NOVEL COMPOUNDS AS DUAL INHIBITORS OF HISTONE METHYLTRANSFERASES AND DNA METHYLTRANSFERASES

摘要

It relates to the use of compounds of formula (I′), or their pharmaceutically or veterinary acceptable salts, or their stereoisomers or mixtures thereof, as anticancer agents and as agents for generating induced pluripotent stem cells. Compounds of formula (I′), wherein R2′ is an alcoxy group, a hydrocarbon chain or a ring system, and R1, R3, and R4 are as defined herein, are dual inhibitors of histone methyltransferases and DNA methyltransferases. It also relates to the compounds of formula (I′), or their pharmaceutically or veterinary acceptable salts, or their stereoisomers or mixtures thereof, wherein R2′ is phenyl or 5- to 6-membered heteroaromatic ring, both optionally fused to another rings (i.e., compounds of formula (I)). It also relates to pharmaceutical or veterinary compositions containing compounds of formula (I).;

主权项

1. A compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures thereof, either of the compound of formula (I) or of any of its pharmaceutically or veterinary acceptable salts wherein: R1 is Ra; R2 is a known ring system selected from the group consisting of:
(i) phenyl;(ii) 5- to 6-membered heteroaromatic ring;(iii) phenyl fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring;(iv) 5- to 6-membered heteroaromatic ring fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring;(v) phenyl fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro-fused; and(vi) 5- to 6-membered heteroaromatic ring fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro-fused; wherein R2 is optionally substituted with:
a) one Cy1 or one Cy2, and/orb) one or more substituents Rb, and/orc) one or more substituents Z1 optionally substituted with one or more substituents Rb and/or one Cy1; wherein Cy1 or Cy2 are optionally substituted with one or more substituents independently selected from Rb, and Z2 optionally substituted with one or more substituents Rb; R3 is selected from H, Rc, halogen, —NO2, —CN, —ORc′, —OC(O)Rc′, —OC(O)ORc′, —OC(O)NRc′Rc′, —NRc′Rc′, —NRc′C(O)Rc′, —NRc′C(O)ORc′, —NRc′C(O)NRc′Rc′, —NRc′S(O)2Rc′, —NRc′SO2NRc′Rc′, —SRc′, —S(O)Rc′, —S(O)ORc′, —SO2Rc′, —SO2(ORc′), —SO2NRc′Rc′, —SC(O)NRc′Rc′, —C(O)Rc′, —C(O)ORc′, —C(O)NRc′Rc′, and —C(O)NRc′ORc′, and —C(O)NRc′SO2Rc′; R4 is selected from —ORa and —NRaRc′; each Ra is independently Cy2, or Z3 optionally substituted with one or more substituents Rb and/or one Cy3; wherein Cy2 is optionally substituted with:
a) one Cy4; and/orb) one or more substituents Rb, and/orc) one or more substituents Z4 optionally substituted with one or more substituents Rb and/or one Cy4;wherein Cy4 is optionally substituted with one or more substituents independently selected from Rb, and Z5 optionally substituted with one or more substituents Rb; and wherein Cy3 is optionally substituted with:
a) one Cy5; and/orb) one or more substituents Rb, and/orc) one or more substituents Z6 optionally substituted with one or more substituents Rb and/or one Cy5;wherein Cy5 is optionally substituted with one or more substituents independently selected from Rb, and Z7 optionally substituted with one or more substituents Rb; each Rb is independently selected from halogen, —NO2, —CN, —ORc′, —OC(Y)Rc′, —OC(Y)ORc′, —OC(Y)NRc′Rc′, —NRc′Rc′, —NRc′C(Y)Rc′, —NRc′C(Y)ORc′, —NRc′C(Y)NRc′Rc′, —NRc′S(O)2Rc′, —NRc′SO2NRc′Rc′, —SRc′, —S(O)Rc′, —S(O)ORc′, —SO2Rc′, —SO2(OR), —SO2NRc′Rc′, —SC(Y)NRc′Rc′, —C(Y)Rc′, —C(Y)ORc′—C(Y)NRc′Rc′, —C(Y)NRc′ORc′, and —C(O)NRc′SO2Rc′; each Rc′ is independently H or Rc; each Rc is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)hydrocarbon chain having one or more double bonds and one