Lipophilic derivatives of anticancer compounds

Abstract

Novel compounds with protein kinase inhibitory activity are disclosed. The compounds comprise a lipophilic targeting moiety having affinity to a cell membrane, such as a saturated or unsaturated hydrocarbon chain. The invention is further directed to pharmaceutical compositions comprising such compounds, and to the use of the compounds or compositions as medicines, in particular in the treatment of cancer.

Description

[0001]GTM22P01PC1 LIPOPHILIC^DERIVATIVES^OF^ANTICANCER^COMPOUNDS Description BACKGROUND OF THE INVENTIONThe invention relates to biologically active compounds which act as protein kinase inhibitors,formulations containing such compounds and the use of such compounds for treating kinase- mediated diseases such as cancer. Various protein kinases are believed to play a role in the pathophysiology of cancers, such asVEGFR, PDGFR and RAF kinases. RAF kinases are downstream effectors of ras, and keymediators of signal-transduction pathways from cell surface receptors to the cell nucleus(Moelling, K.; Heimann, B.; Beimling, P; Rapp, U. Nature 1984, 312, 558; Monia, B.; Johnston, J; Geiger, T; Muller, M.; Fabbro, D. Nat.Med.1996, 2(6), 668).Certain small-molecule inhibitors of protein kinases have been found effective in thetreatment of hyperproliferative disorders such as cancer. An example is sorafenib, Sorafenib which acts as an inhibitor of various protein kinases including RAF, and which displays considerable activity in improving progression-free survival and overall survival rates of cancer patients in the clinic (Iacovelli R, Sternberg CN, Porta C, Verzoni E, de Braud F,Escudier B, et al. Curr Drug Targets 201;16(2)164-70). It was found that the antitumorefficacy of sorafenib is attributed to its ability to suppress cell proliferation, induce cellapoptosis and prevent angiogenesis (Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A,Rong H, et al. Cancer Res 2004;64(19):7099-109; Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ, Clin Cancer Res 2005;11(15):5472-80). Sorafenib has been shown to trigger cell cycle arrest, autophagy and apoptosis by regulating various protein kinases and signal transduction pathways such as the signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR) (Chen KF, Tai WT, Hsu CY, Huang JW, GTM22P01PC1 Liu CY, Chen PJ et al. Eur J Med Chem 2012;55:220-7; Tai WT, Cheg AL, Schiau CW, Huang HP,Huang JW, Chen PJ, et al. J Hepatol 2011;55(5):1041-1048). Sorafenib is used in the treatmentof primary kidney cancers such as advanced renal cell carcinoma, as well as primary livercancer such as hepatocellular carcinoma and differentiated thyroid carcinoma.A related protein kinase inhibitor is the compound regorafenib, which also inhibits variouskinases including receptor tyrosine kinases (RTK) such as VEGFR2: Regorafenib Regorafenib is therapeutically used, for example, in the treatment of patients with metastatic colorectal cancer and other advanced gastrointestinal stromal tumors. Although the introduction of these compounds has brought an improvement in the treatment of patients suffering from the respective cancers, they still display significant shortcomings interms of efficacy and safety. A main problem of these compounds is the high toxicity that theyimpose on the patients. This high toxicity manifest itself in the frequent occurrence of adverse effects, including grave adverse effects, that very frequently lead to a reduction of the administered dose of the respective drugs, interruption or even discontinuation of treatment.It is thus an object of the present invention to provide small-molecule protein kinaseinhibitors, such as inhibitors of RAF kinases, which overcome one or more of the drawbacksof the existing compounds and which can be effectively used in the treatment of a variety ofcancer types. SUMMARY OF THE INVENTIONIn a first aspect, the invention relates to a compound of formula I GTM22P01PC1 wherein one of R1 and R2 represents a lipophilic targeting moiety having affinity to a cell membrane; the other one of R1 and R2 is hydrogen, methyl or chlorine; R3 is hydrogen or fluorine; or a stereoisomer or salt thereof.In a further aspect, the present invention provides for a pharmaceutical compositioncomprising the compound of formula I and at least one pharmaceutically acceptable carrieror excipient.In a still further aspect, the invention provides the use of the compound of formula I, or thepharmaceutical composition comprising the compound of formula I and at least onepharmaceutically acceptable carrier or excipient, as a medicament and, in a still further aspect, for use in the treatment of a subject having been diagnosed with cancer and other illnesses in which the targeted kinases are involved.In yet a further aspect, the invention provides a method for the preparation of a compoundaccording to formula I, comprising the steps of: (a) hydrolysing the compound of formula II (sorafenib or regorafenib) such as toobtain the compound of formula III; and (b) reacting the compound of formula III with the compound R-NH2 such as to obtainthe compound according to formula I.It has been found that the compounds of formula I provide a higher level of cytotoxicity thanprior art compounds such as sorafenib and regorafenib that do not have a lipophilic targeting moiety having affinity to a cell membrane at the R1or R2position and, accordingly, have increased potency. Without wishing to be bound by theory, it is suggested that thecompounds of the present invention may be directed more extensively towards the plasmamembrane and other intracellular membranes and their concentration is increased in thiscell compartment. Accordingly, the molecules of the present invention are present in higherconcentration close to the receptor kinases with which they have to interact. An increasedconcentration at their target structures leads to an increased potency of the respective compounds, thus enabling the use of lower amounts of the active compound to achieve a therapeutically effective treatment. The undesired side effects of the active compoundmoiety, including toxicity are therefore decreased in view of the lower administration dosis.It has been shown that when administered in high doses VEGF-inhibitors and other chemotherapy mobilise circulating bone-marrow-derived cells such as endothelial progenitors for angiogenesis, which promotes the growth of tumors. In contrast the approach GTM22P01PC1 of administering smaller doses of VEGF-inhibitors and other chemotherapy with breaksbetween the sessions - an approach called metronomic chemotherapy, has been shown tosuppress the mobilisation of circulating endothelial progenitors. Thus, the prospect of reaching comparable effects with Sorafenib (respectively Regorafenib) derivatives than with higher doses of Sorafenib (respectively Regorafenib) bears the potential of slowing down tumor growth by not mobilising endothelial progenitor cells and thereby promoting tumor growth. DETAILED DESCRIPTION OF THE INVENTIONIn a first aspect, the invention relates to a compound of formula I wherein one of R1and R2represents a lipophilic targeting moiety having affinity to a cell membrane; the other one of R1and R2is hydrogen, methyl or chlorine; R3is hydrogen orfluorine; or a stereoisomer or salt thereof. In this context, the expression "one of R1 and R2"should be understood such that only one, and not both, of the two substituents R1and R2represents a lipophilic targeting moiety having affinity to a cell membrane. In other words, either R1 is a lipophilic targeting moiety and R2 is hydrogen, methyl or chlorine; or R2 is a lipophilic targeting moiety and R1is hydrogen, methyl or chlorine. As used herein, the lipophilic targeting moiety having affinity to a cell membrane may also be simply referred to as lipophilic targeting moiety. The invention further includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers. In addition, all tautomeric forms of compounds of formula I are also encompassed by the present invention. The lipophilic targeting moiety is preferably selected such that it does not cause an inferiorinhibition, but possibly even superior inhibition, of RAF kinase and other target kinases of therespective compound I compared to a compound having substantially the same formula but without the lipophilic targeting moiety, such as sorafenib or regorafenib. In an embodiment of the present invention, the lipophilic targeting moiety having affinity to a cell membrane (i.e. R1or R2) comprises a hydrocarbon chain having a chain length defined by GTM22P01PC1an uneven number of carbon atoms, wherein the number is in the range from 3 to 19 carbonatoms. For example, the hydrocarbon chain may have a length of 3 to 11 carbon atoms, whichrepresents one of the preferred embodiments. In other preferred embodiments, the length isfrom 3 to 7 carbon atoms, respectively. In some of the further preferred embodiments, thehydrocarbon chain has 3 carbon atoms, or 7 carbon atoms. In another embodiment, the hydrocarbon chain is saturated, such as a saturated hydrocarbonchain having 3 to 11 carbon atoms, such as a saturated hydrocarbon chain having 3 to 7carbon atoms.In a further embodiment, the hydrocarbon chain is linear. For example, the chain may be alinear hydrocarbon chain having 3 to 11 carbon atoms, or 3 to 7 carbon atoms, respectively. Alternatively, and in accordance with still another embodiment of the present invention, thehydrocarbon chain may be branched.Currently preferred are