Novel photoinducible kinase inhibitors for treating proliferative and vasoproliferative diseases

Abstract

In the present invention azidation is used to render a molecule photoactivable and to influence its binding to its cognate specific binding partner in the eye. Thus, the invention relates to a compound for use in a method of treating a subject with an ocular disease said compound comprising - a conjugated electron system - an active agent moiety, - an azide (N3) moiety comprising an azido group, wherein the π electrons of the azido group extend the conjugated electron system to form an extended conjugated electron system, whereby the active agent moiety can be bound to the binding site of the biological target, and the azide moiety can be photoactivated by the light entering via the optical system of the eye, whereby the engineered molecule becomes linked to the biological target via a covalent bond, whereby the compound modulates the said biological target in the eye to provide an improved treatment for said subject.

Description

[0001]Novel photoinducible kinase inhibitors for treating proliferative and vasoproliferative diseases FIELD OF THE INVENTION In the present invention azidation is used to render a molecule photoactivable and to influence its 5 binding to its cognate specific binding partner in the eye. The ambient light is focused onto the said ocular tissue by the optical system of the eye itself, without using an artificial photoactivation step by medical personnel. The photoactivation of the said molecule results in the formation of a covalent chemical bond between the said molecule and its said cognate specific binding partner, that leads to: (1) the targeting of the said molecule to the said ocular tissue, 10 (2) the enrichment of the said molecule in the said ocular tissue, (3) modification of the biological effect of the said molecule as compared to its non-azidated counterpart (hereinafter referred to as “parent molecule”) in a way that is beneficial for the subject to be treated. BACKGROUND ART 15 Gaining access to the retina for the purpose of drug delivery is extremely challenging given the known and well described ocular anatomical barriers [Yamada et al., 2016]. Any method for local delivery would offer the advantage of using extremely small doses of medication and minimizing the potential systemic toxicity in addition to providing a route of delivery. The corneal and conjunctival epithelium, furthermore, the diffusion across the cornea and scleral stroma constitute an important barrier for any 20 molecule applied as eyedrops [Grass et al., 1988], while the blood retinal barrier strictly regulates the transport between the plasma circulating in the retinal capillaries and extracellular space of the neuroretina [Díaz-Coránguez, 2017] thereby restricting the access of drug molecules present in the circulation (such as molecules taken per os and absorbed by the gut). However, if a method for local delivery is achieved for a given condition, the therapy will likely 25 require extremely small doses relative to the amount required to achieve similar tissue levels using systemic therapy. Local therapy minimizes systemic drug levels and thus limits potential systemic toxicity in addition to providing a route for the therapeutic compounds to reach the retinal tissue [Yamada et al., 2016]. Therefore, several methods have been elaborated for local administration of compounds to the retina, the most important ones include the suprachoroideal, subretinal and the intravitreal delivery route. The 30 suprachoroideal administration can target specific chorioretinal tissues, and provides circumferential spread of the administered molecules that can reach the posterior segment of the eye without affecting the untargeted anterior segment [Wan et al., 2021]. The subretinal injections are most often used for the delivery of viral vectors to locally express therapeutic transgenes [Peng et al., 2017]. Finally, the intravitreal injections are very frequently used to deliver drug molecules into the vitreus [Fagan et al.2013] 35 and according to the estimations 24.4 million of such injections were performed globally in 2019 [Wan et al., 2021]. Photodynamic therapy (PDT) uses a photosensitizer compound for destruction of an undesired tissue like tumor tissue or blood vessels arising via neovascularization, by introducing said compound to a target tissue of a patient followed by activation of the photosensitizer by low energy directed light. Photoreactive 40 chemicals are typically injected into the patient and irradiated with laser light as they pass through the 2 neovascular elements. This light should be strong enough to activate the chemicals, causing them to emit free radicals that destroy the undesired tissue e.g. blood vessels formed via neovascularization, but should not be strong enough to cause damage to the overlying retina. Clearly this constitutes a danger for healthy tissues and the laser should carefully be focused onto the undesired tissue. Therefore, laser irradiation when 5 used as a part of PDT requires a trained doctor [Wormald 2005]. Of note, PDT never relies on a specific interaction between a drug molecule reaching the eye and its specific target molecule present in the eye. Similarly, PDT never relies on the formation of a covalent bond between a drug molecule photoactivated within the eye and its specific target molecule present in the eye. In the last decade, the therapeutic decrease of the vascular endothelial growth factor (VEGF) 10 signaling using intravitreally injected molecules became the gold standard to suppress ocular neovascularization. This approach is currently being used almost exclusively to treat, among others, age- related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), diabetic macular oedema (DME), and has almost completely replaced the more invasive PDT that required the intravenous injection of a photosenzitizer substance and the subsequent laser irradiation of the eye to damage and eliminate the 15 undesired blood vessels formed by neovascularization. Nonetheless, in addition to psychological and medical burden that intravitreal injections still place on the patient and thereby decrease the patient compliance, the risks of endophthalmitis [Seong et al., 2022] and submacular haemorrhages [Khoo et al., 2022] associated to intravitreal injections remain unacceptably high which necessitates the elaboration of novel ocular administration routes. 20 The present inventors have found a new, unexpected way of retinal targeting which also eliminates the need for intravitreal injections. As an exemplary application, a tailored modification of a small molecule VEGFR2 inhibitors such as sunitinib have been carried out to obtain their azido-derivatives. Fahrenholtz et al. have suggested that an azidated vazopressine peptide hormone analogue of eight amino acids, after photolysis, binds covalently to hormonal receptors in toad bladder and forms an active 25 hormone-receptor complex and proposed the use of this analog for studies of hydroosmotic receptor function and for receptor isolation [Fahrenholtz et al., (1983)]. However, as a light source activating a molecule carrying an azido group, the light naturally projected onto the retina by the optical system of the eye has never been proposed. WO2011 / 084571 [Rajagopalan, R. 2011] provides preparations and formulations comprising azide derivatives as Type I optical 30 (phototherapeutic) agents in in vivo or ex vivo biomedical procedures, wherein selective tissue injury can be induced with light when the azide-photosensitizers bind to the target tissues, either directly or through attachment to a bioactive carrier or targeting moiety. Preferably the compounds have a photolabile azido group capable of undergoing photoactivation-mediated bond dissociation and / or nitrogen extrusion processes to produce reactive species, that achieve a desired therapeutic effect, such as selective and / or 35 localized tissue damage and / or cell death. The optical agents typically include compositions having a substituted phenyl group with a combination of electron donating and electron withdrawing groups as ring substituents. Importantly, WO2011 / 084571 uses the principle of photodynamic therapy. Correspondingly (i) it does not rely on the formation of a covalent bond between the azidated molecule and the target molecule P138182SG 3 (ii) it does not rely on a specific binding between the azidated molecule and the target molecule before covalent bond formation triggered by photoactivation (iii) it does not rely on the light naturally arriving into the eye, instead, it uses artificial irradiation (iv) it relies on the catalytic production of reactive species (such as radicals) to destroy the nearby tissue in a random manner. 5 The present Inventors have recognized that rendering a molecule photoactivable by azidation allows its covalent binding to its cognate specific binding partner (preferably receptor or enzyme) in any ocular tissue (including but not limited to the retina), using the ambient light that is focused onto the said ocular tissue by the optical system of the eye itself. As a particular example, a high number of inhibitors of VEGF signaling, in particular VEGFR2 10 inhibitor, is known in the art [Peng, Fan-Wei et al., 2017, Farghaly, TA et al.2021, Khanwelkar, R.R, .2010, Yang T-H et al. 2017A and 2017B]. In an embodiment the present invention aims at converting such inhibitors by azidation to a compound which is still capable of inhibiting VEGF signaling and useful in the present invention. The compounds of the present invention are designed in such a way that they have a cognate binding partner in the eye (such as a receptor or enzyme), e.g. a biological target, e.g. a receptor in 15 the VEGF signaling pathway, in particular VEGFR2. Therefore, the compounds of the present invention can be administered by routes other than injection, e.g. orally, the active agent moieties specifically bind to their cognate binding partner (e.g. a receptor) in the eye whereas covalent binding is reached due to activation of the azido group by natural light seen by the patient or animal to be treated. Thereby the active agents accumulate in the eye even when a low dose of the compounds is administered and a low 20 concentration is maintained in the circulation by a correctly designed regimen of dosing, taking into consideration the pharmacokinetic properties of the azidated compound. It is well known for a person skilled in the art, that receptor tyrosine kinase inhibitors with structural similarity to sunitinib and sunitinib itself are well positioned to heal inflammatory and / or angiogenic diseases of the eye, and their targeted delivery to the ocular tissue is a critical problem that awaits a solution 25 (Hussain et al, 2021). However, no attempt has yet been made to azidate sunitinib directly with the purpose of creating a molecule that is photoactivable within the eyeball. Of note, US 2021 / 0170039 describes a slow release formulation to heal ocular diseases and mentions azidation as well. This proposal relies on the azidation of a linker molecule (azido-PEG-6-acid) that is meant to create a bridge between sunitinib and a PAMAM dendrimer. Crutially, the azido group is used in US 2021 / 0170039 only to prepare an intermediate 30 of the drug, does not rely on photoactivation or light, and the azido group is not even present anymore in the final formulation that is to be administered to the subjects. BRIEF DESCRIPTION OF THE INVENTION In the present invention azidation is used to render a molecule photoactivable and to influence its 35 binding to its cognate specific binding partner (preferably receptor or enzyme) in a tissue, preferably ocular tissue or tumor tissue, which is exposed to ambient light (including but not limited to the retina), using the ambient light that is focused onto the tissue. P138182SG 4 In an embodiment invention relates to a compound for use according to claim 1 for use in a method of treating a subject with an receptor tyrosine kinase mediated disease, preferably an ocular disease or a tumor disease, said compound comprising - a conjugated electron system, 5 - an a receptor tyrosine kinase inhibitor moiety, said moiety being a ligand of a receptor tyrosine kinase, - an azide (N3) moiety comprising an azido group, wherein the p electrons of the azido group extend the conjugated electron system , whereby the receptor tyrosine kinase inhibitor moiety can be bound to the binding site of a receptor 10 tyrosine kinase at a light exposed, wherein the azide moiety can be photoactivated and linked to the biological target via a covalent bond, whereby the compound inhibits said receptor tyrosine kinase in the subject to provide improved treatment for said subject. In an embodiment the is receptor tyrosine kinase is a VEGF, PDGF or FGF receptor. 15 In a preferred embodiment said tissue is ocular tissue and ambient light is focused by the optical system of the eye itself. In a preferred embodiment said molecule is photoactivated without using an artificial photoactivation step by medical personnel (Figure 1.). The photoactivation of the said molecule results in the formation of a covalent chemical bond between the said molecule and its said cognate specific binding partner, that leads to: 20 (1) the targeting of the said molecule to the said ocular tissue, (2) the enrichment of the said molecule in the said ocular tissue, (3) modification of the biological effect of the said molecule as compared to its non-azidated counterpart (hereinafter referred to as “parent molecule”) in a way that is beneficial for the subject to be treated. 25 In another embodiment said tissue is a proliferating tissue, preferably a tumor tissue and said photoactivable molecule is activated by ambient light contacting the tumor tissue treated by the photoactivable molecule; i.e. the photoactivable molecule is targeted by ambient light to treat said tissue. In a preferred embodiment the photoactivable molecule is a photoinducible kinase inhibitor. Ambient light may be provided by natural light or by artificial light of an appropriate wavelength 30 range. The light is never laser light, i.e. is always different from a laser light. In case of ocular tissue the light seen by the patient. In a preferred embodiment the ambient light is visible light. In case of a tumor tissue the light is ambient light, e.g. light illuminating the tumor tissue. For example, the illumination may be provided by a light source, e.g. lamp in a room where the patient resided for a period of treatment. Or, alternatively, illumination may be provided by sunlight during 35 a period when the patient perambulated an outdoor area. In case of a tumor tissue the light is preferably a light source, e.g. a lamp. In an alternative embodiment the ambient light is provided by a wearable device, like an “eye-glass”, which mildly illuminates the eye i.e. the ocular tissues (such as the retina) the light is naturally projected onto. P138182SG 5 1. Thus, the invention relates to a compound for use in a method of treating a subject with an ocular disease said compound comprising - a conjugated electron system - an active agent moiety, said moiety being a modulating entity (preferably a ligand or a substrate, 5 including a functional analogue of a natural ligand or a functional analogue of a natural substrate) and thereby being useful for treatment of said ocular disease, - an azide (N3) moiety comprising an azido group, wherein the π electrons of the azido group extend the conjugated electron system to form an extended conjugated electron system, 10 whereby the active agent moiety can be bound to the binding site of the biological target, and the azide moiety can be photoactivated and linked to the biological target via a covalent bond, whereby the compound modulates the said biological target in the eye to provide treatment for said subject, in particular an improved treatment for said subject. Thus, the invention also relates to a compound for use in a method of treating a subject with an ocular 15 disease said compound comprising - an active agent moiety, said moiety being a modulating entity (preferably a ligand or a substrate, including functional analogues of a natural ligand or functional analogues of a natural substrate) of a biological target (preferably a receptor or an enzyme), preferably exerting full or partial activating or inhibiting effect, and thereby being useful for treatment of said ocular disease, 20 - a conjugated moiety having a conjugated electron system, - an azide (N3) moiety comprising an azido group, wherein the π electrons of the azido group form a conjugated electron system together with the conjugated electron system of the conjugated moiety, whereby the active agent moiety can be bound to the binding site of the biological target, the azide 25 moiety can be photoactivated and linked to the biological target via a covalent bond, whereby the compound modulates the said biological target in the eye to provide treatment for said subject. In a preferred embodiment the conjugated moiety is part of the active agent moiety. In a preferred embodiment the conjugated moiety is a moiety different from the active agent moiety. 30 In a preferred embodiment the conjugated moiety is a linker moiety having a conjugated electron system. In an embodiment the conjugated moiety and the active agent moiety overlap, optionally identical or optionally forming part of each other. In a possible embodiment the linker moiety provides flexibility between (i) the active agent moiety and (ii) the azide moiety in a conjugated position with a π-electron system to bind to an appropriate amino 35 acid of the biological target. In none of the cases described herein is the azide moiety isolated from the conjugated moiety by more than one sigma bond. This is an essential part of the present invention, and ensures that the photolysis of the azide moiety can harness the energy absorbed by a larger resonating electron system. This mechanism P138182SG 6 ensures that the N2extrusion from the azide moiety (photolysis) can be triggered by photons having lower energy. Preferably the conjugated π (pi) electron system of the compound comprises at least 3, more preferably at least 4, even more preferably at least 5 non-sigma electron pairs. 5 Preferably the extended conjugated π (pi) electron system of the compound comprises at least 3, more preferably at least 4, even more preferably at least 5 non-sigma electron pairs conjugated with the π (pi) electron system of the azide moiety. Preferably, due to the conjugated system, the azide moiety is excitable with a light of a wavelength of at least 350 nm, preferably at least 400 nm, and up to 800 nm, preferably up to 600 nm. Preferably the 10 light is white light, in particular 400-800 nm, preferably 400-600 nm. Preferably the azide moiety, upon excitation forms a reactive radical capable of covalently binding to the biological target in the illuminated eye tissue. The activated azide moiety may form, preferably, a nitrene group or a reactive cyclic ketene-imine created via ring-expansion. In a highly preferred embodiment the conjugated moiety is a part of the active agent moiety. The conjugated moiety may be the 15 same as the active agent moiety. In the present invention the active agent moiety and thus the compound of the invention can be bound to the binding site of the biological target which can be tested by a binding assay. Such binding assays are known to a person skilled in the art. For example, the active agent moiety or the compound of the invention is contacted with the biological target and binding is measured. As an other example, the 20 active agent moiety or the compound of the invention is contacted with the biological target and the activity of the biological target (or a change in activity thereof) is measured. In case the active agent moiety is an inhibitor the compound is an inhibitor of the biological target. For example, the active agent moiety or the compound of the invention is contacted with the biological target and the activity of the biological target (or a reduction of the activity thereof) is measured. 25 In a further embodiment said compound is an inactive prodrug, comprising a metabolizable group linked to the molecule. In an embodiment the metabolizable group may be linked to a ring nitrogen atom. 1. A compound for use in a method of treating a subject with a disease said compound comprising - a conjugated electron system (including but not limited to the 2-oxo-indolin-3-ylidene moiety directly coupled to a pyrrol ring as in paragraphs below, or the 2-oxo-indolin-3-ylidene moiety directly 30 coupled to a phenyl group, - an active agent moiety (including but not limited to the sunitnib scaffold or vorolanib scaffold, or the nintedanib scaffold, said moiety being a modulating entity, preferably a ligand or a substrate of a biological target (including but not limited receptor tyrosine kinases, preferably FGFR, PDGFR or VEGFR in claim 6) and thereby being useful for treatment a disease, 35 - an azide (N3) moiety comprising an azido group, wherein the π electrons of the azido group extend the said conjugated electron system , whereby the active agent moiety can be bound to the binding site of the biological target, the azide moiety can be photoactivated to trigger N2extrusion and radical generated by this process can become linked to the biological target via a covalent bond, P138182SG 7 whereby the compound inhibits said biological target in the subject to provide improved treatment for said subject as compared to the compound not linked covalently to the target and consequently 2. The compound for use according to claim 1 wherein said compound is - intended to treat an ocular disease 5 - can be photoactivated by natural light entering via the optical system of the eye - is delivered into the site of treatment wherein its azido group is converted to a reactive radical upon exposure to ambient light and such exposure is an inseparable part of the treatment; preferably, wherein it is administered orally and / or formulated for oral administration and is delivered into the eye wherein its azido group is converted to a reactive radical upon exposure to ambient 10 light, or preferably wherein it is administered to treat a tumor, the azido group is converted into a reactive radical exclusively within the tumor and its neovessels by targeting the illumination onto the tumor or onto the location where malignuous cells are located. preferably wherein it is administered to treat a tumor the said compound is not photoactivated in 15 the healthy tissue of the subject. In a preferred embodiment said azidated compound is administered orally and / or formulated for oral administration and is delivered into the eye wherein its azido group is converted to a reactive radical upon exposure to ambient light. In a preferred embodiment light protection is provided by a protective coating e.g. a capsule wall. 20 Preferably the azidated compound is formulated to allow transfer of the compound through the blood-retina barrier. In an embodiment, the azidated compound comprises a moiety that permits the active transporter (such as vitamin transporter) mediated uptake into the desired part of the retinal tissue or into the desired cell. Preferably the azidated compound is a ligand or an enzyme substrate and therefore in the eye (once transferred through the blood-retina barrier) is targeted to its receptor or enzyme. 25 3. Preferably said compound for use is an aryl-azide compound, wherein the azido group forms a reactive radical upon illumination by light, preferentially a nitrene radical or a reactive cyclic ketene-imine in the eye via contacting ambient light, e.g. light naturally entering into the eye. The π electrons of the azido group extend the conjugated electron system to form an extended conjugated electron system. 4. Preferably said compound for use according to any of paragraphs 1 to 3 in treating the said 30 subject suffering from an ocular disease that involves a targetable endogenous biomolecule (such as a receptor or an enzyme). Preferably in the ocular disease a targetable endogenous biomolecule is part of the pathomechanism. The group of the said ocular diseases includes but is not limited to ocular neovascularization. Preferably the said ocular disease is selected from the group of ocular diseases defined in paragraph 35 9 and preferred groups defined therein. 5. Preferably the compound for use according to any of paragraphs 1 to 4 (and thus the active agent moiety) is a VEGF, PDGF or FGF signaling inhibitor, preferably a VEGF receptor (VEGFR) inhibitor (in particular a VEGFR inhibitor selected from the group consisting of VEGFR1, VEGFR2 and VEGFR3 inhibitors), more preferably a VEGFR2 inhibitor. P138182SG 8 In this preferred embodiment of the invention the active agent moiety and thus the compound of the invention can be bound to a VEGFR inhibitor selected from the group consisting of VEGFR1, VEGFR2 and VEGFR3 inhibitors, preferably to VEGFR2 which can be tested by a VEGFR2 binding assay or a VEGFR2 signaling assay. In the preferred embodiment described in this paragraph, the second option is 5 preferred given that it yields functional results. Such an assay is known to a person skilled in the art and, as is described in the present document as tool to demonstrate the efficiency of our exemplary compounds. Briefly, the compound is applied in an assay where VEGFR2-dependent signaling can be measured and the effect of the light is quantified in the said assay. 