or more triple bonds, and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, wherein each Rc is optionally substituted with one or more halogen atoms, Y is O, S, or NRc′; Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are independently selected from the group consisting of (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, and (C2-C6)hydrocarbon chain having one or more double bonds and one or more triple bonds; Cy1, Cy4 and Cy5 are independently a known ring system selected from the group consisting of phenyl; 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, saturated or partially unsaturated; and 5- or 6-membered heteroaromatic ring; Cy2 and Cy3 are independently a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and heteroaromatic rings one or more ring members are selected from N, O, and S; and wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(O) and/or C(NH) and/or C[N(C1-C4)alkyl]; with the proviso that the compound of formula (I) is other than: 2-[(7-methoxy-2-phenyl-4-quinolyl)amino]ethanol; 2-[(7-methoxy-2-phenyl-4-quinolyl)amino]ethanol hydrochloride salt; 2-(2-chlorophenyl)-6,7-dimethoxy-N-(4-pyridyl)quinolin-4-amine; 1-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]-3-(methylamino)propan-2-ol; 1-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]-3-(methylamino)propan-2-ol hydrochloride salt; 2-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]ethanol; 2-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]ethanol hydrochloride salt; 1-amino-3-[(7-methoxy-2-phenyl-4-quinolyl)amino]propan-2-ol; 1-amino-3-[(7-methoxy-2-phenyl-4-quinolyl)amino]propan-2-ol hydrochloride salt; 2-[[2-(3,4-dichlorophenyl)-7-methoxy-4-quinolyl]amino]ethanol; 2-[[2-(3,4-dichlorophenyl)-7-methoxy-4-quinolyl]amino]ethanol hydrochloride salt; (2S)-1-[(7-methoxy-2-phenyl-4-quinolyl)amino]propan-2-ol; (2S)-1-[(7-methoxy-2-phenyl-4-quinolyl)amino]propan-2-ol hydrochloride salt; 1-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]-3-(methylamino)propan-2-ol; 1-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]-3-(methylamino)propan-2-ol hydrochloride salt; 1-amino-3-[[2-(3,4-dichlorophenyl)-7-methoxy-4-quinolyl]amino]propan-2-ol; 1-amino-3-[[2-(3,4-dichlorophenyl)-7-methoxy-4-quinolyl]amino]propan-2-ol hydrochloride salt; 2-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]ethanol; 2-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]ethanol hydrochloride salt; 3-[(7-methoxy-2-phenyl-4-quinolyl)amino]propane-1;2-diol; 3-[(7-methoxy-2-phenyl-4-quinolyl)amino]propane-1;2-diol hydrochloride salt; 1-amino-3-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]propan-2-ol; 1-amino-3-[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]propan-2-ol hydrochloride salt; 1-amino-3-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]propan-2-ol; 1-amino-3-[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]propan-2-ol hydrochloride salt; 1-amino-3-[[7-methoxy-2-(4-methoxyphenyl)-4-quinolyl]amino]propan-2-ol; 1-amino-3-[[7-methoxy-2-(4-methoxyphenyl)-4-quinolyl]amino]propan-2-ol hydrochloride salt; 2-[[7-methoxy-2-(4-methoxyphenyl)-4-quinolyl]amino]ethanol; 2-[[7-methoxy-2-(4-methoxyphenyl)-4-quinolyl]amino]ethanol hydrochloride salt; 5-[[[2-(4-chlorophenyl)-7-methoxy-4-quinolyl]amino]methyl]oxazolidin-2-one; 5-[[[7-methoxy-2-(p-tolyl)-4-quinolyl]amino]methyl]oxazolidin-2-one; Benzyl-N-(7-methoxy-2-phenyl-4-quinolyl)carbamate; N-benzyl-7-methoxy-2-phenyl-quinolin-4-amine; N1,N1-diethyl-N4-(7-methoxy-2-phenyl-4-quinolyl)pentane-1,4-diamine; N1,N1-diethyl-N4-(7-methoxy-2-phenyl-4-quinolyl)pentane-1,4-diamine triphosphate salt; and 2-(4-fluorophenyl)-N7-[(3-methoxyphenyl)methyl]-N4-(4-pyridyl)quinoline-4,7-diamine.