also hydrocarbon chains that are linear and saturated, for example alinear saturated hydrocarbon (or linear alkyl) chain having 3 to 11 carbon atoms, or 3 to 7carbon atoms, respectively. Again, in this context, the number of carbon atoms that define the length of the hydrocarbon or alkyl chain is an uneven number. It was found that the biologicalprofiles of compounds with such chains in the lipophilic targeting moiety are particularlyuseful.In a further embodiment, the lipophilic targeting moiety comprises a group selected from afatty acyl group, an alkoxy group and an alkyl amino group. Optionally, the hydrocarbon chainor alkyl chain as described above forms part of such fatty acyl group, alkoxy group, or alkylamino group. According to some further preferred embodiments, R2is chlorine if R1is the lipophilictargeting moiety. If, however, R2 is the lipophilic targeting moiety, then R1 is according tosome preferred embodiments selected to be methyl.In some embodiments, R1 is a linear alkyl group with 3 to 11 carbon atoms, R2 is chlorine, andR3 is hydrogen or fluorine. The linear alkyl group may, for example, be n-propyl or n-octyl.In some specific embodiments, R1 is n-propyl, R2 is chlorine, and R3 is hydrogen, i.e. thecompound is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-N-n-propyl-pyridine-2-carboxamide; or R1 is n-heptyl, R2 is chlorine, and R3 is hydrogen, i.e. the GTM22P01PC1compound is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-N-n-heptyl-pyridine-2-carboxamide. As mentioned, the lipophilic targeting moiety may also take the R2position, in which case R1is selected from hydrogen, chlorine or more preferably methyl. For example, according tosome embodiments, R1is methyl, R2is a linear alkyl group with 3 to 11 carbon atoms, and R3is hydrogen or fluorine. In a specific embodiment, R1 is methyl, R2 is n-propyl, and R3 ishydrogen. As described above, R3may also be fluorine. This alternative option is generally applicable to all selections R1and R2as well as their combinations described herein. Accordingly, R1mayrepresent a linear alkyl group with 3 to 11 carbon atoms, such as n-propyl or n-heptyl, whileR2 is chlorine and R3 is fluorine. Alternatively, R2 may represent a linear alkyl group with 3 to11 carbon atoms, such as n-propyl or n-heptyl, while R1is methyl and R3is fluorine. In further embodiments, the lipophilic targeting moiety is a linear or branched chain structure represented by the formula -[CH2-CH2-O]x-CH2-CH2-R4,wherein x is an integer from 1 to about 10, wherein R4 is optionally selected from hydroxyl orprimary, secondary or tertiary amino groups. It was found that such compound in which the targeting moiety has a moderate degree of lipophilicity, also exhibit attractive biological activity profiles, such as protein kinase inhibition profiles. As mentioned, x may be selected from 1 to about 10. In some embodiments, x is in the range from 1 to 3, and in one embodiments, x is 2. For example, x may be selected as 2 in combination with R4 being hydroxyl or an amino group. The amino group may be a primary amino group, i.e. -NH2. Alternatively, a secondary amino group such as an alkylamino groupmay be selected, for example a methylamino, ethylamino, n- or isoproylamino or n-, s- or t-butylamino group. Moreover, R4 may represent a tertiary amino group, for example a dialkylamino group wherein the two alkyls may be independently selected, e.g. from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In one specific embodiments, x is 2 and R4is an n-butyl(methyl)amino group (see Example 8). Another aspect of the present invention is a pharmaceutical composition comprising acompound of formula (I) as described above and at least one pharmaceutically acceptablecarrier or excipient. GTM22P01PC1 The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceuticalpreparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées,hard and soft gelatine capsules, solutions, emulsions or suspensions. Alternatively, the administration can be also effected parenterally, e.g. in the form of sterile liquids for injectionor infusion; or the composition may be administered transdermally, e.g. in form of a patch ora transdermal gel, or rectally or vaginally, e.g. in form of suppositories, or topically, e.g. in theform of ointments, lotions, emulsions or creams. The compounds of formula (I) and pharmaceutically acceptable salts thereof can be combined and processed with pharmaceutically acceptable carriers and other excipients suitable for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as suchexcipients for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers forsoft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyolsand the like. Suitable carriers for the production of solutions and syrups are, for example,water, polyols, sucrose, invert sugar, glucose and the like. Excipients such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I) if necessary. Suitable carriers for suppositories are,for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. It will be appreciated by those skilled in the art that a particular method of administration will depend on a variety of factors, all of which are routinely considered when administering therapeutics. Another aspect of the present invention is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuablesubstances into a galenical dosage form together with one or more therapeutically inertcarriers. GTM22P01PC1 A further aspect of the present invention are the compounds of formula (I) described above for use as a medicament. Still another aspect of the present invention are the compounds of formula (I) for use in the treatment of a subject having been diagnosed with cancer and, moreparticularly, with a cancer which is associated with an abnormal activity profile of certainprotein kinases, and potentially other illnesses involving the respective target kinases.The compounds of formula (I) are used in the treatment of a subject in need thereof inquantities which are therapeutically effective against proliferative diseases, including but not limited to colon, gastric, lung, pancreatic, ovarian, prostate, leukemia, melanoma,hepatocellular, renal, head and neck, glioma, thyroid and mammary cancer. The treatmentmay comprise contacting cells, one or more tissues or one or more body fluids of the subject with a pharmaceutical composition or a product of this invention.While the compounds of formula (I) are effective for cancers involving abnormal kinaseactivities, such RAF kinase-mediated cancers, they are also effective for cancers mediated byother kinases or other cancer drivers.It will be appreciated by those skilled in the art that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compoundemployed, the age, the gender, the body weight, the general health, the diet of the subject inneed of the treatment. It will also depend on the route of administration and the severity ofthe condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e. the mode of treatment and the daily number of doses of the compounds of formula (I) given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. The compounds of formula (I) can be administered to a subject in need thereof at a dosage which can range from about 0.1 to about 300 mg / kg of total body weight. The daily dose for oral administration will preferably be from 0.1 to 300 mg / kg of total body weight. The daily dosage for administration by injection which includes intravenous, intramuscular,subcutaneous and parenteral injection, as well as infusion techniques, will preferably be from0.1 to 300 mg / kg of total body weight. The daily vaginal dosage regime will preferably be from 0.1 to 300 mg / kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 300 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 1 to 300 mg / kg. For all the above mentioned routes of administration, the preferred dosage is 0.1 to GTM22P01PC1 300 mg / kg. The daily inhalation dosage regimen will preferably be from 0.1 to 300 mg / kg of total body weight.The administered dosage of the compounds of formula (I) may be modified depending on anysuperior or unexpected results which may be obtained as routinely determined with this invention. In a further aspect, the present invention relates to a method for treating cancer to a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound of formula (I) any claim or a pharmaceutical composition comprising one or more compounds of formula (I). Compounds of formula (I) in which R1 is the lipophilic targeting moiety may, for example, bemanufactured by hydrolysis of a compound II, for example 4-[4-[[4-chloro-3(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide), orregorafenib according to the following two step reaction pathway, shown below for sorafenib: Compound II undergoes basic hydrolysis in presence of sodium hydroxide to provide thecompound of formula III (free acid form). The compound of formula III is subsequentlyreacted with an amine (for example, with n-propylamine or n-octylamine) to form an amiderepresenting the compound of formula (I). By analogy, regorafenib may be hydrolysed andsubsequently reacted with an amine to form an amide.Compound II can, for example, be synthetized according to the following reaction scheme: GTM22P01PC1 Picolinic acid of formula IV is reacted with thionyl chloride to give the 4-chloro derivative V which, on treatment with methanol, gave the methyl ester of formula VI. Compound of formula VI is reacted with methylamine to get the corresponding amide of