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Details for Patent: 7,244,721

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Details for Patent: 7,244,721

Title:Peptides as NS3-serine protease inhibitors of hepatitis C virus
Abstract: The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
Inventor(s): Saksena; Anil K. (Upper Montclair, NJ), Girijavallabhan; Viyyoor Moopil (Parsippany, NJ), Lovey; Raymond G. (West Caldwell, NJ), Jao; Edwin (Warren, NJ), Bennett; Frank (Piscataway, NJ), Mc Cormick; Jinping L. (Edison, NJ), Wang; Haiyan (Cranbury, NJ), Pike; Russell E. (Stanhope, NJ), Bogen; Stephane L. (Somerset, NJ), Chan; Tin-Yau (Edison, NJ), Liu; Yi-Tsung (Morris Township, NJ), Zhu; Zhaoning (East Windsor, NJ), Njoroge; F. George (Warren, NJ), Arasappan; Ashok (Bridgewater, NJ), Parekh; Tejal (Mountain View, CA), Ganguly; Ashit K. (Upper Montclair, NJ), Chen; Kevin X. (Iselin, NJ), Venkatraman; Srikanth (Woodbridge, NJ), Vaccaro; Henry A. (South Plainfield, NJ), Pinto; Patrick A. (Morris Plains, NJ), Santhanam; Bama (Bridgewater, NJ), Kemp; Scott Jeffrey (San Diego, CA), Levy; Odile Esther (San Diego, CA), Lim-Wilby; Marguerita (La Jolla, CA), Tamura; Susan Y. (San Diego, CA), Wu; Wanli (Edison, NJ), Hendrata; Siska (Rockaway, NJ), Huang; Yuhua (Scotch Plains, NJ), Wong; Jesse K. (Monroe Township, NJ), Nair; Latha G. (Scotch Plains, NJ)
Assignee: Schering Corporation (Kenilworth, NJ) Dendreon Corporation (Seattle, WA)
Filing Date:Jan 18, 2002
Application Number:10/052,386
Claims:1. A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I: ##STR02428## wherein: Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, arylheteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkylaryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X.sup.11 or X.sup.12; X.sup.11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X.sup.11 may be additionally optionally substituted with X.sup.12; X.sup.12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X.sup.12; R.sup.1 is COR.sup.5 wherein R.sup.5 is COOR.sup.8, CONR.sup.9R.sup.10, CF.sub.3, C.sub.2F.sub.5, C.sub.3F.sub.7, CF.sub.2R.sup.6, or R.sup.6, wherein R.sup.6, R.sup.8, R.sup.9 and R.sup.10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R.sup.1')].sub.pCOOR.sup.11, [CH(R.sup.1')] .sub.pCONR.sup.12R.sup.13, [CH(R.sup.1')].sub.pSO.sub.2R.sup.11, [CH(R.sup.1')].sub.pCOR.sup.11, [CH(R.sup.1')].sub.pCH(OH)R.sup.11, CH(R.sup.1')CONHCH(R.sup.2') COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONR.sup.12R.sup.13, CH(R.sup.1')CONHCH(R.sup.2')R', CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3') COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3') CONR.sup.12R.sup.13, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3') CONHCH(R.sup.4') COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')CON- R.sup.12R.sup.13, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3') CONHCH(R.sup.4') CONHCH(R.sup.5')COO R.sup.11 and CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')CONHCH(R.sup.- 5')CONR.sup.12R.sup.13, wherein R.sup.1', R.sup.2', R.sup.3', R.sup.4', R.sup.5', R.sup.11, R.sup.12, and R.sup.13 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkylheteroaryl, aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W may be present or absent, and if W is present, W is selected from C.dbd.O, C.dbd.S, C(.dbd.N--CN), or SO.sub.2; Q may be present or absent, and when Q is present, Q is CH, N, P, (CH.sub.2).sub.p, (CHR).sub.p, (CRR').sub.p, O, NR, S, or SO.sub.2; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L; A is O, CH.sub.2, (CHR).sub.p, (CHR--CHR').sub.p, (CRR').sub.p, NR, S, or SO.sub.2; E is CH, N, CR, or a double bond towards or L; G is absent, and E is directly connected to the carbon atom in Formula I as G is linked to; J is present, J is (CH.sub.2).sub.p, (CHR) p, or (CRR').sub.p, SO.sub.2, NH, NR or O; L is present, L is CH, CR, O, S or NR; M may be present or absent, and when M is present, M is O, NR, S, SO.sub.2, (CH.sub.2).sub.p, (CHR).sub.p (CHR--CHR').sub.p, or (CRR').sub.p; p is a number from 0 to 6; and R, R', R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H; C.sub.1 C.sub.10 alkyl; C.sub.2 C.sub.10 alkenyl; C.sub.3 C.sub.8 cycloalkyl; C.sub.3 C.sub.8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; alkylheteroaryl; and further with respect to R.sub.2, the group ##STR02429## wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term "substituted" referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R.sup.2, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; further wherein said unit N-C-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N-C-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring.

