Compounds and compositions as protein kinase inhibitors

A compound of Formula (I):

• where
• the following fragments referred to hereinafter as the “left hand ring” and the “right hand ring”, respectively:
• wherein X is C—R5, and Y and Z are both N, whereby the left hand ring has the structure of Fragment (A):
• n is 0, 1, 2, 3, 4 or 5;
• X1 is oxygen,
• R1 is of the formula Rz—NRa— wherein Ra is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein hydrocarbyl has from 1 to 15 carbon atoms, is optionally interrupted by an —O— or —NH— linkage and is unsubstituted or is substituted by hydroxy, halo, amino or mono- or di-(C1-C4)alkylamino, alkanoyl having 4 in-chain atoms, trifluoromethyl, cyano, azo or nitro;
• and Rz is selected from:
• (i) linear or branched alkyl having 1, 2, 3 or 4 carbon atoms,
• (ii) linear or branched alkyl having 1, 2, 3 or 4 carbon atoms substituted by one or more halogens and/or one or two functional groups selected from hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 1, 2, 3 or 4 carbon atoms, acyloxy having 1, 2, 3 or 4 carbon atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionally substituted on at least one heteroatom by one or, where possible, more linear or branched alkyl groups having 1, 2, 3 or 4 carbon atoms, and
• (iii) a group of the formula
• where:
• ring A represents a 6-membered carbocyclic or heterocyclic ring;
• m is 0, 1 or 2;
• each Rb is independently selected from -L2-NRcRd;
• -L2-RING where RING is a mono- or bi-cyclic ring optionally substituted as defined below;
• halogen;
• hydroxy;
• protected hydroxyl;
• amino;
• amidino;
• guanidino;
• hydroxyguanidino;
• formamidino;
• isothioureido;
• ureido;
• mercapto;
• acyl having 4 in-chain atoms;
• acyloxy having 4 in-chain atoms;
• carboxy;
• sulfo;
• sulfamoyl;
• carbamoyl;
• cyano;
• azo;
• or nitro;
• and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro;
• all of which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionally substituted on at least one heteroatom by one or, where possible, more C1-C7 aliphatic groups, wherein L2 is a direct bond;
• a linkage selected from —O—;
• —S—;
• —C(O)—;
• —OC(O)—;
• —NRaC(O)—;
• —C(O)—NRa —;
• —OC(O)—NRa —;
• cyclopropyl and —NRa—;
• or is a linear or branched alkyl group having 1, 2, 3 or 4 carbon atoms optionally interrupted and/or terminated at a single end or at both ends by a said linkage;
• and wherein Rc and Rd are each independently selected from hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens, by an optionally substituted 5- or 6- membered heterocyclic or carbocyclic ring, and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionally substituted on at least one heteroatom by one or more C1-C7 aliphatic groups,
• or Rc and Rd together with their adjoining nitrogen form a 5- or 6- membered ring optionally substituted as described below,
• said optionally substituted rings independently of each other being substituted by 0, 1, 2, 3, 4 or 5 substituents selected from halogen;
• hydroxy;
• protected hydroxy;
• amino;
• amidino;
• guanidino;
• hydroxyguanidino;
• formamidino;
• isothioureido;
• ureido;
• mercapto;
• acyl having 4 in-chain atoms;
• acyloxy having 4 in-chain atoms;
• carboxy;
• sulfo;
• sulfamoyl;
• carbamoyl;
• cyano;
• azo;
• nitro;
• C1-C7 aliphatic optionally substituted by one or more halogens and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro;
• all of the aforesaid hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally being substituted on at least one heteroatom by one or, where possible, more C1-C7 aliphatic groups;
• R2 is H, halo, alkyl, alkyl interrupted by an —O— or —NH— linkage and/or linked to the left hand ring by a said linkage, trifluoromethyl, hydroxy, amino, mono- or dialkylamino;
• any alkyl moiety (interrupted or not) having 1, 2, 3 or 4 carbon atoms;
• R3 is H, a straight chain or branched C1-C4 alkyl or a straight chain or branched C1-C4 alkyl substituted by a 5- or 6- membered saturated or unsaturated carbocyclic or heterocyclic ring;
• R4 is selected from hydroxy, protected hydroxy, alkoxy, alkyl, trifluoromethyl and halo, wherein alkyl and the alkyl part of alkoxy are branched or straight chain and have 1, 2, 3, or 4 carbon atoms, or;
• R5 is H, halo, alkyl, alkyl interrupted by an —O— or —NH— linkage and/or linked to the left hand ring by a said linkage, trifluoromethyl, hydroxy, amino, mono- or dialkylamino;
• any alkyl moiety (interrupted or not) having 1, 2, 3 or 4 carbon atoms,
• or pharmaceutically acceptable salts, esters, N-oxides, protected derivatives, individual isomers and mixture of isomers thereof.