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US 6,642,255 B2Granted
1,2,-Disubstituted cyclic inhibitors of matrix metalloproteases and TNF-alpha
AssigneeBristol-Myers Squibb Pharma Company
InventorsChu-Biao Xue, Carl Decicco, Xiaohua He
Life of this patent
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Abstract
The present application describes novel 1,2-disubsituted cyclic derivatives of formula I: or pharmaceutically acceptable salt forms thereof, wherein ring B is a 3-8 membered non-aromatic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p and the other variables are defined in the present specification, which are useful as metalloprotease and as TNF-α inhibitors.
Claims30
A compound of formula I:
- or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
- A is CONHOH,
- ring B is a 5 membered heterocyclic ring consisting of:
- 4 carbon atoms, 0-1 carbonyl groups 0-2 double bonds, and 1 heteroatom selected from N—, and NR2, provided that N—R2 forms other than an N—O, N—N, or N—S bond;
- Z is phenyl substituted with 0-5 Rb;
- Ua is O, NRa1, or C(O);
- Xa is methylene;
- Ya is absent or is selected from O, NRa1, S(O)p, and C(O);
- Za is quinoline substituted with 0-5 Rc;
- R1a is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
- R1b is selected from H, C1-4 alkyl, phenyl, benzyl, CH2OR3, and CH2NRaRa1;
- R2 is selected from Q, C1-10 alkylene-Q substituted with 0-3 Rb1, C2-10 alkenylene-Q substituted with 0-3 Rb1, C2-10 alkynylene-Q substituted with 0-3 Rb1, (CRaRa1)r1O(CRaRa1)r-Q,(CRaRa1)r1NRa(CRaRa1)r-Q, (CRaRa1)r1C(O)(CRaRa1)r-Q,(CRaRa1)r1C(O)O(CRaRa1)r-Q, (CRaRa1)r1OC(O)(CRaRa1)r-Q,(CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)r-Q,(CRaRa1)r1NRaC(O)(CRaRa1)r-Q, (CRaRa1)r1OC(O)O(CRaRa1)r-Q,(CRaRa1)r1OC(O)NRa(CRaRa1)r-Q, (CRaRa1)r1NRaC(O)O(CRaRa1)r-Q,(CRaRa1)r1NRaC(O)NRa(CRaRa1)r1-Q, (CRaRa1)r1S(O)p(CRaRa1)r-Q,(CRaRa1)r1SO2NRa(CRaRa1)r-Q, (CRaRa1)r1NRaSO2(CRaRa1)r-Q, and (CRaRa1)r1NRaSO2NRa(CRaRa1)r-Q;
- R2a is H,
- R2b is H;
- Q is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle consisting of:
- carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-5 Rd;
- R3, at each occurrence, is selected from Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CH2)r-Q1, (CRaRa1)r1NRa(CRaRa1)r-Q1, (CRaRa1)r1NRaC(O)(CRaRa1)r-Q1, (CRaRa1)r1C(O)NRa(CRaRa1)r-Q1, (CRaRa1)r1C(O)(CRaRa1)r-Q1,(CRaRa1)r1C(O)O(CRaRa1)r-Q1, (CRaRa12)r1S(O)p(CRaRa1)r-Q1 and (CRaRa1)r1SO2NRa(CRaRa1)r-Q1;
- alternatively, when two R3s are attached to the same carbon atom, they combine to form a 3-8 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 0-3 Rd;
- Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl consisting of:
- carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rd;
- Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
- Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
- alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
- Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
- Rb, at each occurrence, is independently selected from C1-6alkyl, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, and CF2CF3;
- Rb1, at each occurrence, is independently selected from ORa, Cl, F, Br, I, ═O, —CN, NO2, and NRaRa1;
- Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle consisting of:
- carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
- Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle consisting of:
- carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
- p, at each occurrence, is selected from 0, 1, and 2;
- p1 is 0, 1, or 2;
- r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
- and,
- r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
33 more elements
Dependencies are inferred from the claim text.