2. The compound of claim 1, wherein R.sup.1 is COCONR.sup.9R.sup.10, and R.sup.9 is H, R.sup.10 is H, R.sup.14, CH(R.sup.1')COOR.sup.11, CH(R.sup.1')CH(R.sup.1')COOR.sup.11, CH(R.sup.1')CONR.sup.12R.sup.13, CH(R.sup.1')CH(R.sup.1')CONR.sup.12R.sup.13, CH(R.sup.1')SO.sub.2R.sup.11, CH(R.sup.1')SO.sub.2NR.sup.12R.sup.13, CH(R.sup.1')CH(R.sup.1')COR.sup.11, CH(R.sup.1')CONHCH(R.sup.2')COOR.sup.11, CH(R.sup.1')CONHCH(R.sup.2') CONR.sup.12R.sup.3, or CH(R.sup.1')CONHCH(R.sup.2')(R'), wherein R.sup.14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkylheteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl; wherein R.sup.1' is H or alkyl, and R.sup.2' is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and wherein R.sup.11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, .alpha.-methylbenzyl, .alpha.,.alpha.-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; R' is hydroxymethyl or CH.sub.2CONR.sup.12R.sup.13; R.sup.2' is independently selected from the group consisting of: ##STR02430## wherein: U.sup.1 and U.sup.2 maybe same or different and are selected from H, F, CH.sub.2COOH, CH.sub.2COOMe, CH.sub.2CONH.sub.2, CH.sub.2CONHMe, CH.sub.2CONMe.sub.2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl; U.sup.3 and U.sup.4 maybe same or different and are selected from O and S; U.sup.5 is selected from the moieties consisting of alkyl sulfonyl, aryl, sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof; and NR.sup.12R.sup.13 is selected from the group consisting of: ##STR02431## wherein U.sup.6 is H, OH, or CH.sub.2OH, and R.sup.14 is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropy, n-butyl, 1-but-3-ynyl, benzyl, .alpha.-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.

3. The compound of claim 2, wherein R.sup.2 is selected from the group consisting of the following moieties: ##STR02432## ##STR02433##

4. The compound of claim 3, wherein R.sup.3 is selected from the group consisting of: ##STR02434## wherein R.sup.51=H, COCH.sub.3, COOtBu or CONHtBu ##STR02435## wherein R.sup.31 OH or O-alkyl; Y.sup.19 is selected from the following moieties: ##STR02436## and Y.sup.20 is selected from the following moieties: ##STR02437##

5. The compound of claim 4, wherein R.sup.3 is selected from the group consisting of the following moieties: ##STR02438##

6. The compound of claim 5, wherein Z is N and R.sup.4 is H.

7. The compound of claim 6, wherein W is C.dbd.O.

8. The compound of claim 7, wherein Y is selected from the following moieties: ##STR02439## ##STR02440## ##STR02441## ##STR02442## ##STR02443## ##STR02444## ##STR02445## wherein: Y.sup.11 is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH(Me).sub.2, 1-triazolyl, 1-imidazolyl, and NHCH.sub.2COOH; is selected from H, COOH, COOMe, OMe, F, Cl, or Br; Y.sup.13 is selected from the following moieties: ##STR02446## Y.sup.14 is selected from MeSO.sub.2, Ac, Boc, iBoc, Cbz, or Alloc; Y.sup.15 and Y.sup.16 are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl; Y.sup.17 is CF.sub.3, NO.sub.2, CONH.sub.2, OH, COOCH.sub.3, OCH.sub.3, OC.sub.6H.sub.5, C.sub.6H.sub.5, COC.sub.6H.sub.5, NH.sub.2, or COOH; and Y.sup.18 is COOCH.sub.3, NO.sub.2, N(CH.sub.3).sub.2, F, OCH.sub.3, CH.sub.2COOH, COOH, SO.sub.2NH.sub.2, or NHCOCH.sub.3.