formula VII. Compound of formula VII is reacted with 4-aminophenol to get the ether derivative of formula VIII. Compound of formula VIII is reacted with 4-chloro-3- trifluoromethylphenylisocyante to sorafenib base of formula II.The following examples serve to illustrate the invention. They should not, however, beunderstood as restricting the scope of the invention. EXAMPLES Example 1: Preparation of C3-sorafenib (R1=n-propyl; Step 1: Hydrolysis of sorafenib into 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido) phenoxy)picolinic acid Under a nitrogen atmosphere, sorafenib 1 (2.0 g, 1 equiv, 4.3 mmol), sodium hydroxide (2.6 g, 15 equiv, 65 mmol) and ethanol (43 mL, 0.1 molar) were heated at 80 °C. After 4 days, water was added.1 M aqueous hydrochloric acid was added until pH reached 3. A yellow solid precipitated which was filtered. The filter cake was dried to obtain a tan powder corresponding to 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid 2 (1.77 g, 3.92 mmol, 91 %). GTM22P01PC11H^NMR^(400^MHz,^DMSO) δ 10.01 (s, 1H), 9.68 (s, 1H), 8.58 (d, J = 5.8 Hz, 1H), 8.11 (d, J =2.4 Hz, 1H), 7.70 – 7.55 (m, 4H), 7.47 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 5.8, 2.7 Hz, 1H), 7.19 (d, J= 8.9 Hz, 2H).19F^NMR^(376^MHz,^DMSO) δ -61.74 (3F).Step 2: Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N- propylpicolinamide (C3-sorafenib) To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid 2 (100 mg, 1 equiv, 221 μmol) in dimethylformamide (2.21 mL, 0.1 molar) was added 1- hydroxybenzotriazole-hydrate (40.7 mg, 1.2 equiv, 266 μmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (50.9 mg, 1.2 equiv, 266 μmol) and diisopropylethylamine (77.1 μL, 2.0 equiv, 443 μmol). After the addition of a solution of propane-1-amine hydrochloride salt (21.2 mg, 1 equiv, 221 μmol) in dimethylformamide, the mixture was stirred at room temperature for 16 h. The reaction was partitioned between water and methyl tert-butyl ether. The aqueous phase was extracted with methyl tert-butyl ether. The combined organics were washed with brine three times, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an orange residue (108 mg). Purification by silica chromatography using a 20-80% ethyl acetate in cyclohexane gradient provided two fractions of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N- propylpicolinamide TM001 (57 mg, 0.12 mmol, 52%) as a white solid.1H^NMR^(400^MHz,^CDCl3) δ 8.52 (s, 1H), 8.46 (d, J = 5.6 Hz, 2H), 8.28 (s, 1H), 7.67 (d, J = 2.6Hz, 1H), 7.63 (dd, J = 8.7, 2.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.30 (d, J= 8.8 Hz, 2H), 7.16 (dd, J = 5.6, 2.5 Hz, 1H), 6.97 – 6.87 (m, 2H), 3.41 (q, J = 6.8 Hz, 2H), 1.69-1.60 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).19F^NMR (376 MHz, CDCl3) δ -63.03 (3F). R2=chlorine; Step 1 was performed as in Example 1. GTM22P01PC1 Step 2: Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N- heptylpicolinamide from 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy) picolinic acid To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid 2 (67 mg, 1 equiv, 0.15 mmol) in dimethylformamide (11 mg, 1.5 mL, 0.1 molar, 1 equiv, 0.15mmol) was added 1-hydroxybenzotriazole - hydrate (27 mg, 1.2 equiv, 0.18 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (34 mg, 1.2 equiv, 0.18 mmol) anddiisopropylethylamine (52 μL, 2.0 equiv, 0.30 mmol). After the addition of a solution of n- heptylamine (22 μL, 1 equiv, 0.15 mmol) in dimethylformamide, the mixture was stirred at RT for 16 h. The reaction was partitioned between water and methyl tert-butyl ether. The aqueous phase was extracted with methyl tert-butyl ether. The combined organics were washed with brine three times, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an orange residue (154 mg). Purification by silica chromatography using a 20-80% ethyl acetate in cyclohexane gradient provided 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-heptylpicolinamide (46 mg, 84 μmol, 57 %)1H^NMR^(400^MHz,^CDCl3) δ 8.53 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.43 (d, J = 6.2 Hz, 1H), 8.28(s, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 8.6, 2.4 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 5.6, 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 3.43(q, J = 6.8 Hz, 2H), 1.62 (p, J = 7.1 Hz, 2H), 1.36 – 1.10 (m, 8H), 0.83 (t, J = 6.8 Hz, 3H).19F^NMR^(376^MHz,^CDCl3) δ -63.01 (3F).Example 3: Preparation of N-methyl-4-(4-(3-(4-propyl-3-(trifluoromethyl)phenyl)ureido) phenoxy)picolinamide (R1=methyl; R2=n-propyl; R3=hydrogen) Step 1: Synthesis of 4-nitro-1-(prop-2-en-1-yl)-2-(trifluoromethyl)benzene GTM22P01PC1 4-Bromo-3-trifluoromethylnitrobenzene 3 (500.0 mg, 1 equiv, 1.85 mmol), lithium chloride (236 mg, 3.0 equiv 5.56 mmol) were dissolved in dry toluene (15.0 mL, 0.20 M) undernitrogen. The reaction mixture was degassed with a balloon of nitrogen for 5 minutes.Pd(Ph3P)4 (107 mg, 0.05 equiv 92.6μmol) and allyltributylstannane (859 μL, 1.5 equiv, 2.78 mmol) were added subsequently. The reactionmixture was stirred at 120°C for 16 hours. TLC (cyclohexane / ethyl acetate 9 / 1, stain: KMnO4) showedcomplete conversion of the starting material. The mixture is diluted with 15mL of water and extracted3 times with ethyl acetate (3*20mL). The combined organics were washed with 1 M aqueous KF (3*15mL) and brine (15mL), dried over Na2SO4, concentrated, adsorbed onto silica purified using a 0-10% ethyl acetate in cyclohexane gradient. The product containing fractions were combined andconcentrated to provide 4-nitro-1-(prop-2-en-1-yl)-2-(trifluoromethyl)benzene 4 (389 mg, 45% purity,0.76 mmol, 41%) as an orange oil. Both the allyl 4 and styrene 5 product isomers were obtained. They convergently lead to the formation of the n-propyl chain upon hydrogenation in the next step.1H^NMR^(400^MHz,^CDCl3) δ 8.52 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.5, 2.4 Hz, 1H), 7.57 (d, J =8.5 Hz, 1H), 5.93 (ddt, J = 16.8, 10.0, 6.6 Hz, 1H), 5.21 (dq, J = 10.1, 1.3 Hz, 1H), 5.14 (dq, J = 17.0, 1.5 Hz, 1H), 3.67 (dd, J = 6.4, 1.7 Hz, 2H).19F^NMR^(376^MHz,^CDCl3) δ -60.92 (3F).Step 2: Synthesis of 4-propyl-3-(trifluoromethyl)aniline In an autoclave, a mixture of 1-allyl-4-nitro-2-(trifluoromethyl)benzene 4 and (E)-4-nitro-1- (prop-1-en-1-yl)-2-(trifluoromethyl)benzene 5 (919 mg, 2:3, 1.59 mmol) was dissolved in dry methanol (15.9 mL, 0.1 M). The reaction mixture was degassed for 5 minutes under strong stirring and palladium on carbon 10% (169 mg, 10% wt) was subsequently added. The reaction mixture was then put under a nitrogen atmosphere with 3 vacuum / nitrogen cycles and put under 6 bars of hydrogen atmosphere with 3 vacuum / hydrogen cycles. The reaction was stirred for 16 hours at room temperature. LCMS and TLC-MS showed complete conversion and the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (15 mL) and concentrated to afford 4-propyl-3-(trifluoromethyl)aniline 6 as an impure yellow oil (254 mg). GTM22P01PC11H^NMR^(500^MHz,^CDCl3) δ 7.09 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.2,2.6 Hz, 1H), 2.62 (m, 2H), 1.70 – 1.52 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).19F^NMR^(470^MHz,^CDCl3) δ -59.93 (3F).Step 3: Synthesis of N-methyl-4-(4-(3-(4-propyl-3-(trifluoromethyl)phenyl)ureido)phenoxy) picolinamide 4-propyl-3-(trifluoromethyl)aniline 6 (33.3 mg, 50% Wt, 1 equiv, 81.9 μmol) was stirred with CDI (13.3 mg, 1.00 equiv, 81.9 μmol) in dichloromethane (0.5 mL, 0.15 molar) until Starting materials disappeared.4-(4-aminophenoxy)-N-methylpicolinamide (19.9 mg, 1 equiv, 81.9 μmol) was added. The mixture was stirred at rt for 1 h and concentrated. The crude was dry loaded on a 4 g silica column. Purification was performed using a 50-100 % ethyl acetate incyclohexane gradient (5 CV, 10 CV, 5 CV). The product containing fractions were combinedand concentrated to provide N-methyl-4-(4-(3-(4- propyl-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide (8.9 mg, 19 μmol, 23%) as a white solid.1H^NMR^(400^MHz,^DMSO) δ 8.98 (s, 1H), 8.90 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.50 (d, J = 5.6Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.57 – 7.49 (m, 2H), 7.45 – 7.29 (m,1H), 7.16 (d, J = 8.8 Hz, 2H), 7.15-7.10 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H), 2.64 (t, J = 8.0 Hz, 2H), 1.58 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).19F^NMR^(377^MHz,^DMSO) δ -58.45 (3F).Example 4: Preparation of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)-N-propylpicolinamide (C3-regorafenib; R1=n-propyl; R2=chlorine; R3=fluorine) Step 1: Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)picolinic acid GTM22P01PC1 Under nitrogen protection, 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide 18 (1.00 g, 1.0 equiv, 2.07 mmol), sodium hydroxide(1.24 g, 15 equiv, 31.1 mmol) and EtOH (20.7 mL, 0.1 M) were placed at 55 °C and stirred over weekend. HPLC-MS shows close to full conversion to product after 4 days. Water was added, and 1 M aqueous hydrochloric acid was added until pH reached 3. A grey solid precipitated which was suction filtered and washed with water. The filter cake was dried intoa vacuum oven (200 mbar, 80°C) to give a grey powder. NMR shows 5% impurity of SM. Theproduct 19 was used without further purification.Step 2: Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)- N-propylpicolinamide To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinic acid 19 (40 mg, 1 equiv, 85 μmol), 1-hydroxybenzotriazole -hydrate (17 mg, 1.3 equiv, 0.11 mmol) and propan-1-amine hydrochloride (11 mg, 1.3 equiv, 0.11 