Claims for Patent: 8,552,002

Summary for Patent: 8,552,002

Title:	Compounds and compositions as protein kinase inhibitors
Abstract:	The invention relates to compounds of formula (I) wherein the substituents X1, R1, R2, R3 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.
Inventor(s):	Qiang Ding, Nathanael Schiander Gray, Bing Li, Yi Liu, Taebo Sim, Tetsuo Uno, Guobao Zhang, Carole Pissot Soldermann, Werner Breitenstein, Guido Bold, Giorgio Caravatti, Pascal Furet, Vito Guagnano, Marc Lang, Paul William Manley, Joseph Schoepfer, Carsten Spanka
Assignee:	Novartis AG
Application Number:	US11/570,983
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,552,002
Patent Claims:	1. 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. 2. The compound of claim 1 wherein R5 is H or halo. 3. The compound of claim 2 wherein R5 is H. 4. The compound of claim 1 wherein, R2 is H. 5. The compound of claim 1 wherein the left hand ring has the structure of Fragment (B): 6. The compound of claim 1 wherein Rz is of the formula 7. The compound of claim 6 which comprises at least one Rb which is -L2-NRcRd or -L2-RING, wherein L2 is a direct bond, linear alkyl, linear alkyl terminated adjacent ring A by a linkage selected from —O—; —S—; —C(O)—; —OC(O)—; —NRaC(O)—; —C(O)—NRa —; —OC(O)—NRa —; cyclopropyl and —NRa—; or is a linkage selected from —O—; —S—; —C(O)—; —OC(O)—; —NRaC(O)—; —C(O)—NRa—; —OC(O)—NRa—; cyclopropyl and —NRa—. 8. The compound of claim 7 wherein said linkage is —O—. 9. The compound of claim 6 wherein ring A is phenyl, cyclohexenyl or cyclohexyl. 10. The compound of claim 6 wherein there is a single Rb group which is selected from -L2-NRcRd and -L2-RING and there are 0, 1 or 2 additional substituents which are selected from halogen,alkyl, alkoxy, hydroxy, amino and trifluoromethyl, wherein alkyl and the alkyl part of alkoxy have 1, 2, 3 or 4 carbon atoms. 11. The compound of claim 1 wherein m is 1. 12. The compound of claim 11 wherein ring A is phenyl or cyclohexyl and Rb is selected from -L2-NRcRd and -L2-RING. 13. The compound of claim 12 wherein the substituent is at the 3-position or 4-position of ring A. 14. The compound of claim 1 wherein the left hand ring has a structure corresponding to Fragment (D1), (D2), (E1) or (E2): 15. The compound of claim 14 wherein Ra is H. 16. The compound of claim 14 wherein the phenyl ring of said Fragments has 1, 2, 3 or 4 further substituents, selected from halogen, methyl, methoxy and trifluoromethyl. 17. The compound of claim 14 wherein RING is a saturated heterocycle which contains an in-ring nitrogen. 18. The compound of claim 14 which contains a moiety NRcRd and wherein Rc and Rd are the same or different and selected from straight chain or branched alkyl having 1, 2, 3 or 4 carbon atoms. 19. The compound of claim 14 which contains a moiety NRcRd and wherein Rc and Rd together with the adjoining nitrogen form a 5- or 6- membered heterocyclic ring, optionally substituted as by 0, 1, 2, 3, 4 or 5 substituents selected from straight chain or branched C1, C2, C3 or C4 alkyl, halogen and C1, C2, C3 or C4 alkoxy, wherein alkyl and the alkyl part of alkoxy are unsubstituted or substituted by halogen. 20. The compound of claim 19 wherein the heterocycle is saturated. 21. The compound of claim 20 wherein L2NRcRd is selected from the group consisting of piperazine, morpholine, —OCH2piperazine, —OCH2morpholine, —OCH2CH2piperazine, —OCH2CH2morpholine, —OCH2CH2CH2piperazine, —OCH2CH2CH2morpholine, —CH2piperazine, —CH2morpholine, —CH2CH2piperazine, —CH2CH2morpholine, —CH2CH2CH2piperazine, —CH2CH2CH2morpholine, —C(O)piperazine and —C(O)morpholine, piperazine optionally being N-substituted by straight chain or branched C1, C2, C3 or C4 alkyl. 22. The compound of claim 14 wherein the left hand ring has the structure of the following Fragment (F): 23. The compound of claim 1 wherein n is 1, 2, 3 or 4. 24. The compound of claim 1 wherein 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. 25. The compound of claim 24 wherein R4 is selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl. 26. The compound of claim 1 wherein the right hand ring corresponds to Fragment (G): where: Q is selected from F and Cl; U is selected from H, F, Cl, methyl, trifluoromethyl and methoxy; T and V are the same or different and selected from H, methyl, trifluoromethyl and methoxy. 27. The compound of claim 26 wherein the right hand ring is Fragment (H): 28. The compound of claim 1 wherein the right hand ring corresponds to Fragment (I): where: Q is selected from F and Cl; Ua and Ub are each independently selected from H, F, Cl, methyl, trifluoromethyl and methoxy. 29. The compound of claim 1 which is selected from the following formulae (IV), (V), (VI) and (VII): where L2NRcRd is piperazine, morpholine, —OCH2piperazine, —OCH2morpholine, —OCH2CH2piperazine, —OCH2CH2morpholine, —OCH2CH2CH2piperazine, —OCH2CH2CH2 morpholine, —CH2piperazine, —CH2morpholine, —CH2CH2piperazine, —CH2CH2morpholine, —CH2CH2CH2piperazine, —CH2CH2CH2morpholine, —C(O)piperazine or —C(O)morpholine, wherein morpholine is optionally substituted by C1-C4 alkyl and piperazine is optionally substituted by C1-C4 alkyl; L2RING is -RING, —OCH2RING, —OCH2CH2RING, —OCH2CH2CH2RING, —CH2RING, —CH2CH2RING, —CH2CH2CH2RING, and, or is —C(O)RING, where RING is a heterocycle optionally substituted by C1-C4 alkyl or C1-C4 haloalkyl and selected from pyrrolidine, piperidine, piperazine or morpholine; R3 is H; R4 is selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl; n is 0, 1, 2, 3, 4 or 5. 