4-(3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

A compound of formula (I):

• wherein:
• R1 is selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered heterocyclyl;
• wherein R1 may be optionally substituted on carbon by one or more R6;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R7;
• R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, (C1-6alkyl)2N—S(O)2—NH—, (C1-6alkyl)NH—S(O)2—NH—, NH2—S(O)2—NH—, (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-, (C1-6alkyl)NH—S(O)2—N(C1-6alkyl)-, NH2—S(O)2—N(C1-6alkyl)-, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—;
• wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9;
• R4 is selected from cyano, carboxy, carbamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, carbocyclyl or heterocyclyl;
• wherein R4 may be optionally substituted on carbon by one or more R10;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R11;
• R5 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl;
• wherein R5 may be optionally substituted on carbon by one or more R12;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R13;
• n=0, 1, 2 or 3;
• wherein the values of R5 may be the same or different;
• R6, R8, R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl;
• wherein R6, R8, R10 and R12 independently of each other may be optionally substituted on carbon by one or more R14;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R15;
• R7, R9, R1I, R13 and R15 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• wherein R7, R9, R11, R13 and R15 independently of each other may be optionally substituted on carbon by on or more R16;
• R14 and R16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl;
• wherein R14 and R16 independently of each other may be optionally substituted on carbon by one or more R17;
• and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R18;
• R17 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;
• and
• R19 and R21 are independently selected from a direct bond, —O—, —N(R22)—, —C(O)—, —N(R23)C(O)—, —C(O)N(R24)—, —S(O)s—, —SO2N(R25)— or —N(R26)SO2—;
• wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl and s is 0-2;
• and
• R18 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• or a pharmaceutically acceptable salt thereof,