WO2025157389A1 - Combinations of halogenated heterocyclic kinase inhibitors and vegfr inhibitors - Google Patents

Abstract

The present invention relates to combination therapies useful for the treatment of proliferative disorders such as cancer diseases. In particular, the invention relates to compounds and compositions useful as a combination therapy which comprises an specific halogenated heterocyclic kinase inhibitor and an inhibitor of the vascular endothelial growth factor receptor (VEGFR) pathway.

Description

COMBINATIONS OF HALOGENATED HETEROCYCLIC KINASE INHIBITORS AND VEGFR INHIBITORS DESCRIPTION_{[1] The present invention relates to combination therapies useful for the treatment of proliferative disorders such} as cancer diseases. In particular, the invention relates to compounds and compositions useful as a combination therapy which comprises an specific halogenated heterocyclic kinase inhibitor and an inhibitor of the vascular endothelial growth factor receptor (VEGFR) pathway._{[2] Protein tyrosine kinases have been identified as crucial targets in the therapeutic treatment of cancer. Growth} factor ligands and their respective receptor tyrosine kinases are required for tumor angiogenesis and growth. Vascular_{endothelial growth factor (VEGF) is a critical component in the process leading to the branching, extension, and survival} of endothelial cells forming new blood vessels during angiogenesis. Unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer_{(including solid tumors) Folkman, Nature Med., 1, 27-31 (1995). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein} produced by normal cell lines and tumor cell lines. It is an endothelial cell-specific mitogen, shows angiogenic activity in in vivo test systems, e. g. , rabbit cornea, is chemotactic for endothelial cells and monocytes, and induces plasminogen activators in endothelial cells, which are then involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as placenta growth factor and VEGF-C. VEGF receptors are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e. g., VEGFR-1, VEGFR-2 and VEGFR-3._{[3] Vascular endothelial growth factor receptor (VEGFR) inhibitors have been approved for the treatment of} various types of cancer, including advanced and metastatic renal-cell carcinoma, gastrointestinal stroma! tumors and hepatocellular carcinoma, and continue to be investigated in the clinical setting. It has been proposed that the efficacy of such inhibitors might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune enhancing agents._{[4] SIK3 is an intracellular serine/threonine kinase belonging to the AMPK superfamily. Salt-inducible kinases} (SIKs) constitute a serine tyrosine kinase subfamily, belonging to the adenosine monophosphate-activated kinase (AMPK) family. Three members (SIK1, -2, and -3) have been identified so far. Amino acid homology of SIK1 with SIK2 and SIK3 is 78% and 68%, respectively, in the kinase domain. The cloning of SIK1 (also known as SIK and SNF1LK), abundantly expressed in the adrenal glands of high-salt, diet-fed rats, led to subsequent cloning of SIK2 (also known as QIK, KIAA0781 and SNF1LK2), mainly expressed in adipose tissues and the rather ubiquitous SIK3 (also known as QSK, KIAA0999 or L19) (Katoh et al. 2004, Mol. Cell. Endocrinol. 217:109). The three SIKs have a similar structure, with an N-terminal kinase domain (catalytic domain), a middle ubiquitin-associated domain (believed important for phosphorylation by LKB1) and a long C-terminal sequence (believed to be a site for further phosphorylation by PKA). However, there are very diverse roles implicated for the various SIKs. For example, various SIKs have been implicated in biological processes as diverse as osteocyte response to parathyroid hormone (Wein et al. 2016, Nature Commun. 7:13176) to induction of SIK1 by gastrin and inhibition of migration of gastric adenocarcinoma cells (Selvik et al.2014, PLoS ONE 9:ell2485). Other potential roles of salt-inducible kinases (in particular SIK3), described in WO2018/193084A1 (to the present applicant, and published 25-Oct-2018), are furthermore that SIK3 is involved in tumour cell resistance to cell-mediated immune responses, in particular tumour cell resistance to TNF._{[5] As well as playing a role in various inflammatory responses (Clark et al 2014; Sundberg et al 2016) andoncology - especially the sensitisation of tumour cells to immune responses (WO2018/193084A1) - it has been known} since 2011 that inhibition of SIK2 promotes melanogenesis in B16F10 melanoma cells (Kumagai et al 2011, PLoS ONE 6(10): e26148). It was subsequently described that the pigmentation pathway including in human skin explants can_{be efficaciously induced by (topical) treatment with SIK inhibitors, including those structurally related to YKL-05-099} (Mujahid et al 2017, Cell Reports 19:2177). Indeed, using such results, it has subsequently been sought to claim methods of increasing (the appearance of) skin pigmentation in a subject by administering topically to the subject skin_{an effective account of a SIK inhibitor (WO2018/160774), including using kinase inhibitors previously known to be SIK} inhibitors (W02016/023014)._{[6] Using a high-throughput genetic screening platform (Khandelwal et al, 2015; EMBO molecular medicine 7:450)} the applicants have previously reported on the novel role of SIK3 in conferring TNF resistance to tumour cells (WO2018/193084A1; Michels et al, 2019; Abstract A184 CICON, Paris 25-28 September 2019). SIK3 mediates this effect by retaining HDAC4 in the cytoplasm via direct phosphorylation, which MHC potentiates the nuclear activity of pro-tumorigenic transcription factor NFKB in response to TNF._{[7] Current methods of cancer treatment are not selective enough. Surgery removes the diseased tissue;} radiotherapy shrinks solid tumors; and chemotherapy kills rapidly dividing cells. Chemotherapy, in particular, results in numerous side effects, in some cases so severe as to limit the dosage that can be given and thus preclude the use of potentially effective drugs. Moreover, cancers often develop resistance to chemotherapeutic drugs. Thus, there is an urgent need for specific and more effective cancer therapies. SUMMARY OF THE INVENTION_{[8] Generally, and by way of brief description, the main aspects of the present invention can be summarised as} follows:_{[9] In a first aspect the invention provides a compound or composition for use in a treatment of a proliferative} disorder in a subject, wherein the compound or composition is a combination of: (_{i) A kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A,_{and E are as in WO 2021/214117; and (ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor.[10] In a second aspect, the present invention provides a compound or composition for use in a treatment of a} proliferative disorder in a subject, wherein the compound or composition is a kinase inhibitor according to formula (Ia) and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117; wherein the treatment comprises a sequential or concomitant administration of the kinase inhibitor with a VEGFR signalling inhibitor to the subject._{[11] In a third aspect, the present invention provides a compound or composition for use in a treatment of a} proliferative disorder in a subject, wherein the compound or composition is a VEGFR signalling inhibitor, and wherein the treatment comprises a sequential or concomitant administration of the VEGFR signalling inhibitor with a kinase inhibitor to the subject; wherein the kinase inhibitor is a compound according to formula (Ia) 2 and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117._{[12] In a fourth aspect, the present invention provides a pharmaceutical composition, comprising: (i) A kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117; and (_{ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor.[13] In a fifth aspect, the present invention provides a method for treating a proliferative disease in a subject,} the method comprising administering to the subject a combination therapy which comprises a kinase inhibitor and a_{VEGFR signalling inhibitor, wherein the kinase inhibitor is a compound according to formula (Ia):} 2_{[14] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers,} enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117._{[15] In a fifth aspect, the present invention provides a pharmaceutical kit which comprises a first container, a} second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a kinase inhibitor as recited in any one of the preceding claims, the second container comprises at least one dose of a medicament comprising a VEGFR signaling inhibitor, and the package insert comprises instructions for treating a subject for a proliferative disorder the medicaments BRIEF DESCRIPTION OF THE FIGURES_{[16] The figures show:[17] Figure 1: depicts tumor growth inhibition (A) and survival (B) of kinase inhibitor compound E9 in PD-1} resistant syngeneic RCC RENCA tumor model. X-axes: day after start of therapy; Y-axes = (A) tumor volume (mm³) and (B) % survival; a = vehicle; b = mIgG1e control; c = anti-PD-1; d = compound E9 5mg/kg; e = compound E9 12.5mg/kg; f = compound E925mg/kg._{[18] Figure 2: depicts tumor growth inhibition of kinase inhibitor compound E9 in RCC PDX model CTG-1529} model. X-axis: day after start of therapy; Y-axes = tumor volume (mm³); a = vehicle; b = E950mg/kg; T = treatment break._{[19] Figure 3: depicts tumor growth inhibition (A) and survival (B) in combination studies of kinase inhibitorcompound E9 with VEGFR2 targeting (Axitinib) therapy in RENCA tumor studies X-axes: day after start of therapy; Y-} axes = (A) tumor volume (mm³) and (B) % survival; a = vehicle; b = Axitinib 5mg/kg; c = Axitinib 12.5mg/kg; d = compound E9 50mg/kg; e = compound E9 50mg/kg + Axitinib 5mg/kg; f = compound E9 50mg/kg + Axitinib 12.5mg/kg. D_{ETAILS OF THE PRESENT INVENTION[20] The present invention, and particular non-limiting aspects and/or embodiments thereof, can be described in} more detail as follows._{[21] Although the present invention may be further described in more detail, it is to be understood that this} invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by what is described, defined or otherwise disclosed herein, in particular in any itemised embodiments or the appended claims._{[22] Herein, certain elements of the present invention are described in more detail. These elements are listed with} specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description of this application should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application_{unless the context indicates otherwise. For example, if in one embodiment of the compound of the invention L is a} bond and in another embodiment of the compound of the invention R³ is H, then in a preferred embodiment of the compound of the invention, L is a bond and R³ is H, or if in one embodiment of the use of a compound of the invention the subject is an adult human and in another embodiment of the use of a compound of the invention the proliferative disorder is prostate cancer, then in a preferred embodiment of the use of a compound of the invention, the subject is an adult human and the proliferative disorder is prostate cancer. General definitions_{[23] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly} understood by one of ordinary skill in the art._{[24] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological} terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B. Nagel, and H. Kölbl, Eds., Helvetica Chimica Acta, CH- 4010 Basel, Switzerland, (1995)._{[25] The practice of the present invention will employ, unless otherwise indicated, conventional methods of} chemistry, biochemistry, and recombinant DNA techniques which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 2^nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989)._{[26] Throughout this specification and the claims which follow, unless the context requires otherwise, the word} "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term "consisting essentially of" means excluding other members, integers or steps of any essential significance or group of members, integers or steps of any essential significance. For example, a pharmaceutical composition consisting essentially of the members/components as defined herein (such as a compound as defined in any of the aspects of the invention and optionally one additional therapeutic agent) would exclude further therapeutic agents (besides the compound as defined in any of the aspects of the invention and the optional one additional therapeutic agent) but would not exclude contaminants (e.g., those from the isolation and purification method) in trace amounts (e.g., the amount of the contaminant (preferably the amount of all contaminants present in the composition) is less than 5% by weight, such as less than 4% by weight, 3% by weight, 2% by weight, 1% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.05% by weight, with respect to the total composition) and/or pharmaceutically acceptable excipients (such as carriers, e.g., phosphate buffered saline, preservatives, and the like). The term "consisting of" means excluding all other members, integers or steps of significance or group of members, integers or steps of significance. For example, a pharmaceutical composition_{consisting of the members/components as defined herein (such as a compound as defined in any of the aspects of the} invention, one excipient, and optionally one additional therapeutic agent) would exclude any other compound (including a second or further excipient) in an amount of more than 2% by weight (such as any other compound in an amount of more than 1% by weight, more than 0.5% by weight, more than 0.4% by weight, more than 0.3% by weight, more than 0.2% by weight, more than 0.1% by weight, more than 0.09% by weight, more than 0.08% by weight, more_{than 0.07% by weight, more than 0.06% by weight, more than 0.05% by weight, more than 0.04% by weight, more} than 0.03% by weight, more than 0.02% by weight, more than 0.01% by weight) with respect to the total composition. The term "comprising" encompasses the term "consisting essentially of" which, in turn, encompasses the term "consisting of". Thus, at each occurrence in the present application, the term "comprising" may be replaced with the term "consisting essentially of" or "consisting of". Likewise, at each occurrence in the present application, the term "consisting essentially of" may be replaced with the term "consisting of"._{[27] Where used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or} components with or without the other. For example, “X and/or Y” is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein._{[28] In the context of the present invention, the terms “about” and “approximately” are used interchangeably and} denote an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect._{[29] The terms "a", "an" and "the" and similar references used in the context of describing the invention (especially} in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context._{[30] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring} individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein._{[31] All methods described herein can be performed in any suitable order unless otherwise indicated herein or} otherwise clearly contradicted by the context._{[32] The use of any and all examples, or exemplary language (e.g., "such as"), provided herein is intended merely} to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention._{[33] Several documents are cited throughout the text of this specification. Each of the documents cited herein} (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.),_{whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an} admission that the invention is not entitled to antedate such disclosure by virtue of prior invention._{[34] The terms “of the [present] invention”, “in accordance with the [present] invention”, “according to the} [present] invention” and the like, as used herein are intended to refer to all aspects and embodiments of the invention described and/or claimed herein._{[35] It is to be understood that the application of the teachings of the present invention to a specific problem or} environment, and the inclusion of variations of the present invention or additional features thereto (such as further aspects and embodiments), will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein._{[36] Unless context dictates otherwise, the descriptions and definitions of the features set out above or below are} not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments that are described._{[37] "Polymorphism" as referred to herein means that a solid material (such as a compound) is able to exist in} more than one form or crystalline structure, i.e., "polymorphic modifications" or "polymorphic forms". The terms "polymorphic modifications", "polymorphic forms", and "polymorphs" are used interchangeable in the present invention. According to the present invention, these "polymorphic modifications" include crystalline forms, amorphous forms, solvates, and hydrates. Mainly, the reason for the existence of different polymorphic forms lies in the use of different conditions during the crystallization process, such as the following: ^ _{solvent effects (the packing of crystal may be different in polar and nonpolar solvents); ^ certain impurities inhibiting growth pattern and favor the growth of a metastable polymorphs; ^ the level of supersaturation from which material is crystallized (in which generally the higher the concentration} above the solubility, the more likelihood of metastable formation); ^ _{temperature at which crystallization is carried out; ^ geometry of covalent bonds (differences leading to conformational polymorphism); ^ change in stirring conditions.[38] Polymorphic forms may have different chemical, physical, and/or pharmacological properties, including but} not limited to, melting point, X-ray crystal and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compactability, and bioavailability. Polymorphic forms may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. According to Ostwald’s rule, in general it is not the most stable but the least stable polymorph that crystallizes first. Thus, quality, efficacy, safety, processability and/or manufacture of a chemical compound, such as a compound of the present invention, can be affected by polymorphism. Often, the most stable polymorph of a compound (such as a compound of the present invention) is chosen due to the minimal potential for conversion to another polymorph. However, a polymorphic form which is not the most stable polymorphic form may be chosen due to reasons other than stability, e.g. solubility, dissolution rate, and/or bioavailability._{[39] The term "crystalline form" of a material as used herein means that the smallest components (i.e., atoms,} molecule or ions) of said material form crystal structures. A "crystal structure" as referred to herein means a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid and is characterized by a pattern, a set of atoms arranged in a particular manner, and a lattice exhibiting long-range order and symmetry. A lattice is an array of points repeating periodically in three dimensions and patterns are located upon the points of a lattice. The subunit of the lattice is the unit cell. The lattice parameters are the lengths of the edges of a unit cell and the angles between them. The symmetry properties of the crystal are embodied in its space group. In order to describe a crystal structure the following parameters are required: chemical formula, lattice parameters, space group, the coordinates of the atoms and occupation number of the point positions._{[40] The term "amorphous form" of a material as used herein means that the smallest components (i.e., atoms,} molecule or ions) of said material are not arranged in a lattice but are arranged randomly. Thus, unlike crystals in_{which a short-range order (constant distances to the next neighbor atoms) and a long-range order (periodical repetition} of a basic lattice) exist, only a short-range order exists in an amorphous form._{[41] The term "complex of a compound" as used herein refers to a compound of higher order which is generated} by association of the compound with one or more other molecules. Exemplary complexes of a compound include, but are not limited to, solvates, clusters, and chelates of said compound._{[42] The term "solvate" as used herein refers to an addition complex of a dissolved material in a solvent (such as} an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A "hydrate" is a solvate wherein the solvent is water._{[43] In isotopically labeled compounds one or more atoms are replaced by a corresponding atom having the same} number of protons but differing in the number of neutrons. For example, a hydrogen atom may be replaced by a deuterium atom. Exemplary isotopes which can be used in the compounds of the present invention include deuterium,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³²P,³²S,³⁵S,³⁶Cl, and¹²⁵I._{[44] The expression "amino protecting group" as used herein preferably refers to any group by which an amino} group contained in a compound can be transferred into a less reactive (i.e., protected) amino group. Preferably, amino protecting groups can be incorporated into the corresponding compound under mild conditions, in a chemoselective and/or regioselective manner, and/or in good yields. Furthermore, the amino protecting groups should be stable under the conditions to which the protected compound is to be subjected (e.g., the conditions of the desired reaction and/or purification conditions). Preferably, the amino protecting groups should minimize the risk of racemization of a_{stereogenic center, when present in the compound. In one embodiment, the amino protecting groups should beremovable from the protected compound under mild conditions and in a selective manner such that the deprotectedcompound is obtained in high yields. Exemplary amino protecting groups include tert-butyloxycarbonyl (BOC), 9-} fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (trityl; Tr), toluenesulfonyl (tosyl; Ts), para- bromophenylsulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrophenylsulfenyl (Nps)._{[45] The term "half-life" relates to the period of time which is needed to eliminate half of the activity, amount, or} number of molecules. In the context of the present invention, the half-life of a compound disclosed herein (eg a_{compound of formula (Ia), (Ib) or (Ic)) is indicative for the stability of said compound.[46] The terms “subject", "patient", "individual", or "animal" relate to multicellular animals, such as vertebrates.} For example, vertebrates in the context of the present invention are mammals, birds (e.g., poultry), reptiles, amphibians, bony fishes, and cartilaginous fishes, in particular domesticated animals of any of the foregoing as well as_{animals (in particular vertebrates) in captivity such as animals (in particular vertebrates) of zoos. Mammals in the} context of the present invention include, but are not limited to, humans, non-human primates, domesticated mammals, such as dogs, cats, sheep, cattle, goats, pigs, horses etc., laboratory mammals such as mice, rats, rabbits, guinea pigs, etc. as well as mammals in captivity such as mammals of zoos. The term "animal" as used herein also includes humans. Particular non-limiting examples of birds include domesticated poultry, and include birds such as chickens, turkeys, ducks, geese, guinea fowl, pigeons, pheasants etc.; while particular non-limiting examples of bony or cartilaginous fish include those suitable for cultivation by aquiculture, and include bony fish such as salmon, trout, perch, carp, cat-fish, etc._{[47] In a first aspect the invention provides a compound or composition for use in a treatment of a proliferative} disorder in a subject, wherein the compound or composition is a combination of: (_{i) A kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117; and_{(ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor.[48] In a second aspect, the present invention provides a compound or composition for use in a treatment of a} proliferative disorder in a subject, wherein the compound or composition is a kinase inhibitor according to formula (Ia) 2 and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117; wherein the treatment comprises a sequential or concomitant administration of the kinase inhibitor with a VEGFR signalling inhibitor to the subject._{[49] In a third aspect, the present invention provides a compound or composition for use in a treatment of a} proliferative disorder in a subject, wherein the compound or composition is a VEGFR signalling inhibitor, and wherein the treatment comprises a sequential or concomitant administration of the VEGFR signalling inhibitor with a kinase inhibitor to the subject; wherein the kinase inhibitor is a compound according to formula (Ia) 2 and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117._{[50] In an alternative aspect of the invention relating to the mentioned first, second and thirs aspect, the invention} provides a use of the above compound or composition for the manufacture of a medicament for the treatment of a_{tumour in a subject, wherein the subject or tumour is resistant to a treatment with a VEGFR signalling inhibitor, or} wherein the subject was treated previously with an VEGFR signalling inhibitor, and wherein the tumour is recurrent. In_{this alternative aspect the compound or composition is as defined in the first, second or third aspect.[51] In a further alternative aspect there is provided a method for treating a tumour disease in a subject, wherein} the subject or tumour is resistant to a treatment with an VEGFR signalling inhibitor; or wherein the subject was treated previously with an VEGFR signalling inhibitor, and wherein the tumour is recurrent; wherein the method comprises a step (i) or (ii): (_{i) administration of a therapeutically effective amount of a composition which comprises the VEGFR signalling inhibitor and the kinase inhibitor to the subject; or (ii) administration of a therapeutically effective amount of a kinase inhibitor to the subject, and wherein the} treatment further comprises a simultaneous, separate or sequential administration of an VEGFR signalling inhibitor._{[52] The invention surprisingly identified an advantageous inhibitory profile of the kinase inhibitor according to} formula (Ia) in respect of components of the VEGF pathway which translated into a surprisingly beneficial therapeutic_{effect in vivo when combining the kinase inhibitor with a VEGFR signalling inhibitor according to the definitions herein.The invention may relate to a coadministration of VEGFR inhbitors and kinase inhibitors of the invention. As used herein} the term “co-administering” as used herein means a process whereby the combination of the VEGFR signalling inhibitor_{and the kinase inhibitor of the invention is administered to the same patient. The kinase inhibitor and the VEGFRsignalling inhibitor may be administered simultaneously, at essentially the same time, or sequentially. kinase inhibitor} and the VEGFR signalling inhibitor need not be administered by means of the same vehicle. The kinase inhibitor and the VEGFR signalling inhibitor may be administered one or more times and the number of administrations of each component of the combination may be the same or different. In addition, the kinase inhibitor and the VEGFR signalling inhibitor need not to be administered at the same site, not by the same route._{[53] As used herein, the term “therapeutically effective” in context of a combination of the invention as used herein} refers to an amount or dose of an kinase inhibitor together with the amount or dose of the VEGFR signalling inhibitor that is sufficient to treat the disease, especially cancer. More preferably, the therapeutically effective in certain_{embodiments shall refer to an amount of VEGFR signalling inhibitor and Kinase inhibitor that elicits a synergistictherapeutic effect. The amount of the Kinase inhibitor in a given therapeutically effective combination may be different} for different individuals and different tumor types, and will be dependent upon the one or more additional agents or_{treatments included in the combination. The “therapeutically effective amount” is determined using procedures} routinely employed by those of skill in the art such that an “improved therapeutic outcome” results. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An_{effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body} weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. Inhibitors of VEGFR and ligands thereof_{[54] As used herein the term “VEGFR inhibitor” or “VEGFR signalling inhibitor” relates to a compound or} composition that is known to anatagonize one or more of the biological functions of VEGF. The term “VEGF” refers to a vascular endothelial growth factor that induces angiogenesis or an angiogenic process. As used herein, the term “VEGF” may include the various subtypes of VEGF. Further, as used herein, the term “VEGF” may include VEGF-related angiogenic factors such as PIGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, which act through a cognate VEFG receptor (e.g., VEGFR) to induce angiogenesis or an angiogenic process. The term “VEGF” may include_{any member of the class of growth factors that binds to a VEGF receptor such as VEGFR-1 (Flt-I), VEGFR-2 (KDR/Flk-} I), or VEGFR-3 (FLT-4). The term “VEGF” can be used to refer to a “VEGF” polypeptide or a “VEGF” encoding gene or nucleic acid._{[55] The term “VEGF antagonist” refers to an agent that reduces, or inhibits, either partially or fully, the activity} or production of a VEGF. In certain embodiments, the VEGF antagonist inhibits one or more of VEGF-A, VEGF-B, VEGF- C and VEGF-D. A VEGF antagonist can directly or indirectly reduce or inhibit the activity or production of a specific VEGF such as VEGFi65. Furthermore, “VEGF antagonists” may include agents that act on either a VEGF ligand or its cognate receptor so as to reduce or inhibit a VEGF-associated receptor signal. Examples of “VEGF antagonists” may include antisense molecules, ribozymes or RNAi that target a VEGF nucleic acid; anti-VEGF aptamers, anti-VEGF antibodies to VEGF itself or its receptor, or soluble VEGF receptor decoys that prevent binding of a VEGF to its cognate receptor; antisense molecules, ribozymes, or RNAi that target a cognate VEGF receptor (VEGFR) nucleic acid; anti- VEGFR aptamers or anti-VEGFR antibodies that bind to a cognate VEGFR receptor; and VEGFR tyrosine kinase inhibitors. In certain embodiments, the VEGF antagonist is a peptide, e.g., a peptide comprising three or more amino acid residues. In certain embodiments, the VEGF antagonist is a bicyclic peptide. In certain embodiments, the VEGF antagonist is a gene therapy, vector, or delivery vehicle delivering a plasmid, gene, or other genetic sequence capable of giving rise to a moiety that antagonizes VEGF_{[56] Preferably, in the various embodiments of the aspects of the invention, the term VEGFR-signalling inhibitor is} a compound known for its activity to antagonize one or more of VEGFR1, VEGFR2 and VEGFR3. The person of skill knows that there are various compounds with varying structural composition but that have such desired VEGFR inhibitory activity. Without being restricted to any specific compound, the invention preferably relates to an VEGFR signalling inhibitor which is selected from the group consisting of axitinib, ramicurimab, bevacuzamab, ranizumab, aflibercept, HLX12, ziv-aflibercept, vanucizumab, TX16, UB-922, BEVZ92, BCD-021, BI695502, CHS-5217, JHL1149, FKB238, Abevmy, ONS1045, PF06439535, HD204, SB8, TAB008, RPH001, BP102, HLX04, CT-P16, IBI305, LY01008,_{Mvasi, apagin, ranibizumab, CHS-3351, PF582, Xlucane, FYB201, razumab, CHS-2020, FYB203, ABP- 201,sevacizumab, brolucizumab, CSL346, faricimab, hPV19, TAB014, UB-924, VGX-100, VX70, STI- A0168, CVX-241, BI} 836880, ABT-165, conbercept, MP0250, MP0260, angiocal, abicipar pegol, anlotinib, apatinib, altiratinib, vandetanib, linifanib, motesanib, necuparanib, HLX12, APX004, CDP791, HLX-06, IBI302, icrucumab, IMC-1C11, IMC-3C5, MSB0254, navicixizumab, tanibirumab, V-DOS47, cabozantib, brivanib, dovitinib lactate, famitinib, foretinib, fruquintinib, golvatinib, henatinib, ponatinib, lenvatinib, lucitanib, sorafenib, nintedanib, orantinib, pegdinetanib, cediranib, rivoceranib, midostaurin, sitravatinib, regorafenib, sunitinib, sulfatnib, tesevatinib, tivozanib, valatanib, or_{pazopanib. In preferred embodiments of the invention the VEGFR signalling inhibitor is axitinib.[57] In an embodiment of the treatment method, medicaments and uses of the present invention, the VEGFR} signalling inhibitor is the compound, N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide or 6- [2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole, of which is known as axitinib or AG- 013736._{[58] Axitinib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3.} These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival (Hu-Lowe, D.D., et al., Clin Cancer Res 14: 7272-7283 (2008); Solowiej, S., et al., Biochemistry 48: 7019-31 (2009)). Clinical trials are currently on-going or have been conducted to study the use of axitinib for the treatment of various cancers, including liver_{cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer, renal cell carcinoma, soft tissue} sarcomas and solid tumors. Inlyta® (axitinib) has been approved in the United States, Europe, Japan and other jurisdictions for the treatment of renal cell carcinoma._{[59] Axitinib, as well as pharmaceutically acceptable salts thereof, is described in U.S. Patent No. 6,534,524.} Methods of making axitinib are described in U.S. Patent Nos. 6,884,890 and 7,232,910, in U.S. Publication Nos. 2006- 0091067 and 2007-0203196 and in International Publication No. WO 2006/048745. Dosage forms of axitinib are described in U.S. Publication No. 2004-0224988. Polymorphic forms and pharmaceutical compositions of axitinib are also described in U.S. Patent No. 8,791,140 and U.S. Publication Nos. 2006-0094763, 2008-0274192, and 2014- 0248347. Uses of axitinib, including use as a single agent or in combination treatment, are described in U.S. Patent No. 7,141,581 and in U.S. Publication No. 2014-0288125. The patents and patent applications listed above are incorporated herein by reference._{[60] Axitinib is understood to include reference to salts thereof, unless otherwise indicated. Axitinib is basic in} nature and capable of forming a wide variety of salts with various inorganic and organic acids. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids. Pharmaceutically acceptable salts of axitinib may be formed, for example, by reacting axitinib with an amount of acid, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization._{[61] Exemplary acid addition salts of axitinib include acetates, ascorbates, benzoates, benzenesulfonates,} bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto._{[62] All such acid salts are intended to be pharmaceutically acceptable salts within the scope of axitinib, as used} in the present invention and all acid salts are considered equivalent to the free forms of the corresponding compound for purposes of the invention._{[63] Prodrugs of axitinib are also contemplated for use in the methods, medicaments and uses of the present} invention. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield axitinib or a salt thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,_{American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.[64] In context of the present invention, axitinib is preferably used as a solid formulation as a 1 mg tablet or a 5} mg tablet._{Kinase Inhibitor Compound of the Invention (e.g. SIK3 inhibitors)[65] “Salt-inducible kinase 3” or “SIK3” (synonyms QSK and KIAA0999) is a member of a subfamily of} serine/threonine protein kinases including SIK1, SIK2, and SIK3 that belong to an AMP-activated protein kinase (AMPK) family. A SIK3 protein in context of the invention is, typically, a protein kinase. Pertinent information on the human SIK3 protein is accessible on UniProt: Q9Y2K2 (Entry version 138 of 15-Mar-2017) and a SIK3 protein in context of the invention has, preferably, an amino acid sequence shown in SIK3, Entry version 138 of 15-Mar-2017 or Entry version 144 of 28-Mar-2018, which sequences are incorporated herein by reference. SIK3 is a cytoplasmatic protein with serine/threonine kinase activity which is regulated through phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex; a phosphorylation which is reported as essential for catalytic activity of SIK3 (Lizcano, J. M. et al.; EMBO J. 23, 833–843 (2004)). For the purposes of the herein disclosed invention the term “phosphorylated SIK3” shall denote a SIK3 protein that is phosphorylated substantially as SIK3 protein can be (eg is) phosphorylated by LKB1, wherein preferably such phosphorylated SIK3 comprising a phosphor- threonine at amino acid position 163. A phosphorylated SIK3 in context of the invention is an SIK3 protein that is activated in its cell-biological context. At least four protein isoforms (SIK3-001 to SIK3-004) generated by alternative_{splicing of the SIK3 gene product are known. The human SIK3 gene is located at chromosomal position 11q23.3 (HGNC} gene Symbol Acc: HGNC:29165), and is conserved in many species such as in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. The term SIK3 in some embodiments of the invention may also pertain to variants of the human SIK3 protein having an amino acid sequence that is substantially identical to, or of at least 80%, preferably 85%, more preferably 90, 95, 96, 97, 98, 99, or 100% sequence identity to, the amino acid sequence of SIK3 as described above, as determined using, e.g., the “Blast 2 sequences” algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and which (preferably) retain biological activity identical or substantially identical to the respective reference SIK3 (eg to phosphorylate one or more class II (eg IIa) HDACs, such as HDAC4). Preferred variants of SIK3 protein comprise sequence variants thereof due to sequence polymorphism between and within populations of the respective species, as well as mutations compared to the wild-type sequence of SIK3 which are located in or in close proximity to the activity loop or activation loop (T-loop) of SIK3. A preferred variant of SIK3 protein is a SIK3 T163 mutation, such as a mutation affecting the activation of SIK3. In preferred embodiments a SIK3 protein of the invention is not a SIK1 (synonyms: SIK and SNF1LK) protein and/or is not a SIK2 (synonyms: QIK, KIAA0781 and SNF1LK2) protein. The amino acid sequence of human SIK1 (UniProt: P57059; entry version 168 of 15- Mar-2017) and human SIK2 (UniProt: Q9H0K1; entry version 153 of 15-Mar-2017) are incorporated herein by reference. The term SIK3 can mean, as applicable to the context (if not more specifically indicated), a SIK3 protein (such as one described above) or an mRNA molecule encoding such a SIK3 protein. The analogous meaning with respect of “SIK1” and “SIK2” is to be understood._{[66] In the present invention the use of the term “kinase inhibitor” as being part of the combination for medicinal} use in context of the herein disclosed compounds, compositions and therapies, in preferred embodiments pertains to_{a kinase inhibitor as disclosed herein. In particular preferred is that the kinase inhibitor in context of the invention a} small molecular compound according to formula (Ia) as defined herein below._{[67] In a first embodiment, in the various aspects of the present inventionand and as may be further described,defined, claimed or otherwise disclosed herein, the present invention provides pertains to a use of kinase inhibitorwhich is a compound selected from the group consisting of a kinase inhibitor of the formula:} 2 and solvates, salts, N-oxides, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein:_{Hy is a heteroaryl or heterocyclyl which is optionally substituted with one or more independently selected R1e;} each R^1e is independently selected from the group consisting of R^1a, R^1b, R^1c and R^1d;_{each of R1a and R1d is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,} heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR¹¹, -N(R¹²)(R¹³), -N(R¹¹)(OR¹¹), -S(O)0-2R¹¹, -S(O)1-2OR¹¹, -OS(O)_1-2R¹¹, -OS(O)_1-2OR¹¹, -S(O)_1-2N(R¹²)(R¹³), -OS(O)_1-2N(R¹²)(R¹³), -N(R¹¹)S(O)_1-2R¹¹, -NR¹¹S(O)_1-2OR¹¹, -NR¹¹S(O)_1-2N(R¹²)(R¹³), -P(O)(OR¹¹)₂, -OP(O)(OR¹¹)₂, -C(=X)R¹¹, -C(=X)XR¹¹, -XC(=X)R¹¹, and -XC(=X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted with one or more independently selected R³⁰; each of R^1b and R^1c is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_{3-7 cycloalkyl, C6-10 aryl, 3- to 7-membered heteroaryl, 3- to 7-membered heterocyclyl, -O(CH2)0-2(C3-7 cycloalkyl),-O(CH2)0-2(C6-10 aryl), -O(CH2)0-2(3- to 7-membered heteroaryl), -O(CH2)0-2(3- to 7-membered heterocyclyl),-NH(CH2)0-2(C3-7 cycloalkyl), -NH(CH2)0-2(C6-10 aryl), -NH(CH2)0-2(3- to 7-membered heteroaryl), -NH(CH2)0-2(3- to 7-} membered heterocyclyl), halogen, -CF₃, -CN, azido, -NO₂, -OH, -O(C_1-6 alkyl), -OCF₃, -S(C_1-6 alkyl), -NH₂, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, -NHS(O)₂(C_1-6 alkyl), -S(O)₂NH_2-z(C_1-6 alkyl)_z, -C(=O)(C_1-6 alkyl), -C(=O)OH, -C(=O)O(C_1-6 alkyl), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O)(C1-6 alkyl), -NHC(=NH)NHz-2(C1-6 alkyl)z, and -N(C1-6 alkyl)C(=NH)NH2-z(C1-6 alkyl)z,_{wherein z is 0, 1, or 2 and each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-10 aryl, 3- to 7-memberedheteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two, or three moieties} independently selected from the group consisting of -OH, methyl, ethyl, -OCH3, -SCH3, and -NH2-z(CH3)z; R² is H;_{R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen,} -CN, azido, -NO₂, -OR¹¹, -N(R¹²)(R¹³), -N(R¹¹)(OR¹¹), -S(O)_0-2R¹¹, -S(O)_1-2OR¹¹, -OS(O)_1-2R¹¹, -OS(O)_1-2OR¹¹, -S(O)1-2N(R¹²)(R¹³), -OS(O)1-2N(R¹²)(R¹³), -N(R¹¹)S(O)1-2R¹¹, -NR¹¹S(O)1-2OR¹¹, -NR¹¹S(O)1-2N(R¹²)(R¹³), -P(O)(OR¹¹)2, -OP(O)(OR¹¹)₂, -C(=X)R¹¹, -C(=X)XR¹¹, -XC(=X)R¹¹, and -XC(=X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted with one or more independently selected R³⁰; R⁴ is H; R⁵ is -L-R⁶;_{L is selected from the group consisting of a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, and} -(CH2)m-[Y-(CH2)n]o-, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1; Y is independently selected