Claims for Patent: 8,921,357

Summary for Patent: 8,921,357

Title:	Pyridazinone derivatives
Abstract:	Compounds of the formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.4' have the meanings indicated in Claim 1, are inhibitors of tyrosine kinases, in particular Met kinase, and can be employed, inter alia, for the treatment of tumors.
Inventor(s):	Dorsch; Dieter (Ober-Ramstadt, DE), Stieber; Frank (Heidelberg, DE), Schadt; Oliver (Rodenbach, DE), Blaukat; Andree (Muehltal, DE)
Assignee:	Merck Patent GmbH (Darmstadt, DE)
Application Number:	13/785,471
Patent Claims:	1. A compound of formula I ##STR00209## in which R.sup.1 denotes Ar or Het, R.sup.2 denotes an unsaturated, saturated or aromatic 6-membered heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, N.dbd.CR.sup.3N(R.sup.3).sub.2, SR.sup.3, NO.sub.2, CN, COOR.sup.3, CON(R.sup.3).sub.2, NR.sup.3COA, NR.sup.3SO.sub.2A, SO.sub.2N(R.sup.3).sub.2, S(O).sub.mA, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet, O[C(R.sup.3).sub.2].sub.pOR.sup.3, O[C(R.sup.3).sub.2].sub.nN (R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nC.ident.C[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.- 2, O[C(R.sup.3).sub.2].sub.nN.sup.+O.sup.-(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet, S[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, S[C(R.sup.3).sub.2].sub.nHet, NR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.nHet, NHCON(R.sup.3).sub.2, NHCONH[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NHCONH[C(R.sup.3).sub.2].sub.nHet, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nHet, CON(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nNR.sup.3COOA, CONR.sup.3[C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, COHet, COA, CH.dbd.CH--COOR.sup.3, CH.dbd.CH--N(R.sup.3).sub.2 and/or .dbd.O, with the proviso that R.sup.2 is not pyrimidinyl, R.sup.3 denotes H or A, R.sup.4, R.sup.4' each, independently of one another, denote H, Hal, A, OR.sup.3, CN, COOR.sup.3, CON(R.sup.3).sub.2, NR.sup.3COA, NR.sup.3SO.sub.2A, SO.sub.2N(R.sup.3).sub.2 or S(O).sub.mA, Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, SR.sup.3, NO.sub.2, CN, COOR.sup.3, CON(R.sup.3).sub.2, NR.sup.3COA, NR.sup.3SO.sub.2A, SO.sub.2N(R.sup.3).sub.2, S(O).sub.mA, CO-Het, Het, O[C(R.sup.3).sub.2].sub.n-N(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet, NHCOOA, NHCON(R.sup.3).sub.2, NHCOO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NHCOO[C(R.sup.3).sub.2].sub.nHet, NHCONH[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NHCONH[C(R.sup.3).sub.2].sub.nHet, OCONH[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, OCONH[C(R.sup.3).sub.2].sub.nHet, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nHet and/or COA, Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, SR.sup.3, NO.sub.2, CN, COOR.sup.3, CON(R.sup.3).sub.2, NR.sup.3COA, NR.sup.3SO.sub.2A, SO.sub.2N(R.sup.3).sub.2, S(O).sub.mA, CO-Het.sup.1, [C(R.sup.3).sub.2].sub.nHet.sup.1, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet.sup.1, NHCOOA, NHCON(R.sup.3).sub.2, NHCOO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NHCOO[C(R.sup.3).sub.2].sub.nHet.sup.1, NHCONH[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NHCONH[C(R.sup.3).sub.2].sub.nHet.sup.1, OCONH[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, OCONH[C(R.sup.3).sub.2].sub.nHet.sup.1, CO-Het.sup.1, CHO, COA, .dbd.S, .dbd.NH, .dbd.NA and/or .dbd.O, and where a ring nitrogen is optionally oxidized, Het.sup.1denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or disubstituted by A, OA, OH, Hal and/or .dbd.O, A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms are optionally replaced by F and/or in which one or two non-adjacent CH.sub.2 groups are optionally replaced by O, NH, S, SO, SO.sub.2 and/or by CH.dbd.CH groups, or cyclic alkyl having 3-7 C atoms, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, and p denotes 1, 2, 3 or 4, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 2. A compound according to claim 1, in which R.sup.2 denotes an unsaturated, saturated or aromatic 6-membered heterocycle having 1 to 4 N and/or O atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, N.dbd.CR.sup.3N(R.sup.3).sub.2, CN, COOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet, O[C(R.sup.3).sub.2].sub.pOR.sup.3, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nC.ident.C[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.- 2, O[C(R.sup.3).sub.2].sub.nN.sup.+O.sup.