6. Preferably the compound for use according to any of paragraphs 1 to 5, in particular paragraph 10 5, is an indole derivative comprising an indole moiety, even more preferably it comprises an indole-2-one moiety (hereinafter also referred to as an “oxindole” moiety) wherein the benzene ring of the oxindole is substituted with an azido group. Such preferred compound can be considered (and will be hereinafter referred to) as an oxindole derivative. 7. In a preferred embodiment the oxindole derivative is an oxindole derivative VEGFR-inhibitor, 15 preferably an oxindole derivative with stronger inhibitory potential against VEGFR2 than against other VEGFR proteins (such as VEGFR1 or VEGFR3), preferably a compound for use according to any of paragraphs 1 to 6, in particular paragraph 6. In the paragraphs below the compounds of the invention are considered as limited to medical indications. However, it is contemplated that the compounds themselves are provided for by the invention 20 and can be the subject matter of a claim for the present invention. 8. In a preferred embodiment the invention relates to a compound for use according to any of paragraphs 1 to 7, in particular paragraph 6 or 7, wherein preferably the oxindole derivative VEGFR2 inhibitor has a general formula (X) or optionally (X.1) 25 wherein in the formula at least one of R2, R3, R4 and R5 is an azido group (N3); preferably at least one of R3 and R4 is an azido group (N3); more preferably one of R3 and R4 is an azido group (N3); wherein any one of R2, R3, R4 and R5 which is different from an azido group, is selected independently from the group consisting of P138182SG 9 -H, Me, halogenide, pseudohalogenide, -OH, -SH, -Ome, -Oet, -NO2, -NH2, -NHMe, -COOH, CONH2-CF3; preferably H, halogenide, pseudohalogenide, -Ome, -OH, -SH, in particular H or halogenide, more particularly halogenide, -substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C1- 5 C8 alkenyloxy, C1-C8 alkynyloxy, C1-C8 alkylamide, C1-C8 alkenylamide, C1-C8 alkynylamide, (wherein optionally C8 alkenyloxy, C1-C8 alkynyloxy, C1-C8 alkenylamide C1-C8 alkynylamide are left out) C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- heteroaryl, C1-C5 amide a C1-C8 carbonyl, (preferably a C2-C8 alkylcarbonyl, C3-C8 alkenylcarbonyl, C3-C8 alkynylcarbonyl,) a C1-C8 carboxyl, (preferably a C2-C8 alkylcarboxyl, C3-C8 alkenylcarboxyl 10 or C3-C8 alkynylcarboxyl), a C2-C8 carboxylate ester (preferably a C2-C8 alkylester, C3-C8 alkenylester or C3-C8 alkynylester), said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, - NR21R22, wherein R21and R22are, independently selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C8 alkyl and C1-C8 alkoxy, said15 substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, - NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R21and R22is H, Me or Et, - SO2NR23R24, wherein R23and R24are, independently selected from H, substituted or unsubstituted C1-C8 alkyl, preferably C1-C4 alkyl, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 20 membered heteroaryl, 6-12 membered alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R23and R24is H, Me or Et -ureido, preferably aryl-ureido or heteroaryl-ureido, preferably C1-C20 aryl-ureido, more preferably a phenyl-ureido optionally substituted with (preferably in para position) C1-C4 alkyl, C2-C4 25 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 carbonyl (preferably C2-C4 alkylcarbonyl, C3-C4 alkenylcarbony or C3-C4 alkynylcarbonyl), C1-C4 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl-heteroaryl, C1-C5 amide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 alkenylcarboxyl, a C3-C6 alkynylcarboxyl), C2- C6 carboxylate ester, halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, highly 30 preferably (para-metoxy-phenyl)-ureido, R6is selected from H and an in vivo metabolizable (preferably an intracellularly metabolizable) moiety whereby the compound is a prodrug; and / or a moiety selected from the group consisting of the following moieties: - a substituted or unsubstituted C1-C4 alkyloxy group linked via a carbon to the nitrogene atom 35 of the oxindole structure (in particular a C1-alkoxy, preferably a CH2-O- moiety) preferably acylated to be an ester by an -C(O)-R31group, wherein R31is selected from the group consisting of OR32, SR32, and N(R32)2; and R31or R32is selected from the group consisting of P138182SG 10 -H, unsubstituted or substituted C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C4 alkenyl, in particular a C1-C6 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or 5 a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1- C6 alkyl, C1-C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, 10 said substituent of the C1-C4 alkyloxy group if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, and -NHMe, wherein it is noted that esters can typically be cleaved by intracellular esterases that are not 15 present in the extracellular space, or R6is a C(O)-R33group forming an amide bond with the ring N, wherein R33group is selected from C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl, preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C6 alkenyl, in particular a C1-C4 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably 20 a C1-C8 or a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1- C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, wherein in a particular embodiment said R33group is selected from a C1-C8 alkyl, in 25 particular a C1-C4 alkyl, wherein the said alkyl, has a substituent (is substituted by a group selected from) a 4-15 membered heterocyclyl, in a particularly preferred embodiment R6comprises a biotinyl group with or without a linker, or in an alternative embodiment R6is selected from a substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C8 alkylester, C3-C8 alkenylester or C3-C8 alkynylester, said30 substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, - NHMe, or R6is a substituted or unsubstituted C1-C4 alkyloxy group linked via the alkyloxy oxygen to the ring N forming an N-O bond, said substituent on the C1-C4 alkyloxy group (in particular a C1- alcoxy, preferably a CH2-O- moiety), if any, being selected from the group consisting of H, C1-C6 alkyl, 35 C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, and - NHMe, R7and R8are independently selected from the group consisting of a substituted or unsubstituted aryl, in particular a C6-C10 aryl, a heteroaryl, in particular a 5 to 10 membered heteroaryl, a H, amine, P138182SG 11 preferably a C1-C5 amine, -NHC6-C10 aryl, amide, preferably a C1-C5 amide, C2-C6, preferably a C2- C3 alkenyl, a C1-C6 carbonyl, (preferably a C2-C6 alkylcarbonyl, C3-C6 alkenylcarbonyl, C3-C6 alkynylcarbonyl,) a C1-C6 carboxyl, (preferably a C2-C6 alkylcarboxyl, C3-C6 alkenylcarboxyl, C3- C6 alkynylcarboxyl) a C1-C6 carboxylate ester, (preferably a C2-C6 alkylester, C3-C6 alkenylester or 5 C3-C6 alkynylester), wherein if any of R7and R8is substituted, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, with the proviso that at least one of R7and R8is different from H, preferably at least one, preferably one of R7and R8is selected from the group consisting of a substituted aryl, in particular a C6-C10 aryl, and a substituted heteroaryl, in particular a 5 to 10 10 membered heteroaryl and preferably at least one of R7and R8is selected from a group having the formula A1 or in the non-N-substituted form A1.1 15 wherein (1) means the point of attachment to general formula (X) or optionally (X.1) wherein R14is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2- 20 C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R14is selected from H and methyl, (or in an alternative embodiment R14is a group as defined for R16below, provided that R16is a group as defined for R14in the previous paragraph), R15is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair25 of said C2-C3 alkenyl is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15is selected from H and methyl, (or in an alternative embodiment R15is a group as defined for R16below, provided that R16is a group as defined for R15in the previous paragraph), 30 R16is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C6 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- P138182SG 12 heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, and a substituted amine or amide wherein preferably said amide is bound via the carbonyl to the pyrrole 5 ring thereby the π electrons of the oxo group forming part of the conjugated system of the pyrrole ring, said amine or amide substituent in R16being selected from - substituent 1 (S1) being a C1-C8 alkyl (preferably C1-C4 or C2-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 10 alkyl or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertier amine, (i.e. said amine being a secondary or tertiary amine), and a group as defined as substituent S2below, - substituent 2 (S2) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group 15 having the formula X-R10wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl and C1-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, and R10is selected from a 5 to 10 membered heterocycle or a C6-C10 aryl, optionally further substituted with 1 to 4 membered group selected from alkyl, alkenyl, amide, carboxyl alkylcarbonyl, alkoxy and halogenide, 20 - substituent 3 (S3) being a polyether, preferably a polyethylene glycol, wherein the number ether - O- is 2 to 12, preferably 3 to 9, (or in an alternative embodiment R16is a group as defined for R15or a salt or solvate thereof, - substituent 4 (S4) and substituent 5 (S5), together with the N atom to which they are attached form a 5 to 10 membered (preferably 5 to 6 membered) heterocycle optionally further containing 125 additional N heteroatom, said heterocycle may be substituted with a group having the formula X- R100wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C1-C3 alkenyl, and R100is selected from C1-C3 alkyl and OH; and R17, if present, is selected from H and optionally an in vivo metabolizable group whereby the 30 compound is a prodrug; preferably an intracellularly metabolizable group; preferably R17, once present, is - a substituted or unsubstituted C1-C4 alkyloxy group linked via a carbon to the nitrogen atom of the oxindole structure (in particular a C1-alcoxy, preferably a CH2-O- moiety) preferably acylated to be an ester by an -C(O)-R41group, wherein R41is selected from the group consisting of OR42, SR42, and 35 N(R42)2; and R41or R42is selected from the group consisting of -H, unsubstituted or substituted C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C4 alkenyl, in particular a C1-C6 P138182SG 13 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1- C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a 5 substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, said substituent of the C1-C4 alkyloxy group if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, 10 and -NHMe, or R17is a or a C(O)-R33group forming an amide bond with the ring N, wherein R33group is selected from C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl, preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C6 alkenyl, in particular a C1-C4 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or 15 a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, wherein in a particular embodiment said R33group is selected from a C1-C8 alkyl, in particular a C1-C4 alkyl, 20 wherein the said alkyl, has a substituent (is substituted by a group selected from) a 4-15 membered heterocyclyl, in a particularly preferred embodiment R17comprises a biotinyl group with or without a linker, or in an alternative embodiment R17is selected from a substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C8 alkylester, C3-C8 alkenylester or C3-C8 alkynylester, said25 substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, - NHMe, or R17is a substituted or unsubstituted C1-C4 alkyloxy group linked via the alkyloxy oxygen to the ring N forming an N-O bond, said substituent on the C1-C4 alkyloxy group (in particular a C1- alcoxy, preferably a CH2-O- moiety), if any, being selected from the group consisting of H, C1-C6 alkyl, 30 C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, and - NHMe; or preferably R7 is a C5-C10 aryl, preferably a C6 aryl, more preferably a phenyl, and 35 R8 is a substituted or unsubstituted arylamine, preferably a substituted arylamine, said arylamine comprising a C5-C10 aryl, or 5 or 6 membered heteroaryl, preferably a heteroaryl comprising 1 or 2 nitrogen, wherein preferably R8 is a substituted arylamine preferably phenylamine having the formula (B1) P138182SG 14 wherein R24 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair 5 of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24 is selected from H and methyl, (or in an alternative embodiment R24 is a group as defined for R26 below, provided that R26 is a group as defined for R24 in the previous paragraph), 10 R25 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15 is selected from H and methyl, and 15 R26 is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C6 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 20 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe,), and a substituted amine or amide wherein preferably said amide is bound via the N to the aryl ring of R8, said amine or amide substituent in R26 being selected from 25 - substituent 6 (S6) being a C1-C8 alkyl (preferably C1-C4 or C1-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl and a group as defined as substituent S7 below, 30 - substituent 7 (S7) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably selected from a 5 to 10 membered heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, P138182SG 15 a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, e.g. pyrrolidine, or piperazine, wherein said heterocycle being optionally substituted with one or two C1-C4 or C1-C3 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C3 alkyl; 5 R27is H; In a preferred embodiment the compound for use according to the invention, preferably any of paragraphs 1 to 7, in particular paragraph 6 or 7, has formula (X.1) whereas the substitutents, preferably the substitutents R2, R3, R4, R5, R7and R8, are as defined above or as defined herein: 10 in any one of the respective paragraphs and an azide substituent, wherein at least one of R2, R3, R4and R5is an azide. In a preferred embodiment one or two, preferably one of R2, R3, R4and R5is an azide. In a preferred embodiment one, two or three, in particular two or three, more particularly two of R2, R3, R4and 15 R5is H, even more preferably R2and R5is H, and one of R3and R4is an azide. In a particular embodiment any one of R2, R3, R4and R5which is different from an azido group, is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, OEt, -NO2, -NH2, -NHMe, -COOH, -CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular H or a halogenide, more particularly a halogenide. In particular, one of R3and R4which is 20 different from an azido group is halogenide or pseudohalogenide. In a preferred embodiment the oxindole derivative of the invention for use as defined herein, preferably the oxindole derivative VEGFR2 inhibitor has a general formula (X.2.1) or its N-substituted prodrug variant (X.2.) 25 P138182SG 16 wherein in the formula R1is an azido group and may be connected to any carbon atom of the benzene ring of the indole moiety, preferably to carbon 5 or 6, R7and R8are as defined above or herein. 5 In a preferred embodiment R7and R8are as defined for moiety A1 or A1.1. In further a preferred embodiment R7and R8are as defined for moiety B1 or B1.1. The skilled person will understand that the benzene ring of the oxindole group may be substituted at any other position as taught for any of formulae X1, X.2, I or II, preferably by a single further substitutent, preferably the said single further substituent is a halogenide, preferably in particular Cl or F, preferably as 10 substituent R3or R4, wherein, R6, if present, is as defined herein, in paragraph 8. 9. The invention relates to a compound for use in treating a subject suffering from an ocular disease that involves a targetable endogenous biomolecule (such as a receptor or an enzyme), said compound comprising 15 - a conjugated electron system - an active agent moiety, said moiety being a modulating entity (preferably a ligand or a substrate, including a functional analogue of a natural ligand or a functional analogue of a natural substrate) and thereby being useful for treatment of said ocular disease, - an azide (N3) moiety comprising an azido group, 20 wherein the π electrons of the azido group extend the conjugated electron system to form an extended conjugated electron system. In a preferred embodiment the invention relates to a compound for use according to any of paragraphs 1, 2, 3, 4, 5, 6, 7 or 8, in particular any one of paragraphs 5 to 8, for use in treating a subject suffering from an ocular disease that involves a targetable endogenous biomolecule (such as a receptor or 25 an enzyme). Preferably the subject suffers from ocular neovascularization and / or the mechanism of action of the said compound is based on inhibiting the said ocular neovascularization. Preferably the pharmaceutical composition is for use in the prevention or reduction of ocular neovascularization in the subject. 30 Preferably the said ocular disease being selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), 35 - retinal vein occlusion (RVO), - open angle glaucoma (OAG), - angle closure glaucoma (ACG), - congenital glaucoma (CoG). P138182SG 17 Preferably said ocular disease being selected from neurodegenerative conditions in glaucoma, preferably neurodegeneration in OAG, ACG or CoG. Preferably said ocular disease being selected from any other ocular disease where a targetable endogenous biomolecule is part of the pathomechanism. 5 More preferably the said ocular disease involves neovascularization, preferably neovascularization that can be blocked by the inhibition of ocular VEGF signaling or by the inhibition of the ocular VEGFR2 receptor. 10. In a particularly preferred embodiment the invention relates to a compound having general formula (I.1) or the non-N-substituted variant (I.1.1), preferably a compound for use according to any of 10 paragraphs 1 to 9, in particular paragraphs 1, 2, 3, 4, 5 or 9, preferably said compound having general formula (I.1) or (I.1.1) has general formula (I.3) or (I.3.1), respectively,15 i.e. said compound comprising a „pyrrol-methylidene-oxindole” (3-[(1H-pyrrol-2-yl)methylidene]- 1,3-dihydro-2H-indol-2-one) moiety, wherein in the formula wherein R2, R3, R4and R5and, if present, R6, are as defined in paragraph 8 and at least one of R2, 20 R3, R4and R5is azido, preferably at least one of R2, R3, R4and R5is an azido group (N3); P138182SG 18 wherein any one of R2, R3, R4and R5which is different from an azido group, is selected from the group consisting of -H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular H or 5 halogenide, -substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1- C4 alkenylcarbonyl, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl- heteroaryl, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, - NO2, -NH2, -NHMe, preferably -OH, -OMe, -NH2, -NHMe and halogenide, more preferably halogenide, 10 wherein preferably at least one of R21and R22is H, Me or Et, preferably H or Me, -NR21R22, wherein R21and R22are, selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, preferably -OH, -OMe, -NH2, -NHMe and halogenide, more preferably halogenide, wherein preferably at 15 least one of R21and R22is H, Me or Et, preferably H or Me, -SO2NR23R24, wherein R23and R24are, independently selected from H, substituted or unsubstituted C1-C4, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, - OMe, - NO2, -NH2, -NHMe, preferably -OH, -OMe, -NH2, -NHMe and halogenide, more preferably halogenide, 20 wherein preferably at least one of R21and R22is H, Me or Et, preferably H or Me, wherein preferably at least one of R23and R24is H, Me or Et, -ureido, preferably aryl-ureido or heteroaryl-ureido, preferably phenyl-ureido optionally substituted with (preferably in para position) C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular C1-C2 alkoxy, 25 halogenide, methyl or unsubstituted, highly preferably (para-metoxy-phenyl)-ureido, wherein at least one of R2, R3, R4and R5is azido (preferably one or two, preferably one of R2, R3, R4and R5is azido); R6is selected from H and a group as described above in paragraph 8, preferably H; and R7is selected from the group consisting of H, a substituted or unsubstituted amine, preferably a 30 C1-C5 amine, amide, preferably a C1-C5 amide, C1-C6 alkyl, C2-C6 alkenyl, preferably a C2-C3 alkenyl, a C1-C6 carbonyl, (preferably a C2-C6 alkylcarbonyl, C3-C6 alkenylcarbonyl, C3-C6 alkynylcarbonyl,) a C1-C6 carboxyl, (preferably a C2-C6 alkylcarboxyl, C3-C6 alkenylcarboxyl, C3- C6 alkynylcarboxyl) a C1-C6 carboxylate ester, (preferably a C2-C6 alkylester, C3-C6 alkenylester or C3-C6 alkynylester), wherein if R7is substituted, said substituent, if any, being selected from 35 halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, wherein R7is preferably H, R32is selected from the group consisting of H, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1- C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkyl amido and phosphate group, P138182SG 19 said substituent on the C1-C4 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety), if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, and -NHMe, 5 R14is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, R14is selected from H and methyl, R15is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair 10 is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, R15is selected from H and methyl, R16is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, 15 -C(O)H, C2-C4 alkylcarbonyl, C3-C4 alkenylcarbonyl, C3-C4 alkynylcarbonyl, C1-C4 alkylamide, C1-C4 amide, carboxyl, C2-C4 alkylcarboxyl, a C3-C4 alkenylcarboxyl, a C3-C4 alkynylcarboxyl, and a C2-C4 carboxylate ester said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, - OMe, -NO2, -NH2, -NHMe, and, preferably, a substituted amine or amide wherein preferably said amid is bound via the carbonyl to 20 the pyrrole ring thereby the π electrons of the oxo group forming part of the conjugated system, said amine or amide substituent being selected from - substituent S1being a C1-C4 alkyl (preferably C1-C4 or C2-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl 25 or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertier amine, (i.e. said amine being a secondery or tertiery amine), and a group as defined as substituent S2below, - substituent S2being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group 30 having the formula X-R10wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C1-C3 alkenyl and C1-C3 alkoxy), O, S, C1-C3 alkyl and C1-C3 alkenyl, and R10is selected from a 5 to 10 membered heterocycle or a C6-C10 aryl, optionally further substituted with 1 to 4 membered group selected from alkyl, alkenyl, amide, carboxyl alkylcarbonyl, alkoxy and halogenide, 35 substituent S3being a polyether, preferably a polyethylene glycol, wherein the number ether -O- is 2 to 12, preferably 3 to 9, (or in an alternative embodiment R16is a group as defined for R15- substituent S4and substituent S5, together with the N atom to which they are attached form a 5 to 6 membered heterocycle, optionally further containing 1 additional N heteroatom, said heterocycle may be substituted with a group having the formula X-R100wherein X is selected P138182SG 20 from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, and R100is selected from C1-C3 alkyl and OH. In a particular embodiment wherein R2, R3, R4and R5is selected from ureido (preferably phenyl- ureido optionally substituted with (preferably in para position) C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 5 C1-C4 alkoxy, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular C1-C2 alkoxy, halogenide, methyl or unsubstituted, highly preferably (para-metoxy-phenyl)-ureido), then R14and R15are, independently, selected from H and C1-3, preferably C1-C2 alkyl, in particular methyl, R16is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 10 C1-C4 alkoxy, -C(O)H, C2-C4 alkylcarbonyl, C3-C4 alkenylcarbonyl, C3-C4 alkynylcarbonyl, C1-C4 alkylamide, C1-C4 amide, carboxyl, C2-C4 alkylcarboxyl, a C3-C4 alkenylcarboxyl, a C3-C4 alkynylcarboxyl, and a C2-C4 carboxylate ester said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, preferably H, carboxyl and C2-C4 alkylcarboxyl, 15 R17, if present, is selected from H and a group as defined in paragraph 8; and R42is selected from the group consisting of H, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1- C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkyl amido and phosphate group, said substituent C1-C4 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety), if 20 any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, and -NHMe. The skilled person will understand that the biological effect is particularly present in case of Z configuration shown in formulae I.3 and I.3.1. 