Claims for Patent: 7,232,818

Summary for Patent: 7,232,818

Title:	Compounds for enzyme inhibition
Abstract:	Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
Inventor(s):	Mark S. Smyth, Guy J. Laidig, Ronald T. Borchardt, Barry A. Bunin, Craig M. Crews, John H. Musser
Assignee:	Onyx Therapeutics Inc
Application Number:	US11/106,879
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,232,818
Patent Claims:	1. A compound having a amacuire of formula (I) or a pharmaceutically acceptable salt thereof, wherein each A is independantly selected from C═O, C═S, and SO2; or A is optionally a covalent bond when adjacent to an occurrence of Z; L in absent or is selected from C═O, C═S, and SO2; M is absent or is C1-12alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is selected from O, NH, and N—C1-6alkyl; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; or Z is optionally a covalent bond when adjacent to an occurrence of A; R1, R2, R3, and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, caiboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZAZ-C1-8alkyl-, R11Z-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ-C1-6alkyl-, R8ZAZ-C1-8alkyl-ZAZ-C1-8alkyl-, heterocyclylMZAZ-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-12alkyl-, (R10)3N+-C1-12alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H or CH3 and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), beozoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 2. A compound of claim 1, wherein R1, R2 R3, and R4 are independently selected from C1-6alkyl and C1-6aralkyl. 3. A compound of claim 2, wherein R1 and R3 are both C1-6aralkyl and both R2 and R4 are C1-6alkyl. 4. A compound of claim 3, wherein X is O, R1 is 2-phenylethyl, R2 is isobutyl, R3 is phenylmethyl, and R4 is isobutyl. 5. A compound of claim 4, wherein L and Q are absent and R6 is C1-6alkyl. 6. A compound of claim 5, wherin R7 is selected from C1-6alkyl. C1-6alkenyl, C1-6alkynyl, C1-6aralkyl, and C1-6heteroaralkyl. 7. A compound of claim 6, wherein R7 is C1-6alkyl. 8. A compound of claim 7, wherein R7 is butyl. 9. A compound of claim 6, wherein R7 is C1-6alkenyl. 10. A compound of claim 9, wherein R7 is allyl. 11. A compound of claim 6, wherein R7 is C1-6alkynyl. 12. A compound of claim 11, wherein R7 is propargyl. 13. A compound of claim 6, wherein R7 is C1-6aralkyl. 14. A compound of claim 13, wherein R7 is phenylmethyl. 15. A compound of claim 6, wherein R7 is C1-6heteroaralkyl. 16. A compound of claim 15, wherein R7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl. 17. A compound of claim 4, wherein Q is absent and L is SO2. 18. A compound of claim 17, wherein R7 is selected from C1-6alkyl and C1-6aralkyl. 19. A compound of claim 18, wherein R7 is C1-6alkyl. 20. A compound of claim 19, wherein R7 is methyl. 21. A compound of claim 18, wherein R7 is C1-6aralkyl. 22. A compound of claim 21, wherein R7 is phenyl. 23. A compound of claim 4, wherein L is C═O. 24. A compound of claim 23, wherein R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6hetcroaralkyl, R8ZA-C1-8alkyl-, R11Z-C1-8alkyl (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ-C1-6alkyl-, (R8O)(R9O)P(═O)O—C1-6alkyl-Z-C1-8alkyl-, R8ZA-C1-8 alkyl-ZAZ-C1-8alkyl, heterocyclylMZAZ-C1-8alkyl, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N++—C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alky-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-A or C1-6alkyl-A, thereby fomiing a ring; and each occurrence of Z and A is independently other than a covalent bond. 25. A compound of claim 24, wherein Q is absent. 26. A compound of claim 25, wherein R6 and R7 are C1-6alkyl. 27. A compound of claim 26, wherein R7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl. 28. A compound of claim 25, wherein R7 is C1-6aralkyl. 29. A compound of claim 28, wherein R7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl. 30. A compound of claim 25, wherein R6 is C1-6alkyl and R7 is aryl. 31. A compound of claim 30, wherein R7 is substituted or unsubstituted phenyl. 32. A compound of claim 24, wherein Q is absent or O and R7 is carbocyclylM-. 33. A compound of claim 32, wherein carbocyclyl is cyclopropyl or cyclohexyl. 34. A compound of claim 25, wherein R7 is selected from R8ZA-C1-6alkyl-, R11Z-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ-C1-8alkyl, (R8O)(R9O)P(═O)O—C1-8alkyl-Z-C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ-C1-8alkyl-, heteroeyclylMZAZ-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, A is C═O, and Z is O or NH. 35. A compound of claim 34, wherein Z is O. 36. A compound of claim 35, wherein R7 is heterocyclylMZAZ-C1-8alkyl- and heterocyclyl is oxodioxolenyl or N(R12)(R13), wherein R12 and R13 together arc C1-6alkyl-Y—C1-6alkyl, thereby forming a ring. 37. A compound of claim 36, wherein R7 is selected from (R10)2N—C1-8alkyl- and (R10)3N+(CH2)n—, and R10 is C1-6alkyl. 38. A compound of claim 25, wherein R7 is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino. 39. A compound of claim 24, wherein Q is O or NH. 40. A compound of claim 39, wherein R6 is C1-6alkyl and R7 is selected from C1-6alkyl, C1-6aralkyl, and C1-6heteroaralkyl. 41. A compound of claim 40, wherein R7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl. 42. A compound of claim 24, wherein R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, or C1-6alkyl-A, thereby forming a ring. 43. A compound of claim 42, wherein L is C═O, Q and Y are absent, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 44. A compound of claim 1, wherein L and Q are absent, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 45. A compound of claim 42, wherein L is C═O, Q is absent, Y is selected from NH and N—C1-6alkyl, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 46. A compound of claim 42, wherein L is C═O, Y is absent and R6 and R7 together are C1-2alkyl-Y—C1-3alkyl. 47. A compound of claim 42, wherein L and A are C═O and R6 and R7 together are C1-2alkyl-ZA-C1-2alkyl. 48. A compound of claim 42, wherein L and A are C═O and R6 and R7 together are C2-3alkyl-A. 49. A compound having a structure of formula II or a pharmaceutically acceptable salt thereof, wherein each A is independently selected from C═O, C═S, and SO2; or A is optionally a covalent bond when adjacent to an occulTence of Z; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-12alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is selected from O, NH, and N—C1-6alkyl; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; or Z is optionally a covalent bond when adjacent to an occunence of A; R2 and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R11ZAZ-C1-8alkyl-, R11Z-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ-C1-6alkyl-, R8ZAZ-C1-8alkyl-ZAZ-C1-8alkyl-, heteroeyelylMZAZ-C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-; (R10)2N—C1-12alkyl-, (R10)3N—C1-12alkyl, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ, or C1-6alkyl-A; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, hoterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H or CH3 and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benayloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 50. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.