Patent
Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme
| العنوان: | Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme |
|---|---|
| Patent Number: | 7,102,008 |
| تاريخ النشر: | September 05, 2006 |
| Appl. No: | 10/632197 |
| Application Filed: | July 31, 2003 |
| مستخلص: | The present invention provides compounds of Formula (I): [chemical expression included] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein the variables A, R1, R2, R3, R4, Z, U, X, Y, Za, and n are defined are as defined herein, which are useful as inhibitors of matrix metalloproteinases (MMP) and/or TNF-α converting enzyme (TACE), or a combination thereof. |
| Inventors: | Maduskuie, Thomas P. (Wilmington, DE, US) |
| Assignees: | Bristol-Myers Squibb Company (Princeton, NJ, US) |
| Claim: | 1. A compound of Formula (I): [chemical expression included] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is —C(O)NHOH, —C(O)NHOR 5 , —C(O)NHOR 6 , —N(OH)COR 5 , or —N(OH)CHO; U is absent or is O, NR a1 , C(O), CR a (OH), C(O)O, OC(O), C(O)NR a1 , NR a1 C(O), OC(O)O, OC(O)NR a1 , NR a1 C(O)O, NR a1 C(O)NR a1 , S(O) p , S(O) p NR a1 , NR a1 S(O) p , or NR a1 SO 2 NR a1 ; X is absent or is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; Y is absent or is O, NR a1 , S(O) p , or C(O); provided that U—X—Y form a linker of at least two atoms between Z and Z a and is other than OC(O) or OC(O)alkylene; Z is phenyl substituted with 0–1 R b , naphthyl substituted with 0–1 R b , pyridyl substituted with 0–1 R b , or pyrimidyl substituted with 0–1 R b ; Z a is a C 3-13 carbocycle substituted with 1–5 R c or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 1–5 R c , provided that if Z a is bicyclic, it does not contain a bridging nitrogen atom; provided that U, Y, Z, and Z a do not combine to form a N—N, N—O, O—N, O—O, S(O) p —O, O—S(O) p , or S(O) p —S(O) p group; R 1 is Q, C 1-6 alkylene-Q, C 2-6 alkenylene-Q, C 2-6 alkynylene-Q, —(CR a R a1) r O(CR a R a1) s -Q, —(CR a R a1) r NR a (CR a R a1) s -Q, —(CR a R a1) r C(O)(CR a R a1) s -Q, —(CR a R a1) r C(O)O(CR a R a1) s -Q, —(CR a R a1) r OC(O)(CR a R a1) s -Q, —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r C(O)NR a (CR a R a1) s -Q, —(CR a R a1) r NR a C(O)(CR a R a1) s -Q, —(CR a R a1) r OC(O)O(CR a R a1) s -Q, —(CR a R a1) r OC(O)NR a (CR a R a1) s -Q, —(CR a R a1) r NR a C(O)O(CR a R a1) s -Q, —(CR a R a1) r NR a C(O)NR a (CR a R a1) s -Q, —(CR a R a1) r S(O) p (CR a R a1) s -Q, —(CR a R a1) r SO 2 NR a (CR a R a1) s -Q, —(CR a R a1) r NR a SO 2 (CR a R a1) s -Q, or (CR a R a1) r NR a SO 2 NR a (CR a R a1) s -Q; R 2 is Q 1 , C 1-6 alkylene-Q 1 , C 2-6 alkenylene-Q 1 , C 2-6 alkynylene-Q 1 , —(CR a R a1) r O(CR a R a1) s -Q 1 , —(CR a R a1) r NR a (CR a R a1) s -Q 1 , —(CR a R a1) r C(O)(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)O(CR a R a1) s -Q 1 , —(CR a R a1) r OC(O)(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r C(O)NR a (CR a R a1) s -Q 1 , —(CR a R a1) r NR a C(O)(CR a R a1) s -Q 1 , —(CR a R a1) r OC(O)O(CR a R a1) s -Q 1 , —(CR a R a1) r OC(O)NR a (CR a R a1) s -Q 1 , —(CR a R a1) r NR a C(O)NR a (CR a R a1) s -Q 1 , —(CR a R a1 2) r S(O) p (CR a R a1) s -Q 1 , —(CR a R a1) r SO 2 NR a (CR a R a1) s -Q 1 , —(CR a R a1) r NR a SO 2 (CR a R a1) s -Q 1 , or —(CR a R a1) r NR a SO 2 NR a (CR a R a1) s -Q 1 ; provided that when n is 0 and CR 1 R 2 is CHNH 2 , then Z a is other than unsubstituted phenyl; Q is, independently at each occurrence, H, CHF 2 , CH 2 F, CF 3 , a C 3-13 carbocycle substituted with 0–5 R d , or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–5 R d ; Q 1 is, independently at each occurrence, H, a C 3-13 carbocycle substituted with 0–5 R d , or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–5 R d ; alternatively, R 1 and R 2 , when attached to the same carbon atom, combine to form a 3–7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O) p and substituted with 0–2 R d ; alternatively, when two R 1 groups are present they and the two carbon atoms to which they are attached combine to form a 4–7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O) p and substituted with 0–2 R d , provided that when R 1 s combine to form a ring Z is other than naphthylene; R 3 is H or C 1-6 alkyl; R 4 is H, C 1-6 alkyl, phenyl, orbenzyl; provided that when R 4 is other than H and n is 0, then one or both of R 1 and R 2 are other than H; alternatively, R 3 and R 4 together with the carbon and oxygen atoms to which they are attached form a 5–6 membered ring consisting of, in addition to the carbon and oxygen atom shown, carbon atoms and 0–1 ring double bonds and substituted with 0–2 R c ; R a is, independently at each occurrence, H, C 1-6 alkyl, phenyl, or benzyl; R a1 is, independently at each occurrence, H, C 1-6 alkyl substituted with 0–1 R c1 , C 2-6 alkenyl substituted with 0–1 R c1 , C 2-6 alkynyl substituted with 0–1 R c1 , or —(CH 2) r -3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NR a2 , O, and S(O) p , and substituted with 0–3 R c1 ; alternatively, R a and R a1 when attached to a nitrogen, together with the nitrogen to which they are attached, combine to form a 5 or 6 membered heterocycle consisting of carbon atoms and from 0–1 additional heteroatoms selected from N, NR a2 , O, and S(O) p ; R a2 is, independently at each occurrence, C 1-4 alkyl, phenyl, or benzyl; R a3 is, independently at each occurrence, H, C 1-6 alkyl substituted with 0–1 R c1 , C 2-6 alkenyl substituted with 0–1 R c1 , C 2-6 alkynyl substituted with 0–1 R c1 , or —(CH 2) r -3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NR a2 , O, and S(O) p , and substituted with 0–3 R c1 ; R b is, independently at each occurrence, C 1-6 alkyl substituted with 0–1 R c1 , OR a , SR a , Cl, F, Br, I, ═O, CN, NO 2 , —NR a R a1 , —C(O)R a , —C(O)OR a , —C(O)NR a R a1 , —C(S)NR a R a1 , —NR a C(O)NR a R a1 , —OC(O)NR a R a1 , —NR a C(O)OR a , —S(O) 2 NR a R a1 , —NR a S(O) 2 R a3 , —NR a S(O) 2 NR a R a1 , —OS(O) 2 NR a R a1 , —S(O) p R a3 , CF 3 , CF 2 CF 3 , CHF 2 , CH 2 F, or phenyl; R c is, independently at each occurrence, H, OR a , Cl, F, Br, I, ═O, CN, NO 2 , CF 3 , —CF 2 CF 3 , CH 2 F, CHF 2 , —(CR a R a1) r NR a R a1 , —(CR a R a1) r C(═NCN)NR a R a1 , —(CR a R a1) r C(═NR a)NR a R a1 , —(CR a R a1) r C(═NOR a)NR a R a1 , —(CR a R a1) r C(O)NR a OH, —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(S)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r C(S)NR a R a1 , —(CR a R a1) r OC(O)NR a R a1 , —(CR a R a1) r NR a C(O)OR a1 , —(CR a R a1) r NR a C(O)NR a R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , —(CR a R a1) r NR a SO 2 R a3 , —(CR a R a1) r NR a SO 2 NR a R a1 , C 1-6 alkyl substituted with 0–2 R c1 , C 2-6 alkenyl substituted with 0–2 R c1 , C 2-6 alkynyl substituted with 0–2 R c1 , (CR a R a1) r —C 3-10 carbocycle substituted with 0–2 R c1 , or (CR a R a1) r -5–4 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–2 R c1 ; alternatively, when two R c groups are attached to the same carbon atom, they form a 3–8 membered carbocyclic or heterocyclic spiro ring C substituted with 0–2 R c1 and consisting of carbon atoms, 0–4 ring heteroatoms selected from O, N, and S(O) p , and 0–2 double bonds, provided that ring C contains other than a S—S, O—O, or S—O bond; alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–7 membered carbocyclic or heterocyclic ring D substituted with 0–2 R c1 and consisting of: carbon atoms and 0–2 heteroatoms selected from N, O, and S(O) p ; R c1 is, independently at