25 In a preferred embodiment said compound having general formula (I.1) or (I.1.1) has general formula (I.2) or (I.2.1), respectively, 30 wherein R1 is an azido group and any or each other substitutents are as defined in the present paragraph or in any numbered paragraph below. P138182SG 21 10.b In a particularly preferred embodiment the invention relates to a compound having general formula (I.4) or (I.5) preferably a compound for use according to any of paragraphs 1 to 9, in particular paragraphs 1, 2, 3, 4, 5 or 9, 5 wherein R2, R3, R4, R5 and R7 are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), (I.3) or (I.3.1) R24is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair10 of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24is selected from H and methyl, (or in an alternative embodiment R24 is a group as defined for R26 below, provided that R26 is a group as defined for R24 in the previous paragraph), 15 R25is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15is selected from H and methyl, and 20 R26 is selected from P138182SG 22 H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C6 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 5 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe,) and a substituted amine or amide wherein preferably said amide is bound via the N to the aryl ring of R8, said amine or amide substituent in R26being selected from 10 - substituent 6 (S6) being a C1-C8 alkyl (preferably C1-C4 or C1-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl and a group as defined as substituent S7below, 15 - substituent 7 (S7) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably selected from a 5 to 10 membered heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, 20 a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, e.g. pyrrolidine, or piperazine, wherein said heterocycle being optionally substituted with one or two C1-C4 or C1-C3 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C3 alkyl; R27 is H. 25 Figure I.5 is preferred for the purpose of medical treatment, as the skilled person will understand that the biological effect is particularly present in case of Z configuration shown in formula I.5. Preferably the subject to be treated suffers from ocular neovascularization and / or the mechanism of action of the said compound is based on inhibiting the said ocular neovascularization. Preferably, the pharmaceutical composition is for use in the prevention or reduction of ocular neovascularization in the 30 subject. Preferably said ocular disease being selected from any other ocular disease where a targetable endogenous biomolecule is part of the pathomechanism. Preferably the said ocular disease being selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), 35 - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), - retinal vein occlusion (RVO), - open angle glaucoma (OAG), P138182SG 23 - angle closure glaucoma (ACG), - congenital glaucoma (CoG). Preferably said ocular disease being selected from neurodegeneration in glaucoma, preferably neurodegeneration in OAG, ACG or CoG. 5 The invention also relates to a compound for use according to the invention in reducing, arresting or blocking the growth of a localized tumor that is present in a subject, or reducing, arresting or blocking the spreading of tumor metastases within the body of a subject, in a method comprising photoactivation of said compound at the tumor site. More preferably the said ocular disease involves neovascularization, preferably neovascularization 10 that can be blocked by the inhibition of ocular VEGF signaling. 11. In a preferred embodiment the compound has general formula (II) or (II.1) or (II.2), preferably a compound for use according to paragraph 10, R12O R15 15 (II) (II.1) (II.2) wherein in the formula R2, R3, R4 and R5 are selected from the group as defined above in paragraph 20 7, 8 or in paragraph 10, preferably paragraph 8 or 10 (preferably for formula X.1 or preferably for formula I.1), wherein at least one of R2, R3, R4 and R5 is azido or preferably one of R2, R3, R4 and R5 is an azido group (N3); P138182SG 24 wherein any one of R2, R3, R4and R5which is different from an azido group, is selected from the group consisting of - -H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, - COOH, CONH2-CF3; preferably -H, halogenide, pseudohalogenide, -OMe, -OH, -SH, 5 -substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkenylcarbonyl, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl-heteroaryl, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, preferably halogenide, -OH, -OMe, -NH2, -NHMe, preferably H and halogenide, 10 -NR21R22, wherein R21and R22are, selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C3 alkyl and C1-C3 alkoxy, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, preferably -OH, -OMe, -NH2, -NHMe and halogenide, more preferably halogenide, wherein preferably at least one of R21and R22is H, Me or Et, preferably H or Me, 15 -SO2NR23R24, wherein R23and R24are, independently selected from H, substituted or unsubstituted C1-C3, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R23and R24is H, Me or Et, 20 - phenyl-ureido optionally substituted in para position with C1-C3 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 alkoxy, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular C1-C2 alkoxy, halogenide, methyl or unsubstituted, highly preferably (para-metoxy- phenyl)-ureido, wherein R14, R15and R7is as defined in paragraph 8 or 10, preferably as defined paragraph 10, 25 wherein preferably R12and R13is independently selected from H, C1-C4 or C2-C3 alkyl, preferably substituted with a substituent selected from one or two C1-C4 or C2-C3 alkyl, N(C1-C3alkyl)2or a polyether, preferably a polyethylene glycol, wherein the number ether -O- is 2 to 12, preferably 3 to 9, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine), wherein optionally R15and R13or R14(together with the backbone atoms) form a 5 to 8 membered 30 heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered, in particular a 6 membered heterocycle, or a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, e.g. pyrrolidine, that is optionally substituted with -C(O)N(C1-C3alkyl)2; or R12and R13together with the N atom to which they are attached form a 5 to 6 membered 35 heterocycle, optionally further containing 1 additional N heteroatom, e.g. pyrrolidine or piperazine, said heterocycle may be substituted with hidroxy-C1-C3 alkyl or N(C1-C3alkyl)2In a preferred embodiment in formula (II) one of R2, R3, R4and R5is azido, P138182SG 25 and one or two preferably one of R2, R3, R4and R5is a halogen, pseudohalogen, OH, or OMe, preferably a halogen and the other one or two preferably two of R2, R3, R4and R5is H. Preferably, R14, R15and R7is as defined in paragraph 10, preferably 5 R14is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair is conjugated with the π electron system of the pyrrole ring, R15is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair is conjugated with the π electron system of the pyrrole ring, R7is H or a C6-C10 aryl or a 5 to 10 membered heterocycle, preferably heteroaryl; preferably H 10 R12and R13is selected from H, C1-C8 alkyl (preferably C1-C4 or C2-C3 alkyl) preferably substituted with a substituent selected from one or two C1-C4 or C2-C3 alkyl or a polyether, preferably a polyethylene glycol, wherein the number ether -O- is 2 to 12, preferably 3 to 9, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine), wherein optionally R15and R13or R14(together with the backbone atoms) form a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 15 membered, preferably a 5 or 6 membered, in particular a 6 membered heterocycle, or amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine), R6and R17are, independently, as defined in paragraph 8 or 9, or preferably, 20 R6is selected from H and a substituted or unsubstituted C1-C4 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety) preferably acylated to be an ester by an -C(O)-R31group, wherein R31is selected from the group consisting of OR32, SR32, and N(R32)2; and R31and / or R32is / are, independently, as defined in paragraph 8 or 9, or in a particularly preferred embodiment R6is a biotinyl group 25 R17, if present, is selected from H and an intracellularly metabolizable group; preferably R17, once present, is a substituted or unsubstituted C1-C4 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety) preferably acylated to be an ester by an -C(O)-R41group, wherein R41is selected from the group consisting of OR42, SR42, and N(R42)2; and R31and / or R42is / are, independently, as defined in paragraph 8 or 9 30 or in a particularly preferred embodiment R6comprises a biotinyl group. 11.b. In a preferred embodiment the compound has general formula (II.4), preferably a compound for use according to paragraph 10.a, P138182SG 26 wherein R2, R3, R4, R5and R7are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), (I.3) or (I.3.1), preferably R7 is phenyl 5 R24 and R25 are, independently, selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24 is selected from H and methyl, R28 and R29 are, independently, 10 R28 and R29 is independently selected from H, C1-C4 or C2-C3 alkyl, preferably substituted with a substituent selected from one or two C1-C4 or C2-C3 alkyl, or a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, e.g. pyrrolidine, that is optionally substituted with a C1-C4 or C2-C3 alkyl or R28 and R29 together with the N atom to which they are attached form a 5 to 6 membered 15 heterocycle, optionally further containing 1 additional N heteroatom, e.g. pyrrolidine or piperazine, said heterocycle may be substituted with a C1-C4 or C1-C3 alkyl, preferably R28 and R29 together with the N atom to which they are attached form a piperazine, wherein said piperazine may be substituted with a C1-C4 or C1-C3 alkyl or C1-C2 alkyl, 20 preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C2 alkyl; R27 is H; R30, if present, is selected from H and C1-C4 alkyl, preferably H and C1-C2 alkyl. 25 12. The invention relates to a compound for use according to any of paragraphs 10 to 11 for use in the treatment of a disease as defined in paragraph 9. 13. The invention relates to a compound for use according to any of paragraphs 10 to 11 for use in the treatment of an ocular disease selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), P138182SG 27 - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), - retinal vein occlusion (RVO), 5 - open angle glaucoma (OAG), - angle closure glaucoma (ACG), - congenital glaucoma (CoG). Preferably said ocular disease being selected from neurodegenerative conditions in glaucoma, preferably neurodegeneration in OAG, ACG or CoG. 10 Preferably said ocular disease being selected from any other ocular disease that involves neovascularization, preferably neovascularization that can be blocked by the inhibition of ocular VEGF signaling. In a particular embodiment the invention relates to a compound for use according to any of paragraphs 10 to 11 for use in the treatment of an ocular disease where ocular neovascularization is part of 15 the pathomechanism. In a particular embodiment the invention relates to a compound for use according to any of paragraphs 10 to 11 for use in the prevention or reduction of ocular neovascularization in a mammalian subject. 14. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13, said 20 compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), P138182SG 29 ) or in an embodiment said compound having general formula selected from the group consisting of 5 general formulae (V), (VI), (VII), (VIII), (IX: (VI) P138182SG 30 (IX) 5 wherein R1is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or an azido group connected to carbon 6 of the indole-2-one moiety, and R4is selected from the group consisting of P138182SG 31 H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular halogenide, highly preferably F or Cl; and in preferred embodiments, R6group on the nitrogen atom of the indoline-2-one moiety is present 5 to create a prodrug and is as defined in paragraphs 8, 9, 10 or 11. In still alternative, less preferred embodiments, R17group is present on the nitrogen atom of the indoline-2-one moiety may be present and is as defined in paragraphs 8, 9, 10 or 11. 14.b. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13, said compound having general formula selected from the group consisting of general formula (XI.1) 10 wherein R1 is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or an azido group connected to carbon 6 of the indole-2-one moiety, and R4 is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, 15 CONH2 -CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular halogenide, highly preferably F or Cl, in preferred embodiments, R6 group on the nitrogen atom of the indoline-2-one moiety is present to create a prodrug and is as defined in paragraphs 8, 9, 10 or 11 or R6 is H. or in an embodiment said compound having general formula (XI): P138182SG 32 wherein R1 and R4 are as defined above. Alternatively, in any of formulae (XI) and (XI.1) R1 is selected from the group consisting of 5 H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2 -CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular halogenide, highly preferably F or Cl, and R4 is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or an azido group connected to carbon 6 of the indole-2-one moiety, 10 and R6, if present, is as defined above. 15. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13, said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1), (VIII.1), (IX.1) and (XI.1) 15 or in an embodiment general formulae (V), (VI), (VII), (VIII), (IX) and (XI): wherein R1 is connected to carbon 4, 6 or 7 of the indole-2-one moiety or connected to carbon 6 of the indole-2-one moiety and is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular H and halogenide, highly preferably F or Cl and R4 is an azido group, and 20 in preferred embodiments, R6 group on the nitrogen atom of the oxindole moiety is present to create a prodrug and is as defined in paragraphs 8, 9, 10 or 11. In still alternative less preferred embodiments, R17 group on the nitrogen atom of the oxindole moiety is present and is as defined in paragraphs 8, 9, 10 or 11. 16. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13, 25 obtained by modifying benzene ring of the PMO in sunitinib and is selected from the following compounds having formula (1), (2), (3), (4), (5), and (6), that were also synthetized to provide a proof-of-concept of the invention (Figures 2-7) or compounds having the same formula but having an R6 group on the nitrogen P138182SG 33 atom of the oxindole moiety to create a prodrug and said R6group being defined in any of paragraphs 8, 9, 10 or 11. (1) 5-desfluoro-5-azido-sunitinib / 5- [(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]-2,4-dimethyl-1H- 5 pyrrole-3-carboxamide (Ex.2) (EYE1052) (2) 5-desfluoro-6-azido-sunitinib / 5- [(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4-dimethyl- 1H-pyrrole-3-carboxamide (Ex 1) (EYE1028) 10 (4) 5-desfluoro-5-azido-6-fluoro- sunitinib / 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (Ex 6) (EYE1091) P138182SG 34 (5) 5-desfluoro-5-azido-6-chloro-sunitinib / 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino) ethyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide (Ex 17) (EYE1090) (6) 5-desfluoro-5-azido-6-bromo- 5 sunitinib / 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Ex 7) (EYE1093) 17. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13, preferably obtained by modifying benzene ring of the PMO in vorolanib and is selected from the following 10 compounds that were also synthetized to provide a proof-of-concept of the invention (Figures 8-9), and compounds having the same formula but having an R6 group on the nitrogen atom of the oxindole moiety to create a prodrug and said R6 group being defined in any of paragraphs 8, 9, 10 or 11: 5-desfluoro-6-azido-vorolanib / 5- [(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethylcarbamoyl )pyrrolidin- 15 3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Ex 8) (EYE1088) P138182SG 35 (dimethylcarbamoyl )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Ex.13) (EYE1118). Alternatively, the compound is selected from the group consisting of 5 Ex.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1013) Ex.5) ethyl 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1056) Ex.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl 10 carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1114) Ex.10.) Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1063) Ex.11) 5-[(Z)-(6-azido-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1087) 15 Ex.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1116) Ex.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1112) Ex.15) (3Z)-6-azido-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- 20 yl]methylene]indolin-2-one (EYE1068) Ex.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one (EYE1094) 18. In a preferred embodiment the compound for use according to any of paragraphs 1 to 13,25 preferably obtained by modifying N-[4-[[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)-phenyl- methyl]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2831N) to obtain an azidated variant thereof: P138182SG 36 (9) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide Ex.18, (EYE1309). 5 In a preferred embodiment said compound is capable of binding to the biological target (preferably a receptor or an enzyme) in an assay, preferably in vitro. 19. In a preferred embodiment said compound is capable of inhibiting VEGFR2 in a VEGFR2 inhibition assay, preferably in vitro. In an embodiment the compound is capable of modulating, preferably inhibiting multiple kinases, 10 i.e. preferably is a multikinase inhibitor; wherein said kinases are preferably biological targets as defined herein. These functional features can be tested by a skilled person and a particularly useful compound can be selected by a person skilled in the art. 20. The invention also relates to a pharmaceutical composition, including but not limited to oral 15 compositions for ophthalmic use said composition comprising a compound as defined in any one of paragraphs 1 to 19, in particular in any one of paragraphs 8, 10, 11, 14, 16 or 17 and a pharmaceutically acceptable excipient. Preferably said oral compositions are protected from ambient light in their packaging. The invention also relates to a pharmaceutical composition, including but not limited to eyedrop compositions for ophthalmic use, the said composition comprising a compound as defined in any one of 20 paragraphs 1 to 19, in particular in any one of paragraphs 8, 10, 11, 14, 16 or 17 and a pharmaceutically acceptable excipient. The said eyedrop compositions are protected from ambient light in their packaging. The active compound in of the eyedrop formulation is also protected from light when applied on the corneal surface by using (i) a fully solubilized complex with a photoprotective cyclodextrin, (ii) a suspension with photoprotective liposomes, (iii) or an equivalent solution that serves the protection of the active product 25 ingredient from light. 21. The invention preferably relates to an oral pharmaceutical composition for ophthalmic use, said pharmaceutical composition being protected from light. In one possible embodiment a non-transparent P138182SG 37 capsule protects the formulation from light. In a further embodiment a photoprotective liposome or a photoprotective cyclodextrin protects the compound. 22. The invention preferably relates to an oral pharmaceutical composition for use according to any of paragraphs 20 to 21 against a disease as defined in any of paragraphs 1 to 9, preferably paragraph 4, 9 5 or 13, preferably paragraph 9. 23. In a preferred embodiment the pharmaceutical composition is for use in the treatment of an ocular disease where a targetable ocular biomolecule is part of the pathomechanism, preferably as defined in any one of the respective paragraphs herein. Preferably, the pharmaceutical composition is for use in the prevention or reduction of ocular 10 neovascularization in a subject. Preferably the invention relates to the pharmaceutical composition for use according to any of paragraphs 8, 10, 11, 14, 16 or 17 in particular any of paragraphs 10, 11, 16, 17 for use in the treatment of an ocular disease selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), 15 - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), - retinal vein occlusion (RVO). In an embodiment the ocular disease is glaucoma. 20 24. The invention also relates to a method of treating a patient in need of ophthalmic treatment, having a disease as defined in any of the above paragraphs, preferably in any of paragraphs 4, 9 and 13 comprising administering the pharmaceutical composition to said patient. In an embodiment the patient’s eye is illuminated after administration by ambient light. The invention also relates to and teaches a method for treatment of a disease as defined in paragraph 25 9 in a subject in need thereof comprising - administering orally a compound as defined in any of paragraphs 1 to 18, preferably in paragraph 8, 10, 11, 16 or 17 or a pharmaceutical composition according to any of paragraphs 20 to 22, - allowing ambient light entering the eye to photoactivate said compound and elicit the covalent binding of the said compound to the ocular target biomolecule. 30 The invention also relates to a method of treating a patient in need of ophthalmic treatment, having a disease as defined in any of the above paragraphs, preferably in any of paragraphs 4, 9 and 13 comprising administering the orally formulated pharmaceutical composition orally to said patient. The invention also relates to a method of treating a patient in need of ophthalmic treatment, having a disease as defined in any of the above paragraphs, preferably in any of paragraphs 4, 9 and 13 comprising 35 administering the pharmaceutical composition, formulated as an eye-drop, to said patient via direct application onto the eye. The invention also relates to and teaches a method for treatment of a disease as defined in paragraph 4, 9, 13 or 23, preferably in paragraph 9 in a subject in need thereof comprising: P138182SG 38 - administering an eyedrop formulation that comprises the azidated compound and a photoprotective coating (such as a liposome,a cyclodextrin or an equivalent photoprotective agent) to target the said compound to the desired part of the eye. - allowing enough time for the photoprotected active product ingredient to leave the surface of the 5 eye, to be absorbed and to accumulate in the targeted ocular tissue - allowing ambient light entering the eye to photoactivate said compound an elicit the covalent binding of the said compound to the ocular target biomolecule. 25. The method for treatment as defined in paragraph 24 wherein the ambient light is provided artificially, preferably by illumination by a light source providing polychromatic light. 10 Preferably the light has a spectrum having a wavelength of at least 350 nm, preferably at least 400 nm, and up to 800 nm, preferably up to 600 nm or as defined herein. Preferably the light has a spectrum of at least 100 nm wide, preferably at least 200 nm wide, in a wavelength-range spanning from at least 350 nm, preferably at least 400 nm, and up to 800 nm, preferably up to 600 nm. 15 Preferably the light is or comprises visible light. Preferably the light is white light. 26. The invention also relates to and teaches a method of treatment wherein the light is provided artificially. In an embodiment the light is provided by a wearable apparatus. 20 In an embodiment the light is provided by an apparatus which can engage the subject. In an embodiment the light is provided in a room wherein the subject is present. 27. According to the invention, preferably in any one of paragraphs 1 to 26, the subject is a vertebrate subject, preferably a mammalian subject. Highly preferably the subject is a human subject. Preferably the subject is a patient diagnosed with an ocular disease. 25 Preferably the patient is diagnosed with a disease as defined in paragraph 9. Preferably the patient is diagnosed with a disease as defined in paragraph 23. 28. A compound having general formula (I.1) or (I.1.1) 30 P138182SG 39 wherein in the formula R2, R3, R4, R5R7, R14, R15and R16are as defined in paragraph 10, preferably, where appropriate, as defined in paragraph 11. Preferably said compound having general formula (I.1) has general formula (I.3) or (I.1.1) has 5 general formula (I.3.1), (I.3) (I.3.1) i.e. compound comprising a „pyrrol-methylidene-oxindole” (3-[(1H-pyrrol-2-yl)methylidene]-1,3- dihydro-2H-indol-2-one) moiety, 10 wherein any or each of the substituents are R2, R3, R4, R5 R7, R14, R15 and R16 are as defined in paragraph 10, preferably, where appropriate, as defined in paragraph 11. In a preferred embodiment said compound having general formula (I.1) has general formula (I.2), (I.2) 15 wherein R1 is an azido group and any or each other substutents are as defined in the present paragraph or in any numbered paragraph below. 