9. The compound of claim 8, wherein Y is selected m the group consisting of: ##STR02447## ##STR02448## ##STR02449## wherein: Y.sup.17=CF.sub.3, NO.sub.2, CONH.sub.2, OH, NH.sub.2, or COOH; Y.sup.18=F, COOH.

10. The compound of claim 9, wherein Y is selected from the group consisting of: ##STR02450## ##STR02451##

11. The compound of claim 3, wherein R.sup.2 is the moiety: ##STR02452##

12. The compound of claim 10, wherein G and M are absent.

13. The compound of claim 10, wherein: ##STR02453## wherein G is absent and J is selected from the group consisting of (CH.sub.2).sub.p, (CHR).sub.p, (CHR--CHR').sub.p, and (CRR').sub.p; A and M are independently selected from the group consisting of O, S, SO.sub.2, NR, (CH.sub.2).sub.p, (CHR).sub.p, (CHR--CHR').sub.p, and (CRR').sub.p; and Q is CH.sub.2, CHR, CRR', NH, NR, O, S, SO.sub.2, NR, (CH.sub.2) p, (CHR).sub.p, and (CRR').sub.p.

14. The compound of claim 13, wherein structure c is selected from the following structures: ##STR02454## ##STR02455## ##STR02456##

15. The compound of claim 10, wherein: ##STR02457## is selected from the following structures: ##STR02458## ##STR02459## ##STR02460## ##STR02461##

16. The compound of claim 15, wherein: ##STR02462## is selected from the following structures: ##STR02463##

17. The compound of claim 15, wherein: ##STR02464## is selected from the following structures: ##STR02465##

18. A pharmaceutical composition comprising as an active ingredient a compound of claim 1.

19. The pharmaceutical composition of claim 18 suitable for use in treating disorders associated with hepatitis C virus.

20. The pharmaceutical composition of claim 18 additionally comprising a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, additionally containing an antiviral agent.

22. The pharmaceutical composition of claim 21, further containing an interferon.

23. The pharmaceutical composition of claim 22, wherein said antiviral agent is ribavirin and said interferon is .alpha.-interferon or pegylated interferon.

24. The compound of claim 4, wherein R.sup.3 is: ##STR02466##

25. A method of treating disorders associated with the hepatitis C virus, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of claim 1.

26. The method of claim 25, wherein said administration is oral or subcutaneous.

27. The use of a compound of claim 1 for the manufacture of a medicament to treat disorders associated with the hepatitis C virus.

28. A compound of claim 1 suitable for use in the manufacture of a medicament to treat disorders associated with the hepatitis C virus.

29. A method of treating disorders associated with the hepatitis C virus (HCV), said method comprising administering to a patient in need of such treatment, a compound of claim 1 and an interferon.

30. The method of claim 29, wherein said interferon is alpha-interferon or pegylated interferon.

31. The method of claim 30, wherein said administration is oral or subcutaneous.

32. The method of claim 29, wherein said treatment further comprises administering an antiviral agent.

33. A compound exhibiting hepatitis C virus protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the compounds of structures listed below: ##STR02467## ##STR02468## ##STR02469## ##STR02470## ##STR02471## ##STR02472## ##STR02473## ##STR02474## ##STR02475## ##STR02476## ##STR02477## ##STR02478## ##STR02479## ##STR02480## ##STR02481## ##STR02482## ##STR02483## ##STR02484## ##STR02485## ##STR02486## ##STR02487## ##STR02488## ##STR02489## ##STR02490## ##STR02491## ##STR02492## ##STR02493## ##STR02494## ##STR02495## ##STR02496## ##STR02497## ##STR02498## ##STR02499## ##STR02500## ##STR02501## ##STR02502## ##STR02503## ##STR02504## ##STR02505## ##STR02506## ##STR02507## ##STR02508## ##STR02509## ##STR02510## ##STR02511## ##STR02512## ##STR02513## ##STR02514## ##STR02515## ##STR02516## ##STR02517## ##STR02518## ##STR02519## ##STR02520## ##STR02521## ##STR02522## ##STR02523## ##STR02524## ##STR02525## ##STR02526## ##STR02527## ##STR02528## ##STR02529## ##STR02530## ##STR02531## ##STR02532## ##STR02533## ##STR02534## ##STR02535## ##STR02536## ##STR02537## ##STR02538## ##STR02539## ##STR02540## ##STR02541## ##STR02542## ##STR02543## ##STR02544## ##STR02545## ##STR02546## ##STR02547## ##STR02548## ##STR02549## ##STR02550## ##STR02551## ##STR02552## ##STR02553## ##STR02554## ##STR02555## ##STR02556## ##STR02557## ##STR02558##