mmol) in anhydrous DMF (0.85 mL, 0.1 M). EDC (21 mg, 1.3 equiv, 0.11 mmol) and DIEA (44 µL, 3 equiv, 0.26 mmol) were added. Mixture was stirred at room temperature overnight. HPLC and TLC-MS (Hex:EA 1:1) show full conversion to product. The mixture was quenched with water and washed with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate aqueous solution, water and brine (x3). After drying over Na2SO4, the solid was filtered and the solvent was evaporated under vacuum. The crude was purified on silica using a 20-50% gradient of ethyl acetate in cyclohexane. The product containing fractions were combined and concentrated. The product was dissolved in acetonitrile and water and freeze-dried. Upon lyophilization 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-propylpicolinamide (31 mg, 61 µmol, 77%) was obtained as a white powder. GTM22P01PC11H^NMR^(400^MHz,^DMSO) ^ 9.53 (s, 1H), 8.80 (t, J = 6.2 Hz, 1H), 8.77 – 8.70 (m, 1H), 8.53 (d,J = 5.6 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.63 (d, J = 1.9 Hz, 2H), 7.42 (d, J = 2.6 Hz, 1H), 7.34 (dd, J =11.6, 2.7 Hz, 1H), 7.20 (dd, J = 5.6, 2.6 Hz, 1H), 7.07 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 3.22 (q, J = 6.7 Hz, 2H), 1.55-1.48 (m, , 2H), 0.85 (t, J = 7.4 Hz, 3H).19F^NMR^(377^MHz,^DMSO) ^ -61.50 (3F), -124.40 (1F).Example 5: Preparation of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)-N-heptylpicolinamide (C7-regorafenib; R1=n-heptyl; R2=chlorine; R3=fluorine) Step 1 was the same as in Example 5. Step 2 was conducted as follows: To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)picolinic acid 19 (100 mg, 1.0 equiv, 213 μmol), 1-hydroxybenzotriazole - hydrate (30 μL, 1.3 equiv, 277 μmol) and n-neptylamine (41 μL, 1.3 equiv, 277 μmol) in anhydrous DMF (2.13 mL, 0,1 M. EDC (53 mg, 1.3 equiv, 277 μmol) and DIEA (111 μL, 3 equiv, 639 μmol) were added. Mixture was stirred at room temperature overnight. HPLC and TLC- MS (Hex:EA 2:1) shows full conversion to product. The Mixture was quenched with water and washed with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate aqueous solution, water and brine (x3). After drying over Na2SO4, the solid was filtered and the solvent was evaporated. The residue was purified on silica using a 10-30% ethyl acetate in cyclohexane gradient to provide 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-heptylpicolinamide (71 mg, 213 μmol, 59%) as a white solid.1H^NMR^(400^MHz,^DMSO) δ 9.52 (s, 1H), 8.77 (t, J = 6.1 Hz, 1H), 8.75-8.70 (m, 1H), 8.52 (d, J= 5.6 Hz, 1H), 8.16 (t, J = 9.1 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J = 1.5 Hz, 2H), 7.42 (d, J = 2.6 Hz, 1H), 7.32 (dd, J = 11.6, 2.7 Hz, 1H), 7.18 (dd, J = 5.5, 2.6 Hz, 1H), 7.06 (ddd, J = 8.9, 2.7, 1.2 Hz,1H), 3.25 (q, J = 6.8 Hz, 2H), 1.50 (t, J = 7.0 Hz, 2H), 1.35 – 1.06 (m, 8H), 0.99 – 0.73 (m, 3H).19F^NMR^(377^MHz,^DMSO) δ -61.53 (3F), -124.55 (1F). GTM22P01PC1 Example 6: Preparation of 4-(3-fluoro-4-(3-(4-propyl-3-(trifluoromethyl)phenyl)ureido) phenoxy)-N-methylpicolinamide (R1=methyl; R2=n-propyl; R3=fluorine) CDI (259 mg, 1.3 equiv, 1.60 mmol) was added to a suspension of 4-propyl-3- (trifluoromethyl)aniline 6 (250 mg, 1.0 equiv, 1.23 mmol) in dichloromethane (12.3 mL, 0.1 M). The mixture was stirred at room temperature until starting material disappeared (2 h, TLC and HPLC). The mixture was added to a separation funnel and washed with 5 mL of water. The organic layer was placed into a round bottom flask and 4-(4-amino-3- fluorophenoxy)-N-methyl-2-pyridinecarboxamide 20 (321 mg, 1.0 equiv, 1.23 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with water and washed with a saturated sodium bicarbonate aqueous solution and brine. After drying over Na2SO4, the solid was filtered and the solvent was evaporated. The crude was purified on silica using a 33-67% gradient of ethyl acetate in cyclohexane. The product containing fractions were combined and concentrated. The product was dissolved in acetonitrile and water and freeze-dried. Upon lyophilization N-methyl-4-(4-(3-(4-propyl-3- (trifluoromethyl)phenyl)ureido)phenoxy)picolinamide Rex003 (69 mg, 0.14 mmol, 11%) was obtained as a white solid.1H^NMR^(400^MHz,^DMSO) δ 9.32 (s, 1H), 8.78 (q, J = 4.8 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.53(d, J = 5.6 Hz, 1H), 8.19 (t, J = 9.1 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.4, 2.3 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 11.7, 2.7 Hz, 1H), 7.18 (dd, J = 5.6, 2.6 Hz, 1H), 7.06 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H), 2.65 (t, J = 8.0 Hz, 2H), 1.63-1.56 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).19F^NMR^(377^MHz,^DMSO) δ -58.49 (3F), -124.96 (1F).Example 7: Preparation of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N- (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)picolinamide (R1=2-(2-hydroxyethoxy)ethoxy)ethyl; GTM22P01PC1 Step 1 was performed as in Example 1. Step 2: Synthesis of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-(2-(2- (2-hydroxyethoxy)ethoxy)ethyl)picolinamide from 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy) picolinic acid To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid 2(500 mg, 1 equiv, 1.11 mmol) in dimethylformamide (11.1 mL, 0.1 molar) was added 1-hydroxybenzotriazole hydrate (203 mg, 1.2 equiv, 1.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (255 mg, 1.2 equiv, 1.33 mmol) anddiisopropylethylamine (386 μL, 2.0 equiv, 2.21 mmol). After addition of a solution of 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (153 μL, 1.0 equiv, 1.11 mmol) in dimethylformamide themixture was stirred at RT for 16 h. LCMS showed full starting material consumption. Thereaction was partitioned between brine and ethyl acetate. The aqueous layer was extractedwith ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to a black residue. Purification by silica chromatography using a 0-20% methanol in dichloromethane gradient (5-5-5 CV) provided 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)picolinamide 9 (495 mg, 0.73 mmol, 66%, 86% Purity) as anorange oil.1H^NMR^(400^MHz,^CDCl3) δ 8.49 (t, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 5.6 Hz, 1H), 8.18(s, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 8.9Hz, 2H), 7.28 (d, J = 8.7 Hz, 1H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 3.77 –3.70 (m, 2H), 3.66 – 3.57 (m, 10H). GTM22P01PC119F^NMR^(376^MHz,^CDCl3) δ -62.98 (3F). Step 1 was carried out as in Example 1. Step 2: Preparation of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-methylbutan-1-amine N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-methylbutan-1-amine, a compound having the structure was prepared from 2-((2-chloroethoxy)ethoxy)ethanol and N-butyl(methyl)amine, leading to2-(2-(2-(n-butyl(methyl)amino)ethoxy)ethoxy)ethan-1-ol, in which the hydrogen atom of the hydroxyl group was subsequently replaced by tosyl such as to result in The 4-methylbenzenesulfonate group was then replaced by an azide groups by reacting theintermediate with sodium azide, leading to N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-N- methylbutan-1-amine, which was then reduced with hydrogen to N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-N-methylbutan-1-amine. Step 3: Synthesis of the target compound was then achieved by reacting 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid with N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-N-methylbutan-1-amine: GTM22P01PC1 To a solution of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid 2(103 mg, 1.00 equiv, 229 μmol) in N,N-dimethylformamide (2.29 mL, 0.1 molar) was added 1-hydroxybenzotriazole hydrate (42.1 mg, 1.2 equiv, 275 μmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (52.7 mg, 1.2 equiv, 275 μmol) anddiisopropylethylamine (79.8 μL, 2.0 equiv, 458 μmol). After the addition of a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-methylbutan-1-amine (50.0 mg, 1.0 equiv, 229 μmol) indimethylformamide the mixture was stirred at RT for 16 h. LCMS showed full starting material consumption. The reaction was directly purified by reverse phase chromatography using a 40 g column and a 5-95% gradient of methanol and 0.1% formic acid in water over 20 CV. Upon freeze-drying a N-(2-(2-(2-(butyl(methyl)amino)ethoxy)ethoxy)ethyl)-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide (75 mg, 0.12 mmol, 50%)was obtained as an orange sticky oil.1H^NMR^(400^MHz,^CDCl3) δ 9.37 (s, 1H), 9.14 (s, 1H), 8.37 (dd, J = 7.6, 5.5 Hz, 2H), 7.88 (d, J= 2.6 Hz, 1H), 7.63 (dd, J = 8.8, 2.6 Hz, 1H), 7.55 – 7.45 (m, 3H), 7.32 (d, J = 8.7 Hz, 1H), 6.98(dd, J = 5.6, 2.6 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.65 – 3.50 (m, 8H), GTM22P01PC12.88 (t, J = 5.4 Hz, 2H), 2.77 – 2.62 (m, 2H), 2.49 (s, 3H), 1.53 (tt, J = 8.0, 6.3 Hz, 2H), 1.27 (h, J =7.4 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).19F^NMR^(376^MHz,^CDCl3) δ -62.83 (3F).Example 9: Kinase inhibitionThe compounds prepared according to Examples 1 (E-1), 2 (E-2), and 4 (E-4), which may beconsidered derivatives of sorafenib, and the compound prepared according to Example 6 (E-6), which may be considered a derivative of regorafenib which differs from the latter in thatthe chlorine atom of regorafenib has been replaced by an n-propyl group, were tested for itskinase inhibitory activity. As controls, sorafenib (S) and regorafenib (R) were tested inparallel. The method of this assay is based on the use of radiolabeled [g-33P]ATP. The mechanism ofphosphorylation of a peptide or protein substrate by a kinase is based on the