30. A combination of the compound of claim 1 with (N—{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine. 31. A compound of claim 1 selected from 3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-6-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3-Methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-py-rimidin-4-yl}-urea; 1-(3-Methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(3,5-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(3,5-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(2,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-trimethoxy-phenyl)-urea; 1-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-trimethoxy-phenyl)-urea; 1-(2,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(2,4-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(3,5-Dimethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3,5-Dimethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3-Chloro-4-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(3-Chloro-4-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(5-Methoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(5-Methoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-5-methoxy-phenyl)-3-{6-[4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-5-methoxy-phenyl)-3-{6-[3-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(3,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(3,4-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea ; 1 -(4-Fluoro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(4-Fluoro-3-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-methylamino-pyrimidin-4-yl)-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-phenylamino-pyrimidin-4-yl)-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]pyrimidin-4-yl}-urea; 1 -(2-Chloro-3,5-dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]pyrimidin-4-yl}-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1 -(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,3-Dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-phenylamino-pyrimidin-4-yl)-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-}1-1-methyl-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[3-(2-dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-thiophen-2-ylmethyl-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1-(6-phenylamino-pyrimidin-4-yl)-urea; 3-(2-Chloro-3,5-dimethoxy-phenyl)-1-(6-phenylamino-pyrimidin-4-yl)-1-(2-pyridin-2-yl-ethyl)-urea; 3-(2,6-Dichloro-3-methoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3-methoxy-phenyl)-1-(6-methoxy-pyridin-3--yl-methyl)-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-6-methyl-phenyl)-3-(6-isopropylamino-pyrimidin-4-yl)-urea; (2,6-dichloro-phenyl)-carbarnic acid 4-{6-[3 -(2,6-dichloro-phenyl)-ureido]-pyrimidin-4yl-amino}-cyclohexylester; 1-(6-Isopropylamino-pyrimidin-4-yl)-3-(2,4,6-trichloro-phenyl)-urea; 1-(2,6-Dichloro-phenyl)-3-(6-isopropylamino-pyrimidin-4-yl)-urea; 1-{6-[4-(1-Methyl-piperidin-4-yl-methoxy)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yl-methoxy)-phenylamino]pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6[4-(1-methyl-piperidin-4-yl-methoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,5-Dichloro-phenyl)-3-{6[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,5-trichloro-phenyl)-urea; 1-(3,4-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,3-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(5-Chloro-2-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-6-methyl-phenyl)-3-{6-[3-(1-methyl-piperidin-4yl-methoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yl-methoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-{6-[3-(1-Methyl-piperidin-4-yl-methoxy)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-urea; 1-{6-[4-(4-Methyl-piperazin-1-ylmethy-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-{6-[4-(4-Methyl-piperazin-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-}-3-(2,4,6-trichloro-phenyl)-urea; 1-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea; 1-[6-((trans)-4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-3-(2,4,6-trichloro-phenyl)-urea; 1-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-4-yl}-3-(2-chloro-6-methyl-phenyl)-urea; 1-(2-Chloro-6-methyl-phenyl)-3-[6-((trans)-4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-urea; 1-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-4-yl}-3-(2,6-dichloro-phenyl)-urea; 1-(2,6-Dichloro-phenyl)-3[6-((trans)-4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-urea; 1-(2-Chloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Bromo-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Bromo-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Bromo-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}- urea; 