29. The compound according paragraph 28, wherein said compound has general formula (II) or (II.1) P138182SG 40 wherein R2, R3, R4, R5R7, R12, R13, R14, R15and R16are as defined in paragraph 11. 30. The compound according to any of paragraphs 28 to 29, said compound having general formula 5 selected from the group consisting of general formulae (V.1), (VI.1), (VII.1), (VIII.1), (IX.1) and (XI.1) or general formulae (V), (VI), (VII), (VIII), (IX) and (XI) as defined in paragraph 14, preferably wherein R1is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or an azido group connected to carbon 6 of the indole-2-one moiety, and R4is selected from the group consisting of 10 H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, in particular halogenide, highly preferably Cl or F; and in preferred embodiments, R6group on the nitrogen atom of the indoline-2-one moiety is present to create a prodrug and is as defined in paragraphs 8, 9, 10 or 11. 15 31. The compound according to any of claims 28 to 29, said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1), (VIII.1), (IX.1) and (XI.1) or general formulae (V), (VI), (VII), (VIII), (IX) and (XI) as defined in paragraph 14, preferably wherein R1is connected to carbon 4, 6 or 7 of the indole-2-one moiety or connected to carbon 6 of the indole-2-one moiety and is selected from the group consisting of H, Me, halogenide, pseudohalogenide, 20 -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular H and halogenide, highly preferably Cl or F and P138182SG 41 R4is an azido group. 32. The compound according to any of paragraphs 28-29, preferably obtained by modifying benzene ring of the PMO in sunitinib, wherein said compound is selected from the following compounds: 5-desfluoro-5-azido-sunitinib, shown on formula (1), 5 5-desfluoro-6-azido-sunitinib, shown on formula (2), 6-azido-sunitinib, shown on formula (3), 5-desfluoro-5-azido-6-fluoro-sunitinib, shown on formula (4), 5-desfluoro-5-azido-6-chloro-sunitinib, shown on formula (5), 5-desfluoro-5-azido-6-bromo-sunitinib, shown on formula (6), 10 that were also synthetized to provide a proof-of-concept of the invention (Figures 2-7): 33. The compound according to any of paragraphs 28-29, preferably obtained by modifying benzene ring of the PMO in vorolanib, said compound being selected from the following compounds that were also synthetized to provide a proof-of-concept of the invention (Figures 8-9): (7) 5-desfluoro-5-azido-vorolanib, shown on formula (7) 15 (8) 5-desfluoro-5-azido-6-chloro-vorolanib, shown on formula (8). Preferably, unless otherwise defined herein, C1-C8 may be C1-C6, in particular C1-C4, highly preferably C1-C3, C2-C8 may be C2-C6, in particular C2-C4, highly preferably C2-C3, and 20 C3-C8 may be C3-C6, in particular C3-C4, highly preferably C3, throughout the paragraphs above or the claims. 34. Use of a compound described in any of paragraphs 1 to 17 or a compound according to any of paragraphs 23 to 33 in an assay, said compound binding to the biological target (preferably a receptor or an enzyme) preferably in vitro. 25 35. Use of a compound described in any of paragraphs 1 to 17 or a compound according to any of paragraphs 23 to 33 in an assay said compound inhibiting VEGFR2 in a VEGFR2 inhibition test, preferably in vitro. 36. The compound according to paragraph 28 selected from E.1) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 30 2,4-dimethyl-1H-pyrrole-3-carboxamide E.2) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide E.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide 35 E.4) 5-[(Z)-(6-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide E.5) Ethyl 5-[(Z)-(5-azido-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylate P138182SG 42 E.6) 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide E.7) 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 5 E.8) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide E.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide E.10. Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- 10 pyrrole-3-carboxylate E.11) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one E.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 15 E.13) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide E.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide 3156A1 E.15) (3Z)-6-azido-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- 20 yl]methylene]indolin-2-one BSZ2758AAT E.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one E.17) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 25 40. The compound according to paragraph 28 selected from E.18) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (EYE1309) 30 DEFINITIONS A “subject” as used herein is an individual of an animal species, preferably a vertebrate, more preferably a mammalian or avian species, in particular a mammalian species, highly preferably the individual is a primate, a hominid or a human. A “patient” is a subject who is or intended to be under medical or veterinarian observation, supervision, diagnosis or treatment. 35 A “treatment” of a subject refers to any process, action, therapy, or the like, wherein the subject or patient is under aid, in particular medical or veterinarian aid with the object of improving the subject’s or patient’s condition, either directly or indirectly. Improving the subject’s condition may include restoring or maintaining normal function of an organ or tissue, preferably at least partly restoring or maintaining health P138182SG 43 (medical or veterinarian treatment). Treatment typically refers to the administration of an effective amount of a compound or composition described herein. In a broader sense treatment includes both medical or veterinarian treatment and prevention (or prophylaxis) i.e. prevention of the onset of a disease as well, in a more limited sense prevention is not covered. 5 “Ambient light” in accordance with the invention is the light useful for illumination of the eye of the patient which is provided by a natural or artificial light source and which is the light actually seen by the patient and which illuminates the area of retina onto which light is projected by the optical apparatus of the eye; said light is polychromic and always covers a wavelength range including the wavelength activating the compounds of the invention. The ambient light is different from a coherent monochromatic 10 light in particular a laser light. In a preferred embodiment the ambient light is not artificially focused (i.e. is non-directed); preferably it is not focused or directed on the retina artificially. In an embodiment the light is or comprises visible light. In an embodiment the light is white light. Preferably “white light” as used herein is a combination of lights of different wavelengths, preferably a polychromatic light having a spectrum of at least 100 nm, preferably at least 200 nm in particular at least 300 nm wide in the range of at 15 least 350 nm and up to 800 nm. Particular ranges are defined in the Brief description of the invention an in the appended claims. A “pharmaceutical composition” of the invention is a composition of matter which comprises at least one compound of the invention comprising an active agent and at least one further substance. Preferably the compound of the invention is present in an effective amount. Compositions may also 20 comprise further biologically active substances useful e.g. in a combination therapy. Furthermore, the compositions may comprise biologically acceptable carriers, formulation agents, excipients etc. which may be known in the art. The term “effective amount” qualifies the amount of a compound required to exert the effect of the active agent in a composition. A “therapeutically effective amount” is sufficient to relieve or prevent (or 25 prevent worsening of) one or more of the symptoms or characteristic parameters of a condition, e.g. a disorder or disease. A “moiety” is used herein as a part of a molecule which can be derived in principle by removing another part, even a hydrogen atom or a group or any part thereof. An “active agent moiety” as used herein is a part of the compound of the invention which carries 30 the biological effect of said compound and which is capable of specifically binding to its biological target molecule. The active agent moiety carries this biological effect even if present in a separate (non-azidated) molecule. The said biological effect includes partial or full inhibition and partial or full activation of the biological target molecule. A “conjugated moiety” is a part of the compound of the invention which carries a conjugated system 35 even without the azido group. In an embodiment the active agent moiety is the conjugated moiety itself i.e. “conjugated active agent moiety”. In an embodiment the conjugated moiety is bound to an active agent moiety. For example it may serve as a linker between the azide moiety and the active agent moiety. P138182SG 44 A “parent molecule” as used herein is a molecule from which the compound of the invention can be derived by azidation; in particular the parent molecule is a non-azidated counterpart of the compound of the invention. In an embodiment parent molecule is formed by or consists of the active agent moiety and the conjugated moiety. In an embodiment parent molecule is formed by or consists of the conjugated active 5 agent moiety, or the active agent moiety. The term “PMO” is used herein to refer to a molecular substructure „pyrrol-methylidene-oxindole”, formally named 3-[(1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one that is a common element of numerous receptor tyrosine kinase inhibitors such as semaxanib, sunitnib, toceranib, vorolanib, famitinib. A ”prodrug” according to the invention is a compound which is a derivative of an active agent, e.g. 10 biologically active molecule, e.g. a medicament, which can be administered to a subject and which is metabolized to an active agent in the subject. Typically a prodrug comprises a functional group that renders the active agent inactive and the said functional group can be cleaved off to release the original active agent or can be metabolized into the original functional group in the body of the subject, the chemical derivatization moiety being characterized as a “metabolizable group”. 15 As used herein, the term “alkyl” alone or in combinations means a straight or branched-chain (if appropriate) hydrocarbon group containing preferably 1 to 15, 1 to 10 or 1 to 8 carbon atom(s) or in particular1 to 6 or 1 to 4, 1 to 3 or 1 to 2 carbon atom(s) [i.e. “C1-15”, “C1-10”,“C1-8”, “C1-6” or in particular “C1-6”, “C1-4”, “C1-3” or “C1-2” alkyl groups, or lower alkyl, respectively], such as particularly preferably methyl, ethyl, propyl or isopropyl groups. 20 As used herein, the term “alkoxy” means an alkyl-O- group in which the alkyl group is as previously described. The bond to the rest of the molecule or complex, i.e. the parent moiety is through the oxygen (if to a carbon atom, ether oxygen). The term “alkoxy alkyl” means an alkyl group which is substituted by an alkoxy group, i.e. an alkyl-O- group as previously described. The bond to the alkyl moiety is through the oxygen, i.e. it is an 25 ether oxygen. As used herein, the terms “carbonyl”, “alkyl-carbonyl”, “alkenyl-carbonyl” and “alkynyl- -carbonyl” mean a moiety having carbonyl group optionally substituted with an alkyl group, alkenyl group and alkynyl group, respectively. In a wider sense the group can be connected by either the alkyl, alkenyl or alkynyl or via the carbonyl group. In a preferred embodiment, i.e. narrower sense, the group bond to the 30 parent moiety is through the carbon of the carbonyl group. In a preferred embodiment the “alkyl-carbonyl”, “alkenyl-carbonyl” and “alkynyl-carbonyl” is alkanoyl, alkenoyl and alkynoyl, respectively. This definition of wider sense and narrower sense pertains to any analogous groups with a functional group used herein even if not defined separately. As used herein, the terms “carboxyl”, “alkyl-carboxyl”, “alkenyl- carboxyl” and “alkynyl- 35 - carboxyl” are defined to mean a moiety having carboxyl group optionally substituted with an alkyl group, alkenyl group and alkynyl group, respectively, wherein bond to the parent moiety is through the carboxyl group. The group can be connected by either the alkyl, alkenyl or alkynyl or via the carboxyl group (in the latter case being an esther). P138182SG 45 An “alkenyl” as used herein, alone or in combinations, means a straight or branched-chain unsaturated hydrocarbon group containing at least one carbon–carbon double bond, said hydrocarbon group containing preferably from 2 to 20, preferably 2 to 15, 2 to 10 or 2 to 8 carbon atoms or 2 to 6, 2 to 4, 2 to 3 or 2 carbon atoms [i.e. “C2-20”, “C2-15”, “C2-10”,“C2-8”, “C2-6” or “C2-4”,“C2-3” or “C2” alkyl groups, 5 respectively or in particular “C2-6” , “C2-4”, “C2-3” or “C2” alkenyl groups or lower alkenyl, respectively]. An “alkynyl” as used herein is defined analogously to alkenyl mutatis mutandis. A “heterocyclic” ring as used herein is a cyclic moiety that has, besides carbon atom(s), atoms of at least one non-carbon element as member(s) of its ring(s). A heterocycle may comprise multiple rings, e.g. it may comprise an aromatic heterocycle and, fused to the aromatic heterocycle another ring which may or 10 may not be aromatic; i.e. if it is not aromatic it may form a cyclic substituent of the aromatic heterocycle. In a preferred embodiment, if the heteroaryl comprises multiple, in particular two fused rings, both rings are aromatic. Preferably the ring(s) of the heterocyclic moiety is / are 5 to 6 membered ring(s). A “heterocyclyl” group is a group comprising a heterocyclic moiety, preferably one or more, e.g. one or two “heterocyclic” ring, which may be substituted or unsubstituted; is substituted, without limitation, 15 it may be substituted with a functional group, e.g. an oxo, hydroxyl, amino, halogen, nitro, carboxyl, lower alkyl, alkenyl or alkyinil, etc. The term “heterocycloalkyl” refers to a “heterocyclic” ring which is derivable from cycloalkyl group as defined above, wherein at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen or oxygen. 20 An “aromatic” moiety as used herein can be described as a planar cyclic moiety (a ring) wherein the single bonds (called σ-bonds) between the ring-forming atoms are formed from overlap of hybridized atomic sp2-orbitals in line between the carbon nuclei, wherein a system of delocalized π-bonds are formed from overlap of atomic p-orbitals of each of the ring forming atoms above and below the plane of the ring and wherein the number of π electrons, which is provided by the ring-forming atoms, participates in 25 according to molecular orbital theory, must be equal to 4n + 2 (Hückel’s rule), in which n = 1, 2, 3, etc., preferably 1 or 2, for a single ring with six π electrons, n = 1. The ring-forming atoms typically provide one or two π electrons to the delocalized π electron system. A “conjugated system” as used herein can be described as a planar moiety having a carbon and / or heteroatom skeleton wherein the single bonds (called σ-bonds) are formed from overlap of hybridized 30 atomic sp2-orbitals in line between skeleton carbon or heteroatom nuclei of the system, wherein a system of delocalized π-electrons are formed from overlap of atomic p-orbitals of each of the skeleton atoms above and below the plane of the ring from π electrons in one or more double bond(s), non-binding (lone) pair(s) (and in some cases radical electron(s) or electrons of carbenium ion(s)) to form an interrelated delocalized π electron system. Preferably the conjugated system comprises an aromatic system like that of an aryl 35 moiety, to which preferably the azide moiety is linked. In a conjugated π-system, electrons are able to capture photons. Typically, the more extended the conjugated π-system is, the longer the wavelength of photon can be captured. Preferably a conjugated system of the invention comprises at least 3, preferably 4, more preferably at least 5 non-sigma electron pairs without (excluding) the π electron pair of the azide. P138182SG 46 The term ”heteroaryl” is defined herein as a group or molecule that contains an aromatic heterocycle, preferably a moiety that has at least one heteroatom, as "member", incorporated within an aromatic ring. Examples of heteroatoms include nitrogen, oxygen and sulfur, preferably nitrogen and oxygen. In an embodiment a heteroaryl may comprise an aromatic heterocycle and, fused to the aromatic 5 heterocycle another ring which may or may not be aromatic; i.e. if it is not aromatic it may form a cyclic substituent of the aromatic heterocycle. In a preferred embodiment, if the heteroaryl comprises multiple, in particular two fused rings, both rings are aromatic. Members of a heteroaryl relate to the ring-forming atoms, either carbon atom(s) or heteroatom(s). The term “aryl” as used herein is a group that contains any carbon-based aromatic ring which is 10 preferably a mono- or bicyclic group, wherein the bicyclic group preferably comprises two fused rings. In a preferred embodiment the aryl group consists of carbon as ring atoms, i.e. “members” only. In a broader meaning the term aryl also includes optionally “heteroaryl”. Optionally, the term “aryl” is limited to non- -heteroaryl which is also included into the term aryl and defines a group that contains an aromatic group that does not contain a heteroatom. 15 An aryl group may be substituted or unsubstituted (i.e. optionally substituted). If the aryl group is substituted it may be substituted with any substituent, and examples of the substituent include C1-4alkyl, C2-4alkenyl, C1-3alkyloxy, C1-3alkanoyl, C1-3alkylamine, C1-3alkylamide, halogen, etc. The term “aralkyl” as used herein refers to an aryl alkyl group which is linked to the parent molecule through the alkyl group, which may be further optionally substituted with one or more, preferably one to 20 three or one to two alkyl substituents. Thus, the aryl group may be substituted with an alkyl substituent, preferably each substituent being not larger than a C1-4alkyl. „Aryl” or „heteroaryl” may comprise a monocyclic ring, a condensed ring, or a polycyclic ring in which a single ring is bounded by a single bond, preferably a monocyclic or bicyclic ring. As used herein, the term “fused ring” means that the ring is fused with at least one other ring to form 25 a group of a compound which comprises two or more rings wherein a single bond between two member atoms of the rings is, together with said two members, common in, i.e. shared by the two rings. An example of fused rings is a polycyclic aryl. A polycyclic aryl is understood herein as a group that contains multiple rings of a carbon-based group among which at least one ring is an aryl and which optionally may also comprise a cycloalkyl and / or a heterocycloalkyl. 30 A “substituted” moiety comprises a substituent selected from the groups and moieties as defined herein; however, a substituent is preferably smaller, i.e. shorter, i.e. consists of not more, preferably less atoms than the moiety which is / are substituted thereby. In the present invention, “optionally substituted”, i.e. “unsubstituted or substituted” means that it may be substituted with any substituent. In general formulae of the description H atoms are typically not shown, however, a skilled person is 35 able to understand said formulae and recognize the full structure. The singular forms “a”, “an” and “the”, or at least “a”, “an”, include plural reference unless the context clearly dictates otherwise. The term “comprises” or “comprising” or “including” are to be construed here as having a non- -exhaustive meaning and allow the addition or involvement of further features or method steps or P138182SG 47 components to anything which comprises the listed features or method steps or components. “Comprising” can be substituted by “including” if the practice of a given language variant so requires or can be limited to “consisting essentially of” if other members or components are not essential to reduce the invention to practice. 5 BRIEF DESCRIPTION OF THE DRAWINGS / AZ ÁBRÁK RÖVID LEÍRÁSA Figure 1.: Illustration of the principle of the invention Figure 1a: The optical system of the eye processing the incoming ambient light Figure 1b: A magnified portion of the Figure 1 illustrating the transient binding of the azidated compound to the receptor in the retina, activation of the compound by ambient light and covalent binding 10 of the compound to the receptor it was transiently associated to Figure 2.: UV-VIS spectrum of EYE1052 (“5-desfluoro-5-azido-sunitinib”) Figure 3.: UV-VIS spectrum of EYE1028 (“5-desfluoro-6-azido-sunitinib”) Figure 4.: UV-VIS spectrum of EYE1089 (“6-azido-sunitinib”) Figure 5.: UV-VIS spectrum of EYE1091 (“5-desfluoro-5-azido-6-fluoro-sunitinib”) 15 Figure 6.: UV-VIS spectrum of EYE1090 (“5-desfluoro-5-azido-6-chloro-sunitinib”) Figure 7.: UV-VIS spectrum of EYE1093 (“5-desfluoro-5-azido-6-bromo-sunitinib”) Figure 8.: UV-VIS spectrum of EYE1088 (“5-desfluoro-6-azido-vorolanib”) Figure 9.: UV-VIS spectrum of EYE1118 (“5-desfluoro-5-azido-6-chloro-vorolanib”) Figure 10.: Inhibitory effect of the parental compound sunitinib on VEGFR2-HEK cells 20 Figure 11.: Inhibitory effect of EYE1052 on VEGFR2-HEK cells Figure 12.: Inhibitory effect of EYE1028 on VEGFR2-HEK cells Figure 13.: Inhibitory effect of EYE1089 on VEGFR2-HEK cells Figure 14.: Inhibitory effect of EYE1091 on VEGFR2-HEK cells Figure 15.: Inhibitory effect of EYE1090 on VEGFR2-HEK cells 25 Figure 16.: Inhibitory effect of EYE1093 on VEGFR2-HEK cells Figure 17.: Inhibitory effect of EYE1088 on VEGFR2-HEK cells Figure 18.: Inhibitory effect of EYE1118 on VEGFR2-HEK cells Figure 19.: Inhibitory effect of EYE1052 on HRMEC cells Figure 20.: Inhibitory effect of EYE1028 on HRMEC cells 30 Figure 21.: Inhibitory effect of EYE1089 on HRMEC cells Figure 22.: Inhibitory effect of EYE1090 on HRMEC cells Figure 23.: Inhibitory effect of EYE1118 on HRMEC cells Figure 24.: Network of HRMEC cells in the presence of EYE1052 with and without light Figure 25.: Network of HRMEC cells in the presence of EYE1028 with and without light 35 Figure 26.: Network of HRMEC cells in the presence of EYE1089 with and without light Figure 27.: Network of HRMEC cells in the presence of EYE1090 with and without light Figure 28.: Network of HRMEC cells in the presence of EYE1118 with and without light Figure 29: Inhibitory effect of EYE1309 on VEGFR2-HEK cells P138182SG 48 DETAILED DESCRIPTION OF THE INVENTION The idea of the present invention is related to a new way of targeting drug molecules (new chemical entities) to the tissues of the eye (especially the retina) that are reached by natural light seen by the patient 5 or animal to be treated. The optical system of the eye consists of the cornea, the crystalline lens and the iris [Lombardo et al., 2013] and has evolved to focus the light onto the retina. The present invention capitalizes on the fact that through this mechanism the density of photons is higher within the retina than in any other internal, non-exposed tissues of a biological organism (animal or human being). Using proof-of-concept experiments, the present inventors have found that compounds comprising 10 an azido group (N3) linked to a conjugated electron system thereby forming a chemical structure which can be considered as a modification of a parent structure, is a suitable modification to render the given parent molecule sensitive to light. Once the azidated molecule reaches the eye, in particular the retina, the molecule can undergo photoactivation by the ambient light seen by the patient to be treated. Light is known to convert azidated molecules into a reactive nitrene radical or a reactive cyclic ketene-imine (or equivalent reactive 15 intermediate) that can then form a covalent bond with several functional groups of nearby biomolecules. Therefore, an azidated substrate or any azidated substrate analogue can be covalently linked to its cognate ocular binding partner, e.g. enzyme by natural light seen by the patient. Via the same mechanism, any azidated ligand or any azidated ligand analogue can be covalently linked to any cognate ocular receptor by natural light seen by the patient. 20 According to the concept of the invention, the covalent binding of the photoactivated azidated molecules gradually extracts such molecules from the circulation and enrich them in the eye, preferentially the retina, given the fact that from the plasma new, unactivated molecules can diffuse towards their retinal target, occupy their binding cleft on the target molecule and subsequently become photoactivated and covalently bound. Therefore, the application of the azidation is specifically contemplated in the present 25 invention, especially the azidation of any chemical structure having the appropriate conjugated system that permits the natural in situ photoactivation (cleavage of an N2molecule from the azido group) in ocular tissues which are illuminated by ambient light (including but not limited to the retina) when its used with the aim of lowering the plasma concentration to avoid the unwanted side effects of a previously known therapeutic parent molecule that is otherwise effective against a particular ocular disease. 