from O, S, and -N(R¹³)-; and each of the_{C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -(CH2)m-, and -(CH2)n- groups is optionally substituted with one or two} independently selected R³⁰; R⁶ is a 5-membered monocyclic heteroaryl which contains at least one S ring atom and which is substituted with one or more independently selected R⁷; R⁷ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR¹¹, -N(R¹²)(R¹³), -N(R¹¹)(OR¹¹), -S(O)0-2R¹¹, -S(O)1-2OR¹¹, -OS(O)1-2R¹¹, - OS_1- cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted with one or more independently selected R³⁰, wherein at least one of R⁷ is F and/or at least one of R⁷ is substituted with one or more F atoms;_{A is selected from the group consisting of S, O, NR8, and C(R9)2;} R⁸ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted with one or more independently selected R³⁰;_{R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl,} heteroaryl, halogen, -CN, azido, -NO₂, -OR¹¹, -N(R¹²)(R¹³), -S(O)_0-2R¹¹, -S(O)_1-2OR¹¹, -OS(O)_1-2R¹¹, -OS(O)_1-2OR¹¹, -S(O)_1-2N(R¹²)(R¹³), -OS(O)_1-2N(R¹²)(R¹³), -N(R¹¹)S(O)_1-2R¹¹, -NR¹¹S(O)_1-2OR¹¹, -NR¹¹S(O)_1-2N(R¹²)(R¹³), -C(=X)R¹¹, -C(=X)XR¹¹, -XC(=X)R¹¹, and -XC(=X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted with one or more independently selected R³⁰; X is independently selected from the group consisting of O, S, and N(R¹⁴); E is O or S; R¹¹ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R³⁰; each of R¹² and R¹³ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R¹² and R¹³ may join together with the nitrogen atom to which they are attached to form the group -N=CR¹⁵R¹⁶, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R³⁰; R¹⁴ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R³⁰; each of R¹⁵ and R¹⁶ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NHyR²⁰2-y, or R¹⁵ and R¹⁶ may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R³⁰, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R³⁰;_{y is an integer from 0 to 2;} R²⁰ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R³⁰; and R³⁰ is a 1^st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -NO₂, -OR⁷¹, -N(R⁷²)(R⁷³), -S(O)_0-2R⁷¹, -S(O)1-2OR⁷¹, -OS(O)1-2R⁷¹, -OS(O)1-2OR⁷¹, -S(O)1-2N(R⁷²)(R⁷³), -OS(O)1-2N(R⁷²)(R⁷³), -N(R⁷¹)S(O)1-2R⁷¹, -NR⁷¹S(O)_1-2OR⁷¹, -NR⁷¹S(O)_1-2N(R⁷²)(R⁷³), -OP(O)(OR⁷¹)₂, -C(=X¹)R⁷¹, -C(=X¹)X¹R⁷¹, -X¹C(=X¹)R⁷¹, and -X¹C(=X¹)X¹R⁷¹, and/or any two R³⁰ which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form =X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^st level substituent is optionally substituted by one or more 2^nd level substituents, wherein said 2^nd level substituent is, in each case, independently selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_{2-6alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered} heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OR⁸¹, -N(R⁸²)(R⁸³), -S(O)0-2R⁸¹, -S(O)1-2OR⁸¹, -OS(O)1-2R⁸¹, -OS_1- -S_1-2N -OS_1-2N -N S_1- -NR⁸¹S_1- -NR⁸¹S_1-2N_{together to form =X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2nd level} substituent is optionally substituted with one or more 3^rd level substituents, wherein said 3^rd level substituent is, in each case, independently selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C_1-3 alkyl), -OCF₃, -S(C_1-3 alkyl), -NH₂, -NH(C_1-3 alkyl), -N(C_1-3 alkyl)₂, -NHS(O)₂(C_1-3 alkyl), -S(O)₂NH_2-z(C_1-3 alkyl)_z, -C(=O)OH, -C(=O)O(C_1-3 alkyl), -C(=O)NH_2-z(C_1-3 alkyl)_z, -NHC(=O)(C_1-3 alkyl), -NHC(=NH)NH_z-2(C_1-3 alkyl)_z, and -N(C1-3 alkyl)C(=NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl, and/or any two 3^rd level substituents which are bound to the same carbon atom of_{a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form =O, =S,} =NH, or =N(C_1-3 alkyl); wherein each of R⁷¹, R⁷², and R⁷³ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl,_{3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl,wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three} substituents independently selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C_1-3 alkyl), -OCF₃, =O, -S(C_1-3 alkyl), -NH₂, -NH(C_1-3 alkyl), -N(C_1-3 alkyl)₂, -NHS(O)₂(C_1-3 alkyl), -S(O)₂NH_2-z(C_1-3 alkyl)_z, -C(=O)(C_1-3 alkyl), -C(=O)OH, -C(=O)O(C_1-3 alkyl), -C(=O)NH_2-z(C_1-3 alkyl)_z, -NHC(=O)(C_1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z, and -N(C1-3 alkyl)C(=NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; each of R⁸¹, R⁸², and R⁸³ is independently selected from the group consisting of H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl,_{3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl,wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three} substituents independently selected from the group consisting of C_1-3 alkyl, halogen, -CF₃, -CN, azido, -NO₂, -OH, -O(C1-3 alkyl), -OCF3, =O, -S(C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C(=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NH_z-2(C_1-3 alkyl)_z, and -N(C_1-3 alkyl)C(=NH)NH_2-z(C_1-3 alkyl)_z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and each of X¹ and X² is independently selected from O, S, and N(R⁸⁴), wherein R⁸⁴ is H or C1-3 alkyl._{[68] Such compounds are which are kinase inhibitors are in detail defined and exemplified in international patentpublication WO 2021/214117 which shall for the purpose of the definition of kianse inhibitors (or also referred to as} SIK3 inhibitors) of the invention be incorporated herein in its entirety._{[69] A selection of kinase inhibitor compounds of the invention, including those which have been synthesized andtested, within the scope of, or for use within the methods of, the disclosure of WO 2021/214117 - is listed in the} following Table A. Table A: Kinase inhibitors of formula (Ia). Compound H N N H N N_{[70] In particular embodiments, the compound of the invention is selected from the group consisting of E4, E9,} E10, and E16; and also their solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labelled forms, prodrugs, and combinations thereof._{[71] In certain embodiments, the compound of the invention is E9, or a solvate, salt, N-oxide, complex, polymorph,} crystalline form, tautomer, conformer, isotopically labelled form, prodrug, or combination thereof._{[72] In another certain embodiment, the compound of the invention is E4, or a solvate, salt, N-oxide, complex,} polymorph, crystalline form, tautomer, conformer, isotopically labelled form, prodrug, or combination thereof._{[73] In another certain embodiment, the compound of the invention is E10, or a solvate, salt, N-oxide, complex,} polymorph, crystalline form, tautomer, conformer, isotopically labelled form, prodrug, or combination thereof._{[74] In another certain embodiment, the compound of the invention is E16, or a solvate, salt, N-oxide, complex,} polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labelled form, prodrug, or combination thereof._{[75] In certain embodiments, the invention may relate to a solvate, salt, N-oxide, complex, racemic mixture,} diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof, of any of_{the compounds of the invention or of any of the compounds used in the invention; such as a solvate, salt, complex,} racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, or combination thereof, of such compound._{[76] The kinase inhibitor (Sik3 inhibitor) compounds of the invention (and/or the compounds used in the invention)} may be in a prodrug form. Prodrugs of the compounds of the invention (or of the compounds used in the invention) are those compounds that upon administration to an individual undergo chemical conversion under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention (or of the compounds used in the invention) by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention (or to the compounds used in the invention) when, for example, placed in a transdermal patch reservoir with a suitable enzyme or chemical_{reagent. Exemplary prodrugs are esters (using an alcohol or a carboxy group contained in the kinase inhibitor of theinvention (or in the compounds used in the invention)) or amides (using an amino or a carboxy group contained in thekinase inhibitor of the invention (or in the compounds used in the invention)) which are hydrolyzable in vivo.} Specifically, any amino group which is contained in the kinase inhibitor of the invention (or in the compounds used in the invention) and which bears at least one hydrogen atom can be converted into a prodrug form._{[77] In another embodiment, the compounds of the invention exhibit one or more pharmacological properties that} are different to those of dasatinib, of compound B3 (WO 2018/193084), and/or of compound C7 (PCT/EP2019/078751)._{[78] Other than the above small molecular kinase inhibitors, the invention shall also include other strategies to} interfere with the cellular function of SIK3. Other compounds are for example known from WO/2021/219731, WO/2019/202160 and WO/2018/193084._{[79] A compound being an “inhibitor of SIK3” (or "SIK3 inhibitor") is any moiety that inhibits SIK3, which can mean} inhibition of the activity of SIK3, especially of protein of SIK3, and in particular of phosphorylated SIK3. A kinase inhibitor may impair (eg, induces a decrease or reduction in) the efficiency, effectiveness, amount or rate of one or more activities of SIK3, such as one or more of those activities described herein, for example, the activity of SIK3 to phosphorylate class II (eg Ila) HDACs (eg HDAC4) and/or to sensitise a cell involved with a proliferative disorder to a_{cell-mediated immune response. Such a kinase inhibiting moiety can act directly, for example, by binding to a targetof the kinase inhibitors (in particular such kinases as shown in Example 1) and decreasing the amount or rate of oneor more of the properties of the target kinase such as its function, in particular its ability to act as a kinase (eg to} phosphorylate HDAC4)._{[80] The kinase inhibitor is preferably an inhibitor to more than one kineses, including SIK3 and further kinases} involved with VEGFR singalling, such as one or more of the further kinases disclosed herein in Table 1A._{[81] In certain embodiments of these combination aspects, the inhibitor or antagonist of said target kinase or} variant is, preferably, an inhibitory or antagonistic small molecule as described herein. In other embodiments of these combination aspects, said inhibitor or antagonist of said kinase or VERGFR signalling, is a compound selected from a polypeptide, peptide, glycoprotein, a peptidomimetic, an antibody or antibody-like molecule; a nucleic acid such as a DNA or RNA, for example an antisense DNA or RNA, a ribozyme, an RNA or DNA aptamer, siRNA, shRNA and the like, including variants or derivatives thereof such as a peptide nucleic acid (PNA); a targeted gene editing construct, such as a CRISPR/Cas9 construct, a carbohydrate such as a polysaccharide or oligosaccharide and the like, including variants or derivatives thereof; a lipid such as a fatty acid and the like, including variants or derivatives thereof; or a small organic molecules including but not limited to small molecule ligands, small cell-permeable molecules, and peptidomimetic compounds. Pharmaceutical compositions_{[82] In a fourth aspect, the present invention provides a pharmaceutical composition, comprising: (i) A kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117; and (_{ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor.[83] The preferred compounds or compositions for use in the pharmaceutical composition of the invention are (i)} a kinase inhibitor as disclosed herein and a (ii) VEGFR signalling inhibitor according to present disclosure._{[84] The compounds and compositions described in the present invention (in particular those inhibitor compounds} above particularly those given in Table A, or a VEGFR signalling inhibitors specified above) or the compounds used in the present invention are preferably administered to a patient in need thereof via a pharmaceutical composition. Thus,_{in one aspect, the present invention provides a pharmaceutical composition comprising a kinase inhibitor as specifiedabove under the heading "Compounds" (e.g., a kinase inhibitor having the general formula (Ia), complex, polymorph,} crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug,_{or combination thereof and optionally one or more pharmaceutically acceptable excipients.