each occurrence, H, C 1-4 alkyl, OR a , Cl, F, Br, I, ═O, CF 3 , CN, NO 2, —C(O)R a , —C(O)OR a , —C(O)NR a R a , or —S(O) p R a ; R d is, independently at each occurrence, C 1-6 alkyl, OR a , Cl, F, Br, I, ═O, CN, NO 2 , NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , C(S)NR a R a1 , R a NC(O)NR a R a1 , OC(O)NR a R a1 , R a NC(O)O, S(O) 2 NR a R a1 , NR a S(O) 2 R a3 , NR a S(O) 2 NR a R a1 , OS(O) 2 NR a R a1 , S(O) p R a3 , CF 3 , CF 2 CF 3 , C 3-10 carbocycle, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p ; R 5 is, independently at each occurrence, C 1-10 alkyl substituted with 0–2 R b , or C 1-8 alkyl substituted with 0–2 R e ; R e is, independently at each occurrence, phenyl substituted with 0–2 R b , or biphenyl substituted with 0–2 R b ; R 6 is, independently at each occurrence, phenyl, naphthyl, C 1-10 alkyl-phenyl-C 1-6 alkyl-, C 3-11 cycloalkyl, C 1-6 alkylcarbonyloxy-C 1-3 alkyl-, C 1-6 alkoxycarbonyloxy-C 1-3 alkyl-, C 2-10 alkoxycarbonyl, C 3-6 cycloalkylcarbonyloxy-C 1-3 alkyl-, C 3-6 cycloalkoxycarbonyloxy-C 1-3 alkyl-, C 3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C 1-3 alkyl-, phenylcarbonyloxy-C 1-3 alkyl-, C 1-6 alkoxy-C 1-6 alkylcarbonyloxy-C 1-3 alkyl-, [5-(C 1 –C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(R a)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C 1-10 alkyl-NR 7 R 7a , —CH(R 8)OC(═O)R 9 , or —CH(R 8)OC(O)OR 9 ; R 7 is H, C 1-10 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-3 alkyl-, or phenyl-C 1-6 alkyl-; R 7a is H, C 1-10 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-3 alkyl-, or phenyl-C 1-6 alkyl-; R 8 is H or C 1-4 linear alkyl; R 9 is H, C 1-8 alkyl substituted with 1–2 R f , C 3-8 cycloalkyl substituted with 1–2 or phenyl substituted with 0–2 R b ; R f is, independently at each occurrence, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-5 alkoxy, or phenyl substituted with 0–2 R b ; n is 0 or 1; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and s, at each occurrence, is selected from 0, 1, 2, 3, and 4; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 2. A compound according to claim 1 , wherein: U is absent or is O, NR a1 , C(O), CR a (OH), C(O)O, OC(O), C(O)NR a1 , NR a1 C(O), S(O) p , S(O) p NR a1 , or NR a1 S(O) p ; X is absent or is C 1-3 alkylene or C 3-4 alkynylene; Y is absent or is O, NR a1 , S(O) p , or C(O); provided that U—X—Y form a linker of at least two atoms between Z and Z a and is other than OC(O) or OC(O)alkylene; Z is phenyl substituted with 0–1 R b , naphthyl substituted with 0–1 R b , or pyridyl substituted with 0–1 R b ; Z a is a C 3-13 carbocycle substituted with 1–3 R c or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 1–3 R c , provided that if Z a is bicyclic, it does not contain a bridging nitrogen atom; provided that U, Y, Z, and Z a do not combine to form a N—N, N—O, O—N, O—O, S(O) p —O, O—S(O) p , or S(O) p —S(O) p group; R 1 is Q, C 1-6 alkylene-Q, C 2-6 alkenylene-Q, C 2-6 alkynylene-Q, —(CR a R a1) r O(CR a R a1) s -Q, —(CR a R a1) r NR a (CR a R a1) s -Q, —(CR a R a1) r C(O)(CR a R a1) s -Q, —(CR a R a1) r C(O)O(CR a R a1) s -Q, —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r C(O)NR a (CR a R a1) s -Q, —(CR a R a1) r S(O) p (CR a R a1) s -Q, —(CR a R a1) r SO 2 NR a (CR a R a1) p -Q, or —(CR a R a1) r NR a SO 2 (CR a R a1) s -Q; R 2 is Q 1 , C 1-6 alkylene-Q 1 , C 2-6 alkenylene-Q 1 , C 2-6 alkynylene-Q 1 , —(CR a R a1) r O(CR a R a1) s -Q 1 , —(CR a R a1) r NR a (CR a R a1) s -Q 1 , —(CR a R a1) r C(O)(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)O(CR a R a1) s -Q 1 , —(CR a R a1) r OC(O)(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r C(O)NR a (CR a R a1) s -Q 1 , —(CR a R a1) r NR a C(O)(CR a R a1) s -Q 1 , —(CR a R