30 Vorolanib (X-82, CM082), an orally available VEGFR2 inhibitor, initially developed against tumor angiogenesis, was effective in a phase I clinical trial against neovascular AMD [Jackson et al., 2017]. Importantly, the subsequent phase II trial investigating whether the number of standard intravitreal anti- VEGF injections in neovascular AMD can be decreased upon oral vorolanib administration has been prematurely stopped, due to hepatobiliary and gastrointestinal adverse effects [Cohen et al., 2020]. 35 Increasing specific interactions between the VEGFR2 (KDR) and its small molecule inhibitors (especially vorolanib) to replace intravitreal injections in the treatment of AMD and PDR patients would also allow reducing their dose and in turn their side effects. Therefore increasing the strength of the said interaction and turning it into a stable covalent bond addresses an unmet medical need. P138182SG 49 The experiments presented herein demonstrate the capability of the azidated derivatives of vorolanib and sunitinib to inhibit VEGF triggered signaling via the VEGFR2 receptor. Sunitinib has been chosen on the basis that it is a well-described VEGFR2 inhibitor frequently used in anti-tumor therapy [Gan et al., 2009]. The present inventors have demonstrated in proof-of-concept experiments presented herein that 5 irradiation of both the azidated sunitinib molecules and the azidated vorolanib molecules bound to their receptors strongly increases the inhibition that they exert on VEGFR2. Currently the inhibition of VEGF signaling by intravitreal injection is the standard medical treatment of AMD and PDR. Per os taken azidated inhibitors of VEGFR2, as prototype molecules, have the potential to replace the conventional treatment of AMD and PDR. Therefore, the invention relates to the use of the 10 azidation of any chemical structure in combination with the subsequent natural in situ photoactivation in ocular tissues (including but not limited to the retina) with the purpose of inhibiting VEGF signaling in such ocular tissues to medically treat patients suffering from AMD and PDR. A high number of inhibitors of VEGF signaling, in particular small molecule VEGFR2 inhibitors are known in the art. 15 For illustration and by way of an example, Peng, [Peng, Fan-Wei˙et al., 2017] and Farghaly [Farghaly, TA et al. 2021] report a high number of small-molecule inhibitors of and antibodies against VEGFR2 and their potential use as therapeutics against several types of cancers, angiogenesis-related disorders, and Parkinson’s and Alzheimer’s diseases in the patent literature of the period 2012 to the end of 2020. 20 Furthermore, Khanwelkar, Rahul R. et al. report on the synthesis and structure–activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors [Khanwelkar, R.R, .2010]. Yang T-H et al. [Yang T-H et al.2017A and 2017B] and describe the synthesis and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene) methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. 25 From these and other publications it can be seen that there have been a number of VEGFR2 inhibitors present in the art which plausibly can be applied as an active agent moiety in the present invention, once azidated and optionally completed with a linker between the active agent moiety and the naturally photoactivable azide, in a plausible embodiment. Azidation 30 According to the invention azidation is a suitable chemical modification for in vivo retinal targeting of therapeutic molecules because it consists of the addition of minimal number of new atoms to a biologically active therapeutic molecule, therefore this modification has the smallest chance to interfere with the binding of the said therapeutic molecule to its biological target in the retinal tissue. The results of proof-of-concept experiments provided herein show that azidated versions of previously known substrate 35 analogues (e.g. azidated versions of parent molecules) can inhibit their target biomolecule stronger in ambient light, e.g. in white light, than in dark. The requirement of suitability for natural photoactivation within the eye imposes constraints onto the chemical structure of the azidated molecules that are to be used as drugs. Typical aryl-azide molecules can be photoactivated with light having a wavelength of 350 nm [Keana et al., 1990] that is not suitable for in P138182SG 50 situ photoactivation in the human retina by natural light since the lense of the human eye absorbs the light with wavelength under 400 nm [Kessel et al., 2010]. Furthermore, the transparency of the lense drastically decreases with an increasing age, and significant amount of light with wavelength over 450 nm is absorbed in the eye of people over 60 years before it could reach the retina [Kessel et al., 2010]. It has been shown 5 that an increase of wavelength of maximal light absorption of aryl-azides also increases the efficiency of photoactivation [Keana et al., 1990]. Consequently, molecules having an absorption maximum of at least at 400 nm are suitable ones for azidation to obtain naturally photoactivable drug candidates. Therefore, in the prototype application presented in this document, the present inventors used biologically active molecules that can be azidated on a benzene ring that is part of a larger delocalized electron system (π- 10 system) and correspondingly absorb light also at wavelengths higher than 400 nm. In each of the prototype molecule presented here, the azido group (N3) was coupled to a carbon atom that is part of an extended conjugated π-system so that the azido group can directly harness the energy of the light absorbed by such π-system. Inhibition of retinal VEGF signaling 15 Given the extraordinary clinical importance of AMD and PDR, furthermore considering the fact that currently the anti-VEGF therapy is the preponderant, almost exclusive therapy of these conditions we have opted for the inhibition of retinal VEGF signaling as an exemplary application. Therefore, for the purpose of the present invention the exemplary molecules were chosen to be tyrosine-kinase inhibitors that can inhibit the activity of VEGFR2. It is demonstrated herein that the azidated versions of the said small 20 molecule VEGFR2 inhibitors still bind to VEGF2 and inhibit its activity while azidation renders them photoactivable. As a result of the photoactivation, the specific inhibitory potential of these molecules increases. Exemplary scaffolds to prepare photoactivable azido-compounds Sunitinib (3), vorolanib (4) and famitinib (5) are all small molecule tyrosine kinase inhibitors capable 25 of exerting inhibitory effect on VEGFR2 receptor and they all share a common structural element consisting of a 3-[(1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one moiety (hereinafter referred to as „PMO”, as an abbreviation for the simplified name „pyrrol-methylidene-oxindole” for the purpose of the present patent, see general formula (I) wherein the substituens are defined in the Brief Description of the invention as well as in the appended claims). 30 (4) P138182SG 51 The PMO is on one hand side necessary for the binding of these three molecules to the VEGFR2 receptor and contains on the other hand a large delocalized electron system (π-system). The PMO moiety 5 is present in an unchanged form in sunitinib, vorolanib and famitinib, is responsible for the absorption of visible light, and confers a yellow color to these molecules. We therefore decided to place an azido group onto the benzene ring of the PMO to achieve a wavelength of photoactivation higher than 400 nm. This wavelength is required based on the spectral properties of the natural light that can penetrate into the human eye via the cornea and the lens [Kessel et al., 2010]. The exemplary prototype molecules presented here are 10 based either on sunitinib or on vorolanib or variants thereof. For all of the prototype molecules presented here, the azido group (N3) was placed in different positions of benzene ring. Correspondingly, in some of the said prototype molecules, the fluorine atom (F) was omitted. In further exemplary prototype molecules both the fluorine atom and the azido group was present, or, instead of fluorine, other halogen substituents like chlorine atom and bromine atom have been used, as 15 shown in the Examples, see formulae (6) to (8), wherein the azido group is in the 5 while the halogen atom is in the 6 position. In other examples the 5 and 6 positions of the azide and the other substituent may be the opposite (5-halogen 6-azide derivatives). 20 P138182SG 52 (8) Formula (I.3) illustrates this concept of the invention by the example of the scaffold of sunitinib, vorolanib and famitinib and is derivable therefrom e.g. by substitution of F by an azido group R1. It is 5 understood that the newly introduced azido group can be in any position of the aryl ring of the oxindole moiety, as shown by formula I.3. Further groups R7 and R14, R15 and R16 are as defined herein, particularly in the Brief description of the invention or in the appended Claims. To demonstrate the inhibitory effect of the prototype molecules, the inventors have conducted experiments in a biological system designed to report the strength of VEGF signaling. Inventors have used 10 human embryonic kidney (HEK cells) harboring two exogenous genetic constructs, the first one expressing the VEGFR2 targeted to the cell surface, the second one encoding the luciferase gene under the control of a specific promoter (NFAT promoter) that is responsive to the intracellular signaling events triggered by the receptor. This cell culture based system was validated by adding exogenous VEGF with and without well-known previously characterized inhibitors of VEGFR2 and the validation provided proof that the light 15 generated by the luciferase enzyme is suitable to measure the strength of VEGF signaling. Using the validated cell-culture based system, it has been demonstrated that the azidated prototype molecules can bind to their target similarly as their previously known parent molecules. By comparing the results of experiments conducted in the dark and those conducted in illuminated conditions, it has also been demonstrated that light can photoactivate the prototype molecules and can potentiate their biological 20 effect. To further demonstrate the inhibitory effect of the prototype molecules, the inventors have conducted experiments using commercially available human retinal microvascular endothelial cells (hereinafter referred to as “HRMEC”) isolated post mortem from human donors. These cells preserve their endothelial nature, and when cultured on an appropriate extracellular matrix, they spontaneously form a network that 25 corresponds to a network of capillaries. Images of such networks taken with a microscope can be quantified, and several parameters (such as the number of segments, number of closed loops, number of junction points) of the network can be quantified and used as a parameter describing the angiogenesis in vitro [Staton et al., 2009]. The inventors have applied their proprietary azidated inhibitors described in the present patent in an 30 ascending series of concentrations. For all the said azidated inhibitors, the in vitro angiogenesis experiments were carried out both in complete darkness and in defined illumination conditions. The number of closed loops (number of meshes) was identified using an image recognition algorithm, and an IC50 curve was fitted onto the number of meshes plotted against substance concentration. The inventors have found that for several candidate molecules presented here, the IC50 values in the light significantly differed from the 35 IC50 values in the dark. These experiments thus provided further proof, that light increases the inhibitory potential of the novel azidated compounds described in the present patent.Taken together, the experiments presented here demonstrate that azidated small molecule inhibitors can bind to their cognate target, and the newly added azido groups do not prohibit the receptor-inhibitor interaction and do not abrogate the functional consequences of such interaction. Furthermore, the experiments presented here also demonstrate 40 that small molecule inhibitors that are transiently, non-covalently bound to their targets are photoactivated P138182SG 53 by light and such photoactivation can trigger a covalent binding to the biological target which the molecules are already associated to. Finally, the experiments presented here also demonstrate that light-triggered covalent binding between the receptor and the small molecule inhibitor has functional consequences and enhances the inhibitory potential of the azidated small molecules. 5 Receptor tyrosine kinases play a key role in the development of malignous proliferation within tumors and contribute to the growth of several types of cancers. In the present invention, the inventors provide proof that the novel azidated receptor tyrosine kinase inhibitors can bind FGFR, PDGFR and VEGFR stronger than their parent molecules. Furthermore, this inhibition is strongly potentiated by irradiation of the receptor-NCE complex that can underlie specific targeting within a subject. Thus the 10 molecules of the present invention can also be used to inhibit the proliferation of cancer cells, and to inhibit the neovascularization of tumors that provides blood supply indispensable for their growth. For example, the present inventors have performed assays on VEGFR2, PDGFRβ, and FGFR1 both with and without illumination. Photoactivation was proven by the subsequent increase of kinase inhibition of the compounds. Non-illuminated plates were sealed immediately after addition of the kinase, and were 15 placed in a dark environment. It can be seen from Table II that receptor binding was more effective in the case of illumination. Thus the skilled person would understand that targeting these receptors would result in treatment of diseases which are mediated by these receptors. The ocular disease and the tumors mentioned herein are typical examples. 20 Concept of prodrugs The compounds of the invention may be administered in the form of prodrugs. The concept of prodrugs involves the derivatization of a functional group of the compound that renders the molecule inactive, whereas the prodrug is converted, via metabolic processes to the useful active agent in vivo, e.g. in the patient. Typically, the derivatized functional group is metabolized to the original structure. 25 As a preferred example, in a preferred embodiment, a -CH2-OH moiety is attached to the nitrogen atom of the indol-2-one structure, and a suitable further moiety that is recognized by an active transporter expressed in the ocular target cells is attached via forming an ester bond with the said -CH2-OH. Such modification of the molecules offers the advantage of (i) actively taken up by transporter molecules expressed in the cells of the eye and (ii) hidrolyzed by estherase enzymes once the molecule is in the 30 intracellular compartment, this way the molecule becomes active. Examples of such products include those described by Wang et al. [Wang et al., EP3252048A4] and by Buchy E., et al. [ Buchy E., et al.2015]. Preparation of azido compounds Various methods for the synthesis of aryl-azides are well known to a person skilled in the art. Without providing a full review we provide the following summary and refer to the following 35 exemplary methods herein. Aryl azides are traditionally prepared by treatment of diazonium salts with an azide anion, however, several other methods exist. Typically nucleophilic displacement by an azide anion can be accomplished only if the aromatic ring is activated. Mild conditions are reported in the literature to avoid e.g. nitrogen loss or decomposition under harsh conditions [D’Anna et al.2008] P138182SG 54 Aromatic azides can be prepared by various methods including substitution of halogens in activated aryls by the azide anion; interaction of azides (e.g. Me3Si-N3, Tos-N3or NaN3,) with organometallic aryl reagent (eg. Grignard or aryllithium reagents); diazotization of aryl hydrazines or by reacting aromatic amines with TfN3or other reagents, using hydrogen azide reagent on nitrosoarenes; base induced 5 decomposition of triazenes. Direct methods of introduction of azides to arenes also exist and rely on using NaICl2and NaN3[Griganov et al.2016]. A relatively general method is to prepare aryl-azides from aryl-halides. As a pseudohalide, azide readily displaces many leaving groups, e.g. Br−, I−, sulfonate, and others to yield the azido compound. The azide source is most often sodium azide (NaN3), although lithium azide (LiN3) is also applicable. 10 As an example, Andersen, J. et al describe a rapid synthesis of aryl-azides from the corresponding aryl-halides catalyzed by CuI / diamine using sodium ascorbate as a stabilizer of the catalyst system under very mild conditions generally with high yields. [Andersen, J. et al.2005] Alternatively, Hajipour A. R. et al. have developed a method via the reaction of aryl-halides with sodium azide under Cu2O / tetraethylammonium prolinate catalysis. [Hajipour et al.2014] 15 Preferred compounds of the invention depicted in Formula II.1. can be synthesized according to the following Scheme 1: 20 P138182SG 55 An exemplary intermediate (III.3) for preparation of target compounds can be synthesized according 5 to the method as described in Yang et al.2017. Compound (III.3) can be dissolved e.g. in EtOH and a solution of the oxindole derivative carrying the azido group is added in the same solvent e.g. in EtOH in stochiometric amount. The reaction is carried out in the presence of minor amount of piperidine. After stirring, the compound is obtained as a precipitate, which is filtrated, washed and purified. The yield is typically between 40 to 70%. The reaction must be 10 carried out with continuous protection from light to avoid activation of the azide. In an embodiment the synthesis of (III.3) may start from compound (III.1) (2-tert-butyl 4-ethyl 3,5- R14,R15-1H-pyrrole-2,4-dicarboxylate), P138182SG 56 which can be prepared via the Paal-Knorr pyrrole synthesis [Kennedy et al. 2009]. R15 and R14 may be functional group(s). Provided that R15 and R14 are alkyl, e.g. methyl, formyl functionality can be provided by selective oxidation (e.g. with ceric ammonium nitrate (CAN) at room temperature). 5 In case R15and R13should not form a ring the OEt of the 4 carboxylate can be converted into corresponding amide in any known way for amidation to provide -C(O)NR12,R13. Converting esters into amides are well known in the art, see e.g. [Montalbetti et al., 2005; Valeur et al., 2009; Millera et al, 2015 and references cited therein]. In case R15 and R13 should form a ring, for example, a carboxyl (e.g. a formyl) functionality is to be 10 provided, which is then converted into a secondary amine which in turn forms the amide with the 4 ester of the pyrrole ring as described in [Yang et al 2017A; Yang et al.2017B]. The azidated oxindole compounds to be coupled with the aldehyde (III.3.) can be prepared e.g. via a oxindole derivative substituted with halogenide (e.g. I−) wherein said halogenide is subsequently replaced by azide, given the fact that azide is a pseudohalogenide. The oxindole derivative substituted with 15 halogenide is prepared – in one particular embodiment – from 3-iodoaniline or 4-iodoaniline (to be decided on the basis of where the azido group in the final product is intended to be), then preparing the (2E)-N-(4- iodo)-2-(hydroxiamino)acetamide by a condensation reaction, subjecting the product to ring closure to obtain the appropriate isatin derivative, and finally reducing the isatin to produce the oxidole-derivative containing an iodine atom in the required position. 20 It O isR4known by a skill O R3 R3 edR4person that alternative methods can also be applied. O P NHre Rf2erred syn N3thesis N O NH mH R e2thods for the preparation of azide derivatives are as follows: NH Method A wherein R1: halogen, preferably bromine or iodine, more preferably iodine 25 NaN3, Cu(I)iodide, ligand (e.g.:N,N′- Dimethylethylenediamine, (1S,2S)-(+)-N,N'-Dimethylcyclohexane-1,2-diamine), Na-L-ascorbate R2has the same meaning as R15defined herein, particularly in the Brief description of the invention or in the appended Claims and is preferably H, CH3P138182SG 57 R3has the same meaning as R14defined herein, particularly in the Brief description of the invention or in the appended Claims and is preferably CH3R4 has the same meaning as R16 defined herein, particularly in the Brief description of the invention or in the appended Claims and is preferably an aliphatic or cyclic amine (e.g. N,N-Diethylethylenediamine), 5 0.5 mmol iodo-compound (e.g: N-[2-(diethylamino)ethyl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) was suspended in 10 ml (EtOH / water 7:3) under inert atmosphere and 14.3 mg (0.075 mmol) Cu(I)iodide, 9.90 mg (0.05mmol) sodium-L- ascorbate, (8.8mg, 0.1 mmol 9.0 µl) N,N'-Dimethylethylenediamine or (1S,2S)-(+)-N,N'- Dimethylcyclohexane-1,2-diamine (10.6 mg, 0.1 mmol) and 65mg (1 mmol), sodium azide (NaN3) were 10 placed in a microwave tube and underwent microwave irradiation for 2 hours at 120oC. The reaction mixture was allowed to cool to room temperature. The precipitated product was filtered off washed with few ml cold water and dried. Method B 15 R1: NH2R2has the same meaning as R15defined herein, particularly in the Brief description of the invention or in the appended Claims and is preferably H, CH3R3has the same meaning as R14defined herein, particularly in the Brief description of the invention 20 or in the appended Claims and is preferably CH3R4has the same meaning as R16defined herein, particularly in the Brief description of the invention or in the appended Claims and is preferably an aliphatic or cyclic amine (e.g. N,N-Diethylethylenediamine). 0.5 mmol amino-compound (e.g: 5-[(Z)-(5-amino-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]- N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) was suspended in 50 ml water and 25 286 mg (1.5 mmol) p-toluenesulfonic acid hydrate was added to the reaction mixture and stirred until the dissolution of the starting material. The reaction mixture was cooled to 0-5oC and KNO2(170 mg, 2 mmol ) NaNO2138 mg (2 mmol) or in one portion and stirred for 60 min. then 195mg (3 mmol) sodium azide (NaN3) was added to the solution and allowed to warm up to room temperature gradually and stirred overnight. The precipitated product was filtered off. 30 Pharmaceutical compositions P138182SG 58 In the present invention the compounds used are typically rather hydrophobic, light sensitive compounds. Thus, when formulating them into pharmaceutical compositions these problems should be considered. Poor solubility resulting in limited drug loading can occur as a problem which has to be solved. To 5 increase the solubility, cyclodextrins can be used. (In case of sunitinib, marketed under the trade name Sutent, a malate salt is applied.) Typical excipients may include the following categories and examples: Disintegrants, like crosslinked polymers, polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), in particular the latter. 10 Binders, including for example - saccharides e.g. disaccharides (lactose, saccharose); polysaccharides (e.g. cellulose, starches etc.), modified polysaccharides such as microcrystalline cellulose, cellulose ethers etc.; - sugar alcohols such as xylitol, sorbitol or mannitol; in particular mannitol (E421) - protein type binder, like gelatin; (in particular in light gelatin capsule). 15 Lubricants, like magnesium stearate, or other stearate derivative (or talc or silica etc.). Polymers having the role of a stabilizer, surfactant thickening agent, solubility enhancer, e.g. Povidone (polyvinylpyrrolidone, PVP) or other synthetic polymers, like polyethylene glycol (PEG), preferably Povidone. A preferred formulation is capsule, e.g. light gelatin capsule or hard capsule wherein the active agent 20 is protected from light. In an embodiment the package should protect the azidated compounds from light. Non-transparent capsules are preferred for oral administration, the said capsules are to be designed with optical properties suitable to protect the azidated molecules from photoactivation. An example is Sutent gelatine capsules comprising Gelatin, red iron oxide (CI 77491) (E172) and titanium dioxide (CI 77891) (E171) arranged in a way to protect the active agent from light. 