[85] Thus, in one embodiment the pharmaceutical composition comprises a kinase inhibitor as specified above} under the heading "Compounds" (in particular a compound of the first aspect of the invention) and one or more pharmaceutically acceptable excipients. Furthermore, the pharmaceutical composition may further comprise one or more additional therapeutic agents. Thus, in particular embodiments, the pharmaceutical composition comprises (i) a kinase inhibitor as specified above under the heading "Compounds" (in particular a compound of the first aspect of the invention) and one or more additional therapeutic agents; or (ii) a kinase inhibitor as specified above under the heading_{"Compounds" (in particular a compound of the first aspect of the invention), one or more additional therapeutic agents,} and one or more pharmaceutically acceptable excipients._{[86] The term "pharmaceutically acceptable" refers to the non-toxicity of a material which does not interact withthe (e.g., therapeutic) action of the active component (e.g., a kinase inhibitor of the invention (or a compound used} in the invention), either alone or in combination with one or more additional therapeutic agents) of the pharmaceutical composition._{[87] The pharmaceutical composition may be administered to an individual by any route, such as enterally or} parenterally._{[88] The expressions "enteral administration" and "administered enterally" as used herein mean that the drug} administered is taken up by the stomach and/or the intestine. Examples of enteral administration include oral and rectal administration. The expressions "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral administration, usually by injection or topical application, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraosseous, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intracerebral, intracerebroventricular, subarachnoid, intraspinal, epidural and intrasternal administration (such as by injection and/or infusion) as well as topical administration (e.g., epicutaneous, inhalational, or through mucous membranes (such as buccal, sublingual or vaginal))._{[89] Dosage forms for topical and/or transdermal administration of a compound described herein may include} ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active_{ingredient is admixed under sterile conditions with a pharmaceutically acceptable excipient such as one or more} pharmaceutical carriers) and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively, or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel._{[90] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short} needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively, or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid_{jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are} suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable._{[91] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid} preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein._{[92] The compounds of the present invention (or the compounds used in the present invention) are generally} applied in "pharmaceutically acceptable amounts" and in "pharmaceutically acceptable preparations". Such compositions may contain salts, buffers, preserving agents, carriers and optionally other therapeutic agents. "Pharmaceutically acceptable salts" comprise, for example, acid addition salts which may, for example, be formed by_{mixing a solution of compounds with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric} acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3- phenylpropionate, phosphate/diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977))._{[93] The term "excipient" when used herein is intended to indicate all substances in a pharmaceutical composition} which are not active ingredients (e.g., which are therapeutically inactive ingredients that do not exhibit any therapeutic effect in the amount/concentration used), such as, e.g., carriers, binders, lubricants, thickeners, surface active agents, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, colorants, or antioxidants._{[94] The compositions described in the present invention may comprise a pharmaceutically acceptable carrier. As} used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible. The "pharmaceutically acceptable carrier" may be in the form of a solid, semisolid, liquid, or combinations thereof. Preferably, the carrier is suitable for enteral (such as oral) or parenteral administration (such as intravenous, intramuscular, subcutaneous, spinal or epidermal administration (e.g., by injection or infusion)). Depending on the route of administration, the active_{compound, e.g., the compound of the present invention (or the compound used in the present invention), either alone} or in combination with one or more additional therapeutic agents, may be coated in a material to protect the active compound(s) from the action of acids and other natural conditions that may inactivate the active compound._{[95] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical} compositions according to the present invention include water (e.g., water for injection), ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), aqueous solutions of a salt, carbohydrate, sugar alcohol, or an amino acid (such as saline or an aqueous amino acid solution), and suitable mixtures and/or buffered forms thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants._{[96] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for} the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active compounds is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions according to the present invention is contemplated._{[97] The pharmaceutical composition described herein may comprise, in addition to the kinase inhibitor of theinvention and the VEGFR signalling inhibitor (and/or the compound or composition used in the invention), at least one,} e.g., 1, 2, 3, 4, 5, 6, 7 or 8, additional therapeutic agents. According to the present teaching, the at least one additional_{therapeutic agent may be formulated together with the kinase inhibitor of the invention (and/or with the compoundused in the invention) in a single pharmaceutical composition. Alternatively, the pharmaceutical composition may be} structured as kit of parts, wherein the kinase inhibitor of the invention (or the compound used in the invention) is provided in a first formulation and the at least one additional therapeutic agent is provided in a second formulation, i.e., a second pharmaceutical composition. The first and the second pharmaceutical compositions may be combined_{prior to use. In other words, before administering the pharmaceutical composition, a formulation comprising the} additional therapeutic agent may be added to the first pharmaceutical composition comprising the kinase inhibitor of_{the invention (or the compound used in the invention). Alternatively, the present teaching envisages administering the} kinase inhibitor of the invention (or the compound used in the invention) formulated in a first pharmaceutical composition and administering the at least one additional therapeutic agent formulated in a second pharmaceutical composition. The pharmaceutical compositions may be administered concomitantly or in succession. For example, the first pharmaceutical composition may be administered at a first point in time and the second pharmaceutical composition may be administered at a second point in time, wherein the points in time may be separated by, for example, 0, or up to 1, 2, 3, 4, 5 or 10 min, up to 1, 2, 3, 4, 5 or 10 hours, up to 1, 2, 3, 4, 5 or 10 days, up to 1, 2, 3, 4, 5 or 10 weeks, up to 1, 2, 3, 4, 5 or 10 months or up to 1, 2, 3, 4, 5 or 10 years._{[98] The compositions may also contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifying} agents, pH buffering agents, and dispersing agents. Prevention of the presence of microorganisms may be ensured by sterilization procedures and/or by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin._{[99] Regardless of the route of administration selected, the active compounds, which may be used in a suitable} hydrated form, and/or the pharmaceutical compositions according to the present invention, are formulated into_{pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art (cf., e.g.,} Remington, "The Science and Practice of Pharmacy" edited by Allen, Loyd V., Jr., 22nd edition, Pharmaceutical Sciences, September 2012; Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999)._{[100] A pharmaceutical composition can be administered by a variety of methods known in the art. As will be} appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. The pharmaceutical compositions containing one or more active compounds can be prepared with carriers that will protect the one or more active compounds against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for the preparation of such compositions are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978._{[101] To administer a compound of the present invention (or a compound used in the present invention) by certain} routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the compound may be administered to an individual in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J. Neuroimmunol. 7: 27(1984))._{[102] Pharmaceutical compositions typically are sterile and stable under the conditions of manufacture and storage.} The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin._{[103] An injectable composition should be sterile and fluid to the extent that the composition is deliverable by} syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example,_{glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Sterile injectable} solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration._{[104] Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains} a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof._{[105] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For} example, a single bolus may be administered, several divided doses may be administered over time or the dose may_{be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially} advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms used according to the present invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals._{[106] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as} ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble_{antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,} propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like._{[107] For the therapeutic/pharmaceutical formulations, compositions according to the present invention include} those suitable for enteral administration (such as oral or rectal) or parenteral administration (such as nasal, topical (including vaginal, buccal and sublingual)). The compositions may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient (in particular, the amount of a compound according to the present invention) which can be combined with a carrier material to produce a pharmaceutical composition (such as a single dosage form) will vary depending upon the individual being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect._{[108] Generally, out of 100% (for the pharmaceutical formulations/compositions), the amount of active ingredient(in particular, the amount of the compound according to the present invention (or of the compound used in the present} invention), optionally together with other therapeutically active agents, if present in the pharmaceutical formulations/compositions) will range from about 0.01% to about 99%, preferably from about 0.1% to about 70%, most preferably from about 1% to about 30%, wherein the reminder is preferably composed of the one or more pharmaceutically acceptable excipients._{[109] The amount of active ingredient, e.g., a compound according to the present invention (or a compound used} in the present invention), in a unit dosage form and/or when administered to an individual or used in therapy, may range from about 0.1 mg to about 1000 mg (for example, from about 1 mg to about 500 mg, such as from about 10 mg to about 200 mg) per unit, administration or therapy. In certain embodiments, a suitable amount of such active ingredient may be calculated using the mass or body surface area of the individual, including amounts of between about 1 mg/kg and 10 mg/kg (such as between about 2 mg/kg and 5 mg/kg), or between about 1 mg/m² and about 400 mg/m² (such as between about 3 mg/m² and about 350 mg/m² or between about 10 mg/m² and about 200 mg/m²)._{[110] Actual dosage levels of the active ingredients in the pharmaceutical compositions according to the present} invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts._{[111] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the (e.g.,} therapeutically) effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start with doses of the compounds according to the present invention (or of the compounds used in the present invention) at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition according to_{the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic} effect. Such an effective dose will generally depend upon the factors described above. It is preferred that administration be oral, intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of_{the target. If desired, the (e.g., therapeutically) effective daily dose of a pharmaceutical composition may be} administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound according to the present invention (or for the compound used in the present invention) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation/composition._{[112] For oral administration, the pharmaceutical composition according to the present invention can take the form} of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulphate). Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparation can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl- p-hydroxycarbonates, sorbic acids). The preparations can also contain buffer salts, flavouring, coloring and sweetening agents as deemed appropriate. Preparations for oral administration can be suitably formulated to give controlled release of the pharmaceutical composition of the invention._{[113] In one embodiment, the compound is orally administered in a concentration of, for example, at most 100} mg/kg body weight (such as at most 50 mg/kg body weight, at most 40 mg/kg body weight, at most 30 mg/kg body weight, at most 20 mg/kg body weight, at most 10 mg/kg body weight, at most 5 mg/kg body weight, at most 4 mg/kg body weight, at most 3 mg/kg body weight, at most 2 mg/kg body weight, at most 1 mg/kg body weight)._{[114] In one embodiment, the compound is parenterally administered (e.g., intravenously, intramuscularly, orsubcutaneously), in a concentration of, for example, at most 10 mg/kg body weight (such as at most 5 mg/kg body} weight, at most 4 mg/kg body weight, at most 3 mg/kg body weight, at most 2 mg/kg body weight, at most 1 mg/kg body weight, at most 0.5 mg/kg body weight, at most 0.4 mg/kg body weight, at most 0.3 mg/kg body weight, at most 0.2 mg/kg body weight, at most 0.1 mg/kg body weight)._{[115] The pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such} as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc._{[116] For administration by inhalation, the pharmaceutical composition according to the present invention is} conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, nitrogen, or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatine, for use in an inhaler or insufflator can be formulated containing a powder mix of the pharmaceutical composition according to the present invention and a suitable powder base such as lactose or starch._{[117] The pharmaceutical composition according to the present invention can be formulated for parenteral} administration by injection, for example, by bolus injection or continuous infusion. In one embodiment, the compounds or compositions according to the present invention may be administered by slow continuous infusion over a long period, such as more than 24 hours, in order to reduce toxic side effects. The administration may also be performed by continuous infusion over a period of from 2 to 24 hours, such as of from 2 to 12 hours. Such regimen may be repeated one or more times as necessary, for example, after 6 months or 12 months._{[118] In yet another embodiment, the compounds or compositions according to the present invention are} administered by maintenance therapy, such as, e.g., once a week for a period of 6 months or more._{[119] Formulations for injection can be presented in units dosage form (e.g., in phial, in multi-dose container), and} with an added preservative. The pharmaceutical composition according to the present invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, or dispersing agents. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration._{[120] Compositions according to the present invention which are suitable for vaginal administration also include} pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration of compositions according to the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active_{compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any} preservatives, buffers, or propellants which may be required._{[121] Therapeutic/pharmaceutical compositions can be administered with medical devices known in the art. For} example, in a preferred embodiment, a therapeutic/pharmaceutical composition according to the present invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in US 5,399,163; US_{5,383,851; US 5,312,335; US 5,064,413; US 4,941,880; US 4,790,824; or US 4,596,556. Examples of well-known} implants and modules useful in the present invention include those described in: US 4,487,603, which discloses an_{implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a} therapeutic device for administering medicaments through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and US 4,475,916, which discloses an osmotic drug delivery system._{[122] Many other such implants, delivery systems, and modules are known to those skilled in the art. In certain} embodiments, the compounds according to the present invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the compounds according to the present invention cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., US 4,522,811; US 5,374,548; and US 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, and thus enhance targeted drug delivery (see, e.g., V.V. Ranade (1989) J. Clin. Pharmacol. 29: 685). Exemplary targeting moieties include folate or biotin (see, e.g., US 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun.153: 1038); antibodies (P.G. Bloeman et al. (1995) FEBS Lett.357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother.39: 180); and surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol.1233: 134)._{[123] In one embodiment, the compounds according to the present invention (or the compounds used in the present} invention) are formulated in liposomes. In a more preferred embodiment, the liposomes include a targeting moiety. In a most preferred embodiment, the compounds in the liposomes are delivered by bolus injection to a site proximal to the desired area. Such liposome-based composition should be fluid to the extent that easy syringability exists, should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi._{[124] A "therapeutically effective dosage" for therapy/treatment can be measured by objective responses which can} either be complete or partial. A complete response (CR) is defined as no clinical, radiological or other evidence of a condition, disorder or disease. A partial response (PR) results from a reduction in disease of greater than 50%. Median time to progression is a measure that characterizes the durability of the objective tumor response._{[125] A "therapeutically effective dosage" for therapy/treatment can also be measured by its ability to stabilize the} progression of a condition, disorder or disease. The ability of a compound to inhibit one or more protein kinases or to reduce the viability of cells associated with a proliferative disorder, such as cancer cells can be evaluated by using_{appropriate in-vitro assays known to the skilled practitioner, such as those described herein (in particular in the} Examples below). Alternatively, the properties of a compound described in the present invention can be evaluated by_{examining the ability of the compound in appropriate animal model systems known to the skilled practitioner such as} those described herein (in particular in the Examples below). A therapeutically effective amount of a compound according to the present invention can cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the condition, disorder or disease or the symptoms of the condition, disorder or disease or the predisposition toward the condition, disorder or disease in an individual. One of ordinary skill in the art would be able to determine such amounts based on such factors as the individual's size, the severity of the individual's symptoms, and the particular composition or route of administration selected._{[126] The pharmaceutical composition according to the invention can also, if desired, be presented in a pack, ordispenser device which can contain one or more (e.g., unit) dosage forms containing the active compound. The pack} can for example comprise metal or plastic foil, such as blister pack. The pack or dispenser device can be accompanied with a leaflet or other information; in particular, that describing (either to the patient and/or the administering physician) salient information or details on the pharmaceutical composition contained in the package, such as how to administer, recommended dosages, safety and/or side-effect information._{[127] In a particular embodiment, a pharmaceutical composition of the invention is formulated for oral} administration, and in an alternative particular embodiment, a pharmaceutical composition of the invention is formulated for intravenous administration._{[128] In one embodiment, a pharmaceutical composition of the invention is in unit dose form, and in particular may} be in a unit dose form that is formulated for oral administration._{[129] Each of such a unit dose form may comprise (e.g., it may contain) between 1 and 950mg of the compound,such as the kinase kinase inhibitor of the first aspect or a compound used in the other aspects, complex, polymorph,} crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof. In particular, (e.g., each of) such a unit dose form may comprise (e.g., it may contain) between 2 and 150mg of such compound; and suitably, between 10 and 150mg of such compound._{[130] In particular of such embodiments, a pharmaceutical composition of the invention that is in unit dose form} (and in particular one be in a unit dose form that is formulated for oral administration) may comprise (e.g., it may_{contain) - for each unit dose form - about an amount of such compound selected from the list of amounts consisting} of: 2mg, 5mg, 15mg, 20mg, 50mg, 70mg, 80mg, 100mg and 140mg; in particular, comprising (e.g., containing) an_{amount of about 20mg, 50mg, 70mg or 100mg of a compound of the invention (or of a compound used in the} invention)._{[131] In one particular embodiment, the pharmaceutical composition of the invention is (e.g., is formed as) a tablet,} caplet or capsule; suitably the pharmaceutical composition of the invention (e.g., a unit dose form thereof) is a caplet._{Methods to form (e.g., manufacture) tablets and caplets are, for example, described elsewhere herein.[132] Suitable excipients for the pharmaceutical compositions of the invention, in particular when formed as a tablet} or caplet, include, and particular embodiments of such a pharmaceutical composition of the invention include those that further comprise one or more (e.g., all of) the excipients selected from the list consisting of: lactose (e.g., lactose monohydrate), microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose and magnesium stearate._{[133] The kinase inhibitor and VEGFR signalling inhibitor medicaments described herein may be provided as a kit} which comprises a first container and a second containiner and a package insert. The first container contains at least_{one dose of a medicament comprising a kinase inhibitor as disclosed herein, the second container contains at least one} dose of a medicament comprising a VEGFR signalling inhibitor, and the package insert, or label, which comprises instructions for treating a patient for cancer using the medicaments. The first and second containers may be comprised of the same or different shape (e.g., vials, syringes and bottles) and/or material (e.g., plastic or glass). The kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes._{[134] In some preferred embodiments of the kit, the kinase inhibitor is a compound of table A (preferably E9) as} disclosed herein, the VEGFR singalling inhibitor is axitnib. Therapeutic and other applications_{[135] The present application provides a compound or composition as specified above under the heading kinaseinhibitors and/or VEGFR signalling inhibitors, or a pharmaceutical composition as specified above under the heading} "Pharmaceutical compositions" for use as a medicament, for example for use in therapy, in a coadministration, or_{combination therapy in a subject suffering from a PD-1 therapy resistant tumour.[136] Treatment including or utilising such compounds may be provided at home, the doctor's office, a clinic, a} hospital's outpatient department, or a hospital. Treatment generally begins under medical supervision so that medical personnel can observe the treatment's effects closely and make any adjustments that are needed. The duration of the treatment depends on the age and condition of the patient, as well as how the patient responds to the treatment._{[137] A person having a greater risk of developing a condition, disorder or disease may receive prophylactic} treatment to inhibit or delay symptoms of the condition, disorder or disease._{[138] The term "treatment" is known to the person of ordinary skill, and includes the application or administration} of a therapeutic agent (e.g., a pharmaceutical composition containing said agent) or procedure to a patient or application or administration of a therapeutic agent (e.g., a pharmaceutical composition containing said agent) or procedure to a cell, cell culture, cell line, sample, tissue or organ isolated from a patient, who has a condition, disorder or disease, a symptom of the condition, disorder or disease or a predisposition toward a condition, disorder or disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, affect or prevent the condition, disorder or disease, the symptoms of the condition, disorder or disease or the predisposition toward the condition, disorder or disease. Hence, the term “treatment” can include prophylactic treatment of a condition, disorder or disease, or the symptom of a condition, disorder or disease. A therapeutic agent, when used in treatment, includes the kinase inhibitors of the invention (or the compounds used in the fifth aspect of the present invention) and includes, but is not limited to, additional therapeutic agents that may be small molecules, peptides, peptidomimetics,_{polypeptides/proteins, antibodies, nucleotides such as DNA or RNA, cells, viruses, ribozymes, siRNA, and antisense} oligonucleotides._{[139] The disease, disorder or a condition, in the context of the herein described invention, is, in certain} embodiments, a proliferative disorder (including a condition or symptom associated with such disorder)._{[140] A “proliferative disorder” refers to a disorder characterised by abnormal proliferation of cells. A proliferative} disorder does not imply any limitation with respect to the rate of cell growth, but merely indicates loss of normal controls that affect growth and cell division. Thus, in some embodiments, cells of a proliferative disorder can have the same cell division rates as normal cells but do not respond to signals that limit such growth. Within the ambit of “proliferative disorder” is neoplasm or tumour, which is an abnormal growth of tissue or cells. Cancer is art understood, and includes any of various malignant neoplasms characterised by the proliferation of cells that have the capability to invade surrounding tissue and/or metastasise to new colonisation sites. Proliferative disorders include cancer, atherosclerosis, rheumatoid arthritis, idiopathic pulmonary fibrosis and cirrhosis of the liver. Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinisation (e.g., actinic keratosis, senile keratosis), scleroderma, and the like._{[141] A preferred tumour is a solid tumour. In another particular embodiment the proliferative disorder is (eg, the} subject suffers from, or is suspected of suffering from) a solid tumour being one of those described elsewhere herein, such as pancreatic cancer, breast cancer, lung, prostate, melanoma, ovarian cancer, oesophageal cancer, sarcoma and colorectal cancer. In a certain of such embodiments, the proliferative disorder is (eg, the subject suffers from. or is suspected of suffering from) pancreatic cancer; in another of such embodiments, the proliferative disorder is (eg, the subject suffers from, or is suspected of suffering from) prostate cancer; and in yet another of such embodiments, the proliferative disorder is (eg, the subject suffers from, or is suspected of suffering from) lung cancer (eg, non-small cell lung cancer)._{[142] A preferred embodiment of the invention is a combination treatment as described herein wherein the} proliferative disorder to be treated is a cancer that is known to benefit from an anti-angiogenic treatment, such as a treatment with a VEGFR signalling inhibitor. Preferably, the caner is a renal cancer, such as renal cell carcinoma (RCC) or advanced RCC._{[143] Other tumours that are preferably targeted by the combination therapy of the present invention are bladder} cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal_{cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute} myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL)._{[144] In more particular embodiments, the proliferative disorder is a cancer or tumour, in particular a solid tumour} (including a condition or symptom associated with such cancer or tumour). Preferred tumours treatable according to_{the invention are tumours that are known to respond to or that are resistant to VEGFR signalling inhibitor therapy,such as a tumour in a patient that received previously a VEGFR signalling inhibitor therapy and which tumour isrecurrent and may be in need of additional therapy. The invention provides overcoming PD-1 inhbitor therapy byproviding a combination of a kinase inhbitor therapy with VEGFR signalling inhibitor therapy in accordance with the} invention._{[145] According to a further aspect and advantageously in relation to the treatment of a cancer, the inventionconcerns a composition comprising a kinase inhibitor for use in increasing the sensitivity of a subject to a VEGFRsignalling inhibitor therapy. As used therein, the expression “resistant to VEGFR signalling inhibitors” can refer to the} fact that: the majority of the patients having a given disease do not respond to these treatments (VEGFR signalling inhibitors) and/or have a poor prognostic. In that case, the disease is considered to be globally resistant to anti-PDl treatments, whereas other diseases are sensitive to said treatments. As an example, certain types of cancer are known to be more resistant than others to VEGFR signalling inhibitors; and/or even if a disease is globally known to be_{sensitive to VEGFR anatagonist treatments.