Substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic arylsulfonylamino hydroxamic acid derivatives

摘要

A compound of the formula I wherein; the dashed lines represent optional double bonds; A is nitrogen or CR7; B is -NR1R2, -CR1R2R10, -C(=CR2R11)R1, -NHCR1 R2Rl0, -OCR1R2R10, -SCR1R2R10, -CR2R10NHR1, -CR2Rl0ORl, -CR2R10SR' or -COR2, and is single bonded to D; or B is -CRR, and is double bonded to D and D is carbon; D is nitrogen or CR4 and is single bonded to all atoms to which it is attached, or D is carbon and is double bonded to E or double bonded to B; E is oxygen, nitrogen, sulfur, C=O, C=S, CR8R12, NRs or CR6; or E is a two atom spacer, wherein one of the atoms is oxygen, nitrogen, sulfur, C=O, C=S, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9 K and G are each, independently, C=O, C=S, sulfur, oxygen, CHR8 or NR8 when single bonded to both adjacent ring atoms, or nitrogen or CR8 when it is double bonded to an adjacent ring atom; the 6- or 7-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two C=O or C=S groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring; R1 is alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, C1 -C4 alkoxy, CF3, -C(=O)(C1-C4alkyl), -C(= O)-O-(C1-C4)alkyl, -OC(= O)(C1-C4 alkyl), -OC(= O)N(C1-C4 alkyl)(C1-C2 alkyl), -NHCO(C1-C4 alkyl), -COOH, -COO(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CON(C1-C4 alkyl)(Cl-C2 alkyl), -S(C1-C4 alkyl), -CN, -NO2, -SO(C1-C4 alkyl), -SO2(C1-C4 alkyl), -SO2NH(C1-C4 alkyl) and -SO2N(C1-C4 alkyl)(Cl-C2 alkyl), wherein each of the Cl -C4 alkyl groups in the foregoing R1 groups may optionally contain one or two double or triple bonds; R2 is C1 -C12 alkyl which may optionally contain from one to three double or triple bonds, aryl or (C1 -C4 alkylene)aryl, wherein said aryl and the aryl moiety of said (C1 -C4 alkylene)aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C3-C8 cycloalkyl or (C1-C6 alkylene)(C3-C8 cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C1 -C6 alkylene)(C3-CB cycloalkyl may optionally and independently be replaced by an oxygen or sulfur and wherein each of the foregoing R2 groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C1-C4 alkyl, or with one substituent selected from Cl-Ce alkoxy, -OC(=O)(C1-C6 alkyl), -OC(=O)N(Cl-C4 alkyl)(C,-C2 alkyl), -S(C1-C6 alkyl), amino, -NH(Cl-C2 alkyl), -N(C1-C2 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)-CO-(C1-C4 alkyl), -NHCO(Cl-C4 alkyl), -COOH, -COO(Cl-C4 alkyl), -CONH(Ct-C4 alkyl), -CON(Cl-C4 alkyl)(C,-C2 alkyl), -SH, -CN, -NO2, -SO(C,-C4 alkyl), -SO2(C1-C4 alkyl), -SO2NH(C1-C4 alkyl) and -SO2N(C1-C4 alkyl)(Cl-C2 alkyl); -NR1R2 or CR1R2R10 may form a ring selected from saturated 3 to 8 membered rings, the 5 to 8 membered rings of which may optionally contain one or two double bonds, and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ3 wherein Z3 is hydrogen or C1-C4 alkyl; R3 is hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), chloro, fluoro, bromo, iodo, -S(C1-C4 alkyl) or -SO2(C1-C4 alkyl) R4 is hydrogen, C1-C2 alkyl, hydroxy or fluoro; each R6, R8 and R9 that is attached to a carbon atom is selected, independently, from hydrogen, Cl-C2 alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro, -O(C1-C2 alkyl), -N(C1-C2 alkyl)(C1-C2 alkyl), -S(C1-C2 alkyl), -CO(C1-C2 alkyl), -C(=O)H or -C(=O)O(C1-C2 alkyl), wherein each of the C1-C2 alkyl moieties in the foregoing R6, R8, and B9 groups may optionally contain one double or triple bond; and each R6, RB, and R9 that is attached to a nitrogen atom is selected, independently, from hydrogen and C1-C4 alkyl; R5 is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein each of the foregoing R5 groups is substituted with from two to four substituents R'5, wherein from one to three of said substituents may be selected, independently, from chloro, C1-C6 alkyl, -O(Cl-Ce alkyl) and -(C1-C6alkylene)O(C1-C8alkyl), and wherein one of said substituents may be selected, independently, from bromo, iodo, formyl, cyano, trifluoromethyl, nitro, amino, -NH(C1 -C4 alkyl), -N(C1-C2 alkyl)(C1 -C6 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)(C1-C4 alkyl), -COOH, -S02NH(C,-C4 alkyl), -SO2N(C1-C2 alkyl)(Cl-C4 alkyl), -SO2NH2, -NHSO2(C1-C4 alkyl), -S(Cl-Ce alkyl) and -SO2(C1-C alkyl), and wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties in the foregoing R5 groups may optionally be substituted with one ortwo substituents independently selected from fluoro, hydroxy, amino, methylamino, dimethylamino and acetyl; R7 is hydrogen, methyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy, methoxy, -C(=O)(C1-C2 alkyl), -C(=O)O(C1-C2 alkyl), trifluoromethoxy, hydroxymethyl, trifluoromethyl or formyl; R10 is hydrogen, hydroxy, methoxy or fluoro; R11 is hydrogen or C1-C4 alkyl; R12 is, hydrogen or methyl; and Z is NH, oxygen, sulfur, -N(C1-C4 alkyl), or CR'3R14 wherein R13 and R14 are independently selected from hydrogen, and methyl with the exception that one of R'3 and R14 may optionally be cyano; with the proviso that: (a) in the six or seven membered rings of structures in formula I, there can not be two double bonds adjacent to each other; and (b) when D is carbon and is double bonded to B, then B is CR1 R2; or a pharmaceutically acceptable salt of such compound. The compounds are useful for the treatment, prevention or inhibition of conditions effected or facilitated by antagonizing CRF.