Patent EA-004883-B1 (EA)
Title: Alkynyl containing hydroxamic acid compounds and use thereof as tace inhibitors
Inventor: LEVIN JEREMY IAN
IPC: C07D335/02
Filed: 2000-01-27
Abstract: 1. A compound of formula wherein: R1 is alkyl of 1-6 carbon atoms; each of R2 and R3 is hydrogen; R8 is hydrogen; alkyl of 1-10 carbon atoms, which can be optionally substituted with cyano; aryl (lower alkyl) which can be optionally substituted with piperidinyl (lower) alkoxy; heteroaryl (lower) alkyl; cycloalkyl of 3-6 carbon atoms; aryl; 5-7-membered heterocyclyl comprising heteroatoms selected from N, NR7, O, S, SO or SO2, wherein R7 is hydrogen, lower alkyl, lower alkoxy, (lower) alkoxyphenyl or benzoyl; or a radical of formula R4-(CH2)k-C(O)NH-(CH2)l- or R4-(CH2)k-C(O)NH-CH2-C(O)NH-(CH2)l-, wherein R4 is phenyl optionally substituted with halogen or phenethyl; diphenylmethyl; phthaloylamido; heteroaryl or xanthenyl; K is 0-3, and L is 0-6, R9 is hydrogen or halogen-substituted phenyl; A is O, S, SO, SO2 or CH2; X is O; Y is phenyl; with the proviso that A and X are not bonded to adjacent atoms of Y; and n is 0-2; each of R10, R11 and R12 is hydrogen; wherein lower alkyl is straight or branched alkyl of 1-6 carbon atoms; aryl is phenyl or naphthyl rings, which can be optionally mono- or disubstituted with lower alkoxy, halogen or thienyl; heteroaryl is 5-10-membered mono or bicyclic ring having 1-3 heteroatoms selected from N, O or S; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 selected from the group consisting of: 2-(4-But-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-3-pyridin-3-yl-propionamide; 2-(4-But-2-ynyloxy-phenylsulfanyl)-N-hydroxy-propionamide; 2-(4-But-2-ynyloxy-benzesulfonyl)-N-hydroxy-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide; 3-Biphenyl-4-yl-2-(4-but-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-propionamide; 2-(4-But-2-ynyloxy-phenysulfanyl)-octanoic acid hydroxamide; 2-(But-2-ynyloxy-benzenesulfonyl)-octanoic acid hydroxamide; (S)-2[(R)-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide; (S)-2[(S)-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide; 3-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-propionamide; 4-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-butyramide; 2-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-acetamide; 4-(4-But-2-ynyloxy-phenyl)-N-hydroxy-butyramide; Quinoline-2-carboxylic acid[5-(4-but-2-ynyloxy-phenylthio)-5-hydroxy-carbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy-phenylthio)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide; N-[5-(4-But-2-ynyloxy-phenylthio)-5-hydroxycarbamoyl)pentyl]-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy-phenylthio)-6-[2-(3,4-dichloro)phenyl)-acetylamino]-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid[5-(4-but-2-ynyloxy)phenylthio)-5-hydroxy-carbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy-phenylthio]-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide; 9H-Xanthene-9-carboxylic acid[5-(4-but-2-ynyloxy)phenylthio]-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylthio]-6-diphenylacetylamino-hexanoic acid hydroxyamide; Isoquinoline-1-carboxylic acid[5-(4-but-2-ynyloxy-phenylthio]-5-hydroxycarbamoyl-pentyl]-amide; 6-(2-Benzo [b] thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy)phenylthio]-hexanoic acid hydroxyamide; Quinoline-2-carboxylic acid[5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide; N-[5-(4-But-2-ynyloxy)phenylsulfinyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-[2-(3,4-dichloro-phenyl)-acetyl-amino]-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfinyl)-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide; 9H-Xanthene-9-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfinyl)-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-diphenylacetylamino-hexanoic acid hydroxyamide; Isoquinoline-1-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfinyl)-5-hydroxycarbamoyl-pentyl]-amide; 6-(2-Benzo [b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy)phenylsulfinyl)-hexanoic acid hydroxyamide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-(2-1H-indol-3-yl-acetylamino)-hexanoic acid hydroxyamide; Quinoline-2-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfonyl)-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylsulfonyl)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide; N-[5-(4-But-2-ynyloxy)phenylsulfonyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy)phenylsulfonyl)-6-[2-(3,4-dichloro-phenyl)-acetyl-amino]-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfonyl)-5-hydroxycarbamoyl-pentyl]-amide; 9H-Xanthene-9-carboxylic acid[5-(4-but-2-ynyloxy)phenylsulfonyl)-5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy)phenylsulfonyl)-6-diphenyl acetylaminohexanoic acid hydroxyamide; Isoquinoline-1-carboxylic