a1 2) r S(O) p (CR a R a1) p -Q 1 , —(CR a R a1) r SO 2 NR a (CR a R a1) s -Q 1 , or —(CR a R a1) r NR a SO 2 (CR a R a1) s -Q 1 ; provided that when n is 0 and CR 1 R 2 is CHNH 2 , then Z a is other than unsubstituted phenyl; Q is, independently at each occurrence, H, CHF 2 , CH 2 F, CF 3 , a C 3-13 carbocycle substituted with 0–3 R d , or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–3 R d ; alternatively, R 1 and R 2 , when attached to the same carbon atom, combine to form a 5–6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O) p and substituted with 0–2 R d ; R a is, independently at each occurrence, H, C 1-6 alkyl, phenyl, or benzyl; R a1 is, independently at each occurrence, H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or —(CH 2) r -3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NR a2 , O, and S(O) p ; alternatively, R a and R a1 when attached to a nitrogen, together with the nitrogen to which they are attached, combine to form a 5 or 6 membered heterocycle consisting of carbon atoms and from 0–1 additional heteroatoms selected from N, NR a2 , O, and S(O) p ; R c is, independently at each occurrence, H, OR a3 , Cl, F, Br, ═O, CN, NO 2 , CF 3 , CH 2 F, CHF 2 , CF 2 CF 3, —(CR a R a1) r NR a R a1 , —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , —(CR a R a1) r NR a SO 2 R a3 , C 1-6 alkyl substituted with 0–1 R c1 , C 2-6 alkenyl substituted with 0–1 R c1 , C 2-6 alkynyl substituted with 0–1 R c1 , —(CH 2) r —C 3-6 carbocycle substituted with 0–2 R c1 , or —(CH 2) r -5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–2 R c1 ; alternatively, when two R c groups are attached to the same carbon atom, they form a 3–8 membered carbocyclic or heterocyclic spiro ring C substituted with 0–2 R c1 and consisting of carbon atoms, 0–4 ring heteroatoms selected from O, N, and S(O) p , and 0–2 double bonds, provided that ring C contains other than a S—S, O—O, or S—O bond; alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–7 membered carbocyclic or heterocyclic ring D substituted with 0–2 R c1 and consisting of: carbon atoms and 0–2 heteroatoms selected from N, O, and S(O) p ; R d is, independently at each occurrence, C 1-6 alkyl, OR a , Cl, F, Br, ═O, CN, NO 2 , —NR a R a1 , —C(O)R a , —C(O)OR a , —C(O)NR a R a1 , —S(O) 2 NR a R a1 , —NR a S(O) 2 R a3 , —S(O) p R a3 , CF 3 , C 3-6 carbocycle, or a 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p ; R 5 is, independently at each occurrence, C 1-6 alkyl substituted with 0–2 R b , or C 1-4 alkyl substituted with 0–2 R e ; R 7 is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-3 alkyl-, or phenyl-C 1-6 alkyl-; R 7a is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-3 alkyl-, or phenyl-C 1-6 alkyl-; R 9 is H, 1–6 alkyl substituted with 1–2 R f , C 3-6 cycloalkyl substituted with 1–2 or phenyl substituted with 0–2 R b ; and R f is, independently at each occurrence, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-5 alkoxy, or phenyl substituted with 0–2 R b ; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 3. A compound according to claim 2 , wherein: A is —C(O)NHOH or —N(OH)CHO; U is absent or is O, NR a1 , C(O), CR a (OH), C(O)NR a1 , NR a1 C(O), S(O) p , S(O) p NR a1 , or NR a1 S(O) p ; X is absent or is methylene, ethylene, propynylene, or butynylene; provided that U—X—Y form a linker of at least two atoms between Z and Z a ; Z a is a C 5-10 carbocycle substituted with 1–3 R c , or a 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 1–3 R c , provided that if Z a is bicyclic, it does not contain a bridging nitrogen atom; provided that U, Y, Z, and Z a do not combine to form a N—N, N—O, O—N, O—O, S(O) p —O, O—S(O) p , or S(O) p —S(O) p group; R 1 is Q, C 1-6 alkylene-Q, C 2-6 alkenylene-Q, C 