transfer of aphosphate group from ATP onto the peptide or protein substrate. This transfer is catalyzed by the respective kinase. As the radiolabelled phosphate group of ATP can be detected radiometrically, an experimental setup can be devised that allows quantification of the catalytic activity of a specific kinase. For that purpose, a peptide or protein substrate is incubated with a particular kinase and radiolabeled [g-33P]ATP is added. Subsequently, thepositively charged peptides or protein substrates bind to the negatively chargedphotocellulose paper and the amount of 33P incorporated in the respective peptides / target substrates can be detected. The catalytic activity measured in this setup will then be compared to the catalytic activity measured in the presence of a particular kinase inhibitor. The measured difference of incorporation of 33P into the peptides and protein substrates with or without the respectivekinase inhibitor provides a way of quantifying the efficiency of the kinase inhibitor. For allassays, a concentration of 10 uM of the respective kinase inhibitor was used. Initially, the inhibitor is incubated with the kinase and the peptide and protein substrate for 5 minutes. Then [g-33P]ATP is added and incubation occurs at room temperature for 30 minutes. Assays are stopped by addition of 5 µl of 0.5 M (3%) orthophosphoric acid and then harvested onto P81 Unifilter plates with a wash buffer of water. The results are shown in Table 1 below. The numbers represent the mean activity remaining(in %) for the test compounds versus the controls sorafenib and regorafenib, each at a GTM22P01PC1concentration of 10 µM. The percentage expresses the catalytic activity in the presence of therespective inhibitor compared to the catalytic activity of the enzyme in its natural state, i.e. inthe absence of an inhibitor. Table 1Kinase S E-1 E-2 E-3 R E-6MKK1 97±1 100±7 99±8 92±10 104±15 81±10MKK2 118±0 120±27 117±11 45±1 98±4 99±4MKK6 52±7 63±3 68±11 52±6 56±10 49±5ERK1 80±1 86±5 99±6 86±4 78±2 77±16ERK2 105±0 126±6 111±5 107±7 101±3 95±11ERK5 91±21 97±3 92±20 81±5 66±10 76±11JNK1 85±4 89±6 100±7 83±12 61±1 83±14JNK2 26±2 57±11 84±5 79±1 24±1 37±4JNK3 64±8 73±9 73±9 99±5 57±4 71±3p38a MAPK 4±1 5±1 23±1 17±2 17±1 16±5p38b MAPK 4±2 3±3 26±2 90±5 33±4 27±1p38g MAPK 65±5 91±2 94±9 92±1 33±1 68±10p38d MAPK 39±0 84±10 110±5 74±0 33±1 55±3ERK8 7±1 13±3 49±0 42±3 16±0 18±1RSK1 60±1 92±1 86±5 74±6 39±1 45±2RSK2 51±2 110±5 78±4 59±3 53±15 44±13PDK1 69±2 77±2 76±9 91±8 88±2 95±7PKBa 87±3 94±3 95±6 101±2 113±15 92±12PKBb 103±3 102±4 109±13 70±6 89±2 94±9SGK1 123±5 100±6 111±3 98±2 95±4 110±3S6K1 25±1 75±4 93±3 54±8 23±1 22±1PKA 95±11 92±6 100±2 94±8 83±8 73±5 GTM22P01PC1Kinase S E-1 E-2 E-3 R E-6ROCK 2 74±2 89±8 104±11 109±4 85±13 93±9PRK2 89±8 96±3 94±2 17±2 87±6 106±8PKCa 92±6 85±2 81±1 90±13 83±10 106±6PKCγ 106±6 106±5 107±1 78±10 106±9 107±5PKCz 97±9 85±5 106±9 126±6 104±2 95±9PKD1 103±7 91±8 109±3 95±8 86±3 99±12STK33 49±1 69±8 104±9 85±1 95±2 78±2MSK1 81±9 130±6 104±4 101±5 71±4 81±5MNK1 47±8 103±4 85±8 45±0 72±15 92±8MNK2 34±2 48±3 77±3 8±9 121±15 25±1MAPKAP-K2 113±10 79±5 89±1 93±4 89±2 107±3MAPKAP-K3 85±6 91±3 80±4 109±6 68±2 88±5PRAK 92±8 121±14 116±2 106±8 87±0 93±4CAMKKb 46±3 66±1 92±2 73±6 81±9 72±4CAMK1 73±6 82±2 89±6 90±4 66±14 80±9SmMLCK 82±7 82±8 85±13 105±5 113±14 78±4PHK 103±14 130±12 121±5 93±4 95±2 78±2DAPK1 97±0 101±7 101±7 94±2 101±7 94±6CHK1 50±10 92±2 89±0 96±12 88±12 85±9CHK2 87±0 92±1 106±9 111±9 95±6 81±3GSK3b 58±2 81±6 63±9 108±11 70±13 57±4CDK2-Cyclin A 111±7 102±2 105±10 103±11 108±17 112±7CDK9-Cyclin T1 96±9 93±1 96±4 96±11 99±6 100±6PLK1 99±3 104±5 101±0 105±5 72±13 103±1Aurora A 86±1 88±1 107±3 123±15 50±6 66±8Aurora B 14±0 43±3 77±5 45±2 88±3 85±4 GTM22P01PC1Kinase S E-1 E-2 E-3 R E-6TLK1 112±2 112±2 121±2 118±4 100±10 96±3LKB1 84±2 88±12 105±11 115±10 85±5 93±7AMPK (hum) 91±13 88±0 96±7 101±4 104±2 107±12MARK1 99±15 116±15 116±8 95±7 92±1 107±9MARK2 80±3 99±0 95±2 96±3 86±7 78±3MARK3 108±9 101±1 95±7 107±1 94±4 98±5MARK4 81±13 122±13 70±4 82±9 94±10 103±1BRSK1 81±5 89±2 81±8 105±0 107±5 96±4BRSK2 65±12 62±11 68±6 104±7 60±5 57±1MELK 95±7 88±5 91±3 93±10 97±2 79±2NUAK1 71±3 90±4 107±20 95±2 94±2 93±9SIK2 31±9 94±2 115±12 90±2 88±14 93±4SIK3 72±12 91±2 88±3 118±6 90±10 95±8TSSK1 59±3 68±4 86±12 74±6 96±10 94±1CK1γ2 105±2 88±7 107±13 95±5 93±1 90±2CK1δ 108±6 79±3 106±6 107±6 86±4 102±0CK2 106±11 97±4 103±7 83±4 106±8 131±13TTBK1 112±10 109±0 103±7 87±12 104±5 107±11TTBK2 91±15 95±1 99±5 107±15 113±10 113±15DYRK1A 68±6 83±0 82±6 95±3 90±0 94±3DYRK2 51±5 63±1 82±5 86±11 44±2 61±9DYRK3 23±1 54±4 57±14 54±3 32±5 71±6NEK2a 111±6 100±11 119±12 99±9 76±14 77±12NEK6 76±13 63±9 69±15 83±4 88±7 56±11IKKb 89±7 94±1 102±17 119±9 94±12 100±2IKKe 114±3 102±16 114±5 101±10 40±9 73±4 GTM22P01PC1Kinase S E-1 E-2 E-3 R E-6TBK1 89±8 88±1 82±5 101±1 110±6 93±16PIM1 69±1 61±1 76±3 86±13 65±0 79±3PIM2 114±8 104±4 111±0 101±6 86±4 102±0PIM3 86±1 89±4 86±1 98±1 78±3 95±7SRPK1 70±1 73±5 112±1 84±1 67±11 86±5EF2K 104±5 98±5 102±9 97±1 109±5 77±1EIF2AK3 44±3 100±8 103±8 23±6 49±13 18±1HIPK1 20±1 99±11 107±8 63±2 17±1 22±2HIPK2 3±1 23±0 74±10 6±1 9±0 6±5HIPK3 6±1 42±6 74±15 34±1 15±3 15±0CLK2 78±2 98±1 97±3 76±4 71±3 62±6PAK2 97±4 103±14 109±3 86±10 74±7 85±6PAK4 77±2 118±7 135±6 87±1 80±11 87±7PAK5 99±2 92±10 84±1 71±2 101±7 76±1PAK6 102±2 95±5 101±9 89±13 98±1 102±6MST2 49±2 98±1 100±2 45±11 111±1 96±19MST3 94±5 83±7 102±4 62±3 107±4 83±4MST4 90±5 88±6 96±3 85±9 75±2 92±8GCK 29±4 104±10 103±10 58±2 66±0 61±9MAP4K3 5±2 37±6 70±7 33±5 32±6 38±15MAP4K5 13±2 86±3 98±10 56±4 15±3 42±3MINK1 37±1 76±1 90±10 82±6 32±0 56±2MEKK1 57±5 87±0 86±8 96±15 94±0 74±1MLK1 49±4 87±1 104±10 85±2 57±4 67±4MLK3 37±0 80±3 93±1 62±1 86±3 78±0TESK1 30±3 72±1 66±15 44±5 40±9 60±3 GTM22P01PC1Kinase S E-1 E-2 E-3 R E-6TAO1 15±2 69±3 71±13 37±0 41±1 63±3ASK1 96±7 95±0 86±6 93±8 114±8 97±7TAK1 12±2 49±1 88±11 5±1 23±13 20±1IRAK1 18±1 62±9 92±10 43±6 82±10 85±1IRAK4 76±5 119±11 109±26 137±3 105±9 112±4RIPK2 5±2 12±2 82±4 12±0 99±10 113±15OSR1 116±3 121±8 125±13 113±11 85±0 91±7TTK 45±3 67±0 81±14 78±6 84±6 99±5MPSK1 112±1 117±22 113±20 105±3 94±11 77±12WNK1 108±7 113±8 104±6 114±0 97±11 6±3ULK1 79±2 94±8 94±1 75±5 103±2 84±2ULK2 55±4 92±6 97±9 66±1 109±0 103±15TGFBR1 82±12 106±12 81±1 105±1 107±12 69±0Src 19±3 102±11 99±0 4±2 14±1 3±0Lck 17±3 92±1 72±14 19±4 76±8 31±8CSK 39±0 91±14 101±1 114±0 59±7 104±8YES1 13±5 103±6 87±0 11±6 13±2 7±0ABL 12±1 84±6 89±3 11±1 7±2 3±1BTK 74±5 72±4 91±5 67±3 80±10 81±4JAK3 79±2 96±0 115±8 91±1 48±12 66±6SYK 68±6 74±5 77±11 71±3 99±3 49±1ZAP70 95±6 81±6 106±4 101±11 77±10 81±9TIE2 78±6 91±3 96±2 37±5 95±7 83±6BRK 31±3 50±1 70±2 73±0 61±10 80±7EPH-A2 9±0 92±6 98±8 11±0 10±0 7±0EPH-A4 12±2 78±7 99±8 16±1 7±3 5±1 GTM22P01PC1Kinase S E-1 E-2 E-3 R E-6EPH-B1 25±1 89±8 110±15 53±5 37±1 52±1EPH-B2 0±0 44±2 82±8 2±1 3±0 2±0EPH-B3 4±0 78±0 93±5 20±1 5±0 7±1EPH-B4 20±3 112±6 124±10 22±8 58±2 80±10FGF-R1 14±2 69±7 86±15 7±0 55±6 60±1HER4 91±8 103±3 95±1 74±6 128±3 109±8IGF-1R 93±6 92±13 110±1 97±12 68±1 59±2IR 107±9 99±14 91±13 56±4 92±2 77±0IRR 77±8 86±12 95±11 90±2 67±9 78±12TrkA 23±5 64±11 78±9 19±1 81±7 91±9DDR2 4±4 15±4 46±0 2±0 5±2 3±1VEG-FR 26±5 55±1 32±4 31±3 88±1 60±8PDGFRA 14±1 15±1 25±3 73±0 81±7 91±9PINK 113±3 95±1 119±0 95±4 91±15 101±8RET 32±6 38±9 24±6 48±8 39±4 25±1FLT3 14±4 14±3 10±2 98±12 80±1 81±5c-KIT 5±4 4±1 7±5 17±1 48±1 32±1These results indicate the potential usefulness of the exemplified compounds in thetreatment of certain cancers, based on the following observations. Kinases, in particular receptor tyrosine kinases, are central components of numerous key cancer-driving signalling pathways. Therefore, they represent important targets for the development of anticancerdrugs. Because the drug binding pocket of many kinases shows great structural similarity, itis challenging to design compounds that inhibit one particular or a specific set of kinases. Every kinase inhibitor displays its own profile of kinase inhibition. As this profile does not only determine the therapeutic efficacy of a particular kinase inhibitor, but also its profile of adverse effects, the profile of kinase inhibition serves as a crucial fingerprint for each kinase inhibitor. GTM22P01PC1 In principle, a distinction between single-kinase inhibitors and multi-kinase inhibitors can be made. Both categories of drugs have their own advantages and disadvantages. Single-targeted kinase inhibitors are assumed to cause fewer unwanted effects as they specifically target a signalling pathway that is assumed to be involved in the development of a particular disease. However, the pathogenesis of many diseases involves an array of different signalling pathways, which can be better targeted by multi-kinase inhibitors. In addition, most cancer types are heterogeneous illnesses. That means that single-kinase inhibitors might work extremely well for particular patients, but not work at all for others. In contrast a larger group of patients might respond to multi-kinase inhibitors that target a wider network of signalling pathways. Trends in drug development have gone in both directions: developing more selective single- kinase-inhibitors to reduce toxicity and developing broader multi-kinase inhibitors toimprove therapeutic efficacy. Regardless of that, the availability of different kinase inhibitorsdisplaying distinctive profiles of inhibition of kinase targets represents an important gain in any case. Firstly, the extension of the inhibition profile by additional target kinases might improve the therapeutic efficacy of the compound and