34. A pharmaceutical composition for treating disorders associated with the hepatitis C virus, said composition comprising therapeutically effective amount of one or more compounds in claim 33 and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34, additionally containing an antiviral agent.

36. The pharmaceutical composition of claim 35, additionally containing an interferon or pegylated-interferon alpha conjugate.

37. The pharmaceutical composition of claim 36, wherein said antiviral agent is ribavirin and said interferon is .alpha.-interferon.

38. A method of treatment of a hepatitis C virus (HCV) associated disorder, comprising administering an effective amount of one or more compounds of claim 33.

39. A method of modulating the activity of hepatitis C virus (HCV) protease, comprising contacting HCV protease with one or more compounds of claim 33.

40. A method of treating, or ameliorating one or more symptoms of hepatitis C, comprising administering an effective amount of one or more compounds of claim 33.

41. The method of claim 39, wherein the HCV protease is the NS3/NS4a protease.

42. The method of claim 41, wherein the compound or compounds inhibit HCV NS3/NS4a protease.

43. A method of modulating the activity of hepatitis C virus (HCV) polypeptide, comprising contacting a composition containing the HCV polypeptide under conditions in which the polypeptide is processed with one or more compounds of claim 33.

44. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment, a compound of claim 33 and an interferon.

45. The method of claim 44, wherein said interferon is alpha-interferon or pegylated interferon.

46. The method of claim 45, wherein said administration is oral or subcutaneous.

47. A compound exhibiting hepatitis C virus protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02559##

48. A compound of claim 47 having the formula shown below: ##STR02560##

49. A compound of claim 47 having the formula shown below: ##STR02561##

50. A pharmaceutical composition comprising as an active ingredient a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the following: ##STR02562## ##STR02563## ##STR02564##

51. The pharmaceutical composition of claim 47, additionally containing an antiviral agent.

52. The pharmaceutical composition of claim 50, further containing an interferon or pegylated-interferon alpha conjugate.

53. The pharmaceutical composition of claim 51, wherein said antiviral agent is ribavirin and said interferon is .alpha.-interferon.

54. The pharmaceutical composition of claim 50, wherein said compound is selected from the following: ##STR02565## ##STR02566## ##STR02567## ##STR02568## ##STR02569##

55. The pharmaceutical composition of claim 54, additionally containing an antiviral agent.

56. The pharmaceutical composition of claim 55, additionally containing an interferon or pegylated-interferon alpha conjugate.

57. The pharmaceutical composition of claim 56, wherein said antiviral agent is ribavirin and said interferon is alpha-interferon.

58. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 50 and an interferon.

59. The method of claim 58, wherein said interferon is alpha-interferon or pegylated interferon.

60. The method of claim 59, wherein said administration is oral or subcutaneous.

61. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a compound of any of claims 48 or 49 and an interferon.

62. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 54 and an interferon.

63. A method of treating disorders associated with the hepatitis C virus, said method comprising administering to a patient in need of such treatment, a pharmaceutical composition which comprises therapeutically effective amounts of a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the following: ##STR02570## ##STR02571## ##STR02572##

64. The method of claim 63, wherein said compound is selected from the following: ##STR02573## ##STR02574## ##STR02575## ##STR02576## ##STR02577##