2-6 alkynylene-Q, —(CH 2) r O(CH 2) s -Q, —(CH 2) r NR a (CH 2) s -Q, —(CH 2) r C(O)(CH 2) s -Q, —(CH 2) r C(O)O(CH 2) s -Q, —(CH 2) r C(O)NR a R a1 , —(CH 2) r C(O)NR a (CH 2) s -Q, —(CH 2) r NR a C(O)(CH 2) s -Q, —(CH 2) r S(O) p (CH 2) s -Q, —(CH 2) r SO 2 NR a (CH 2) s -Q, or —(CH 2) r NR a SO 2 (CH 2) s -Q; R 2 is Q 1 , C 1-6 alkylene-Q 1 , C 2-6 alkenylene-Q 1 , C 2-6 alkynylene-Q 1 , —(CR a R a1) r O(CR a R a1) s -Q 1 , —(CR a R a1) r NR a (CR a R a1) s -Q 1 , —(CR a R a1) r C(O)(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)O(CR a R a1) s -Q 1 , —(CR a R a1) r C(O)NR a (CR a R a1) s -Q 1 , —(CR a R a1) r NR a C(O)(CR a R a1) s -Q 1 , —(CR a R a1 2) r S(O) p (CR a R a1) s -Q 1 , —(CR a R a1) r SO 2 NR a (CR a R a1) s -Q 1 , or —(CR a R a1) r NR a SO 2 (CR a R a1) s -Q 1 provided that when n is 0 and CR 1 R 2 is CHNH 2 , then Z a is other than unsubstituted phenyl; Q is, independently at each occurrence, H, a C 3-8 carbocycle substituted with 0–3 R d , or a 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–3 R d ; R a3 is, independently at each occurrence, H, C 1-6 alkyl, C 2-6 alkenyl, or —(CH 2) r -3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NR a2 , O, and S(O) p , and substituted with 0–3 R c1 ; R c is, independently at each occurrence, H, OR a , Cl, F, Br, ═O, CF 3 , CH 2 F, CHF 2 , —(CR a R a1) r NR a R a1 , —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , —(CR a R a1) r NR a SO 2 R a3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituted with 0–1 R c1 , phenyl substituted with 0–2 R c1 , or 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–2 R c1 ; alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–7 membered carbocyclic or heterocyclic ring D substituted with 0–2 R c1 and consisting of: carbon atoms and 0–2 heteroatoms selected from N, O, and S(O) p ; R d is, independently at each occurrence, C 1-6 alkyl, OR a , Cl, F, Br, ═O, —NR a R a1 , —C(O)R a , —C(O)OR a , —C(O)NR a R a1 , —S(O) 2 NR a R a1 , —NR a S(O) 2 R a3 , —S(O) p R a3 , CF 3 , or phenyl; R 5 is, independently at each occurrence, C 1-4 alkyl substituted with 0–2 R b , or C 1-4 alkyl substituted with 0–2 R e ; r, at each occurrence, is selected from 0, 1, 2, and 3; and s, at each occurrence, is selected from 0, 1, 2, and 3; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 4. A compound according to claim 3 , wherein: A is —C(O)NHOH; U is absent or is O, NR a1 , C(O), CR a (OH), C(O)NR a1 , NR a1 C(O), S(O) p NR a1 , or NR a1 S(O) p ; Z is phenyl substituted with 0–1 R b , or naphthyl substituted with 0–1 R b ; Z a is phenyl substituted with 1–3 R c , naphthyl substituted with 1–3 R c , or a heterocycle substituted with 1–3 R c and selected from furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazolyl, pyrrolidinyl, pyrrolyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, methylenedioxyphenyl, quinazolinyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chomen-4-yl, 2H-chomen-4-yl, and pyrazolo[1,5-a]pyridinyl; provided that U, Y, Z, and Z a do not combine to form a N—N, N—O, O—N, O—O, S(O) p —O, O—S(O) p , or S(O) p —S(O) p group; Q 1 is, independently at each occurrence, H, a C 3-10 carbocycle substituted with 0–5 R d , or a 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–3 R d ; R a1 is, independently at each occurrence, H, C 1-6 alkyl, phenyl, or benzyl; R a3 is, independently at each occurrence, H, C 1-6 alkyl, phenyl, or benzyl; R c is, independently at each occurrence, H, OR a3 , Cl, F, Br, ═O, CF 3 , CH 2 F, CHF 2 , —(CR a R a1) r NR a R a1 , —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , —(CR a R a1) r NR a SO 2 R a3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl substituted with 0–2 R c1 , or 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–2 