increase the response rate in a particular population of patients. Secondly, compounds displaying specific profiles of kinase inhibition might also be used to tailor the treatment of particular patients to the genetic profiles of their tumours. And thirdly, the contraction of the inhibition profile by particular kinases might reduce the toxicity experienced by patients. FLt3 is receptor tyrosine kinase that plays a crucial role in cell signalling. Signalling pathwaysmediated by Flt3 have shown to regulate the transcription of genes which are responsible forcell survival, proliferation, and differentiation. It plays a particularly important role in hematopoiesis. Inhibition of FLt3 has been related to the occurrence of a range of side-effects, most importantly the elongation of QT intervals in the electrocardiogram, but also diarrhea and other gastrointestinal adverse reactions, hand-foot syndrome and nausea, and common hematological adverse events such as febrile neutropenia, anemia, and thrombocytopenia. Sorafenib is a strong inhibitor of FLt3, and the elongation of QT-intervals represents a very serious problem for the treatment of patients with kinase inhibitors that are strong inhibitors of Flt3. Therefore, the fact that E3does not show inhibition of Flt3 marks a great advantage over Sorafenib, that could not have been expected based on the structural modification of the derivative. GTM22P01PC1 Janus kinases are members of the tyrosine kinase family that play a key role in conveying extracellular signals into the nucleus, inducing DNA transcription, downstream translation, and the synthesis of effector proteins. The JAK / STAT pathways regulate over 50 cytokines and growth factors and represent a central communication node for the immune system. Inhibition of JAK has been shown to produce a range of side-effects including viral infections such as herpes and influenza, fungal, and mycobacterial infections, musculoskeletal and connective tissue disorders, embolism and thrombosis and neoplasms, especially malignant skin neoplasms and gastrointestinal perforation events. While Sorafenib is a strong inhibitor of Janus kinase 2 (JNK2), E-3 inhibits JNK2 only weakly. Therefore, the derivative might show a markedly better safety profile with respect to viral infections and gastrointestinal perforations compared to Sorafenib, which represents an important advantage that could not been expected based on the structural modification of the derivative. Platelet-derived growth factor receptors (PDGFR)engage a wide range of signalling pathways including, PLC-γ, Src, Akt, MAPK, PI3-kinase, Grb2 / Sos and SHP-2. Stimulation of these signaling pathways leads to transcription of a broad spectrum of genes,including vascular and endothelial growth factor (VEGF) and thrombomodulin. PDGFR playsa key role in embryonic development, healing and cell migration. The inhibition of PDGFR has been shown to lead to a flurry of cardiovascular effects such as contractile abnormalities and microvascular dysfunction. While Sorafenib is a strong inhibitor of PDGFR, E3 inhibits PDGFRonly weakly. Therefore, it can be expected that E-3 might show a markedly better safetyprofile with respect to cardiovascular side-effects compared to Sorafenib, which represents an important advantage that could not been expected based on the structural modification of the derivative. The following examples in the data shown above illustrate the first case, where the extension of the inhibition profile by an additional target kinase might improve therapeutic efficiency. While regorafenib shows no inhibition of MNK2, compound E-6 inhibits the kinase to 25% of its baseline activity. MNK2 has been shown to increase resistance of ovarian cancer bysuppressing autophagy. In addition, Regorafenib shows very little inhibition of the cancerpromoting Lck (76%), while E-6 substantially inhibits the kinase to 31% of its baseline activity. Furthermore regorafenib shows almost no inhibition of Wnk1, while E-6 markedly inhibits the kinase to 6% of its baseline activity. GTM22P01PC1 Examples in the data illustrating the third case, where the contraction of the inhibition profile by particular kinases might reduce the toxicity experienced by patients are the following: While the catalytic activity of the fibroblast growth factor receptor (FGFR) is inhibited bysorafenib down to 14% of its normal activity, inhibition of the kinase by compound E-1 onlyamounts to 69% of its normal activity and inhibition by compound E-2 only to 86%.Furthermore, sorafenib substantially inhibits the Abel kinase down to 12% of its catalyticactivity, inhibition by compound E-1 (84% of its baseline activity) and by compound E-2(89%) are much weaker. In addition, Janus kinase 2 (JNK2) is substantially inhibited by sorafenib (down to 26% of its baseline activity), inhibition of the kinase by compound E-1 (57% of its baseline activity), compound E-2 (84%) and E-3 (79%) are much weaker. In addition, inhibition of Trk2 by sorafenib is substantial (23% of its catalytic activity),inhibition of the kinase by the 3 compounds E-1 (64%), E-2 (78%) and E-3 (19%) is farweaker. As inhibition of all these kinases have been shown to produce adverse effects, it can be expected that a reduced inhibition of them will reduce toxicity of the respective compounds. A good example of such a case is the Abel kinase, the inhibition of which has been shown to lead to considerable cardiovascular toxicities, which often leads to dose reduction, treatment interruption and discontinuation of the respective drugs.Without wishing to be bound by theory, it is suggested that the kinase inhibition profiles arepartly due to a fundamental change in the interaction between the drug compounds and their targets that is caused by the attachment of the alkyl group. It has been shown that compounds which carry alkyl or other hydrophobic groups interact with their respective targets in the plasma membrane in a very different manner than their counterparts that do not carry alkyl or other hydrophobic groups. In the case of compounds without alkyl or other hydrophobic groups, the interaction of the compound with the target receptor can be characterized as a diffusion process in a three-dimensional aqueous space represented by the cytoplasm. In the case of a compound carrying an alkyl or other hydrophobic group, the interaction displays a completely different dynamic. The compound initially hits the plasma membrane in an unspecified area, then bounces off the plasma membrane but remains in close proximity to the membrane because of hydrophobic interactions between the alkyl group and the hydrophobic parts of the lipids of the membrane. After several interactions with unspecified areas of the plasma membrane, the compound then inserts into the lipid bilayer of the plasma membrane and approaches its target through lateral diffusion. Like that, GTM22P01PC1 the three-dimensional approach through diffusion through the cytoplasm in the case of the compound without alkyl group turns into a two-dimensional approach through lateral diffusion through the lipid bilayer in the case of the compound carrying an alkyl group or other hydrophobic group. The two-dimensional lateral diffusion significantly shortens the distance the compound has to travel to reach its target and also positions the compound in a certain way because of the rigidity of the surrounding lipid molecules of the lipid bilayer. This does not only make it more likely for the compound to reach its target within a shorter period of time, but also allows the compound to reach other, allosteric binding sites of thetarget within the lipid bilayer, that are not accessible from the cytoplasm. It is suggested, thatthe changes in the kinase inhibition profile are partly due to the accessibility of these allosteric binding sites through lateral diffusion through the lipid bilayer by the Sorafenib and regorafenib derivatives. Example 10: Further biological profiling Cell Culture, Transfection and Drug Treatments The human cancer cell lines, HepG2 and PLC PRF 5 were maintained in MEM (Invitrogen- Gibco, Carlsbad, CA, USA), HCT116 were grown in RPMI 1640 (Invitrogen-Gibco, Carlsbad, CA, USA) and RPE1 was maintained in DMEM:F12 containing 10% foetal bovine serum, penicillin (50 μg / mL) and streptomycin (100 μg / mL) (Invitrogen-Gibco) at 37 °C in a humidified 5% CO2 incubator. Stock solutions were prepared in DMSO and stored at −20 °C. Unless otherwise indicated, the following compounds were added to cells for 4 h: sorafenib and its derivatives (500 nM); regorafenib and its derivatives (20 nM); the compounds were diluted in a fresh media before each experiment and the final concentration of DMSO was <0.1%. Cell Viability Assay Cells were seeded in a complete growth medium in 96-well plates at 3 × 103cells per well. After 24 h, the cells were incubated with sorafenib and its derivatives or regorafenib and its derivatives or DMSO in the presence of 10% of FBS. After 72 h of treatment, cell viability was determined using the CellTiter-Glo®Luminescent Cell Viability Assay (Promega, Madison, WI, USA). The half-maximal inhibitory concentration (IC50) values were calculated from dose- response curves in the Prism 9.0 software (GraphPad, San Diego, CA, USA). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) cytotoxicity assay is based on the metabolic transformation of MTT to formazan by metabolically active cells. It therefore represents a colorimetric-based measurement of induction of cell death by GTM22P01PC1 anticancer drugs. MTT-assays carried out with the Sorafenib derivative (E-3) yielded an inhibitory concentration of the compound required to reduce the number of cells by 50%(IC50) of 1.6 uM for the E-3 and 15.0 uM for Sorafenib. An almost 10-fold reduction in IC50seen for E-3 is a clear indicator for a significantly superior potency of the derivativecompared to Sorafenib which represents a novelty that cannot be anticipated and expected based on the structural modification of the derivative. Apoptosis Assay Annexin V apoptosis assay (FITC Annexin V, Biolegend) was performed according to manufacturer’s instructions. Cells seeded in 6-well plates were treated either with each compound for 48 h. HCT116 cells were harvested and collected by centrifugation. About 5 × 105cells were incubated in 100 µL Annexin binding buffer, 5 µL Annexin V-FITC and 10 µL propidium iodide (PI) for 15 min on ice. Samples were kept in the dark and diluted in a further 400 µL Annexin binding buffer before analysis by flow cytometry. Samples were processed on a CytoFLEX S flow cytometer (Beckman Coulter) and analysed using Kaluza (Beckman Coulter). Table 2 shows the compounds that were tested. Table 2Code Category CompoundDMSO Control DMSOS Control SorafenibR Control RegorafenibE-3 Sorafenib derivative Compound according to Example 3E-4 Regorafenib derivative Compound according to Example 4E-5 Regorafenib derivative Compound according to Example 5E-6 Regorafenib derivative Compound according to Example 6E-7 Sorafenib derivative Compound according to Example 7E-8 Sorafenib derivative Compound according to Example 8 GTM22P01PC1Three series (series 1, 2 and 3) of Annexin V apoptosis assays with HCT116 cells wereconducted with the compounds of Table 2. The percentages of apoptotic cells after the respective treatment cycles are provided in Tables 3 to 5 below.Table 3: Annexin V apoptosis assay series 1 - alive and apoptotic HCT116 cells [%]Compound Alive ApoptoticEarly Late Dead or dead apoptotic apoptotic DMSO 93.3 6.7 0.7 2.1 3.9E-4 92.5 7.5 0.5 2.1 5.0E-5 89.5 10.5 0.7 3.3 6.5E-6 75.8 24.2 0.3 5.1 18.9R 72.7 27.3 2.4 12.6 12.3E-3 80.0 20.0 0.8 4.9 14.3E-7 42.2 57.8 20.2 25.1 12.5E-8 92.5 7.6 1.1 2.9 3.5Table 4: Annexin V apoptosis assay series 2 - alive and apoptotic CT116 cells [%]Compound Alive ApoptoticEarly Late Dead or dead apoptotic apoptotic DMSO 92.46 7.5 1.85 3.39 2.3E-4 86.23 13.8 2.03 6.81 4.93E-5 86.99 13.0 2.33 5.57 5.11E-6 66.49 33.5 4.25 14.98 14.28R 81.07 18.9 2.02 10.44 6.47E-3 81.58 18.4 3.01 7.75 7.66E-7 50.27 49.7 19.54 24.88 5.31E-8 83.94 16.1 2.59 7.49 5.98 GTM22P01PC1Table 5: Annexin V apoptosis assay series 3 - alive and apoptotic HCT116 cells [%]Compound Alive ApoptoticEarly Late Dead or dead apoptotic apoptotic DMSO 90.52 9.48 1.35 3.81 4.32E-4 81.57 18.43 2.47 7.41 8.55E-5 89.77 10.23 1.68 4.1 4.45E-6 66.86 33.14 2.56 13.22 17.36R 77.81 22.19 1.83 14.48 5.88E-3 74.58 25.42 7.13 11 7.29E-7 69.73 30.27 8.04 16.64 5.59E-8 86.99 13.01 1.91 5.02 6.08S 84.83 15.17 7.61 5.99 1.57The displayed data clearly shows that the apoptotic effect of numerous derivatives of regorafenib and sorafenib is markedly superior compared to that of regorafenib and sorafenib. As it is a key feature of cancer cells to develop mechanisms to evade apoptosis and the ability of inducing apoptosis is an important feature of anticancer drugs. Therefore the data displayed here further corroborates the fact that the derivatives display markedly superior characteristics and therefore represent a genuine progress and innovation in comparison to the respective mother substances. Clonogenic assays Cells were seeded in 6 well dishes and drugs described added the following day for 24 hours. 300 live cells were then seeded into 6 well dishes in triplicate and left to grow for 10-14 days or until colonies of 50 or more cells were visible. Wells were washed with H2O and fixed in 100% methanol for 2 minutes. Colonies were then stained with 0.5% crystal violet (Sigma) for 1 and left to air dry before being counted. To calculate the plating efficiency (PE) of each treatment, the following calculation was used: ^^ = ^^^^^^^ ^^^^^^ ^^ ^^^^^^^^ ^^^^^^^^^^^^^ ^^ ^^^^^ ^^^^^^ ^ 100Using the PE for each treatment, the surviving fraction (SF) was calculated using the following equation: GTM22P01PC1 ^^ = ^^ ^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^ 100Various compounds according to the present disclosure were tested in the clonogenic assay, including the compounds of Examples 1, 2, 3, 7 and 8 (E-1 etc.). As controls, dimethyl sulfoxide (DSMO) and sorafenib (S) were included. For each compound, as dose of 3 µM was applied for 48 h. The clonogenic duration was 12 days. The results are depicted in Figures 1 and 2. The clonogenic assay is a long established and widely used method to analyse the efficacy of drugs to inhibit the ability of cancer cells to survive and reproduce to form colonies. As thedata generated for a range of sorafenib derivatives in HCT116 cells shows, numerousderivatives of sorafenib display a markedly superior efficacy in inhibiting the ability of HCT116 cells to survive, reproduce and form colonies. In addition, the data displayed matches very well the data obtained for the respective compounds in cytotoxicity assays. This corroborates the reliability and validity of the data obtained in these two assays, which represent crucial cornerstones of the preclinical development of anticancer drugs. The clonogenic assay represents the gold standard for measuring how cancer cells retain their ability to reproduce and form colonies over a prolonged period of time. Subjecting these cancer cells to particular cancer drugs makes it possible to assess the impact of the respectivedrug on these important features of cancer cells. The ability of cancer cells to form coloniesover longer periods of time is a particularly crucial feature as it resembles to some extent the formation of tumour relapses after treatment and the development of resistances againstspecific drugs. It also sheds light on the cytotoxic efficacy of the respective compounds onphenotypes of the cancer cells that might require multiple rounds of cell division to emerge. In the light of that, the clonogenic assay ideally complements the MTT cytotoxicity data which reflects the cytotoxic effect that a particular drug exerts on a specific cell line at a specific endpoint. The clonogenic data displayed here perfectly matches the cytotoxicity data obtained for the respective compounds and therefore serves as robust corroboration of the efficacy of theSorafenib derivates to stop growth, proliferation and colony formation of HCT116 cancercells. GTM22P01PC1 Inhibition^of^PKB / Akt^pathway^demonstrated^by^means^of^Western^blots The PI3K / Akt / mTOR pathway cascade is a key signalling pathway that is over-activated in most cancer types. This leads to the carcinogenesis, proliferation, invasion, metastasis, and drug resistance of tumour cells. Notably it promotes survival of cancer cells and their escape from apoptosis, and also promotes normal and tumour angiogenesis. Importantly, Sorafenib has been shown to stimulate the PI3K / Akt / mTOR pathway, which counters its antiproliferative effects. The results are shown in Figure 3, the Sorafenib derivative (E-3) strongly suppresses the PI3K / Akt / mTOR pathway, which explains its more potent cytotoxic effects observed in cancer cell. This effect is remarkable and can by no means be anticipated and expected based on the structural modification of the derivative. Immunofluorescence^imaging^of^phospholipase^C^gamma^2 Immunofluorescence microscopy carried out with the Sorafenib derivative E-3, Sorafenib and a neutral negative control analysed the effect of the various compounds on phospholipase C gamma 2. The results are shown in Fig.4. The distribution patterns of phospholipase C gamma 2 in the images taken with the various compounds clearly indicated that phospholipase C gamma 2 is localised at the plasma membrane after treatment with E-3 while phospholipase C gamma 2 is evenly distributed across the whole cells in cells treated with Sorafenib and the negative control. This observation suggests that binding of E-3 by phospholipase C gamma 2 directs phospholipase C gamma 2 to the plasma membrane. This effect can by no means be expected based on the structural modification of the derivative and therefore clearly constitutes a novelty of the derivative. Impact^of^increased^lipophilicity^on^tissue^distribution Sorafenib and E1 both display very high plasma protein binding of around 99%. E1 shows a significantly higher volume of distribution than Sorafenib. With administration of 5mg / kg the volume of distribution observed for Sorafenib is 0.68 L / kg, while it is 3 L / kg for E1. Thesignificantly better penetration of tissues observed for E3 is most likely a consequence of theincreased lipophilicity of E3 caused by the attachment of the alky group. Lipophiliccompounds can pass more efficiently through plasma membranes and can therefore GTM22P01PC1penetrate tissues more effectively than hydrophilic substances. Therefore, the attachment ofalkyl groups does not only serve the direction of compounds towards the plasma membrane in target tissues but also the enhancement of tissue distribution of the respective compoundsand therefore an increase in the volume of distribution observed for the respectivecompounds. This has a great impact on the exposure of the tumour towards the drug and therefore significant clinical implications