25 Another example is Lonza Capsugel of TiO2-free light-protected capsules (See [Lonza Press Release “Lonza Expands its Capsugel® Capsule Offering to Include Titanium Dioxide-Free White Hard Gelatin Capsules” May 9, 2022, Basel, Switzerland]). Methods for encapsulation or incorporation into polymeric matrices, including nano- and micro- particles, with increased loading are also known, see e.g. WO2016100392A1 [Fu J. et al., 2016]. and related 30 compound is disclosed as a self-nanoemulsifying formulation [Nazari-Vanani et al., 2017]. In a further embodiment, the formulation is an eyedrop. In this case, given the hydrophobic nature of the PMO moiety present in all the compounds, a solubilizing agents, such as encapsulation methods, (e.g. by cyclodextrines) or vesicular systems (e.g. liposomes) are needed. These methods are reviewed by Ioele et al. [Ioele et al., 2017]. Further encapsulation methods may be provided by microparticles 35 surrounded by a coating material. Lipid nanoparticles or polymeric nanoparticles are also useful technologies in providing light protection. Alternative methods may be provided by nanoemulsions which may be oil-in-water (O / W) or water-in-oil (W / O) emulsions. Several of these methods are reviewed by Coelho L et al [Coelho L et al., 2018]. P138182SG 59 These formulations can also be made photoprotective which is of key importance for the photolabile azidated molecules described in the present patent. The present invention is further illustrated by way of non-limiting examples. EXAMPLES 5 General information Commercially available reagents and solvents were used without further purification. The reactions were monitored by TLC, with Kieselgel 60 F 254 (Merck) plates and visualized by UV light. Analytical LC-MS ESI-MS was performed on a Waters Acquity SQD MS detector equipped with separation module 10 Waters Alliance 2795 HPLC and Waters 996 PDA detector. Analytical HPLC / MS was performed by system using reverse phase HPLC column. Method: Waters XBridge C18 (5 cm x 4.6 mm, 5 μm), gradient 0-95 % B over 7.00 min (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 % B, 6.50 min 5 % B, 7.00 min 5 % , Solvent A: MilliQ Water / 0.1% HCOOH, Solvent B: AcCN, flow = 2.0 mL / min. Separation module was Waters Alliance 2795. 15 UV spectra were recorded using a Waters 996 PDA detector. Mass spectra were obtained using Waters SQD MS detector (ionization: ES+ / ES-, source block temp: 120 °C, desolvation temp: 350 °C, desolvation gas: 400 L / h, cone gas: 100 L / h, capillary: 3000 V, cone: 25 V, extractor: 3 V, Rf lens: 0.2 V, scan: 120 to 1000 m / z in 1 sec., interscan delay: 0.1 s). The preparative purifications was made on Waters Sun Fire RP C18 10um column. Instruments: 20 Waters 600 Controller Pump, 2487 Dual Absorbance Detector, 2700 Sample manager equipped with Waters Fraction Collector. Solvent A: Water / 0.1% HCOOH, Solvent B: AcCN, flow = 12.0 mL / min. Gradient elution from 15-to 70% B over 16.00 min. The NMR spectra were recorded on a Bruker Avance 300 spectrometer operating at 7.05 Tesla magnetic field, equipped with a 5 mm dual inverse z-grad probe head, in deuterated 25 dimethylsulfoxide (DMSO-d6) solution, at 30 °C. The instrument was controlled and the data were processed using TopSpin 1.3 software package. List of intermediates: i.1) Methyl 2-(5-chloro-2,4-dinitro-phenyl)acetate BSZ 2824NI i.2) Methyl 2-(5-fluoro-2,4-dinitro-phenyl)acetate BSZ2774 30 i.3) 6-amino-5-chloro-1,3-dihydro-2H-indol-2-one BSZ2834N i.4) 6-amino-5-fluoro-1,3-dihydro-2H-indol-2-one BSZ2814A i.5) 5-[(Z)-(6-amino-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2821N2 i.6) 5-[(Z)-(6-amino-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- 35 (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2817I, BSZ2817_2 i.7) N-[2-(diethylamino)ethyl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide BSZ2695K P138182SG 60 i.8) N-[2-(diethylamino)ethyl]-5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide BSZ2743T i.9) N-[2-(diethylamino)ethyl]-5-[(Z)-(4-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide 5 i.10) ethyl 5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole- 3-carboxylate BSZ2744TKI i.11) Ethyl 5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate BSZ2749N i.12) ethyl 2,4-dimethyl-5-[(Z)-(5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-1H- 10 pyrrole-3-carboxylate SZI3133 i.13) (3Z)-3-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-3,5-dimethyl-1H-pyrrol-2- yl)methylene]-6-iodo-1,3-dihydro-2H-indol-2-one BSZ2755N i.14) Ethyl 5-[(Z)-(5-amino-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate SZI3136B1 15 i.15) 6-fluoro-5-nitro-1,3-dihydro-2H-indol-2-one SZI3150B1 i.16) 6-chloro-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2861NK i.17) 6-bromo-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2821N i.18) 5-[(Z)-(6-fluoro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid BSZ2819A 20 i.19) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid BSZ2882SAV i.20) 5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid i.21) 5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- 25 carboxylic acid i.22) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol- 3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide i.23) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol- 3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 30 i.24) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-fluoro-5-nitro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide i.25) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl)pyrrolidin-3-yl]-4-methyl-1H-pyrrole-3-carboxamide BSZ2882SK2 i.26) (3Z)-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5-dimethyl-1H- 35 pyrrol-2-yl)methylene]-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2824 i.27) (3Z)-5-amino-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one BSZ2861N_8p_kii, BSZ2882SKR P138182SG 61 i.28) 5-[(Z)-(5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2809R2 i.29) 5-[(Z)-(5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2882SKR 5 i.30) 5-[(Z)-(6-bromo-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2822N i.31) 5-[(Z)-(5-amino-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2823N2 10 i.32) (3Z)-1-acetyl-6-chloro-3-[methoxy(phenyl)methylene]-5-nitro-1,3-dihydro-2H-indol-2-one - BSZ3010 i.33) N-(4-{[(Z)-(1-acetyl-6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) (phenyl)methyl]amino}phenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2830) i.34) N-(4-{[(Z)-(1-acetyl-5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) 15 (phenyl)methyl]amino}phenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2831) i.35) N-[4-[[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2831N) List of example compounds: Ex.1) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 20 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1028) Ex.2) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1052) Ex.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1013) 25 Ex.4) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1089) Ex.5) ethyl 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1056) Ex.6) 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- 30 dimethyl-1H-pyrrole-3-carboxamide (EYE1091) Ex.7) 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1093) Ex.8) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1088) 35 Ex.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1114) Ex.10.) Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1063) P138182SG 62 Ex.11) 5-[(Z)-(6-azido-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1087) Ex.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1116) 5 Ex.13) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1118) Ex.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1112) Ex.15) (3Z)-6-azido-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- 10 yl]methylene]indolin-2-one (EYE1068) Ex.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)62yrrolidine-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one (EYE1094) Ex.17) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1090) 15 Ex.18) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (EYE1309) Synthetic procedures of intermediates i.1) Methyl 2-(5-chloro-2,4-dinitro-phenyl)acetate BSZ 2824NI 20 3.68g (21 mmol) methyl 2-(3-chlorophenyl)acetate was dissolved in 45 ml concentrated sulfuric acid at 0oC and 1.04 ml (21 mmol, 1.58 g) 100% nitric acid was added to the solution. The reaction mixture was allowed to warm up to room temperature and 1.2ml (1.81g, 28mmol) 100% nitric acid was added to the solution and stirred for 1 hour at 50-55oC. After the completion, the reaction mixture was allowed to cool Rt and poured onto 350g crushed ice and extracted with 3x 50 ml EtOAc. The organic layer was 25 separated, washed with 20 ml water twice and dried over MgSO4. The crude product was purified by column chromatography. (Kieselgel, hexane-ethyl-acetate 4:1 as eluent) Yield: 3.76g (68%), LCMS purity: 99 %, C9H7ClN2O6, MW calc. monoisotopic 273.9, found [M-H]- 272.9 , Rt 3.80 min , UV-VIS Abs. max 250.7 nm1HNMR δ 8.85 (s, 1H); 8.13 (s, 1H); 4.21(s, 2H); 3.64 (s, 3H). 30 i.2) Methyl 2-(5-fluoro-2,4-dinitro-phenyl)acetate BSZ2774 P138182SG 63 3.36g (20mmol) methyl2-(3-fluorophenyl)acetate was dissolved in 40 ml concentrated sulfuric acid at 0oC and 0.83 ml (20 mmol, 1.26 g) 100% nitric acid was added to the solution. The reaction mixture was allowed to warm up to room temperature and 1.0 ml (1.51g, 24.0mmol) 100% nitric acid was added to the solution and stirred for 1 hour at 50-55oC. After the completion, the reaction mixture was allowed to 5 cool rt and poured onto 350g crushed ice and extracted with 3x 50 ml EtOAc. The organic layer was separated, washed with 20 ml water twice and dried over MgSO4. The crude product was purified by column chromatography. (Kieselgel, hexane-ethyl-acetate 4:1 as eluent) Yield: 3.97g (77%) LCMS purity: 89 %, C9H7FN2O6, MW calc. monoisotopic 258.03, found [M-H]- 257.0 , Rt 3.60 min , UV-VIS Abs. max 242.7nm 10 i.3) 6-amino-5-chloro-1,3-dihydro-2H-indol-2-one BSZ2834N Methyl 2-(5-chloro-2,4-dinitro-phenyl)acetate (1.37g, 5.0 mmol) was dissolved in 60 ml ethanol and 15 iron powder (3.36 g, 60 mmol), ammonium-chloride (2.52g, 40 mmol ), 15 ml water were stirred at reflux temperature for 6 hours. After the completion, the warm dark solution was filtered through a Celit pad and the Celit pad was washed with 20 ml ethanol. The crude material (methyl 2-(2,4-diamino-5-chloro- phenyl)acetate) was used in the next step without purification. Into this ethanolic solution, 3.0ml 37% aq. hydrochloric acid was added and stirred at reflux temperature overnight under inert atmoshere. The reaction 20 mixture was cooled to 0oC and the dark brown precipitated product was filtered off. LCMS purity : 91%, C8H7ClN2O, MW calc. monoisotopic 182.02, found [M+H]+183.1, [M-H]- 181.1 , Rt 2.40 min, UV-VIS Abs. max 222.7 nm, 303.7 nm i.4) 6-amino-5-fluoro-1,3-dihydro-2H-indol-2-one BSZ2814A 25 Methyl (5-fluoro-2,4-dinitrophenyl)acetate (1.37g, 5.0 mmol) was dissolved in 60 ml ethanol and iron powder (3.36 g, 60 mmol), ammonium-chloride (2.52g, 40 mmol ), 15 ml water were stirred at reflux 30 temperature for 6 hours. After the completion, the warm dark solution was filtered throught a Celit pad and P138182SG 64 the Celit pad was washed with 20 ml ethanol. The crude material (methyl 2-(2,4-diamino-5-chloro- phenyl)acetate) was used in the next step without purification. Into this ethanolic solution, 3.0ml 37% aq. hydrochloric acid was added and stirred at reflux temperature overnight under inert atmosphere. The reaction mixture was cooled to 0oC and the dark brown precipitated product was filtered off. LCMS purity 5 : 91%, C8H7FN2O, MW calc. monoisotopic 166.05, found [M+H]+167.1, [M-H]- 181.1, Rt 1.87 min, UV- VIS Abs. max 202.7 nm, 294.6nm The title compound was used in the next step without further purification. i.5) 5-[(Z)-(6-amino-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide BS 10 205 mg (1.13 mmol) 6-amino-5-chloro-1,3-dihydro-2H-indol-2-one and 298 mg (1.13mmol) N-[2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide and 10 µl piperidine were stirred in 5.0 ml ethanol at reflux temperature for 48 hours under inert atmosphere. The reaction mixture was allowed to cool to RT and the precipitated solids were filtered off to give the final deep brown product. 15 Yield: 174 mg (37%), LCMS purity : 95%, C22H28ClN5O2, MW calc. monoisotopic 429.19, found [M+H]+430.1, [M-H]- 428.1, Rt 2.98 min, UV-VIS Abs. max 224.7 nm, 297.7nm, 449.7nm i.6) 5-[(Z)-(6-amino-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2817I, BSZ2817_2 20 180 mg (1.08 mmol) 6-amino-5-fluoro-1,3-dihydro-2H-indol-2-one and 298 mg (1.12 mmol) N- [2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide and 8 µl piperidine were stirred in 4.0 ml ethanol at reflux temperature for 48 hours under inert atmosphere. The reaction mixture 25 was allowed to cool to rt and the precipitated solids were filtered off to give the final deep brown product. Yield: 133 mg (29%), LCMS purity: 79 %, C22H28FN5O2, MW calc. monoisotopic 413.22, found [M+H]+414.1 [M-H]- 412.1, Rt 2.09 min, UV-VIS Abs. max 434.7 nm P138182SG 65 BSZ2817I1H NMR δ13.37 (s, 1H); 10.58 (s, 1H); 7.50 (d, 1H, J=11.6 Hz); 7.31 (s, 1H); 7.28 (d, 1H, J=5.8 Hz); 6.33 (d, 1H, J=7.5); 5.26 (s, 2H); 3.28-3.25 (m, 4H); 2.55-2.54 (m, 4H); 2.40 (s, 3H); 2.35 (s, 3H); 0.97 (t, 6H, J=7.1 Hz) i.7) N-[2-(diethylamino)ethyl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- 5 dimethyl-1H-pyrrole-3-carboxamide 85 mg (0.328mmol)5-iodo-1,3-dihydro-2H-indol-2-one, N-[2-(diethylamino)ethyl]-5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxamide (89mg, 0.335mmol) and 5 µl piperidine were stirred for 48 hours at reflux temperature. The precipitated product was filtered off and dried. Yield:140 mg (84%), LCMS purity:10 98%, C22H27IN4O2, MW calc. monoisotopic 506.12, found [M+H]+507.2, [M-H]- 505.3, Rt 3.55 min, UV- VIS Abs. max 226.7 nm, 279.7 nm, 435.7 nm 1H NMR δ13.54 (s, 1H); 10.95 (s, 1H); 7.68 (s, 1H); 7.61 (d, 1H, J=8.0 Hz); 7.41 (t, 1H, J=5.6 Hz); 7.33 (dd, 1H, J=6.6 Hz, J=1.5 Hz); 7.19 (d, 1H, J=1.4 Hz); 3.28-3.27 (m, 4H); 2.55-2.52 (m, 4H); 2.43 (s, 3H); 2.39 (s, 3H); 0.97 (t, 6H, J=7.1 Hz) 15 i.8) N-[2-(diethylamino)ethyl]-5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide BSZ2743T dimethyl-1H-pyrrole-3-carboxamide (89mg, 0.33 mmol) and 5 µl piperidine were stirred for 48 hours at 20 reflux temperature. The precipitated product was filtered off and dried. Yield:152 mg (91%), LCMS purity: 98%, C22H27IN4O2, MW calc. monoisotopic 506.12, found [M+H]+507.3, [M-H]- 505.3, Rt 3.13 min, UV- VIS Abs. max 229.7 nm, 278.7 nm, 438.7 nm i.9) N-[2-(diethylamino)ethyl]-5-[(Z)-(4-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- 25 dimethyl-1H-pyrrole-3-carboxamide P138182SG 66 100 mg (0.38 mmol), 4-iodo-1,3-dihydro-2H-indol-2-one, N-[2-(diethylamino)ethyl]-5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxamide (74 mg, 0.27 mmol) and 5 µl piperidine were stirred for 48 hours at reflux temperature. The precipitated product was filtered off and dried. LCMS purity: 98%, C22H27IN4O2, 5 MW calc. monoisotopic 506.12, found [M+H]+506.9, [M-H]- 504.8, Rt 3.85 min, UV-VIS Abs. max 225.9 nm, 272.9 nm, 431.9 nm 1H NMR δ 13.60 (s, 1H); 11.04 (s, 1H); 8.75 (s, 1H); 7.50 (dd, 1H, J=7.0 Hz, J=0.8 Hz); 7.46 (t, 1H; 5.62 Hz); 6.95 (dd, 1H, J=6.8 Hz, J=0.8 Hz); 6.87 (t, 1H, J=7.8 Hz); 3.29-3.27 (m, 4H); 2.55-2.51 (m, 4H); 2.45 (s, 3H); 2.44 (s, 3H); 0.97 (t, 6H, J=7.1 Hz) 10 i.10) ethyl 5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylate BSZ2744TKI 6-iodo-1,3-dihydro-2H-indol-2-one130 mg (0.5 mmol) and ethyl 5-formyl-2,4-dimethyl-1H-pyrrole- 15 3-carboxylate 97.50 mg (0.5 mmol) and 8 µl piperidine were stirred for 48 hours at reflux temperature. The precipitated product was filtered off and dried. Yield:138 mg (79 %), LCMS purity: 88%, C18H17IN2O3, MW calc. monoisotopic 436.03, found [M+H]+436.8, [M-H]- 434.8, 5.18 min, UV-VIS Abs. max 231.7 nm, 279.7 nm, 441.7 nm 20 i.11) Ethyl 5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylate BSZ2749N P138182SG 67 5-iodoindolin-2-one 120 mg (0.46 mmol) and ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3- carboxylate 90.00 mg (0.46 mmol) and 5 µl piperidine were stirred for 48 hours at reflux temperature. The precipitated product was filtered off and dried. Yield:146 mg (84 %), LCMS purity: 84%, C18H17IN2O3, 5 MW calc.monoisotopic 436.03, found [M+H]+436.8, [M-H]- 434.9, Rt 5.26 min, UV-VIS Abs. max 231.7 nm, 279.7 nm, 441.7 nm. 1H NMR δ 13.85 (s, 1H); 11.03 (s, 1H); 8.25 (s, 1H); 7.78 (s, 1H); 7.45 (d, 1H, J=8.0 Hz); 6.73 (d, 1H, J=8.0 Hz); 4.21 (t, 2H, 7.0 Hz); 2.54 (s, 3H); 2.51 (s, 3H); 1.30 (t, 3H, J=7.1 Hz) 10 i.12) ethyl 2,4-dimethyl-5-[(Z)-(5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-1H-pyrrole-3- carboxylate SZI3133 300 mg (1.68 mmol) 5-nitro-1,3-dihydro-2H-indol-2-one and 329 mg (1.68 mmol) ethyl 5-formyl- 15 2,4-dimethyl-1H-pyrrole-3-carboxylate and 1-2 droplet of piperidine were stirred in 10 ml anhydrous ethanol at reflux temperature for overnight. The precipitated product was filtered off and dried. Yield: 455 mg (74%), LCMS purity: 85%, C18H17N3O5, MW calc. 355.12, found [M+H]+356.0, [M-H]- 354.0, Rt 4.64 min, UV-VIS Abs. max 259.7 nm, 434.7 nm. 20 i.13) (3Z)-3-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylene]- 6-iodo-1,3-dihydro-2H-indol-2-one BSZ2755N P138182SG 68 110 mg (0.42 mmol) 6-iodo-1,3-dihydro-2H-indol-2-oneand 4-[4-(2-hydroxyethyl)piperazine-1- carbonyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde 117.2 mg (0.42 mmol) and 5 µl piperidine were stirred in 8.0 ml ethanol for 48 hours at reflux temperature. The precipitated product was filtered off and dried. (BSZ2755N) Yield: 130 mg (59%). LCMS purity: 98%, C22H25IN4O3, MW calc. monoisotopic 519.9, found 5 [M+H]+520.9, [M-H]- 518.8, Rt 3.03 min, UV-VIS Abs. max 234.7nm, 280.7 nm, 445.7 nm. i.14) Ethyl 5-[(Z)-(5-amino-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylate SZI3136B1 10 250 mg (0.70 mmol)ethyl 2,4-dimethyl-5-[(Z)-(5-nitro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-1H-pyrrole-3-carboxylate, 390 mg (7.0 mmol) iron powder, (268 mg) 4.22 mmol ammonium-chloride, 2 ml water and 40 ml ethanol were placed into a reaction flask. The reaction mixture were refluxed for 4 hours. The insoluble inorganics was filtered through Celite, washed with mixture of chloroform-methanol. The filtrate was evaporated in vacuum. The residue taken 15 up in the mixture of sodium hydrogencarbonate aqueous solution (10%) and chloroform. LCMS purity: 97%, C18H19N3O3, MW calc. monoisotopic 325.14, found [M+H]+326.1, [M-H]- 324.0, Rt 2.78 min, UV- VIS Abs. max 228.7 nm, 276.7 nm, 425.7 nm i.15) 6-fluoro-5-nitro-1,3-dihydro-2H-indol-2-one SZI3150B1 20 3.00g (19.8 mmol) 6-fluoro-1,3-dihydro-2H-indol-2-one was dissolved in 35 ml sulfuric acid at 0oC and 1.31 g (21 mmol, 0.85 ml) 100% nitric acid was dropped into the reaction mixture and stirred for an hour at 0oC. The reaction mixture was poured onto 250g crushed ice and left to stand undisturbed until the ice was melted. The precipitated crude product was filtered off, washed with 2x30 ml water and dried. 25 Yield: 2.89 g (74%), LCMS purity: 95%, C8H5ClN2O3, MW calc. monoisotopic 196.03, found [M+H]+197.0, [M-H]- 195.0, Rt 2.53 min, UV-VIS Abs. max 247.7 nm, 361.7 nm i.16) 6-chloro-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2861NK P138182SG 69 4.00g (23.9 mmol) 6-chloro-1,3-dihydro-2H-indol-2-one was dissolved in 45 ml sulfuric acid at 0oC and 1.51 g (2.53 mmol, 1.01 ml) 100% nitric acid was dropped into the reaction mixture and stirred for an hour at 0oC. The reaction mixture was poured onto 400 g crushed ice and left to stand until the ice was 5 melted. The crude product was filtered off and dried. Yield: 4.39 g (87%), LCMS purity: 95%, C8H5ClN2O3, MW calc. monoisotopic 211.99, found [M-H]- 211.0, Rt 3.01 min, UV-VIS Abs. max 211.7 nm, 237.7 nm, 326.7 nm. i.17) 6-bromo-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2821N 10 2.00g (9.43 mmol) 6-bromo -1,3-dihydro-2H-indol-2-one was dissolved in 40 ml sulfuric acid at 0 oC and 0.59 g (9.43 mmol, 0.39 ml) 100% nitric acid was dropped into the reaction mixture and stirred for an hour at 0oC. The reaction mixture was poured onto 400 g crushed ice and left to stand until the ice was melted. The crude product was filtered off and dried. Yield: 2.21g (91 %), LCMS purity: 88%, C8H5BrN2O3, 15 MW calc. monoisotopic 255.95, found, [M-H]- 254.9, Rt 3.01 min, UV-VIS Abs. max 241.7 nm, 328.7 nm. i.18) 5-[(Z)-(6-fluoro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid BSZ2819A 20 1.96 g (10mmol) 6-fluoro-5-nitro-1,3-dihydro-2H-indol-2-one and 1.67g (10 mmol) 5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid and 20 µl piperidine were stirred in 70 ml anhydrous ethanol at reflux temperature for 48 hours then the precipitated product was filtered off and dried. It was used in the next step without purification. Yield: 3.11 g (88%) LCMS purity: 98%, C16H12FN3O5, MW calc. monoisotopic 345.07, found [M+H]+346.0, [M-H]- 344.0, Rt 3.71 min, UV-VIS 25 Abs. max 221.7, 261.7 nm, 433.7 nm. 1H NMR δ13.44 (s, 1H); 12.13 (brs, 1H); 11.57 (s, 1H); 8.70 (d, 1H, J=7.5 Hz); 7.89 (s, 1H); 6.87 (s, 1H); 2.51 (s, 6H) P138182SG 70 i.19) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid BSZ2882SAV 5 2.11 g (10mmol) 6-fluoro-5-nitro-1,3-dihydro-2H-indol-2-one and 1.67g (10 mmol) 5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid and 21 µl piperidine were stirred in 80 ml anhydrous ethanol at reflux temperature for 48 hours then the precipitated product was filtered off and dried. It was used in the next step without purification. Yield: 2.92 g (81 %), LCMS purity: 100 %, C16H12ClN3O5, MW calc. monoisotopic 361.05, found [M+H]+362.0, [M-H]- 360.0, Rt 3.87 min, UV-VIS 10 Abs. max 226.7, 241.7 nm, 439.7 nm. 1H NMR δ13.59 (s, 1H); 11.51 (brs, 1H); 8.72 (s, 1H); 7.98 (s, 1H); 7.07 (s, 1H); 2.53 (s, 3H); 2.53 (s, 3H) i.20) 5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- 15 carboxylic acid 259 mg (1 mmol) 6-iodo-1,3-dihydro-2H-indol-2-one 10 µl piperidine were stirred in 5.0 ml anhydrous ethanol at reflux temperature for 48 hours then the precipitated product was filtered off and dried. Yield: 319 mg (76%) LCMS purity: 94 %, C16H13IN2O3 MW calc. monoisotopic 408.19, found [M+H]+ 409.1,20 [M-H]- 407.0, Rt 4.21 min, UV-VIS Abs. max 230.15-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, 272.1 , 449.7 nm. i.21) 5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid P138182SG 71 259 mg (1 mmol) 5-iodo-1,3-dihydro-2H-indol-2-one 10 µl piperidine were stirred in 5.0 ml anhydrous ethanol at reflux temperature for 48 hours then the precipitated product was filtered off and dried. Yield: 319 mg (76%) LCMS purity: 97 %, C16H13IN2O3, MW calc. monoisotopic 408.19, found 5 [M+H]+409.1, [M-H]- 407.0, Rt 4.07 min, UV-VIS Abs. max 448.3 nm. i.22) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-24-dimethyl-1H-pyrrole-3-carboxamide 10 204 mg (0.5 mmol) 5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid, 138 mg g (0.6 mmol) (3S)-3-amino-N,N-dimethylpyrrolidine-1- carboxamide dihydrochloride, 322 mg (4425 µl, 2.5 mmol) DIPEA were suspended in 8.0 ml anhydrous DMF then HATU (228 mg, 0.6 mmol) and stirred at rt for 18 hours. The solvent was removed under reduced pressure and the residue was taken up with 15 ml saturated aq. K2CO3 and 50 ml THF / EtOAc (1:2) The15 suspension was stirred for 10 min and the precipitated product was filtered off, washed with 10 ml ethyl- acetate and dried. The crude product was purified by column chromatography. (Kieselgel, chloroform- methanol (0.5% TEA) 20:1. Yield: 172 mg (63 %), LCMS purity: 88%, C23H26IN5O3, MW calc. monoisotopic 547.39, found [M+H]+548.1, [M-H]- 547.0, Rt 3.79 min, UV-VIS Abs. max 230.7, 465.7 nm. 201H NMR δ 13.63 (s, 1H); 11.02 (brs, 1H); 7.79 (d, 1H, J=6.1 Hz); 7.66 (s, 1H); 7.60 (d, 1H,J=6.1 Hz); 7.31 (d, 1H, J=8.0 Hz); 7.21 (s, 1H); 4.31 (m, 1H); 3.52-3.43 (m, 3H); 3.25-3.22 (m, 2H); 2.73 (s, 6H); 2.39 (s, 3H); 2.35 (s, 3H); 2.01 (sext., 1H, J=6.0Hz); 1.85 (sext., 1H, J=6.0 Hz) i.23) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3- 25 ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide P138182SG 72 204 mg (0.5 mmol) 5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid, 138 mg g (0.6 mmol) (3S)-3-amino-N,N-dimethylpyrrolidine-1- carboxamide dihydrochloride, 322 mg (4425 µl, 2.5 mmol) DIPEA were suspended in 8.0 ml anhydrous 5 DMF then HATU (228 mg, 0.6 mmol) and stirred at rt for 18 hours. The solvent was removed under reduced pressure and the residue was taken up with 15 ml saturated aq. K2CO3 and 50 ml THF / EtOAc (1:2) The suspension was stirred for 10 min and the precipitated product was filtered off, washed with 10 ml ethyl- acetate and dried. The crude product was purified by column chromatography. (Kieselgel, chloroform- methanol(0.5% TEA) 20:1. Yield: 142 mg (52 %), LCMS purity: 88%, C23H26IN5O3, MW calc. 10 monoisotopic 547.39, found [M+H]+548.1, [M-H]- 547.0, Rt 3.79 min, UV-VIS Abs. max 230.7, 465.7 nm. i.24) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-fluoro-5-nitro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 15 1.73 g (5 mmol) 5-[(Z)-(6-fluoro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid, 1.15 g (5 mmol) (3S)-3-amino-N,N-dimethylpyrrolidine-1- carboxamide dihydrochloride, 3.23g (4.43ml, 25 mmol) DIPEA were suspended in 12 ml anhydrous DMF then HATU (2.19g, 5.7 mmol) and stirred at rt for 18 hours. The solvent was