R c1 ; and alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–6 membered carbocyclic or heterocyclic ring D substituted with 0–2 R c1 and consisting of: carbon atoms and 0–2 heteroatoms selected from N, O, and S(O) p ; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 5. A compound according to claim 4 , wherein: U is absent or is O, NR a1 , C(O), CR a (OH), C(O)NR a1 , or NR a1 C(O); X is absent or is methylene or butynylene; Y is absent or is O; R 2 is Q 1 , C 1-6 alkylene-Q 1 , C 2-6 alkenylene-Q 1 , C 2-6 alkynylene-Q 1 , —(CH 2) r O(CH 2) s -Q 1 , —(CH 2) r NR a (CH 2) s -Q 1 , —(CH 2) r C(O)(CH 2) s -Q 1 , —(CH 2) r C(O)O(CH 2) s -Q 1 , —(CH 2) r C(O)NR a (CH 2) s -Q 1 , —(CH 2) r NR a C(O)(CH 2) s -Q 1 , —(CH 2) r S(O) p (CH 2) s -Q 1 , —(CH 2) r SO 2 NR a (CH 2) s -Q 1 , or —(CH 2) r NR a SO 2 (CH 2) s -Q 1 ; provided that when n is 0 and CR 1 R 2 is CHNH 2 , then Z a is other than unsubstituted phenyl; Q is, independently at each occurrence, H, a C 3-6 carbocycle or a 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p ; R a is, independently at each occurrence, H, or C 1-4 alkyl; R a1 is, independently at each occurrence, H, or C 1-4 alkyl; R a3 is, independently at each occurrence, H, C 1-4 alkyl, phenyl, or benzyl; R c is, independently at each occurrence, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a , Cl, F, Br, ═O, CF 3 , CH 2 F, CHF 2 , NR a R a1 , —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , —(CR a R a1) r NR a SO 2 R a3 , or phenyl; and alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–6 membered carbocyclic or heterocyclic ring D substituted with 0–1 R c1 and consisting of: carbon atoms and 0–2 heteroatoms selected from N, O, and S(O) p ; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 6. A compound according to claim 5 , wherein: U is absent or is O, NR a1 , C(O), or CR a (OH); Y is absent; R 1 is H or C 1-6 alkylene; provided that when n is 0 and CR 1 R 2 is CHNH 2 , then Z a is other than unsubstituted phenyl; Q 1 is, independently at each occurrence, H, C 3-6 cycloalkyl substituted with 0–1 R d , phenyl substituted with 0–2 R d , or a 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O) p , and substituted with 0–2 R d ; r, at each occurrence is selected from 0, 1, and 2; and s, at each occurrence, is selected from 0, 1, and 2; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 7. A compound according to claim 6 , wherein: U is O, NR a1 , or CR a (OH); Z a is phenyl substituted with 1–3 R c , naphthyl substituted with 1–3 R c , or a heterocycle substituted with 1–3 R c and selected from pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chomen-4-yl, 2H-chomen-4-yl, pyrazolyl, and pyrazolo[1,5-a]pyridinyl; R b is, independently at each occurrence, C 1-6 alkyl, OR a , Cl, F, Br, NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , S(O) 2 NR a R a1 , NR a S(O) 2 R a3 , S(O) p R a3 , or CF 3 ; R c is, independently at each occurrence, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a , Cl, F, Br, ═O, NR a R a1 , CF 3 , —(CR a R a1) r C(O)R a1 , —(CR a R a1) r C(O)OR a1 , —(CR a R a1) r C(O)NR a R a1 , —(CR a R a1) r NR a C(O)R a1 , —(CR a R a1) r S(O) p R a3 , —(CR a R a1) r SO 2 NR a R a1 , or (CR a R a1) r NR a SO 2 R a3 ; and alternatively, when two R c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–6 membered saturated ring consisting of: carbon atoms and 0–1 heteroatoms selected from N, O, and S(O) p ; provided that: (a) when R 4 , R 1 , and R 2 are all H, then Z a is other than a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle; and (b) when Z a is a benzo-fused 5–6 membered heterocycle attached at the 2- or 3-position of the 5–6 membered heterocycle, then at least one of R 1 , R 2 , and R 4 is other than H. |
