Patent DE-10252969-A1 (DE)
Title: New 3-aminomethylene-indoline-2-(thi)one derivatives, are kinase inhibitors useful for treating proliferative diseases e.g. tumors, rheumatoid arthritis, neovascular glaucoma and arteriosclerosis
Inventor: KLEY JOERG
IPC: C07D403/06
Filed: 2002-11-14
Abstract: 3-(1-Heterocyclyl-1-(N-substituted amino)-methylene)-indoline-2-(thi)one derivatives (I) are new.  3-(1-Heterocyclyl-1-(N-substituted amino)-methylene)-indoline-2-(thi)one derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures), prodrugs and salts are new. X = O or S; R1 = H or prodrug residue (e.g. COT or COOU); T = 1-3C alkyl; U = 1-4C alkyl; R2 = H, F, Cl, Br, CN, NO2, COOH, (1-6C) alkoxycarbonyl, (3-6C) cycloalkoxycarbonyl, COOAr or OCOCH2CH=CH2 (optionally substituted (os)), COOU terminally substituted by Het, Ph, COOH, COOT, CONH2, CONHT or CONT2, (2-6C) alkoxycarbonyl terminally substituted by Cl, OH, OT, NHT or NT2; or CONH2, CONHU or CONU2 (where alkyl moieties (other than Me) are os); R3 = e.g. (i) 6-membered heteroaryl containing 1-3 N or 5-membered heteroaryl containing one NH, N(T), N(T-COOH), N(T-Ph), O or S and optionally 1 or 2 N, both optionally fused to a phenyl ring (os), provided that bonding is via a C-atom of the heterocyclic part or (ii) a 5- or 6-membered cyclic oxime ether bonded via the C-atom adjacent to the N; R4 = (i) 3-7C cycloalkyl (optionally with CH2 in the 4-position of 6-7C cycloalkyl substituted); (ii) phenyl substituted in the 3- or 4-position by R6 and additionally os by 1 or 2 of e.g. halo or 1-5C alkyl, or (iii) 1-(R22)-2-(CONR23R24)-pyrrol-4-yl; R6 = H, halo, CN, NO2, NH2, 1-5C alkyl, 3-7C cycloalkyl, CF3, Ph or Het, tetrazolyl (os by T), 2-pyrrolidon-1-yl (optionally having CH2 adjacent to CO replaced by O, NH or NT), 2,4-dioxo-imidazolidin-5-ylidene-methyl (os), (CH2)n-COR8, (CH2)o-CONR9R10, T-R7, N(R15)-CO-(CH2)s-R16, N(R17)-SO2R18, amino substituted by CO-T-NT2 or SO2-T-NT2 and by T-CO-NT2, A-(CH2)t-R19 or SO2N(R20)-(CH2)u-R21; R8 = OH, OU or 2,5-dihydro-pyrrol-1-yl, 5-7 membered cycloalkyleneimino (os in the 3- or 4-position in the case of 5-7 membered rings, and optionally having the CH2 in the 4-position of 6- or 7-membered rings replaced by O, S, SO, SO2, NH, N(allyl) or NT), os by 1 or 2 T, or 3-7C cycloalkyl (os in the 3- or 4-position in the case of 5-7 membered rings; and optionally with CH2 in the 4-position of 6-7C cycloalkyl replaced by NH, N(allyl) or NT), all singly bonded or fused phenyl rings in R6 are os by 1 or 2 of halo, 1-5C alkyl, CF3, OH, OT, COOH, COOT, CONH2, CONHT, CONT2, SO2NH2, SO2NHT, SO2NT2, NHSO2T, NO2 or CN or by one OCH2O; n = 0-2; R9 = H, allyl, U (os) or 2-4C alkyl terminally substituted by OH or OT;  R10 =  H or T; 2-3C alkyl terminally substituted by OH, OT, NHT or NT2; or 3-7C cycloalkyl (optionally having one CH2 replaced); o = 0-2; R7 = e.g. 3-7C cycloalkyl (os), Ar, Het, triazolyl, OH, OT, NH2, mono- or di-(1-7C alkyl)-amino or N-(1-7C alkyl)-allylamino; R15 = H, allyl, 1-6C alkyl, 3-7C cycloalkyl or pyridinyl, T terminally substituted by Ph, Het, CF2, CONH2, CONHU, CONU2, COT, SO2NHT or SO2NT2; or 2-3C alkyl terminally substituted by OH, OT, NH2, NHT, allylamino, NT2, NHSO2T or N(T)SO2T; s = 0-3; R16 = COOH or as for R7, or may also be H if s = 1-3; R17 = H, allyl, U or CH2CN; or 2-4C alkyl terminally substituted by CN, NH2, NHT, NT2, NHCOCF3 or NTCOCF3; R18 = T, Ph or pyridyl; A = O, S, SO or SO2; R19 = H, OH, OT, Ar, Het or NH2; or 4-7 membered cycloalkyleneimino (os); t = 2 or 3, or may also be 1 if R19 = H, Ar or Het, or may also be 0 if A = SO2; R20 = H, allyl or T; R21 = H, OH, NH2, NHT or NT2; u = 2-4, or may also be 1 if R21 = H; R22 = T; R23 = H or allyl, U (os by CN, COOH, Ph or pyridyl) or 2-4C alkyl terminally substituted by OH or OT; R24 = H or T, 2-3C alkyl terminally substituted by OH, OT, NHT or NT2 or 3-7C cycloalkyl (optionally having one CH2 replaced), or NR23R24 = 2,5-dihydropyrrol-1-yl or 5-7 membered cycloalkyleneimino (os); R5 = H or T; Ar = phenyl or naphthyl (both os); Het = 6-membered heteroaryl (containing 1-3 N) or 5-membered heteroaryl (containing one NH, N(T), N(T-Ph), O or S and optionally 1 or 2 N), both optionally fused to a phenyl ring (os by 1 or 2 T, NH2, NHT or NT2), where bonding is via a C- or N-atom of the heterocyclic part or via a C-atom of