removed under reduced 20 pressure and the residue was taken up with 15 ml saturated aq. K2CO3 and 50 ml THF / EtOAc (1:2) The suspension was stirred for 10 min and the precipitated product was filtered off, washed with 10 ml ethyl- acetate and dried. Yield: 1.69g (70 %), LCMS purity: 100 %, C23H25FN6O5, MW calc. monoisotopic 484.18, found [M+H]+485.1, [M-H]- 483.0, Rt 3.48 min, UV-VIS Abs. max 230.7, 266.5 nm, 444.7 nm. 25 i.25) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2882SK2 P138182SG 73 1.25 g (3.46 mmol) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid, 0.87 g (3.81 mmol) (3S)-3-amino-N,N-dimethylpyrrolidine-1- carboxamide dihydrochloride, 3.06 ml, (18.06 mmol) DIPEA were suspended in 10 ml anhydrous DMF 5 then HATU (1.57 g, 4.15 mmol) and stirred at rt for 18 hours then 50oC for an hour. The solvent was removed under reduced pressure and the residue was taken up with 15 ml saturated aq. K2CO3and 50 ml THF / EtOAc (1:2) The suspension was stirred for 10 min and the precipitated product was filtered off, washed with 10 ml ethyl-acetate and dried. Yield: 1.14g (66 %). LCMS purity: 100 %, C23H25ClN6O5, MW calc. monoisotopic 500.16, found [M+H]+501.0, [M-H]- 498.9, Rt 3.90 min, UV-VIS Abs. max 226.9, 10 266.9 nm, 440.9 nm. i.26) (3Z)-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5-dimethyl-1H-pyrrol-2- yl)methylene]-5-nitro-1,3-dihydro-2H-indol-2-one BSZ2824 15 370 mg (1.02 mmol) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid, 0,91 ml (5.01 mmol) DIPEA, 389 mg HATU, (3S)-N,N-Dimethyl- 3-pyrrolidinamine 116 mg (1.02 mmol) were stirred in 5 ml anhydrous DMF for 16 hours. The solvent was removed under reduced pressure and the oily residue was taken up with 10 ml 20 saturated aq. K2CO3 and 50 ml THF / EtOAc (1:2). The organic layer was separated, dried over Na2SO4 and the dessicant was filtered off. The solvent was removed in vacuo to give the title compound. Yield:410 mg (87%) The title compound was used in the next step without purification. LCMS purity: 100 %, C23H25ClN6O5, MW calc. monoisotopic 457.15, found [M+H]+458.1, [M-H]- 457.0, Rt 3.53 min, UV-VIS Abs. max 231.7, 267.7 nm, 445.7 nm. 25 i.27) (3Z)-5-amino-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5-dimethyl-1H- pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one BSZ2861N_8p_kii, BSZ2882SKR P138182SG 74 230 mg (5 mmol), 281 mg (5.0 mmol) iron powder, 191 mg (3.0 mmol) NH4Cl (1.5 ml water) in 50 ml ethanol were stirred at reflux temperature for 8 hours. After the completion the warm solution was filtered throught a Cellit pad and the solvent was removed under reduced pressure. The residue was taken 5 up with 5 % aq. Na2CO3and extracted with 3x20 ml EtOAc-THF (3:1). The organic layer was separated, dried over Na2SO4. The dessicant was filtered off and the solvent was removed in vacuo to give the title compound. (141mg, 66%). LCMS purity: 90%, C23H27ClN6O3, MW calc. monoisotopic 470.18, found [M+H]+471.1, [M-H]- 469.1, Rt 2.83 min, UV-VIS Abs. max 221.7, 282.7 nm, 423.7 nm. 10 i.28) 5-[(Z)-(5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2809R2 2.30 g (5 mmol) 5-[(Z)-(6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- 15 (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, 2.24g (40 mmol) iron powder, 1.62g (25 mmol) NH4Cl (6 ml water) in 110 ml ethanol and 10 ml DMF were stirred at reflux temperature for 8 hours. After the completion the warm solution was filtered throught a Cellit pad and the solvent was removed under reduced pressure. The residue was taken up with 5 % aq. Na2CO3 and extracted with 3x60 ml EtOAc- THF (3:1). The organic layer was separated, dried over Na2SO4. The dessicant was filtered off and the 20 solvent was removed in vacuo to give the title compound. (1.45g, 66%). LCMS purity: 90%, C23H27ClN6O3, MW calc. monoisotopic 429.19, found [M+H]+430.0, [M-H]- 428.0, Rt 2.44 min, UV-VIS Abs. max 219.7nm, 281.7 nm, 423.7 nm. 1H NMR δ 13.37 (s, 1H); 10.58 (s, 1H); 7.50 (d, 1H, J=11.5 Hz); 7.31 (s, 1H); 7.30 (m, 1H); 6.33 (d, 1H, J=7.6 Hz); 5.26 (s, 2H); 3.29-3.25 (m, 4H); 2.55-2.52 (m, 3H); 2.40 (s, 3H); 2.35 (s, 3H); 0.97 (t, 25 6H; J=7.2 Hz) P138182SG 75 i.29) 5-[(Z)-(5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2882SKR 5 2.50 g (5.00 mmol) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-fluoro-5-nitro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, 2.24g (40 mmol) iron powder, 1.62g (25 mmol) NH4Cl (6 ml water) in 110 ml ethanol and 10 ml DMF were stirred at reflux temperature for 8 hours. After the completion the warm solution was filtered throught a Celit pad and the 10 solvent was removed under reduced pressure. The residue was taken up with 5 % aq. Na2CO3and extracted with 3x60 ml EtOAc-THF (3:1). The organic layer was separated, dried over Na2SO4. The dessicant was filtered off and the solvent was removed in vacuo to give the title compound. (1.45g, 66%), LCMS purity: 90%, C23H27ClN6O3, MW calc. monoisotopic 470.18, found [M+H]+471.1, [M-H]- 469.1, Rt 2.83 min, UV-VIS Abs. max 221.7, 282.7 nm, 423.7 nm. 151H NMR δ 13.58 (s, 1H); 10.57 (s, 1H); 7.76 (d, 1H, J=5.9 Hz); 7.39 (s, 1H); 7.18 (s, 1H); 6.71 (s, 1H); 4.84 (s, 2H); 4.31 (m, 1H); 3.52-3.45 (m, 3H); 3.25-3.23 (m, 1H); 2.73 (s, 6H); 2.39 (s, 3H); 2.33 (s, 3H); 2.02 (sext., 1H, 6.2Hz); 1.85 (sext., 1H, J=6.2Hz) i.30) 5-[(Z)-(6-bromo-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 20 2,4-dimethyl-1 0.65 g (2.53 mmol) 6-bromo-5-nitro-1,3-dihydro-2H-indol-2-one and (0.67 g, 2.53 mmol) N-[2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide and 15 µl piperidine were stirred 50 ml anhydrous ethanol for 48 hours at reflux temperature. The precipitated product was filtered off and 25 dried. Yield:140mg (84%). LCMS purity: 100 %, C22H26BrN5O4, MW calc. monoisotopic 503.12, found [M+H]+504.0, [M-H]- 502.0, Rt 3.07 min, UV-VIS Abs. max 221.7nm, 270.7 nm, 444.7 nm P138182SG 76 1H NMR δ13.47 (s, 1H); 11.39 (s, 1H); 8.68 (s, 1H); 7.96 (s, 1H); 7.49 (t, 1H, J=5.7 Hz); 7.22 (s, 1H); 3.29-3.27 (m, 4H); 2.56-2.51 (m, 4H); 2.45 (s, 3H); 2.44 (s, 3H); 0.97 (t, 6H, J=7.1Hz) i.31) 5-[(Z)-(5-amino-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- 5 (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2823N2 504 mg (1 mmol) 5-[(Z)-(6-bromo-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended in 80 ml ethanol and 560 mg (10 mmol) iron powder, 381 mg (6 mmol) and NH4Cl (in 4 ml water) were to the reaction mixture and 10 stirred for 8 hours at reflux temperature. The hot solution was filtered through a celite pad and the filter cake was washed with 20 ml hot methanol then the combined organic solvent was removed under reduced pressure. The residue was taken up with 20 ml saturated aq. Na2CO3 solution and extracted with 3x 20 ml ethyl-acetate / THF (3:1). The combined organic layer was dried over Na2SO4 then the dessicant was filtered out. The solvent was removed under reduced pressure to give the title compound. 15 Yield: 361 mg (76%) LCMS purity: 83%, C22H28BrN5O2, MW calc. monoisotopic 473.14, found [M+H]+474.0, [M-H]- 471.9, Rt 2.60 min, UV-VIS Abs. max 221.7nm, 280.7 nm, 423.7 nm. 1H NMR δ13.59 (s, 1H); 10.58 (s, 1H); 7.41 (s, 1H); 7.38 (d, 1H, J=7.3 Hz); 7.19 (s, 1H); 6.84 (s, 1H); 4.78 (s, 2H); 3.31-3.26 (m, 4H); 2.55-2.51 (m, 4H); 2.42 (s, 3H); 2.36 (s, 3H); 0.97 (t, 6H, J=7.1Hz) 20 i.32) (3Z)-1-acetyl-6-chloro-3-[methoxy(phenyl)methylene]-5-nitro-1,3-dihydro-2H-indol-2-one - BSZ3010 212 mg (1 mmol) 6-chloro-5-nitro-1,3-dihydro-2H-indol-2-one was suspended in 8 ml acetic anhydride and 546 mg (3 mmol, 0.514 ml) trimethyl orthobenzoate was added to the suspension and stirred 25 for 16 hours at 120oC. The solvent was removed under recuced pressure and the residue was taken up with P138182SG 77 10 ml DIPE. The residue was filtered off and dried to give the title compound. Yield: 289 mg (77%) The tittle compound was used in the next step without purification. LCMS purity: 90% , C18H13ClN2O5, MW calc. monoisotopic 372.05, found [M+H]+373.0, [M-H]- 371.0, Rt 5.15 min , UV-VIS Abs. max 250.9nm, 393.9 nm 5 i.33) N-(4-{[(Z)-(1-acetyl-6-chloro-5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) (phenyl)methyl]amino}phenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2830) 10 105 mg (0.28 mmol) (3Z)-1-acetyl-6-chloro-3-[methoxy(phenyl)methylene]-5-nitro-indolin-2-one was dissolved in 3 ml anhydrous DMF and 73.95 mg (0.28 mmol) N-(4-aminophenyl)-N-methyl-2-(4- methylpiperazin-1-yl)acetamide was added to the solution and stirred at 100 oC for 3 hours. The solvent was removed under pressure and residue was taken up with 10 ml saturated aq. Na2CO3 solution and extracted with 2x20 ml ethyl-acetate. The combined organic layer was dried over Na2SO4, the dessicant 15 was filtered off the solvent was removed under reduced pressure to give the title compound. (137mg, 81%) Rt: 3.64 min. The product was used in the next step without purification. LCMS purity: 81% , C31H31ClN6O5, MW calc. monoisotopic 602.20, found [M+H]+603.1, [M-H]- 601.0, Rt 3.64 min , UV-VIS Abs. max 233.7nm, 271.7, 378.7 nm 20 i.34) N-(4-{[(Z)-(1-acetyl-5-amino-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) (phenyl)methyl]amino}phenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2831) P138182SG 78 137 mg (0.23 mmol) N-[4-[[(Z)-(1-acetyl-6-chloro-5-nitro-2-oxo-indolin-3-ylidene)-phenyl- methyl]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide, 127 mg (2.23 mmol) iron powder, NH4Cl (86 mg,1.36 mmol), 2 ml distilled water and 30 ml ethanol was placed into an 50 ml reaction flask 5 and the reation mixture was stirred at reflux temperature for 6 hours. After the completion the warm solution was filtered through a celite pad and the filter cake was washed with 10-20 ml hot methanol then the combined organic solvent was removed under reduced pressure. The residue was taken up with 20 ml saturated aq. K2CO3solution and extracted with 3x 15 ml ethyl-acetate / THF (4:1). The combined organic layer was dried over Na2SO4then the dessicant was filtered out. The solvent was removed under reduced 10 pressure to give the title compound. Yield: 84 mg (63 %) Rt: 3.28 min. The title compound was used in the next step without purification. LCMS purity: 51% , C31H33ClN6O3, MW calc. monoisotopic 572.23, found [M+H]+573.1, [M-H]- 571.1, Rt 3.28 min , UV-VIS Abs. max 251.7nm, 389.7 nm i.35) N-[4-[[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (BSZ2831N) 15 84 mg (0.15 mmol) N-[4-[[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)-phenyl- methyl]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide was dissolved in 2 ml anhydrous DMF and 23.76 mg (0.45 mmol) sodium-methoxide (25 w / w% solution in methanol) was added and stirred at 85oC for 4 hours. After the completion, the solvent was removed under reduced pressure and the residue 20 was taken up with 5 ml 20% Na2CO3 and extracted with 2x10 ml ethyl-acetate. The combined organic layer was dried over Na2SO4 then the dessicant was filtered out. The solvent was removed under reduced pressure P138182SG 79 to give the title compound. Yield:57 mg (73%). LCMS purity: 51% , C29H31ClN6O2, MW calc. monoisotopic 530.22, found [M+H]+531.1, [M-H]- 529.0, Rt 2.64 min , UV-VIS Abs. max 287.7nm, 376.7 nm. 5 Synthetic procedures of example compounds Ex.1) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide BSZ2727N (EYE1028) 10 N-[2-(diethylamino)ethyl]-5-[(Z)-(6-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide (80mg,0.158 mmol), was dissolved in degassed 5 ml ethanol / water (7:3) and N,N'-dimethylethylenediamine (2.78 mg, 0.031 mM 3.15 µl), sodium azide (20mg, 0.31 mmol), copper(I)iodide (0.0238mmol, 4.5mg) and sodium-L-ascorbate (0.016mmol, 3.13mg) and underwent 15 microwave irradiation for 80 min. The reaction mixture was cooled to room temperature and the crude product was filtered off then washed with 3-4 ml water to give the final product (52 mg, 79%). LCMS purity: 99%, C22H27N7O2, MW calc. monoisotopic 421.22, found [M+H]+422.4, [M-H]- 420.4, Rt 3.09 min, UV-VIS Abs. max 219.7nm, 280.7 nm, 444.7 nm. 1H NMR δ13.48 (s, 1H); 10.96 (s, 1H); 7.82 (d, J = 8.2 Hz, 1H); 7.61 (s, 1H); 7.39 (t, J = 5.5 Hz, 20 1H); 6.75 (dd, J = 8.2 Hz, J = 1.9 Hz, 1H); 6.58 (d, J = 1.8 Hz, 1H); 3.28 (q, J = 6.5 Hz, 4H); 2.57-2.51 (m, 4H); 2.44 (s, 3H); 2.40 (s, 3H); 0.97 (t, J = 7.1 Hz, 6H) Ex.2) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide BSZ2729N5, BSZ2695N (EYE1052) 25 P138182SG 80 N-[2-(diethylamino)ethyl]-5-[(Z)-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide (80mg,0.158 mmol), was dissolved in degassed 5 ml ethanol / water (7:3) and N,N'-dimethylethylenediamine (2.78 mg, 0.031 mM 3.15 µl), sodium azide (20mg, 0.31 mmol), copper(I)iodide (0.0238mmol, 4.5mg) and sodium-L-ascorbate (0.016mmol, 3.13mg) and underwent 5 microwave irradiation for 80 min. The reaction mixture was cooled to rt and the crude product was filtered off then washed with 3-4 ml water to give the final product (57 mg, 83%). LCMS purity: 99%, C22H27N7O2, MW calc. Monoisotopic 421.22, found [M+H]+422.4, [M-H]- 420.3, Rt 3.09 min, UV-VIS Abs. max 234.7nm, 285.7 nm, 412.7 nm 1H NMR δ13.69 (s, 1H); 10.93 (s, 1H); 7.76 (s, 1H); 7.69 (s, 1H); 7.41 (m, 1H); 6.89 (d, J = 8.3 Hz, 10 1H); 6.85 (d, J = 8.3 Hz, 1H); 3.29-3.27 (m, 4H); 2.58-2.51 (m, 4H); 2.44 (s, 6H); 0.98 (t, J = 6.8 Hz, 6H) Ex.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]-2,4- dimethyl 15 120 mg (0.24 mmol) N-[2-(diethylamino)ethyl]-5-[(Z)-(4-iodo-2-oxo-1,2-dihydro-3H-indol-3- ylidene) methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was dissolved in degassed 5 ml ethanol / water (7:3) and N,N'-dimethylethylenediamine (4.18 mg, 0.047 mM 3.15 µl), sodium azide (30.8 mg, 0.47 mmol), copper(I)iodide (6.77 mg 0.036 mmol,) and sodium-L-ascorbate (0.024 mmol, 4.69 mg) and underwent microwave irradiation for 80 min. The reaction mixture was cooled to rt and the crude product was filtered 20 off then washed with 3-4 ml water to give the final product (72 mg, 73 %). LCMS purity: 100%, C22H27N7O2, MW calc. monoisotopic. 421.22, found [M+H]+422.4, [M-H]- 420.5, Rt 3.04 min, UV-VIS Abs. max 222.7nm, 288.7 nm, 430.7 nm Ex.4) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 25 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1089) The title compound was synthesized by two different methods. BSZ2764AZU P138182SG 81 Method A 140 mg (0.27 mmol) N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-6-iodo-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended in degassed 6 ml 5 ethanol / water (7:3) under argon atmosphere and N,N'-dimethylethylenediamine (4.71 mg, 0.053 mM 5.75 µl), sodium azide (34.73 mg, 0.53 mmol), copper(I)iodide (0.04 mmol, 7.63 mg) and sodium-L-ascorbate (0.027 mmol, 5.29 mg) and underwent microwave irradiation for 80 min. The reaction mixture was cooled to RT and the crude product was filtered off then washed with 3-4 ml water to give the final product. (5.0 mg, 11 %) The product was purified by RP-HPLC. 10 LCMS purity 99% , C22H26FN7O2, MW calc. monoisotopic 439.21, found [M+H]+440.1, [M-H]- 438.1, Rt 3.02 min , UV-VIS Abs. max 217.7, 281.7, 450.7 nm Method B: 15 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide 100 mg (0.24 mmol) 5-[(Z)-(6-amino-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N- [2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide were suspended in 40 ml distilled water 20 and 138 mg (0.73 mmol) p-Toluenesulfonic acid monohydrate was added to the suspension and stirred at 50oC for 30 min. The reaction mixture (containing insoluble starting material) was filtered through a G4 sintered glass filter the filtrate transferred to a reaction flask and the filtrate was cooled to 0oC. Sodium nitrite (66.80 mg, 0.97 mmol) or potassium nitrite (82.40 mg, 0.97 mmol) was added to the dark solution and stirred for 45-60 min keeping the temperature between 0-5oC. Finally, 94.40 mg (1.45 mmol) sodium 25 azide was added to the solution and reaction mixture was allowed to warm up to room temperature gradually P138182SG 82 and stirred overnight in dark. 0.4g Na2CO3dissolved in the reaction mixture and the precipitated product was filtered off and washed with 2-3 ml distilled water. Yield: 72mg (69%, first crop) The mother liquor was extracted with 2x30 ml ethyl-acetate, the combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound. (second crop, 19 mg, 18%). 5 LCMS purity 99% , C22H26FN7O2, MW calc. monoisotopic 439.2, found [M+H]+440.1, [M-H]- 438.1, Rt 3.02 min , UV-VIS Abs. max 217.7, 281.7, 450.7 nm. Ex.5) ethyl 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxylate (EYE1056) 10 The title compound was synthesized via Method B. SZI3140BCS 110 mg (0.34 mmol) ethyl 5-[(Z)-(5-amino-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate was suspended in 30 ml distilled water and (193 mg, 1.01 mmol) and the reaction 15 mixture was cooled to 0oC then (93 mg, 1.35 mmol) NaNO2 was added to the solution and stirred for 45 min. Finally NaN3 (116mg, 1.69 mmol) was added to he solution and allowed to warm up to room temperature gradually. The precipitated product was filtered off, washed with water and dried. Yield: 69 mg (58%). LCMS purity: 99% , C18H17N5O3, MW calc. monoisotopic 351.13, found [M+H]+352.0, [M-H]- 350.0, Rt 4.88 min , UV-VIS Abs. max 234.7nm, 284.7nm, 407.7 nm. 201H NMR δ 13.94 (s, 1H); 11.01 (s, 1H); 7.82 (s, 1H); 7.73 (d, J = 1.5 Hz, 1H); 6.89 (dd; J= 8.2 Hz, J = 1.8 Hz, 2H); 4.22 (q, J = 7.1 Hz, 2H); 2.54 (s, 3H); 2.53 (s, 3H); 1.30 (t, J = 7.1 Hz, 3H) Ex.6) 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide BSZ2818 (EYE1091) 25 The title compound was synthesized via Method B. P138182SG 83 Yield:60 mg (24%), LCMS purity: 100% , C22H26FN7O2, MW calc. monoisotopic 439.2, found [M+H]+440.1, [M-H]- 438.1, Rt 3.11 min , UV-VIS Abs. max 230.7nm, 306.7, 433.7 nm. 1H NMR δ 13.53 (s, 1H); 10.92 (s, 1H); 7.88 (d, J = 11.6 Hz, 1H); 7.67 (s, 1H); 7.42 (t, J = 5.5 Hz, 1H); 6.66 (d, J = 7.0 Hz, 1H); 3.28 (q, J = 6.5 Hz, 4H); 2.57-2.50 (m, 4H); 2.44 (s, 3H); 2.41 (s, 3H); 0.98 5 (t, J = 7.1 Hz, 6H) Ex.7) 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino) 10 237 mg (0.5 mmol) 5-[(Z)-(5-amino-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended in 23 ml distilled water and 286 mg (1.5 mmol) TosOH hydrate was added to the suspension and the reaction mixture was warmed up to 50oC and stirred for 30 min. The reaction mixture was cooled to 0oC using ice bath and filtered into an one-necked reaction flask via G4 sintered glass filter. To this solution 138 mg (2.0 mmol) NaNO2 was 15 added in one portion and stirred for 60 min. then NaN3195 mg (3.0 mmol ) was added to the reaction mixture in one portion. The reaction mixture was allowed to warmed up to room temperature gradually (not removing the ice bath, allowing the ice melted) and stirred overnight in dark. Na2CO3 (5-600 mg ) was dissolved in the reaction mixture and the precipitated product was filtered off and washed with 2-3 ml water (first crop, 181 mg (72%). The aqueous layer was saturated with NaCl and extracted with 2x25 20 EtOAc / THF 3:1, the combined organic dried over Na2SO4. The dessicant was filtered off, the organic layer was evaporated under reduced pressure to give the title compound. (second crop, 35 mg (13%) The title compound was purified by HPLC. LCMS purity:100%, C22H26BrN7O2, MW calc. monoisotopic 499.1, found [M+H]+500.0, [M-H]- 498.0, Rt 3.56 min , UV-VIS Abs. max 239.7nm, 310.7, 443.7 nm. 251H NMR δ 13.64 (s, 1H); 11.01 (s, 1H); 8.16 (s, 1H) formiate salt; 7.96 (s, 1H); 7.86 (s, 1H); 7.47 (m, 1H); 7.06 (s, 1H); 3.31 (q, J ~ 6.5 Hz, 4H);2.64-2.53 (m, 4H); 2.45 (s, 3H); 2.44 (s, 3H); 1.00 (t, J = 7.1 Hz, 6H) Ex.8) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethylcarbamoyl 30 )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2767SC (EYE1088) P138182SG 84 120 mg (0.22 mmol) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(6-iodo-2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended 8 ml EtOH / water (7:3 V / V) and sodium azide (28.5 mg, 0.43 mmol), copper(I)iodide (0.033 mmol, 6.26 mg) 5 and sodium-L-ascorbate (0.021 mmol, 4.34 mg) N,N'-dimethylethylenediamine (3.86 mg, 0.043 mM 3.15 µl), and reaction mixture underwent microwave irradiation for 80 min (120oC) in a sealed tube. The reaction mixture was cooled to rt and the crude product was filtered off then washed with 3-4 ml water to give the final product. (52 mg, 51 %). LCMS purity: 100% , C23H26N8O3, MW calc. monoisotopic 462.2, found [M+H]+463.0, [M-H]- 10 461.0, Rt 3.62 min , UV-VIS Abs. max 226.7nm, 280.7, 442.7 nm 1H NMR δ 13.48 (s, 1H); 10.96 (s, 1H); 7.82 (d, J = 8.2 Hz, 1H); 7.77 (d, J = 6.3 Hz, 1H); 6.75 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H); 6.58 (d, J = 1.9 Hz, 1H); 4.32 (sext, J = 5.8 Hz, 1H); 3.54-3.35 (m, 3H); 3.26- 3.22 (m, 2H); 2.74 (s, 6H); 2.40 (s, 3H), 2.37 (s, 3H); 2.03 (sext, J ~ 6.4 Hz, 1H); 1.86 (sext, J ~ 6.4 Hz, 1H) 15 Ex.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2803NKR (EYE1114) 20 The title compound was synthesized according to Method A. 120 mg (0.22 mmol) N-[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]-5-[(Z)-(5-iodo-2-oxo-indolin- 3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide underwent microwave irradiation in a sealed tube. Yield:47 mg (46%). LCMS purity: 100% , C23H26N8O3, MW calc. monoisotopic 462.2, found 25 [M+H]+463.0, [M-H]- 461.0, Rt 3.62 min , UV-VIS Abs. max 226.7nm, 280.7, 442.7 nm 1H NMR δ 13.69 (s, 1H); 10.93 (s, 1H); 7.79 (d, J = 6.3 Hz, 1H); 7.76 (s, 1H); 7.69 (d, J = 1.9 Hz, 1H); 6.89 (d, J = 8.2 Hz, 1H); 6.85 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 1H); 4.32 (sext, J = 5.7 Hz, 1H); 3.54- P138182SG 85 3.43 (m, 2H); 3.34 (m, 1H); 3.24 (dd, J= 10.8 Hz, J = 4.9 Hz, 1H); 2.74 (s, 6H); 2.40 (s, 3H); 2.40 (s, 3H); 2.04 (sext, J = 6.4 Hz, 1H); 1.86 (sext, J = 6.2 Hz, 1H). Ex.10.) Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- 5 carboxylate BSZ2744TN7_12p (EYE1063) The title compound was synthesized according to Method A. BSZ2744TN7_12p 82 mg (0.18 mmol) Ethyl 5-[(Z)-(6-iodo-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole- 10 3-carboxylate, were suspended in 8 ml EtOH / water (7:3) under argon N,N'-dimethylethylenediamine (3.31 mg, 0.037 mM 5.75 µl), sodium azide (34.73 mg, 0.37 mmol), copper(I)iodide (0.028 mmol, 5.37 mg) and sodium-L-ascorbate (0.019 mmol, 3.72 mg) and underwent microwave irradiation in a sealed tube for 80 min. (110oC)The reaction mixture was cooled to room temperature and the precipitated product was filtered off. The title compound for the biological and enzymatic experiments was purified by HPLC. 15 Yield: 6.2 mg (9%). LCMS purity: 97% , C18H17N5O3, MW calc. monoisotopic 351.13 [M+H]+352.0, [M-H]- 350.0, Rt 5.03 min , UV-VIS Abs. max 231.7nm, 278.7nm, 444.7 nm. Ex.11) 5-[(Z)-(6-azido-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2841 (EYE1087) 20 The title compound was synthesized according to Method B. Yield: (28mg) 34% , LCMS purity: 98% , C22H26ClN7O2, MW calc. monoisotopic 455.18, found [M+H]+456.1, [M- H]- 454.1, Rt 3.71 min , UV-VIS Abs. max 229.7nm, 283.7, 451.7 nm. 251H NMR δ 13.47 (s, 1H); 11.04 (s, 1H); 8.04 (s, 1H); 7.72 (s, 1H); 7.42 (t, J = 5.5 Hz, 1H); 6.80 (s, 1H); 3.28 (q, J = 6.5 Hz, 4H); 2.57-2.51 (m, 4H); 2.44 (s, 3H); 2.42 (s, 3H); 0.97 (t, J = 7.1 Hz, 6H) P138182SG 86 Ex.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ1794UKA(EYE1116) 80 mg (0.18 mmol) 5-[(Z)-(6-amino-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-[1- 5 (dimethylcarbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended in 42 ml distilled water (4 ml N-methylpyrrolidone was added) and p-TosOH hydrate (100mg, 0.52 mmol) was added to the suspension and the mixture was warmed up to 50oC and stirred for 30 min. The reaction mixture was cooled to 0oC using ice bath and filtered into an one-necked reaction flask via G4 sintered glass filter. To this solution 48 mg (0.70 mmol) NaNO2was added in one portion and stirred for 60 min at 10 0oC then NaN368.7 mg (1.05 mmol ) was added to the reaction mixture in one portion. The reaction mixture was allowed to warmed up to room temperature gradually (not removing the ice bath, allowing the ice melted) and stirred overnight in dark. Na2CO3(5-600 mg ) was dissolved in the reaction mixture and the precipitated product was filtered off and washed with 2-3 ml water. Yield: 57mg (67%) The title compound for the biological and enzymatic experiments was purified by HPLC. LCMS 15 purity: 100% , C23H25FN8O3, MW calc. monoisotopic 480.2, [M+H]+481.0, [M-H]- 479.0, Rt 3.83 min , UV-VIS Abs. max 241.7nm, 281.7, 454.7 nm. Ex.13) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2828(EYE1118) 20 240 mg (0.51 mmol) ) 5-[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)methyl]-N-[1- (dimethylcarbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was was suspended in 90 ml distilled water (8 ml N-methylpyrrolidone was added) and p-TosOH hydrate (291 mg, 1.53 mmol) was added to the suspension and the mixture was warmed up to 50oC and stirred for 25 30 min. The reaction mixture was cooled to 0oC (using ice bath) and filtered into an one-necked reaction flask via G4 sintered glass filter. To this solution 141 mg (2.04 mmol) NaNO2 was added in one portion and stirred for 60 min at 0oC then NaN3206.2 mg (3.17 mmol ) was added to the reaction mixture in one P138182SG 87 portion. The reaction mixture was allowed to warmed up to room temperature gradually (not removing the ice bath, allowing the ice melted) and stirred overnight in dark. Na2CO3(8-600 mg ) was dissolved in the reaction mixture and suspension was extracted with 3x30 ml EtOAc / THF (3:1). For fastest separation of the layers, centrifuge was used (4000 rpm, for 3-4 min). The insoluble precipitated product was filtered off 5 to give the title compound. (145 mg, 57%). The organic layers was separated, combined and dried over Na2SO4. The dessicant was filtered out and the solvent was removed under reduced pressure to give the second crop of the title compound. (62 mg, 24%) The title compound (used in the biological and enzymatic experiments) was purified by semipreparative RP-HPLC. 10 LCMS purity: 98% , C23H25ClN8O3, MW calc. monoisotopic 496.17, [M+H]+497.1, [M-H]- 495.1, Rt 3.88 min , UV-VIS Abs. max 239.7nm, 310.7, 445.7 nm. 1H NMR δ 13.62 (s, 1H); 11.01 (s, 1H); 7.96 (s, 1H); 7.81 (d, 1H, J=6.4 Hz); 6.93 (s, 1H); 4.31 (q, 1H, J=5.7Hz); 3.53-3.44 (m, 2H);3.35-3.33(m, 2H); 3.25 (m, 1H); 2.74 (s, 6H); 2.42 (s, 3H); 2.41 (s, 3H); 2.07-2.00 (m, 1H); 1.89-1.83 (m, 1H) 15 Ex.