl or heteroaryl. 23. The compound according to Claim 22, wherein T is pyrazine. 24. The compound according to Claim 3, wherein A<2> is a bond; L is ethyl; X is -O-; Y is -CH2-; V is -N(H)-; and K is -C(O)- or -S(O)2-. 25. The compound according to Claim 24, wherein M is isopropyl. 26. The compound according to Claim 25, wherein Z is aryl or heteroaryl. 27. The compound according to Claim 26, wherein Z is phenyl. 28. The compound according to Claim 27, wherein T is -R<12>, -alkyl-R<12>, -alkenyl-R<12>, -OR<12>, -N(R<12>)2, -C(=NOalkyl)R<12>, or   29. The compound according to Claim 1, wherein A<1> is   and A<2> is   30. The compound according to Claim 29, wherein M is isopropyl and K is -C(O)-. 31. The compound according to Claim 30, wherein T is -R<12>, -alkyl-R<12>, -alkenyl-R<12>, -OR<12>, -N(R<12>)2, -C(=NOalkyl)R<12>, or   32. The compound according to Claim 1, wherein Z is phenyl in which any carbon atom is optionally substituted by J. 33. A pharmaceutically acceptable composition comprising a compound according to any of Claims 1-32 and a pharmaceutically suitable carrier. 34. Use of a compound according to any one of Claims 1-32 for inhibiting serine protease activity. 35. The use according to Claim 34, wherein the serine protease is HCV NS3 protease. 36. A method for treating or preventing a hepatitis C viral infection in a patient comprising using a compound according to any one of Claims 1-32. 37. The method according to Claim 36, wherein said compound is formulated together with a pharmaceutically suitable