| Claim: | 8. A compound of claim 1 selected from: 3,N-dihydroxy-2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 3,N-dihydroxy-2-methyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 3,N-dihydroxy-2,2-dimethyl-3-[6-(2-methyl-quinolin-4-ylmethoxy)-naphthalen-2-yl]-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 4,N-dihydroxy-4-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-butyramide; 2-{hydroxy-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-methyl}-4-methyl-pentanoic acid hydroxyamide; 2-benzyl-3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 2-furan-2-ylmethyl-3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-(tetrahydrofuran-2-ylmethyl)-propionamide; 3,N-dihydroxy-2-(4-methoxy-benzyl)-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 2-(3,5-dimethoxy-benzyl)-3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 2-benzo[1,3]dioxol-5-ylmethyl-3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-pyridin-4-ylmethyl-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-pyridin-2-ylmethyl-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-pyridin-3-ylmethyl-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-morpholin-4-ylmethyl-propionamide; 4-{3-hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-piperidine-1-carboxylic acid tert-butyl ester; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-piperidin-4-ylmethyl-propionamide; 4-{3-hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-piperazine-1-carboxylic acid tert-butyl ester; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-piperazin-1-ylmethyl-propionamide; benzyl-{3-hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-carbamic acid tert-butyl ester; 2-(benzylamino-methyl)-3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionamide; {2-hydroxy-1-hydroxycarbamoyl-2-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-2-(tetrahydropyran-4-yl)-propionamide; 3,N-dihydroxy-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-butyramide; N-hydroxy-2-{2-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-tetrahydro-furan-2-yl}-acetamide; and 3,N-dihydroxy-3-(6-methoxy-naphthalen-2-yl)-2,2-dimethyl-propionamide; or a stereoisomer or a pharmaceutically acceptable salt or prodrug form thereof. |
| Claim: | 9. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof. |
| Claim: | 16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt form thereof. |
| Current U.S. Class: | 546/181 |
| Patent References Cited: | 4769461 September 1988 Musser et al. 5358955 October 1994 Brooks et al. H1992 September 2001 Bender et al. 10-875667 April 1998 WO 98/05635 February 1998 WO 01/36365 May 2001 |
| Other References: | Daheshia, M., Therapeutic inhibition of matrix metalloproteinases for the treatment of chronic obstructive pulmonary disease (COPD), Current Medical Research and Opinion, vol. 21, No. 4, 2005, 587-593. cited by examiner Levin, Jl., “The design and synthesis of aryl hydroxamide acid inhibitors of MMPs and TACE”, Curr. Top. Med. Chem., 2004; 4(12)—abstract. cited by examiner Mannello, et. al., “Matrix metalloproteinase inhibitors as anticancer therapeutics”, Curr. Cancer Drug Targets, Jun. 2005; 5(4), abstract. cited by examiner Lukacova, et al., “A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor Converting Enzyme: Implications for Selectivity”, J. Med. Chem., 2005, 48, 2361-2370. cited by examiner Mackay, et al., “Advances in Immunology”, The New England Journal of Medicine, vol. 345, No. 5, Aug. 2, 2001, pp. 340-350. cited by examiner |
| Assistant Examiner: | Balls, James |
| Primary Examiner: | Tsang, Cecilia |
| Attorney, Agent or Firm: | Sun, Jing G. |
| رقم الانضمام: | edspgr.07102008 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |