| 摘要 |
1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, or solvate of either entity, wherein R<1> is H, OH, C1-4 alkyl, C1-4 alkoxy, or C2-4 alkenyl, R<2> is C1-6 akyl optionally substituted by fluoro, indolyl, imidazolyl, SO2 (C1-4 alkyl), C5-7 cycloalkyl, or by an optionally protected OH, SH, CONH2, CO2 H, NH2 or NHC(=NH)NH2 group, C5-7 cycloalkyl optionally substituted by C1-6 alkyl, or is benzyl optionally substituted by optionally protected OH, C1-6 alkoxy, benzyloxy or benzylthio, wherein the optional protecting groups for said OH, SH, CONH2, NH2 and NHC(=NH)NH2 groups are selected from C1-6 alkyl, benzyl, C1-6 alkanoyl, and where the optional protecting groups for said CO2 H is selected from C1-6 alkyl or benzyl, R<3>, R<5> and R<6> are each independently selected from H and F, R<4> is CH3, Cl or F, X is HO or HONH, Y is a direct link or O, Z is either a group of formula (a): where R<10> is C1-4 alkyl, C1-4 alkoxymethyl, hydroxy(C2-4 alkyl), carboxy(C1-4 alkyl) or (amino or dimethylamino)C2-4 alkyl, and R<11> is phenyl, naphthyl or pyridyl optionally substituted by up to three substituents independently selected from halo and methyl; or (b) R<14> is H, OH, CH, or halo, Ar is a group of formula (c), (d) or (e): wherein A is N or CR<12>, B is N or CR<13>, provided that A and B are not both N, R<7> and R<9> are each independently H or F, and R<8>, R<12> and R<13> are H, CN, C1-6 alkyl, hydroxy(C1-6 alkyl), hydroxy(C1-6)alkoxy, C1-6 alkoxy(C1-6)alkoxy,(amino or dimethylamino)C1-6 alkyl, CONH2, OH, halo, C1-6 alkoxy, (C1-6 alkoxy)methyl, piperazinylcarbonyl, piperidinyl, C(NH2)=NOH or C(=NH)NHOH, with the proviso that at least two of R<8>, R<12> and R<13> are H. 2. The compound according to claim 1wherein R<1> is H, OH, C1-4 alkyl or C1-4 alkoxy. 3. The compound according to any preceding claim wherein R<2> is C1-6 alkyl optionally substituted by indolyl, C1-6 alkylthio, SO2 (C1-4 alkyl), C5-7 cycloalkyl, OH or SH, C5-7 cycloalkyl optionally substituted by C1-6 alkyl, or R<2> is benzyl. 4. The compound according to any preceding claim wherein Z is a group of formula (a): where R<10> is C1-4 alkyl, C1-4 alkoxymethyl or hydroxy(C2-4 alkyl), and R<11> is phenyl or pyridyl, optionally substituted by up to three substituents independently selected from halo and methyl, or Z is 5. The compound according to any preceding claim wherein R<3> is H. 6. The compound according to any preceding claim wherein R<4> is F when Y is O, and R<4> is Cl or CH3 when Y is a direct link. 7. The compound according to any preceding claim wherein R<5> is H. 8. The compound according to any preceding claim wherein R<6> is H. 9. The compound according to any preceding claim wherein Ar is a group of formula (c), wherein A is CR<12> and B is CR<13>, R<7> and R<9> are each independently H or F, R<8> and R<13> are each independently H, F, Cl, CN, CONH2, CH3 or OCH3, and R<12> is H, C1-6 alkyl, CN, hydroxy(C2-6 alkyl), (amino or dimethylamino)C2-6 alkyl, CONH2, OH, halo, C1-6 alkoxy, (C1-6 alkoxy)methyl, piperazinylcarbonyl, piperidinyl, C(NH2)NOH or C(=NH)NHOH. 10. The compound according to any preceding claim wherein R<1> is H, OH, n-propyl or ethoxy. 11. The compound according to any preceding claim wherein R<2> is C1-6 alkyl optionally substituted by OH, SO2 (C1-4 alkyl) or C5-7 cycloalkyl, cyclohexyl optionally substituted by C1-6 alkyl, or R<2> is benzyl. 12. The compound according to any preceding claim wherein Z is a group of formula (a): where R<10> is C1-4 alkyl, C1-4 alkoxymethyl or hydroxy(C24 alkyl), and R<11> is phenyl, pyridin-4-yl or pyridin-3-yl, or Z is 13. The compound according to any preceding claim wherein Ar is a group of formula (c), wherein A is CR<12>, B is CR<13>, and R<7>, R<8> and R<9> are H. 14. The compound according to any preceding claim wherein R<1> is H. 15. The compound according to any preceding claim wherein R<2> is cyclohexylmethyl, isopropyl, 1-methylcyclohexyl, t-butyl, C(CH3)2 SO2 CH3, benzyl or C(CH3)2 OH. 16. The compound according to any preceding claim wherein Z is a group of formula (a): where R<10> is CH3, CH2 OCH3, or CH2 OH, and R<11> is phenyl, pyridin-4-yl or pyridin-3-yl, or Z is 17. The compound according to any preceding claim wherein Ar is a group of formula (c), wherein A is CR<12>, B is CR<13>, R<7>, R<8> and R<9> are H, R<12> is H, C1-6 alkyl, CN, hydroxy(C2-6 alkyl), (amino or dimethylamino)C2-6 alkyl, CONH2, OH, halo, C1-6 alkoxy, (C1-6 alkoxy)methyl, C(NH2)=NOH or C(=NH)NHOH, and R<13> is H, OCH3, CN, CONH2, CH3 or F. 18. The compound according to any preceding claim wherein R<2> is isopropyl, t-butyl or benzyl. 19. The compound according to any preceding claim wherein Z is a group of formula 20. The compound according to any preceding claim wherein Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl. 21. The compound according to any preceding claim wherein R<2> is t-butyl. 22. The compound according to any preceding claim wherein Ar is phenyl or 3-methoxyphenyl. 23. The compound according to Claim 1 wherein R<1> is H, OH, n-propyl or ethoxy, R<2> is t-butyl, isopropyl or benzyl, Z is a group of formula where R<10> is CH, CH2 OCH3, or CH2 OH, and R<11> is phenyl, pyridin-4-yl or pyridin-3-yl, or Z is R<3> is H, R<4> is CH3, Cl or F, R<5> is H, R<6> is H, and Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl. 24. A compound according to Claim 1, selected from the group consisting of: N1-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-(N4-hydroxy)-(2R)-2-{3-[3-methyl-(4-phenyl)phenyl]propyl}butanediamide; N1-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-(2R)-2-[3-(3-fluoro-4-phenoxyphenyl)propyl]-(N4-hydroxy)butanediamide; N1-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-(N4-hydroxy)-(2R)-2-{3-[3-methyl-(4-phenyl)phenyl]propyl}-(3S)-propylbutanediamide; (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-propyl]amino}carbonyl)-6-[(3-methyl-4-phenyl)phenyl]hexanoic acid; (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-propyl]amino}carbonyl)-6-[(3'-methoxy-2-methylbiphen-4-yl)hexanoic acid; (2R)-N-1-[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-2-{3-[(3-methyl-4-phenyl)phenyl]propyl}-(N-4-hydroxy)butanediamide; (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-phenylethyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoic acid; (N4,3S)-dihydroxy-N1-[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-(2R)-2-{3-[3-methyl-(4-phenyl)phenyl]propylbutanediamide; (N4,3S)-dihydroxy-N1-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-(2R)-2-{3-[3'-methoxy-2-methylbiphen-4-yl) propyl]}butanediamide; (N4,3S)-dihydroxy-N1-[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-(2R)-2-{3-[(3'-methoxy-2-methylbiphen-4-yl)propyl]}butanediamide. 25. A pharmaceutical composition comprising the compound according to Claim 1, in admixture with a compatible adjuvant, diluent or carrier. 26. A compound according to any claims 1 to 24 for use as a medicament. 27. The compound according to any claims 1 to 24 for commercial manufacturing a medicament for treating conditions mediated by, in particular, MMP-3 and/or MMP-12 and/or MMP-13. 28. A method for treating or prevention conditions mediated by, in particular, MMP-3 and/or MMP-12 and/or MMP-13, the method comprises administering an effective amount of a compound according to any of claims 1 to 24 or a composition thereof according to claim 25. 29. A process for making a compound according to claim 1 where X is OH, comprising transforming a compound of formula (II) where X1 is a group capable of being transformed to a carboxy group, and the other substituents are as defined in claim 1, for example, by hydrolysis of the compound )II), where X1 is a CO2 (t-butyl or methyl) moiety. 30. A process for making a compound according to claim 1 where X is NHOH and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in Claim 1, comprising reacting a compound of formula (I) according to Claim 1 where X is OH with hydroxylamine or a hydroxylamine derivative. 31. A process for making a compound according to claim 1 where X is NHOH and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in claim 1, comprising reacting a compound of formula (I) where X is OH with O-allylhydroxylamine or a salt thereof, in the presence of a peptide coupling agent to give a compound of formula (III): followed by treating the compound of formula (III) with ammonium formate in the presence of a suitable catalyst. 32. A process for making a compound according to claim 1 where X is NHOH, R<1> is OH and R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in claim 1, comprising reacting a compound of formula (IV) with hydroxylamine or a salt thereof. 33. A process for making the compound according to claim 1 where X is OH and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in claim 1, which comprises cross-coupling a compound of formula (V) with a compound of formula (VI): where X2 is a protected acid such as a CO2 CH3 or CO2 (t-butyl) group and LG is a cross-coupling leaving group such as I, Br or OSO2 CF3, and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar, and Z are as defined in Claim 1, in the presence of a catalyst, to produce a compound or compounds of formula (VIIa) and/or (VIIb) wherein X2 is defined as above for compounds of formula (V) and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in claim 1, followed by reducing the olefinic moiety and deprotecting the protected acid moiety X2. 34. A compound of formula (II) wherein the X1, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, Y, Ar and Z are as defined in claim 29, o |