-(R.sup.3).sub.2, O[C(R.sup.3).sub.2],.sub.nHet, NR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.nHet, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nHet, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nNR.sup.3COOA, CONR.sup.3[C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, COHet, CH.dbd.CH--COOR.sup.3, CH.dbd.CH--N(R.sup.3).sub.2 and/or .dbd.O, with the proviso that R.sup.2 is not pyrimidinyl, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 3. A compound according to claim 1, in which Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, CN, S(O).sub.mA, NR.sup.3COA, CON(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2 and/or CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 4. A compound according to claim 1, in which R.sup.4, R.sup.4' denote H, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 5. A compound according to claim 1, in which Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by A, CHO, COOR.sup.S, CON(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet.sup.1, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet.sup.1 and/or .dbd.O, and where a ring nitrogen is optionally oxidized, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 6. A compound according to claim 1, in which Het.sup.1denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or disubstituted by A and/or .dbd.O, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 7. A compound according to claim 1, in which A denotes unbranched or branched alkyl having 1-8 C atoms, in which 1-7 H atoms are optionally replaced by F, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 8. A compound according to claim 1, in which R.sup.1 denotes Ar or benzo-2,1,3-thiadiazolyl, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 9. A compound according to claim 1, in which R.sup.3 denotes H, methyl, ethyl or propyl, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 10. A compound according to claim 1, in which R.sup.2 denotes pyridazinyl, pyridinyl, 1,3-oxazinanyl, morpholinyl, piperidinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, N.dbd.CR.sup.3N(R.sup.3).sub.2, CN, COOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet, O[C(R.sup.3).sub.2].sub.pOR.sup.3, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nC.ident.C[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.- 2, O[C(R.sup.3).sub.2].sub.nN.sup.+O.sup.-(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet, NR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.nHet, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nHet, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nNR.sup.3COOA, CONR.sup.3[C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, COHet, CH.dbd.CH--COOR.sup.3, CH.dbd.CH--N(R.sup.3).sub.2 and/or .dbd.O, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 11. A compound according to claim 1, in which Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl or benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by A, CHO, COOR.sup.3, CON(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet.sup.1, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet.sup.1 and/or .dbd.O, and where a ring nitrogen is optionally oxidized, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 12. A compound according to claim 1, in which Het.sup.1 denotes pyrrolidine, piperidine, piperazine or morpholine, each of which is unsubstituted or mono- or disubstituted by A and/or .dbd.O, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 13. A compound according to claim 1, in which R.sup.1 denotes Ar or Het, R.sup.2 denotes pyridazinyl, pyridinyl, 1,3-oxazinanyl, morpholinyl, piperidinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R.sup.3).sub.2].sub.nOR.sup.3, N.dbd.CR.sup.3N(R.sup.3).sub.2, CN, COOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet, O[C(R.sup.3).sub.2].sub.pOR.sup.3, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nC.ident.C[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.- 2, O[C(R.sup.3).sub.2].sub.nN.sup.+O.sup.-(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet, NR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.nHet, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nNHCO[C(R.sup.3).sub.2].sub.nHet, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, CONR.sup.3[C(R.sup.3).sub.2].sub.nNR.sup.3COOA, CONR.sup.3[C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, COHet, CH.dbd.CH--COOR.sup.3, CH.dbd.CH--N(R.sup.3).sub.2 and/or .dbd.O R.sup.3 denotes H, methyl, ethyl or propyl, R.sup.4, R.sup.4' denote H, Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, CN, S(O).sub.mA, NR.sup.3COA, CON(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nOR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2 and/or CONR.sup.3[C(R.sup.3).sub.2].sub.nHet, Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl or benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by A, CHO, COOR.sup.3, CON(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nHet.sup.1, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, O[C(R.sup.3).sub.2].sub.nHet.sup.1 and/or .dbd.O and where a ring nitrogen is optionally oxidized, Het.sup.1 denotes pyrrolidine, piperidine, piperazine or morpholine, each of which is unsubstituted or mono- or disubstituted by A and/or .dbd.O A denotes unbranched or branched alkyl having 1-8 C atoms, in which 1-7 H atoms are optionally replaced by F, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, and p denotes 1, 2, 3 or 4, or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 14. A compound, which is one of the following compounds TABLE-US-00020 No. Name and/or structure "A5" 4-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]- phenyl}morpholin-3-one "A6" 3-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]- phenyl}-1,3-oxazinan-2-one ##STR00210## "A7" 3-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]- phenyl}-1,3-oxazinan-2-one "A8" 1-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]- phenyl}-3-methyl-6H-pyridazin-6-one "A9" 6-(3,5-difluorophenyl)-2-[3-(5-methylpyridin-2-yl)benzyl]-2H- pyridazin-3-one "A10" 6-(3,5-difluorophenyl)-2-[3-(5-methoxypyridin-2-yl)benzyl]-2H- pyridazin-3-one ##STR00211## "A11" 2-[3-(5-aminopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H- pyridazin-3-one "A12" 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyridin- 2-yl]benzyl}-2H-pyridazin-3-one "A24" 6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy) pyridin-2-yl]benzyl}-2H-pyridazin-3-one "A27" 6-(3,5-difluorophenyl)-2-{3-[6-(4-methylpiperazin-1-yl) pyridazin-3-yl]benzyl}-2H-pyridazin-3-one "A28" 6-(3,5-difluorophenyl)-2-{3-[6-(3-dimethylaminopropoxy)- pyridazin-3-yl]benzyl}-2H-pyridazin-3-one "A67" 6-(3,5-difluorophenyl)-2-{3-[6-(3-dimethylaminopropylamino)- pyridazin-3-yl]benzyl}pyridazin-3-one "A68" 6-(3,5-difluorophenyl)-2-{3-[6-(2-dimethylaminoethylamino)- pyridazin-3-yl]benzyl}pyridazin-3-one "A69" 6-(3,5-difluorophenyl)-2-{3-[6-(4-dimethylaminobutylamino)- pyridazin-3-yl]benzyl}pyridazin-3-one "A70" 6-(3,5-difluorophenyl)-2-{3-[6-(1-methylpiperidin-4-ylamino)- pyridazin-3-yl]benzyl}pyridazin-3-one "A86" 2-[3-(6-methylpyridin-3-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H- pyridazin-3-one "A94" 2-(3-pyridin-4-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin- 3-one "A258" 2-[3-(5-bromopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H- pyridazin-3-one "A259" 6-(3,5-difluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4- yl)-pyridin-2-yl]benzyl}-2H-pyridazin-3-one "A280" 2-[3-(5-aminopyrazin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H- pyridazin-3-one "A281" 6-(3,5-difluorophenyl)-2-[3-(6-methylpyridazin-3-yl)benzyl]-2H- pyridazin-3-one or "A282" 2-[3-(6-aminopyridazin-3-yl)benzyl]-6-(3,5-difluorophenyl)-2H- pyridazin-3-one or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof. 15. A process for preparing a compound of formula I according to claim 1 or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof, comprising a) reacting a compound of formula II ##STR00212## in which R.sup.1 has the meaning indicated for the compound of formula I, with a compound of formula III ##STR00213## in which R.sup.2, R.sup.3, R.sup.4 and R.sup.4' have the meanings indicated for the compound of formula I and L denotes Cl, Br, I or a free or reactively functionally modified OH group, or b) i) converting a compound of formula I, wherein R.sup.2 denotes an amino group, by acylating or alkylating said amino group, or ii) converting a compound of formula I, wherein R.sup.2 denotes a hydroxyl group, by etherifying said hydroxyl group, or c) liberating a compound of formula I from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, and/or converting a base or acid compound of formula I into one of its salts. 16. A pharmaceutical composition, comprising at least one compound of formula I according to claim 1 or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof, and one or more pharmaceutically acceptable excipients and/or adjuvants. 17. A pharmaceutical composition according to claim 16, further comprising at least one further pharmaceutically active ingredient. 18. A kit, comprising separate packs of (a) a compound of formula I according to claim 1 or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof, and (b) a further pharmaceutically active ingredient. 19. A compound according to claim 1, or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 14, or a pharmaceutically acceptable salt thereof.