Claims

1. GTM22P01PC1 Claims1. A compound of formula I:wherein -one of R1 and R2 represents a lipophilic targeting moiety having affinity to a cellmembrane; -the other one of R1 and R2 is hydrogen, methyl or chlorine;- R3 is hydrogen or fluorine;or a stereoisomer or salt thereof; whereinR1 is a linear alkyl group with 3 to 11 carbon atoms, R2 is chlorine, and R3 is hydrogen or fluorine; or R1 is methyl, R2 is a linear alkyl group with 3 to 11 carbon atoms, and R3 is hydrogen or fluorine; or the lipophilic targeting moiety is a linear or branched chain structure represented by the formula -[CH2-CH2-O]x-CH2-CH2-R4, wherein x is an integer from 1 to about 10, and wherein R4is optionally selected from hydroxyl or primary, secondary or tertiary amino groups.

2. The compound of claim 1, wherein the lipophilic targeting moiety does not cause aninferior inhibition of raf-kinase compared to a compound having substantially the same formula except that R1 is methyl and R2 is chlorine.

3. The compound of claim 1 or 2, wherein the lipophilic targeting moiety comprises ahydrocarbon chain having a length defined by an uneven number of carbon atoms inthe range from 3 to 11.

4. The compound of claim 3, wherein the hydrocarbon chain is saturated and / or linear.

5. The compound of claim 3 or 4, wherein R1 is a linear alkyl group with 3 to 11 carbonatoms, R2 is chlorine, and R3 is hydrogen or fluorine.GTM22P01PC16. The compound of claim 3 or 4, wherein R1 is methyl, R2 is a linear alkyl group with 3 to11 carbon atoms, and R3 is hydrogen or fluorine.

7. The compound of claim 5 or 6, wherein the linear alkyl group is n-propyl or n-octyl.

8. The compound of claim 1 or 2, wherein the lipophilic targeting moiety is a linear orbranched chain structure represented by the formula -[CH2-CH2-O]x-CH2-CH2-R4, wherein x is an integer from 1 to about 10, and wherein R4 is optionally selected fromhydroxyl or primary, secondary or tertiary amino groups.

9. The compound of any one of claims 3 to 8, wherein the lipophilic targeting moietyfurther comprises a group selected from a fatty acyl group, an alkoxy group and an alkyl amino group, and wherein the hydrocarbon chain forms part of the fatty acyl group, the alkoxy group, or the alkyl amino group.

10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9and at least one pharmaceutically acceptable carrier or excipient.

11. The compound of any one of claims 1 to 9 or the pharmaceutical composition of claim10 for use as a medicament.

12. The compound or composition for use according to claim 11, wherein the medicamentis for the treatment of a subject having been diagnosed with cancer.

13. The compound or pharmaceutical composition for use according to claim 12, whereinthe cancer is a kinase-mediated cancer.

14. A method for treating cancer in a subject in need thereof, comprising the step ofadministering to the subject a therapeutically effective amount of the compound of anyone of claims 1 to 9 or the pharmaceutical composition of claim 10.

15. Method for the preparation of a compound according to formula I wherein R1represents the lipophilic targeting moiety, R2 is chlorine and R3 is hydrogen or fluorine, said method comprising the steps of: (a) hydrolysing a compound of formula II:GTM22P01PC1such as to obtain a compound of formula III:and (b) reacting the compound of formula III with a compound R1-NH2 such as toobtain said compound according to formula I.

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