[146] In certain embodiments, the a given patient having said disease can be resistant to anti-PD-1 therapies and} may benefit from a combination therapy involving the kinase inhibitor and VEGFR signalling inhibitor as specified herein. In such aspects it might be further advantegous to include PD1-inhibitor treatment along with the combination therapy of the invention. EXAMPLES_{[147] The examples show:} Example 1: Angiogenic impact of kinase inhibitors of the invention._{[148] The inventors determined the selectivity of kinase inhibition with regard to a selection of kinases known to} be involved in certain cancer associated signalling pathways. It was surprisingly demonstrated that kinase inhibitors of_{formula (Ia) (eg E9) appeared to be have a favorable inhibition profile with respect to certain components associatedwith VEGF receptor signalling.[149] In particular, and by way of example, compound E9 shows selective inhibition of a variety of pathway} components of the VEGFR signalling pathways.. Table 1A: Biological activity of kinase inhibitors Compound E9 in relation to VEGFR-2 pathway C_{ompound E9 Compound E9[150] The kinase inhibition profile of Compound E9 was determined by measuring residual activity values at six} concentrations in singlicates in wild-type protein kinase assays. Additionally, IC50 were calculated based on six residual activities per compound/kinase pair. COMPOUND E9, provided as a solid, was dissolved to 1 x 1002 M/100% DMSO and an aliquot further diluted to 1 x 10 04 M/100% DMSO. The compound was tested at the following final assay concentrations (see Table 1A). The final DMSO concentration in all reaction cocktails (including high and low controls) was 1 %. T_{able 1B: final assay concentrations of the tested compound.} Final Assay_{[151] A radiometric protein kinase assay (33PanQinase® Activity Assay) was used for measuring the kinase activity} of the protein kinases. All kinase assays were performed in 96-well FlashPlatesTM from Perkin Elmer (Boston, MA, USA) in a 50 µl reaction volume. The reaction cocktail was pipetted in 4 steps in the following order: (_{i) 10 µl of non-radioactive ATP solution (in H2O) (ii) 25 µl of assay buffer/ [µ-33P]-ATP mixture (iii) 5 µl of test sample in 10% DMSO (iv) 10 µl of enzyme/substrate mixture[152] The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 µM Na-} orthovanadate, 1.2 mM DTT, 50 µg/ml PEG20000, ATP (variable amounts, corresponding to the apparent ATP-Km of_{the respective kinase), [µ-33P]-ATP (approx. 8 x 1005 cpm per well), protein kinase (variable amounts), and substrate} (variable amounts)._{[153] The protein kinase reaction cocktails were incubated at 30^C for 60 minutes. The reaction was stopped with50 µl of 2 % (v/v) H3PO4, plates were aspirated and washed two times with 200 µl 0.9 % (w/v) NaCl. Incorporation} of 33Pi (counting of “cpm”) was determined with a microplate scintillation counter (Microbeta, Wallac). All protein_{kinase assays were performed with a BeckmanCoulter Biomek 2000/SL robotic system.[154] All protein kinases provided by ProQinase were expressed in Sf9 insect cells or in E.coli as recombinant GST-} fusion proteins or His-tagged proteins, either as full-length or enzymatically active fragments. All kinases were produced from human cDNAs and purified by either GSH-affinity chromatography or immobilized metal. Affinity tags were removed from a number of kinases during purification. The purity of the protein kinases was examined by SDS- PAGE/Coomassie staining, the identity was checked by mass spectroscopy._{[155] Kinases from external vendors (CAR = Carna Biosciences Inc.; INV = Life Technologies (InvitrogenCorporation); MIL = Merck-Millipore (Millipore Corporation)) were expressed, purified and quality-controlled by virtue} of the vendors readings._{[156] For each kinase, the median value of the cpm of three wells was defined as "low control" (n=3). This value} reflects unspecific binding of radioactivity to the plate in the absence of a protein kinase but in the presence of the substrate. Additionally, for each kinase the median value of the cpm of three other wells was taken as the "high control", i.e. full activity in the absence of any inhibitor (n=3). The difference between high and low control of each_{enzyme was taken as 100 % activity.[157] As part of the data evaluation the low control of each kinase was subtracted from the high control value as} well as from their corresponding "compound values". The residual activity (in %) for each compound well was calculated by using the following formula:_{[158] Res. Activity (%) = 100 X [(signal of compound – low control) / (high control – low control)][159] The selectivity score, according to Karaman et al. (Nat. Biotech. 26, 1, 127-132 (2008)), is a compound} concentration-dependent parameter describing the portion of kinases, which are inhibited to more than a predefined degree (e.g. more than 50 %), in relation to all tested kinases of the particular project._{[160] The selectivity score of Compound E9 at the tested concentrations was calculated for a residual activity< 50 %, i.e. an inhibition of > 50 %. The selectivity score at a particular concentration was calculated by using the} following formula:_{[161] Selectivity Score = (count of data points < 50 %)/(total number of data points)[162] Since six distinct concentrations of COMPOUND E9 were tested against each kinase, the evaluation of the raw} data resulted in six values for residual activities per kinase. Based on six residual activities for each compound/kinase pair, IC50 values were calculated using Prism 5.04 for Windows (Graphpad, San Diego, California, USA; www.graphpad.com). The mathematical model used was "Sigmoidal response (variable slope)“ with parameters "top“ fixed at 100% and "bottom“ at 0 %. The fitting method used was a least-squares fit. These "raw IC50" values from the IC50 calculation were subsequently validated for consistency, resulting in "modified IC50" values._{[163] Furthermore, upon in-vivo treatment with E9, the inventors determined changes in the expression of certaingenese in various treated tumor tissuues (e.g. lung and CRC). Surprisingly the inventors could determine adownregulation of the expression of certain components of the VEGFR pathway in multiple tumor models (Table 1C) Table 1C: Change of Gene expression of certain VEGFsignalling associated genes in treated tumor tissues. Gene: Lung Cancer Tissue Colorectal Cancer Tissue} “ “-“ indicates no significant change in gene expression._{Example 2: Strong Anti-tumor Efficacy of kinase inhibitor E9 as single-agent therapy in Renal Cell Carcinoma[164] In this study the in vivo therapeutic efficacy of Compound E9 as a single agent was preclinically evaluated in} comparison to anti-mPD-1 as a single agent in the subcutaneous murine kidney carcinoma syngeneic model (RENCA) in female BALB/c mice._{[165] On Day 0, tumor cells (1.0x106 cells in 100μl PBS) were implanted into the left mammary fat pad of each} mouse. Mice were be monitored daily, and tumors were measured three times weekly. Primary tumor volumes were determined by caliper measurement. Tumor sizes were calculated according to the formula W2 x L/2 (L = length and W = the perpendicular width of the tumor, L > W). Animals were randomized into treatment groups when a mean tumor volume of approx. 100-200mm³ was reached in a cohort. Mice were treated according to the following dosing schedule, and treatment started on day of randomisation. At study completion, percent tumor growth inhibition (%TGI) values were calculated and reported for each treatment group (T) versus control (C) using initial (i) and final (f) tumor_{measurements by the formula (2): %TGI = 1 - (Tf-Ti) / (Cf-C1)*100. Table 2A: Dosing schedule (efficacy)} Group Test Dose Dose Admini- Dosing Number of 4 Compound 5 10 p.o. BID* (Day 1- 14 **BID: 8 hours apart ***BIW: Bi-weekly_{[166] It was demonstrated that Compound E9 therapy surprisingly showed prominent tumor growth inhibition and} almost 30% survival benefit in the PD-1 resistant syngeneic RCC RENCA tumor model (Figure 1A and 1B, Table 2B). Table 2B: Anti-tumor effects of Compound E9 in RENCA Tumor Growth Inhibition Overall Survival_{[167] Additionally, highly effective single-agent efficacy (64% TGI) could also be shown in RCC PDX model CTG-} 1529 (Figure 2)._{[168] Additionally, therapeutic efficacy of Compound E9 as a single agent was demonstrated in RCC PDX modelCTG-1529) in female Athymic Nude-Foxn1nu (Immune-compromised) mice.[169] When sufficient stock animals reach 1000 – 1500 mm³, tumors were harvested for re-implantation into pre-} study animals. Pre-study animals were implanted unilaterally on the left flank with tumor fragments harvested from stock animals. Each animal was implanted from a specific passage lot and documented. Pre-study tumor volumes were recorded for each experiment beginning seven to ten days after implantation. When tumors reach an average tumor volume of 150-300mm³ animals were matched by tumor volume into treatment or control groups to be used for dosing and dosing initiated on Day 0._{[170] Similar as described above, mice were monitored daily, and, beginning on day 0, tumor dimensions were} measured twice weekly by digital caliper and data including individual and mean estimated tumor volumes (Mean TV ± SEM) were recorded for each group; tumor volume was calculated using the formula (1): TV= width2 x length x 0.52). At study completion, percent tumor growth inhibition (%TGI) values were calculated and reported for each treatment group (T) versus control (C) using initial (i) and final (f) tumor measurements by the formula (2): %TGI =_{1 - (Tf-Ti) / (Cf-C1)*100. Mice were treated according to the following dosing schedule, and treatment started on day} of randomisation. T_{able 2C: Dosing schedule (efficacy)} Group Test Dose Dose Admini- Dosing Number of QDx5 on, BID: 11 hours apart, start PM day 0_{[171] Indeed and surprisingly, the highly effective single-agent efficacy of Compound E9 was further demonstrated} by 64% Tumor Growth Inhibition in the RCC PDX model CTG-1529 (Figure 2)._{[172] Those results give rise to promising combination potential, as Compound E9 treatment proved to be superior} to ICI standard therapy._{Example 3: Strong Anti-tumor Efficacy of kinase inhibitor therapy in combination with Anti-Angiogenic Therapy in} RCC_{[173] In this in vivo study the antitumoral efficacy of two Compound E9 concentrations in combination with Axitinib} will be evaluated in the murine kidney carcinoma model RENCA after implantation into the mammary fat pad of female BALB/c mice._{[174] On Day 0, tumor cells (1.0x106 cells in 100μl PBS) will be implanted into the left mammary fat pad of each} mouse. Mice will be monitored daily and tumors will be measured three times weekly. Primary tumor volumes will be determined by caliper measurement. Tumor sizes will be calculated according to the formula W2 x L/2 (L = length and W = the perpendicular width of the tumor, L > W). Animals will be randomized into treatment groups when a mean_{tumor volume of approx. 100 ‒ 200mm³ is reached in a cohort. Mice will be treated according to the following dosing} schedule. T_{able 3A: Dosing schedule (efficacy)} Group Test specimen Dose Dose Admini- Dosing Number of_[1day of randomization). Tumors will be collected and depending on size will be analyzed by Flow, cytokines and histology. Blood will be collected for EDTA-plasma for further PD/PK analyses and remaining full blood will be cryopreserved._{[176] Data of the individual groups will be analyzed using descriptive data analysis (mean with SEM, median with} interquartile range). Statistical analysis of efficacy data will be done using the unpaired Student's t-test and the one- way ANOVA with Dunnett’s post-test. All data analysis will be performed using GraphPad Prism 9 from GraphPad Software, Inc., San Diego, USA._{[177] Surprisingly, up to 86% tumor growth inhibition could be shown for Compound E9 in combination with theVEGFR2 targeting (Axitinib) inhibitor in RENCA tumor studies (Figure 3A and 3B and table 3B)} Table 3B: Anti-tumor effects of Compound E9 and Axitinib in RENCA Tumor Growth Inhibition_{[178] Even as Axitinib treatment alone shows better survival benefits than compound E9 treatment, either as single-} agent therapy or in combination with Axitinib, much higher tumor growth inhibition could be observed for Compound_{E9/Axitinib combination therapy. Angiogenic profiling of Compound E9 /Axitinib single agent activity and corresponding} combination. The data demonstrates that kinase inhibitors of the invention are surpsiginly advantageous in combination with an antiangiogenic therapy such as a therapy with a VEGFR antagonist such as Axitinib.