acid [5-(4-but-2-ynyloxy)phenylsulfonyl)-hydroxycarbamoyl-pentyl]-amide; 6-(2-Benzo [b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy)phenylsulfonyl)-hexanoic acid hydroxyamide; Quinoline-2-carboxylic acid{[5-(4-but-2-ynyloxy)phenylthio)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy-phenylsulfanyl)-6-{2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetylamino]-acetylamino} hexanoic acid hydroxyamide; {[5-(4-But-2-ynyloxy)phenylthio)-5-hydroxycarbamoyl-pentycarbamoyl]-methyl}-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy)phenylthio)-6-{2-[2-(3,(4-But-2-ynyloxy)phenylthio)-6-{2-[2-(3,4-dichloro-phenylacetylamino]-acetylamino}-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid{[5-(4-but-2-ynyloxy)phenylthio)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy)phenylthio)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy)phenylthio)-6-(2-diphenylacetylamino-acetylamino)-hexanoic acid hydroxyamide; Isoquinoline-1-carboxylic acid {[5-(4-but-2-ynyloxy)phenylthio]-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 1-Methyl-1H-pyrrole-2-carboxylic acid{[5-(4-but-2-ynyloxy)phenylthio]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 6-[2-(2-Benzo [b] thiophen-3-yl-acetylamino)-acetylamino]-2-(4-but-2-ynyloxy)phenylthio]hexanoic acid hydroxyamide; Quinoline-2-carboxylic acid{[5-(4-but-2-ynyloxy)phenylsulfinyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy)phenylsulfinyl]-6-{2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide; N-{[5-(4-But-2-ynyloxy)phenylsulfinyl]-5-hydroxycarbamoyl-pentyl carbamoyl]-methyl}-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy)phenylsulfinyl]-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy)phenylsulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl} amide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-[2-(4-thiophen-2-yl-butyrylamino)-acetylamino]-hexanoic acid hydroxyamide; 9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy)phenylsulfinyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy)phenylsulfinyl)-6-(2-diphenylacetylamino-acetylamino)-hexanoic acid hydroxyamide; 1-Methyl-1H-pyrrole-2-carboxylic acid {[5-(4-but-2-ynyloxy)phenylsulfinyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy)phenylsulfonyl]-6-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide; N-{[5-(4-But-2-ynyloxy)phenylsulfonyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy)phenylsulfonyl]-6-{2-[2-(3,4-dichloro-phenylacetylamino]-acetylamino}-hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy)phenylsulfonyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl} amide; 9H-Xanthene-9-carboxylic acid{[5-(4-but-2-ynyloxy)phenylsulfonyl]-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy)phenylsulfonyl]-6-(2-diphenylacetylamino-acetyl-amino)-hexanoic acid hydroxyamide; Isoquinoline-1-carboxylic acid {[5-(4-but-2-ynyloxy)phenylsulfonyl]-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 6-[2-(2-Benzo [b] thiophen-3-yl-acetylamino)-acetylamino]-2-(4-but-2-ynyloxy) phenylsulfonyl] hexanoic acid hydroxyamide; 2-(4-But-2-ynyloxy)phenylsulfonyl]-6-[2-(2-1H-indol-3-yl-acetylamino) acetylamino]-hexanoic acid hydroxyamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-N-hydroxy-4-{4-[2-(1-piperidinyl)-ethoxyphenyl} butanamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-7-cyano-N-hydroxy heptanamide; 2-{[4-(But-2-ynyloxy) phenyl]thio}-2-cyclohexyl-N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy)phenyl] sulfonyl}-2-cyclohexyl-N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy) phenyl]thio}-N-hydroxy-2-(4-methoxyphenyl) acetamide; (2R)-2-{[4-(But-2-ynyloxy) phenyl]sulfinyl}-N-hydroxy-2-(4-methoxyphenyl) ethanamide; (2S)-2-{[4-(But-2-ynyloxy phenyl]sulfinyl}-N-hydroxy-2-(4-methoxyphenyl) ethanamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-N-hydroxy-2-(4-methoxyphenyl) acetamide; 2-{[4-(But-2-ynyloxy)phenyl]thio}-2-(4-chlorophenyl)-N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfinyl}-2-(4-chlorophenyl) N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-2-(4-chlorophenyl)-N-hydroxy-acetamide; 2-{[4-(But-2-ynyloxy)phenyl]thio}-2-(3-chlorophenyl)-N-hydroxyacetamide; 2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-2-(3-chlorophenyl)-N-hydroxyacetamide; 2-(4-bromophenyl)-2-{[4-(But-2-ynyloxy) phenyl]thio}-N-hydroxyacetamide; (2S)-2-(4-bromophenyl)-2-{[4-(But-2-ynyloxy)phenyl]sulfinyl}-N-hydroxyacetamide; (2R)-2-(4-bromophenyl)-2-{[4-(But-2-ynyloxy) phenyl]sulfinyl}-N-hydroxyacetamide; 2-{(4-bromophenyl)-2-{[4-(But-2-ynyloxy) phenyl]sulfonyl}-N-hydroxy-acetamide; 2-{[4-(But-2-ynyloxy) phenyl]thio}-N-hydroxy-2-[4-(2-thienyl) phenyl]-acetamide; (2R)-2-{[4-(But-2-ynyloxy) phenyl]sulfinyl}-N-hydroxy-2-[4-(2-thienyl)-phenyl]ethanamide; 2-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxy-2-[4-(2-thienyl)-phenyl]-acetamide; 2-{[4-(