65. The method of claim 64, further comprising administering an interferon.

66. A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula II: ##STR02578## wherein Y is selected from the group consisting of: ##STR02579## ##STR02580## R.sup.1 is COR.sup.5 and R.sup.5 is H, OH, COOR.sup.8, CONR.sup.9R.sup.10, wherein R.sup.8, R.sup.9 and R.sup.10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R.sup.1')].sub.pCOOR.sup.11, [CH(R.sup.1')].sub.pCONR.sup.12R.sup.13, [CH(R.sup.1')].sub.pCOR.sup.11, [CH(R.sup.1')].sub.pCH(OH)R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONR.sup.12R.sup.13, CH(R.sup.1')CONHCH(R.sup.2')R', CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONR.sup.12R.sup.13, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')COO R.sup.11, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')CONR.sup.12R.- sup.13, CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')CONHCH- (R.sup.5')COO R.sup.11 and CH(R.sup.1')CONHCH(R.sup.2')CONHCH(R.sup.3')CONHCH(R.sup.4')CONHCH(R.sup.- 5') CONR.sup.12R.sup.13, wherein R.sup.1', R.sup.2', R.sup.3', R.sup.4', R.sup.5', R.sup.11, R.sup.12, and R.sup.13 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z is N and R.sup.4 is H; W is C=O; Q may be present or absent, and when Q is present, Q is CH, N, P, (CH.sub.2).sub.p, (CHR).sub.p, (CRR').sub.p, O, NR, S, or SO.sub.2; and when Q is absent, M is directly linked to A; A is O, CH.sub.2, (CHR).sub.p, (CHR-CHR').sub.p, (CRR').sub.p, NR, S, or SO.sub.2; M may be present or absent, and when M is present, M is O, NR, S, SO.sub.2, (CH.sub.2).sub.p, (CHR).sub.p (CHR-CHR').sub.p, or (CRR').sub.p; p is a number from 0 to 6; and R, and R' are independently selected from the group consisting of H; C.sub.1-C.sub.10 alkyl; C.sub.2-C.sub.10 alkenyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.3-C.sub.8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term "substituted" referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; and wherein R.sup.2 is selected from the group consisting of the following moieties: ##STR02581## ##STR02582## and R.sup.3 is selected from the group consisting of the following moieties: ##STR02583## wherein R.sup.51=H, COCH.sub.3, COOtBu or CONHtBu; ##STR02584## wherein R.sup.31=OH or O-alkyl; and Y.sup.19 is selected from the following moieties: ##STR02585## and Y.sup.20 is selected from the following moieties: ##STR02586## wherein R.sup.1 is -C(O)C(O)NR.sup.9R.sup.10; R.sup.9 is H; R.sup.10 is H, -R.sup.14, CH(R.sup.1')COOR.sup.11, CH(R.sup.1')CH(R.sup.1')COOR.sup.11, CH(R.sup.1')CONR.sup.12R.sup.13, CH(R.sup.1')CH(R.sup.1')CONR.sup.12R.sup.13, CH(R.sup.1')CH(R.sup.1')SO.sub.2R.sup.11, CH(R.sup.1')CH(R.sup.1')SO.sub.2N R.sup.12R.sup.13, CH(R.sup.1')CH(R.sup.1')COR.sup.11, CH(R.sup.1')CONHCH(R.sup.2')COOR.sup.11, CH(R.sup.1')CONHCH(R.sup.2') CONR.sup.12R.sup.13, or CH(R.sup.1')CONHCH(R.sup.2')(R'), wherein R.sup.14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl; wherein R.sup.1' is H or alkyl, and R.sup.2' is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and wherein R.sup.11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, .alpha.-methylbenzyl, .alpha., .alpha.-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; R' is hydroxymethyl or CH.sub.2CONR.sup.12R.sup.13; R.sup.2' is independently selected from the group consisting of: ##STR02587## wherein: U.sup.1 and U.sup.2 may be same or different and are selected from H, F, CH.sub.2COOH, CH.sub.2COOMe, CH.sub.2CONH.sub.2, CH.sub.2CONHMe, CH.sub.2CONMe.sub.2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl; U.sup.3 and U.sup.4 may be same or different and are selected from O and S; U.sup.5 is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof; and NR.sup.12R.sup.13 is selected from the group consisting of: ##STR02588## wherein U.sup.6 is H, OH, or CH.sub.2OH, and R.sup.14 is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, .alpha.-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.

67. The compound of claim 66, wherein the portion of Formula II between and including C=O is selected from the following structures: ##STR02589##
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