1-(2,6-Dichloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Bromo-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Chloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2-Bromo-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-[6-(4-Diethylamino-phenylamino)-pyrimidin-4-yl]-3-(2,6-difluoro-phenyl) -urea; 1-(2,6-Difluoro-phenyl)-3-[6-(3-dirnethylamino-phenylamino)-pyrimidin-4-yl]-urea; 1-(2,6-Dichloro-phenyl)-3-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]-urea; 1-(2,6-Dichloro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea; 1-(2,6-Difluoro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea; 3-(2,6-Dichloro-phenyl)-1-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-phenyl)-1-{6-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 1-(2,6-Dichloro-phenyl)-3-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]urea; 3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]urea; 1-[6-(3-Cyano-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea; 1-(2,6-Dichloro-phenyl)-3-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]urea; 1-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3-(4-methoxy-phenyl)-1-methyl-urea; 3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]urea; 3-(2,6-Dichloro-phenyl)-1-[6-(2,4-difluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 1-(2,6-Dichloro-phenyl)-3-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]urea; 3-(2,6-Dichloro-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 1-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(3-trifluoro-methyl-phenyl)-urea; 3-(3-Chloro-phenyl)-1-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea ; 3-(2,6-Dichloro-phenyl)-1-[6-(4-fluoro-phenylamino)- pyrimidin-4-yl]-1-methyl-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea; 1-(2-Chloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-urea bis-hydrochloride salt; 1-(2-Chloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-1-methyl-urea; 3-(2-Chloro-phenyl)-1-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]urea; 1-(2-Bromo-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-fluoro-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3-methoxy-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,5-dimethoxy-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-trifluoromethyl-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(5-methoxy-2-methyl-phenyl)-urea; 1-(3-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,4,5-trimethoxy-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-urea; 1-(4-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,5-dimethoxy-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-urea; 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-phenyl-urea; 1-(2-Chloro-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-ethyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3yl-amino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl- pyridin-3-yl-amino)-pyrimidin-4-yl]urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylaminol}-pyrimidin-4-yl)-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)- phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6[3-(4-isopropyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yl-oxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin-4-yl-oxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4-yl-oxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6[4-(4-ethyl-piperazin-1-yl-methyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl-methyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-yl-methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea; 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yl-oxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin-4-yl-oxy)-phenylamino]-pyrimidin-4-yl}-urea; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea; and 3-(2,6-Dichloro-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea. 32. The compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or N-oxide thereof. 33. The compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt thereof. 34. The compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea. 35. The compound 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea or a pharmaceutically acceptable salt or N-oxide thereof. 36. The compound 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea or a pharmaceutically acceptable salt thereof. 37. The compound 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea. 38. A pharmaceutical composition comprising a compound according to claim 32, or pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier or diluent. 39. A pharmaceutical composition comprising a compound according to claim 33, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 40. A pharmaceutical composition comprising a compound according to claim 34 and a pharmaceutically acceptable carrier or diluent. 41. A pharmaceutical composition comprising a compound according to claim 35, or pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier or diluent. 42. A pharmaceutical composition comprising a compound according to claim 36, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 43. A pharmaceutical composition comprising a compound according to claim 37 and a pharmaceutically acceptable carrier or diluent.