Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators

A combination comprising an ancillary compound and a compound of the formula (I):

• or a salt, solvate, tautomer or N-oxide thereof;
• wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom;
• and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the NR2R3 group and provided that the oxo group when present is located at a carbon atom α with respect to the NR2R3 group;
• E is phenyl or pyridine wherein E is unsubstituted or has up to 4 substituents R8 selected from hydroxy, chlorine, bromine, trifluoromethyl, cyano, C1-4 hydrocarbyloxy optionally substituted by C1-2 alkoxy or hydroxy, and C1-4 hydrocarbyl optionally substituted by C1-2 alkoxy or hydroxy;
• R1 is phenyl or pyridine which is unsubstituted or bears one or more substituents selected from hydroxy;
• C1-4 acyloxy;
• fluorine;
• chlorine;
• bromine;
• trifluoromethyl;
• cyano;
• CONH2;
• nitro;
• C1-4 hydrocarbyloxy and C1-4 hydrocarbyl each optionally substituted by C1-2 alkoxy, carboxy or hydroxy;
• C1-4 acylamino;
• benzoylamino;
• pyrrolidinocarbonyl;
• piperidinocarbonyl;
• morpholinocarbonyl;
• piperazinocarbonyl;
• five and six membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S;
• phenyl;
• phenyl-C1-4 alkyl;
• phenyl-C1-4 alkoxy;
• heteroaryl-C1-4 alkyl;
• heteroaryl-C1-4 alkoxy and phenoxy, wherein the heteroaryl, heteroaryloxy, phenyl, phenyl-C1-4 alkyl, phenyl-C1-4 alkoxy, heteroaryl-C1-4 alkyl, heteroaryl-C1-4 alkoxy and phenoxy groups are each optionally substituted with 1, 2 or 3 substituents selected from C1-2 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, CONH2, C1-2 hydrocarbyloxy and C1-2 hydrocarbyl each optionally substituted by methoxy or hydroxy;
• R2 and R3 are independently selected from hydrogen, C1-4 hydrocarbyl and C1-4 acyl wherein the hydrocarbyl and acyl moieties are optionally substituted by one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy;
• or R2 and R3 together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N;
• or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N;
• or NR2R3 and the carbon atom of linker group A to which it is attached together form a cyano group;
• R4 is selected from hydrogen, halogen, C1-5 saturated hydrocarbyl, C1-5 saturated hydrocarbyloxy, cyano, and CF3;
• and
• R5 is selected from hydrogen, halogen, C1-5 saturated hydrocarbyl, C1-5 saturated hydrocarbyloxy, cyano, CONH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9;
• R9 is a group R9a or (CH2)R9a, wherein R9a is a monocyclic or bicyclic group which may be carbocyclic or heterocyclic;
• the carbocyclic group or heterocyclic group R9a being optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino;
• a group Ra—Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2;
• and Rb is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1;
• Rc is selected from hydrogen and C1-4 hydrocarbyl;
• and
• X1 is O, S or NRc and X2 is ═O, ═S or ═NRc;
• and wherein
• (I) the ancillary compound is selected from:
• (a) the group consisting of trastuzumab, cetuximab, erlotinib, gefitinib, bevacizumab, imatinib and sorafinib;
• (b) an ancillary PKB inhibitor;
• (c) a CDK inhibitor;
• (d) a COX-2 inhibitor;
• (e) a HDAC inhibitor;
• (f) temozolomide;
• (g) bortezimib;
• and
• (h) a combination of two or more of (a) to (g);
• or
• (II) the ancillary compound is a cytotoxic compound selected from:
• (a) camptothecin compounds;
• (b) the group consisting of 5-fluorouracil, fludarabine, gemcitabine, capecitabine, cytarabine, ralitrexed, pemetrexed and methotrexate;
• (c) vinca alkaloids;
• (d) taxanes;
• (e) epothilones;
• (f) platinum compounds;
• (g) the group consisting of an anthracycline derivative, mitoxantrone and a podophyllotoxin derivative;
• (h) the group consisting of nitrogen mustard compound, a nitrosurea, cyclophosphamide, Busulfan and mitomycin C;
• and
• (i) a combination of two or more of (a) to (h);
• or
• (III) the ancillary compound is selected from:
• (a) the group consisting of alemtuzumab, anti-CD20, CD22, CD33, or CD52, rituximab/rituxamab, tositumomab, gemtuzumab ozogamicin and bevacizumab;
• and
• (b) a combination of two or more of (a);
• or
• (IV) the ancillary compound is selected from:
• (a) the group consisting of antiandrogens, antiestrogens, aromatase inhibitors, and GNRAs;
• (b) the group consisting of interferons and interleukins;
• (c) the group consisting of tretinoin, alitretinoin, and bexarotene;
• and
• (d) a combination of two or more of (a) to (c).