Claims

1. A compound or composition for use in a treatment of a proliferative disorder in a subject,_{wherein the compound or composition is a combination of: (i) A kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117; and (_{ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor.2. A compound or composition for use in a treatment of a proliferative disorder in a subject,wherein the compound or composition is a kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5, A, and E are as in WO 2021/214117; wherein the treatment comprises a sequential or concomitant_{administration of the kinase inhibitor with a VEGFR signalling inhibitor to the subject.3. A compound or composition for use in a treatment of a proliferative disorder in a subject,wherein the compound or composition is a VEGFR signalling inhibitor, and wherein the treatment comprises asequential or concomitant administration of the VEGFR signalling inhibitor with a kinase inhibitor to the subject;} wherein the kinase inhibitor is a compound according to formula (Ia) 2_{or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers,} enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy,_{R2, R3, R4, R5, A, and E are as defined in WO 2021/214117.}

_{4. The compound or composition for use of any one of claims 1 to 3, wherein the kinase inhibitor is a} compound having the formula: H (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole-_{5-carboxamide), or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures,} diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof._{5. The compound or composition for use of any one of claims 1 to 4, wherein the VEGFR signalling inhibitoris a pan VEGFR signalling inhibitor, or is a selective inhibitor of one or two of a VEGFR selected from the group ofVEGFR1, VEGFR2 and VEGFR3.6. The compound or composition for use of any one of claims 1 to 5, wherein the VEGFR signalling inhibitor} is selected from the group consisting of a small molecule compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide._{7. The compound or composition for use of any one of claims 1 to 6, wherein the VEGFR signalling inhibitoris selected from axitinib, ramicurimab, bevacuzamab, ranizumab, aflibercept, HLX12, ziv-aflibercept, vanucizumab,} TX16, UB-922, BEVZ92, BCD-021, BI695502, CHS-5217, JHL1149, FKB238, Abevmy, ONS1045, PF06439535, HD204, SB8, TAB008, RPH001, BP102, HLX04, CT-P16, IBI305, LY01008, Mvasi, apagin, ranibizumab, CHS-3351,_{PF582, Xlucane, FYB201, razumab, CHS-2020, FYB203, ABP- 201, sevacizumab, brolucizumab, CSL346, faricimab,hPV19, TAB014, UB-924, VGX-100, VX70, STI- A0168, CVX-241, BI 836880, ABT-165, conbercept, MP0250,} MP0260, angiocal, abicipar pegol, anlotinib, apatinib, altiratinib, vandetanib, linifanib, motesanib, necuparanib, HLX12, APX004, CDP791, HLX-06, IBI302, icrucumab, IMC-1C11, IMC-3C5, MSB0254, navicixizumab, tanibirumab, V-DOS47, cabozantib, brivanib, dovitinib lactate, famitinib, foretinib, fruquintinib, golvatinib, henatinib, ponatinib, lenvatinib, lucitanib, sorafenib, nintedanib, orantinib, pegdinetanib, cediranib, rivoceranib, midostaurin, sitravatinib,_{regorafenib, sunitinib, sulfatnib, tesevatinib, tivozanib, valatanib, or pazopanib; and preferably is axitinib.8. The compound or composition for use of any one of claims 1 to 7, wherein the proliferative disorder is} selected from a tumor disease which is characterized by the expression of Salt Induced Kinase 3 (SIK3) in cells associated with the tumor disease._{9. The compound or composition for use of any one of claims 1 to 8, wherein the kinase inhibitor is (N-(2-} chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-_{carboxamide) and wherein the VEGFR inhibitor is axitinib.10. The compound or composition for use of claim 9, wherein the kinase inhibitor is administered as a solid} dosage form such as a capsule or tablet, which comprises in one 20mg to 100mg of the kinase inhibitor.

_{11. The compound or composition for use of claim 9 or 10, wherein axitinib is used as a solid formulation as} a 1 mg tablet or a 5 mg tablet._{12. A pharmaceutical composition comprising: (i) a kinase inhibitor according to formula (Ia)} 2 and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117; and (_{ii) a Vascular Endothelial Growth Factor Receptor (VEGFR) signalling inhibitor;} together with a pharmaceutical acceptable carrier and/or excipient._{13. The pharmaceutical composition of claim 8, wherein the kinase inhibitor is a compound having the formula:} H (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole-_{5-carboxamide), or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures,} diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof._{14. The pharmaceutical composition of claim 9, wherein the VEGFR signalling inhibitor is selected from axitinib,} ramicurimab, bevacuzamab, ranizumab, aflibercept, HLX12, ziv-aflibercept, vanucizumab, TX16, UB-922, BEVZ92, BCD-021, BI695502, CHS-5217, JHL1149, FKB238, Abevmy, ONS1045, PF06439535, HD204, SB8, TAB008, RPH001, BP102, HLX04, CT-P16, IBI305, LY01008, Mvasi, apagin, ranibizumab, CHS-3351, PF582, Xlucane,_{FYB201, razumab, CHS-2020, FYB203, ABP- 201, sevacizumab, brolucizumab, CSL346, faricimab, hPV19, TAB014,UB-924, VGX-100, VX70, STI- A0168, CVX-241, BI 836880, ABT-165, conbercept, MP0250, MP0260, angiocal,} abicipar pegol, anlotinib, apatinib, altiratinib, vandetanib, linifanib, motesanib, necuparanib, HLX12, APX004, CDP791, HLX-06, IBI302, icrucumab, IMC-1C11, IMC-3C5, MSB0254, navicixizumab, tanibirumab, V-DOS47, cabozantib, brivanib, dovitinib lactate, famitinib, foretinib, fruquintinib, golvatinib, henatinib, ponatinib, lenvatinib, lucitanib, sorafenib, nintedanib, orantinib, pegdinetanib, cediranib, rivoceranib, midostaurin, sitravatinib,_{regorafenib, sunitinib, sulfatnib, tesevatinib, tivozanib, valatanib, or pazopanib; and preferably is axitinib.}

_{15. The pharmaceutical composition of any one of claims 12 to 14, for use in the treatment of a proliferative} disorder in a subject, preferably for use of the treatment of cancer in a subject._{16. A method for treating a proliferative disease in a subject, the method comprising administering tothe subject a combination therapy which comprises a kinase inhibitor and a VEGFR signalling inhibitor, wherein thekinase inhibitor is a compound according to formula (Ia):} 2_{or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers,} enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R², R³, R⁴, R⁵, A, and E are as in WO 2021/214117._{17. The method of claim 16, wherein the subject is a human.18. The method of claim 16 or 17, wherein the proliferative disorder is cancer preferably a solid tumor such} as a renal cell carcinoma._{19. The method of any one of claims 16 to 18, wherein the kinase inhibitor is a compound of formula:} H (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole- 5-carboxamide), or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof._{20. The method of any one of claim 16 to 19, wherein the VEGFR signalling inhibitor is selected from axitinib,} ramicurimab, bevacuzamab, ranizumab, aflibercept, HLX12, ziv-aflibercept, vanucizumab, TX16, UB-922, BEVZ92, BCD-021, BI695502, CHS-5217, JHL1149, FKB238, Abevmy, ONS1045, PF06439535, HD204, SB8, TAB008, RPH001, BP102, HLX04, CT-P16, IBI305, LY01008, Mvasi, apagin, ranibizumab, CHS-3351, PF582, Xlucane,_{FYB201, razumab, CHS-2020, FYB203, ABP- 201, sevacizumab, brolucizumab, CSL346, faricimab, hPV19, TAB014,UB-924, VGX-100, VX70, STI- A0168, CVX-241, BI 836880, ABT-165, conbercept, MP0250, MP0260, angiocal,} abicipar pegol, anlotinib, apatinib, altiratinib, vandetanib, linifanib, motesanib, necuparanib, HLX12, APX004, CDP791, HLX-06, IBI302, icrucumab, IMC-1C11, IMC-3C5, MSB0254, navicixizumab, tanibirumab, V-DOS47, cabozantib, brivanib, dovitinib lactate, famitinib, foretinib, fruquintinib, golvatinib, henatinib, ponatinib, lenvatinib, lucitanib, sorafenib, nintedanib, orantinib, pegdinetanib, cediranib, rivoceranib, midostaurin, sitravatinib,_{regorafenib, sunitinib, sulfatnib, tesevatinib, tivozanib, valatanib, or pazopanib; and preferably is axitinib.21. A pharmaceutical kit which comprises a first container, a second container and a package insert,} wherein the first container comprises at least one dose of a medicament comprising a kinase inhibitor as recited in any one of the preceding claims, the second container comprises at least one dose of a medicament comprising a_{VEGFR signaling inhibitor, and the package insert comprises instructions for treating a subject for a proliferative} disorder the medicaments._{22. The pharmaceutical kit of claim 21, wherein the kinase inhibitor is a compound of formula:} H (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole- 5-carboxamide), or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations_{thereof; preferably formulated as a solid dosage form such as a capsule or tablet, and which comprises in one} 20mg to 100mg of the kinase inhibitor._{23. The pharmaceutical kit according to claim 21 or 22 wherein the VEGFR signalling inhibitor is axitinib} formulated as a 1 mg tablet or a 5 mg tablet._{24. The method, use or kit of any of the above claims, wherein the cancer is selected from a SIK3 positive} cancer, and preferably is renal cell carcinoma.