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide 3156A1 (EYE1112) 20 172 mg (0.9 mmol) p-Toluenesulfonic acid monohydrate was dissolved in 12 ml water, stirred and cooled down to 0-4oC . To this solution 124 mg (0.3 mmol) 5-[(Z)-(7-amino-5-fluoro-2-oxo-indolin-3- ylidene)methyl]-N-(2-diethylaminoethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide derivative and sodium nitrite (62 mg, 0.9 mmol) were added, and stirred at 0-4oC for 2 hours. Then sodium azide (22mg, 0.33 mmol) was added in small portion. This mixture was stirred at 0-4oC Celsius for 25 2 hours and allowed to warmed up to room temperature gradually and stirred overnight. Yield: 32 mg (17 %) Fort he analytical and biological measurement. The title compound in the biological and enzymatic experiments was purified by HPLC. LCMS purity: 97% , C22H26FN7O2, MW calc. monoisotopic 439.21, found [M+H]+440.0, [M-H]- 438.0, Rt 3.11 min , UV-VIS Abs. max 242.7nm, 275.7, 433.7 nm P138182SG 88 Ex.15) (3Z)-6-azido-3-[[4-[4-(2-hy ) azine-1-carbonyl]-3,5-dimethyl-1H-p yl]methylene]indolin-2-one BSZ2758AAT (EYE1068) 5 The title compound was synthesized via Method A. 105 mg (0.2 mmol) (3Z)-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol- 2-yl]methylene]-6-iodo-indolin-2-one was suspended in 7 ml ethanol / water (7:3) and sodium azide (26.2 10 mg, 0.40 mmol), copper(I)iodide (0.03 mmol, 5.75 mg) and sodium-L-ascorbate (0.02 mmol, 3.99 mg) N,N'-dimethylethylenediamine (3.55 mg, 0.04 mM 3.11 µl), and reaction mixture underwent microwave irradiation for 80 min (at 120oC) in a sealed tube. The crude product was purified by HPLC. Yield: 34 mg (39%). LCMS purity: 99%, C22H25N7O3, MW calc. monoisotopic 435.2, found [M+H]+436.0, [M-H]- 434.0, Rt 2.87 min , UV-VIS Abs. max 15 219.7nm, 280.7nm, 448.9 nm. 1H NMR δ 13.43 (s, 1H); 10.95 (s, 1H); 7.80 (d, J = 8.2 Hz, 1H); 7.60 (s, 1H); 6.75 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 1H); 6.58 (d, J = 1.9 Hz, 1H); 4.41 (t, J = 5.2 Hz, 1H); 3.52-3.48(m, 4H); 3.45-3.42 (m, 2H), 2.41-2.39 (m, 6H); 2.28 (s, 3H); 2.24 (s, 3H) 20 Ex.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5-dimethyl-1H- pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one BSZ2826 (EYE1094) The title compound was synthesized via Method B from 120 mg (0.28mmol) (3Z)-5-amino-6- chloro-3-[[4-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- 25 yl]methylene]indolin-2-one. P138182SG 89 Yield: 55 mg (24%) LCMS purity: 98% , C23H25ClN8O3, MW calc. monoisotopic 453.17, found [M+H]+454.1, [M- H]- 452.0, Rt 3.10 min , UV-VIS Abs. max 243.7nm, 444.7 nm. 5 Ex.17) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide BSZ2809F (EYE1090) The title compound was synthesized via Method B. 10 215 mg (0.5 mmol) 5-[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)methyl]-N-(2- diethylaminoethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide was suspended in 30 ml distilled water and p- TosOH hydrate (285 mg, 1.52 mmol) was added to the suspension and the mixture was warmed up to 50 oC and stirred for 30 min. The reaction mixture was cooled to 0oC using ice bath and filtered into an one- necked reaction flask via G4 sintered glass filter. To this solution 138 mg (2.00 mmol) NaNO2(or KNO2- 15 170mg) was added in one portion and stirred for 60 min at 0oC then NaN3195 mg (3.00 mmol ) was added to the reaction mixture in one portion. The reaction mixture was allowed to warmed up to room temperature gradually (not removing the ice bath, allowing the ice melted) and stirred overnight in dark. Na2CO3 (2-300 mg ) was dissolved in the reaction mixture and the precipitated product was filtered off and washed with 2-3 ml water. First crop, yield: 149 mg (65%). The aqueous layer was extracted with 2x 30 ml EtOAc / THF 20 3:1 and the combined organic layers was dried over Na2SO4. The dessicant was filtered off and the solvent was removed under reduced pressure to give the title compound. (second crop, yield: 31 mg, 13%) For the biological experiments, the product was purified by HPLC. LCMS purity: 100% , C22H26ClN7O2, MW calc. monoisotopic 455.18, found [M+H]+456.0, [M- H]- 454.0, Rt 3.22 min , UV-VIS Abs. max 227.7nm, 280.7, 443.7 nm 251H NMR δ 13.62 (s, 1H); 11.02 (s, 1H); 7.96 (s, 1H); 7.84 (s, 1H); 7.47 (m, 2H); 7.11 (d, J = 7.5 Hz, 1H); 6.93 (s, 1H); 2.61-2.51 (m, 6H); 2.45 (s, 3H); 2.45 (s, 3H); 0.99 (t, J = 6.9 Hz, 6H) Ex. 18) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N-methyl- 2-(4-methylpiperazin-1-yl)acetamide (EYE1309) 30 P138182SG 90 The title compound was synthesized via Method B. 50 mg (0.094 mmol) N-[4-[[(Z)-(5-amino-6-chloro-2-oxo-indolin-3-ylidene)-phenyl- methyl]amino] phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide were suspended in 15 ml distilled 5 water and 71.70 mg (0.37 mmol) p-toluenesulfonic acid monohydrate was added to the suspension and stirred at 50oC for 15 min. The reaction mixture (containing insoluble starting material) was filtered through a G4 sintered glass filter the filtrate transferred to a reaction flask and the filtrate was cooled to 0oC. Sodium nitrite (32.48 mg, 0.47 mmol) or potassium nitrite (40.06 mg, 0.47 mmol) was added to the solution and stirred for 45-60 min, keeping the temperature between 0-5oC. Finally, 42.84 mg (0.66 mmol) sodium 10 azide was added to the solution and reaction mixture was allowed to warm up to room temperature gradually and stirred overnight in dark. 0.2 g K2CO3 dissolved in the reaction mixture and was extracted with 2x10 ml ethyl-acetate / THF(4:1) , the combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound. Yield: 39 mg, (75%). LCMS purity: 100% , C29H29ClN8O2, MW calc. monoisotopic 556.21, found 15 [M+H]+557.1, [M-H]- 555.1, Rt 3.28 min , UV-VIS Abs. max 230.7nm, 304.7, 379.7 nm. Fluorescence emission max.600nm 1H NMR δ11.95 (s, 1H); 10.89 (s, 1H); 7.52 (m, 3H); 7.48-7.46 (m, 2H); 7.14-7.10 (m, 2H); 6.93- 6.92 (m, 3H); 5.48 (s, 1H); 3.06 (m, 4H); 2.71 (m, 2H); 2.36-2.28 (m, 7H); 2.21 (s, 3H) 20 Azido derivatives of PMO-containing molecules A) Sunitinib-based compounds Alternative preparation of azide-substituted sunitinib derivatives of the present invention: First, iodine-substituted indol-2-ones are synthesized starting from para-iodo-aniline and meta-iodo- aniline carrying the appropriate substituents, by the corresponding amidation with reaction to form (2E)- 25 N-(4-iodo)-2-(hydroxyimino)acetamide and (2E)-N-(3-iodo)-2-(hydroxyimino)acetamide, respectively, from which the respective product is obtained by ring closure. Subsequently, to prepare the portion of the molecule that is to be coupled to the 3rdcarbon atom of the appropriately substituted indole-2-one structure, 2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4- dicarboxylate (6) is synthesized via the Paal-Knorr pyrrole synthesis [Kennedy et al. 2009]. The 4-ethyl- 30 carboxylate group is amidated with amino-trietylamine (8) in the presence of group (IV) metal alkoxide P138182SG 91 complexes or lanthanum trifluoromethanesulfonate or lithium-hydroxide as catalists [Milleraet al., 2015 and references cited therein]. 5 Scheme 3 To each stirred solution containing compound 7 in EtOH is added, dropwise, a solution of appropriately substituted indole-2-one and then piperidine. After stirring at room temperature for 6 h, the precipitate formed is filtrated, washed with EtOH, and purified by column chromatography (silica gel, 90:10:1 EtOAc-MeOH-TEA) to form the required iodinated sunitinib intermedier. 10 Finally, the azido functionality is built up by replacing iodine on the sunitinib scaffold by using CuI / diamine catalyst, sodium ascorbate as a stabilizer of the catalyst and 2 equivalents of NaN3in a 3:7 medium of EtOH and H2O [Andersen, J. et al.2005]. The formulae of exemplary molecules having sunitinib scaffold that we have used for the experiments described in this patent are shown below as formulae (1) to (6), respectively. 15 (1) 5-desfluoro-5-azido-sunitinib / Ex.2 (2) 5-desfluoro-6-azido-sunitinib / Ex.1 P138182SG 92 (3) 6-azido-sunitinib / Ex.4 (4) 5-desfluoro-5-azido-6-fluoro-sunitinib / Ex. 6 5 (5) 5-desfluoro-5-azido-6-chloro-sunitinib / Ex.18 (6) 5-desfluoro-5-azido-6-bromo-sunitinib / Ex.7 In the sunitinib-based molecules presented above, the covalently attached azido group (N3) becomes 10 part of an extended conjugated π electron system. Sunitinib has an absorbance maximum at 430-431 nm which can be shifted even higher in the azidated versions as shown by Figures 2-7. B) Vorolanib-based compounds 15 Alternative preparation of azide-substituted vorolanib derivatives of the present invention: P138182SG 93 The indole-2-one moiety of these molecules were prepared in an identical manner as described for the molecules based on the sunitinib scaffold. Subsequently 2-acetaldehydo-4-carboxy-3,5-dimethyl-1H- pyrrole is coupled to the appropriate indole-2-one in ethanol, and in the presence of hexafluorophosphate- azabenzotriazole-tetramethyl-uranium (HATU), N,N-diisopropylethylamine (DIPEA) and 5 dimethylformamide (DMF) the required amide [Carpino, 1993] is formed using N'-pyrrolidino-N,N- dimethyl-urea as the cyclic amine to build up the vorolanib scaffold. Finally, the azido functionality is introduced into the molecule by replacing iodine on the indole-2-one moiety of the vorolanib scaffold using CuI / diamine catalyst, sodium ascorbate as a stabilizer of the catalyst and 2 equivalents of NaN3in a 3:7 medium of EtOH and H2O [Andersen, J. et al.2005]. 10 The formulae of exemplary molecules having vorolanib scaffold that we have used for the experiments described in this patent are shown below as formulae (7) and (8), respectively. (7) 5-desfluoro-6-azido-vorolanib / Ex.8 (8) 5-desfluoro-5-azido-6-chloro-vorolanib / Ex.13 15 As evident for a person skilled in the art from the formulae above, the covalently attached azido group (N3) becomes part of an extended conjugated π electron system, therefore the energy of the visible light harvested by the PMO of vorolanib can be transferred to the azido group to propel N2 extrusion. The UV-visible spectra of the prepared vorolanib-based molecules above are shown in Figures 8.-9. 20 Spectroscopic analyses The following test compounds: EYE1013, EYE1028, EYE1052, EYE1090, EYE1118, EYE1309, EYE1056, EYE1068, EYE1088, EYE1091, EYE1093, EYE1087, EYE1114, 16752 were tested in absorbance and fluorescence spectrum analyses. 25 Absorption spectrum analysis P138182SG 94 Test compounds were diluted to 1 mM and to 100 µM concentrations in PBS. 100 µL of diluted samples were used in Corning black wall / transparent bottom 384 test plate. Tecan Infinite® M1000 PRO multimode plate reader equipped with 4 prisms were utilized in absorbance mode. Band width: 5 nm. 5 Fluorescence spectrum analysis Test compounds were diluted to 1 mM and to 100 µM concentrations in PBS. 100 µL of diluted samples were used in Corning black wall / transparent bottom 384 test plate. A Tecan Infinite® M1000 PRO multimode plate reader equipped with 4 prisms were utilized in fluorescence mode. Both emission and excitation scan were performed. Excitation spectrum was non-reliable because of the high autofluorescence 10 of the assay plate in the wavelength range of 350-450 nm. Emission spectrum between 450 and 850 nm emission wavelengths was recorded at constant 410+ / -10 nm excitation wavelength and 2 nm bandwidth. P138182SG 95 Comparative fluorescence analysis at 485 / 520 nm Fluorescence at 485 / 520 nm may interfere with many fluorescence-based assays which use FITC or equivalent wavelength setup. Here we present the relative fluorescence of the test compound compared to 5 PBS buffer measured at 485 / 520 nm. Azidated versions of PMO-containing molecules are capable of specifically inhibiting VEGFR2 in a light-potentiated way The effectiveness of the compounds as inhibitors was evaluated in biochemical VEGFR2, PDGFRβ 10 and FGFR1 kinase assays. The kinase assays constituted of the components described in Table I. Table I. P138182SG 96 The assay buffer was prepared by dissolving the components in Milli-Q®ultrapure water. Poly Glu- Tyr (4:1) and ATP was added to the kinase buffer. The solution was pipetted on Greiner 784900 non- binding, low volume, flat bottom black polystyrene microplates in 6 µL volumes. The inhibitor compounds 5 were dissolved in DMSO and a three-fold dilution series was prepared from each compound. The inhibitors were added to the assay in 12.5 nL volumes, in 12 concentrations, ranging from 7.8 µM to 0.04 nM. Kinase reaction was initiated by addition of the recombinant kinase in 2 µL volumes. Kinase reaction was proceeding for 60 minutes, after which the detection buffer was added to each well in 8 µL volumes. The wells were incubated for another 60 minutes before fluorescence polarization (FP) and fluorescence 10 intensity (FI) was measured using a Tecan Infinite M1000 Pro multireader (Transcreener FP detection method). FP corresponding to minimum enzyme activity was determined by wells containing no enzyme. Calibration curve of fixed ATP / ADP ratios was used for calculation of inhibition values. Assays were performed both with and without illumination. Photoactivation was proven by the subsequent increase of kinase inhibition of the compounds. Non-illuminated plates were sealed 15 immediately after addition of the kinase, and were placed in a dark environemnt. For the illuminated plates, a LED light source (400 lm, 6500K) was used to illuminate assay wells for 10 minutes, starting 1 minute after the addition of the kinase, and the assay plates were sealed afterwards and placed in a dark environment. Measured IC50 values are presented in the Table II below. 20 P138182SG 97 Table II In an alternative set of experiments demonstrated that the azidated versions of sunitinib and vorolanib could bind to the VEGFR2 (KDR) receptor, inhibit its function, and light could potentiate this inhibitory 5 effect. Figure 10 shows the inhibitory effect of sunitinib in the presence of ambient light and without light, in the dark. Luminescence is plotted as a function of the logarithm of concentration in the light or in the dark whereby IC50 (i.e. concentrations at which the inhibition is half of the maximal inhibition) values can be calculated. Essentially the two curves run together and the IC50 values are nearly identical. Thus, binding 10 properties and inhibition are independent of the ambient light. In Figure 11 the inhibitory effect of 5-desfluoro-5-azido-sunitinib is shown in the presence of light and in the absence of light. Ambient light induced photoactivation of this molecule is clearly seen on the plot. Upon illumination, the IC50 value for 5-desfluoro-5-azido-sunitinib is nearly an order of magnitude lower than in the dark. The IC50 (light) is 36.84 nM whereas IC50 in the dark is 262.9 nM. The effect of 15 the light is even more pronounced in the case of 5-desfluoro-6-azido-sunitinib (Figure 12) where the azido P138182SG 98 group occupies a different position of the indole-2-one scaffold, as evidenced by the fact that the IC50 value is more than ten times lower in the light (9.305 nM) than in the dark (93.74 nM). To study the effects of halogen atoms attached to the azido-indole-2-one moiety, 2 fluorine- containing variants have been synthetized: (i) sunitinib azidated in the 6thposition of the indol-2-one moiety 5 displaying an IC50 of 53.25 nM (dark) and of 11.65 nM (light) as shown in Figure 13, and (ii) the same molecule but with the fluorine atom and the azido-group swapped displaying an IC50 of 69.02 nM (dark) and of 8.86 nM (light), as shown in Figure 14. Using halogen atoms of larger molecular weight is supposed (i) to change the polarity of the structure via an inductive effect thereby improving the penetration into the cells and (ii) to change the π-electron 10 density of the indole-2-one moiety via the mesomeric effect. Therefore the inventors have synthetized two derivatives with heavier halogen atoms: (i) 5-desfluoro-5-azido-6-chloro-sunitinib displaying an IC50 of 40.41 nM (dark) and 2.23 nM (light) as shown in Figure 15 and (ii) 5-desfluoro-5-azido-6-bromo-sunitinib displaying an IC50 of 60.38 nM (dark) and 3.50 nM (light) as shown in Figure 16. Taken together it can be concluded that chlorine and bromine atoms greatly enhanced the responsiveness of the molecules to light 15 and increased their suitability for the purpose described in the present patent. Importantly, in addition to sunitinib, a further scaffold, namely vorolanib could be successfully modified to include a photoactivable azido group. By removing the fluorine atom from the 5thposition of the indole-2-one moiety, and introducing an azido group into the 6thposition, the inventors obtained a molecule having an IC50 of 53.4 nM in the dark and 10.1 nM when illuminated with a cold white LED 20 lamp (Table 1., Figure 17.). Of note, orally administered vorolanib has already been investigated in human clinical trials against age-related macular degeneration [Jackson et al., 2017, Cohen et al., 2020] that were prematurely stopped in spite of the promising therapeutic efficacy, due to the intolerable levels of side effects. Therefore, modification of vorolanib according to the invention described herein would particularly be useful to lower the concentration of the medication in the plasma of the patients and thereby reducing 25 the unwanted effects. Motivated by this fact, the inventors have introduced a chlorine substituent into the 6thposition of the oxindole moiety of vorolanib, given that the congruent modification proved to enhance the light-mediated activation of sunitinib. This way the inventors obtained 5-desfluoro-5-azido-6-chloro- vorolanib the IC50 of which was 57.84 nM in the dark and 0.921 nM in the light (Table 1., Figure 18.) displaying therefore a 62.80-fold light effect which qualifies this molecule to be the most efficient example 30 among the compounds listed in Table 1. Summary of IC50 values in VEGFR2 reporter HEK cell based assay system is shown in Table 1. Table 1: IC50 values measured on VEGFR2-HEK cells P138182SG 99 Azidated versions of PMO-containing molecules inhibit in vitro angiogenesis and such inhibition is potentiated by light In vitro angiogenesis (hereinafter referred to as “tubulogenesis”) mimicks several features of 5 angiogenetic processes observed in vivo in vertebrate animals [Staton et al., 2009] and is based on the VEGF-dependent self-organizing capacity of endothelial cells via which tube-like structures emerge that share many properties with in vivo observed blood vessels. Therefore, the inhibitory potential of the newly synthetized molecules of the present invention was also assessed in tubulogenesis assay using human retinal microvascular endothelial cells (HRMEC) derived from post mortem human donors. When seeded onto a 10 collagen and laminin containing matrix, HRMEC spontaneously form a two-dimensional blood-vessel-like network displaying several quantifiable features that can be used to measure angiogenic potential [Staton et al., 2009]. The newly synthetized, PMO-containing VEGFR inhibitors were added to the culture medium in increasing concentrations to test whether they can inhibit the spontaneous formation of the network from HRMEC. The increasing concentrations allowed the inventors to calculate the IC50 values for each 15 inhibitor molecule. The results of these experiments (table 2.) have shown that the new, PMO-containing azidated inhibitors were capable of inhibiting the tubulogenesis. Furthermore, in the presence of light, the inhibition was stronger than in the dark, providing evidence for the photoactivation and the concomitant covalent binding of the azidated inhibitors to their target receptors. The non-halogenated exemplary compounds tested in the tubulogenesis assay showed weaker 20 inhibition, in line with their lower inhibitory potential in the VEGFR2-HEK-based system. Nonetheless the inhibition could clearly be demonstrated, and the effect of the light was straightforward: the illumination potentiated the inhibition by 5-desfluoro-5-azido-sunitinib 3.72-fold (Table 2) and the inhibition by 5- desfluoro-6-azido-sunitinib 2.52-fold (Table 2). Similarly to the tests performed with transgenic HEK cells, the halogenated versions of the molecules showed stronger baseline inhibition, as evidenced by the stronger 25 decrease of the number of meshes (closed loops) in the network. The effect of the light was similar for these molecules: the inhibition by 6-azido-sunitinib increased 2.62-fold (Table 2) while the inhibition by 5- desfluoro-5-azido-6-chloro-sunitinib increased 3.48-fold (Table 2) upon illumination. Finally the inventors could demonstrate that the azidated version of a different scaffold, namely vorolanib, could also inhibit tubulogenesis strongly in the dark (IC50 = 268 nM, Table 2), and this effect was further potentiated by light 30 (IC50 = 135 nM, Table 2). For all of these experiments, 5-desfluoro-5-azido-6-chloro-vorolanib was used, and 500 nM of Ko-143 (Sigma Aldrich, K2144) was added to the medium since it is known in the art that the efflux transporter ABCG2 is strongly expressed on microvascular endothelial cells and expels vorolanib from the intracellular space. Ko-143 was applied in all conditions (ie. with and without light), and the P138182SG 100 authors have proven in control experiments that Ko-143 itself has no effect on tubulogenesis. Ko-143 was not added for testing any azidated molecule based on the sunitinib scaffold. 5 Table 2: IC50 values measured on HRMEC-cells in tubulogenesis experiments 10 Materials and methods To test the effect of light on the inhibitory activity that these compounds exert on VEGF signaling in biological conditions we used a commercially available (BPS BioScience Inc., Cat. No.: 79387) VEGFR2 / NFAT Reporter - HEK293 recombinant cell line that increases its luciferase production upon an increase in VEGF signaling. Thus adding exogenous VEGF to the cell culture increases the luminescence produced 15 by the cells while inhibiting VEGFR2 (the receptor of VEGF molecule) results in a decrease in luminescence allowing measurement of inhibitory effect. We have cultured the cells and conducted the measurements according to the manufacturer’s instructions. On the day preceding the measurement, 40000 recombinant HEK cells were seeded into each well of a 96 well plate in a way that the experiments could be conducted in triplicates. On the day of the 20 measurement, the growth medium (BPS BioScience Inc., Cat. No.: 79528) was replaced with assay medium (BPS BioScience Inc., Cat. No.: 60187-1) and then the cells were pre-incubated with the appropriate inhibitors for one hour (sunitinib, 5-azido-sunitinib, 6-azido-sunitinib). For the conditions requiring irradiation, the plate was placed under a cold white LED light source within the incubator (37°C, 5% CO2) for the first 10 minutes of the 1-hour-long incubation with the inhibitors to imitate day-light, while the other 25 plate was kept in the dark (also at 37°C, 5% CO2). Following the pre-incubation with inhibitors we treated the cells for 4 hours with VEGF without removing the inhibitors. For this purpose we used 20 ng / ml of commercially available human VEGF165 (Sf9 derived, from BPS BioScience Inc., Cat. No.: 91001-1) added directly into the cell-culture medium. All the experiments presented in the figures below included a P138182SG 101 pre-incubation with the appropriate inhibitors (sunitinib, or the indicated azidated moelcules containing the PMO) and a subsequent main incubation of 4 hours with VEGF together with the same inhibitors. After completion of all the incubation steps, the luciferase activity was measured using the comercially available „ONE-step luciferase assay system” (BPS BioScience Inc., Cat. No.: 60690-2) and a 5 CLARIOstar (BMG Labtech) plate reader that quantified luminescence originating from each well of the 96 well plate. The IC50 values were calculated using the GraphPad Prism software. To test the inhibitory effect of the compounds with light and without light on tubulogenesis [Staton et al., 2009], we have used human retinal microvascular endothelial cells (HRMEC) from Cell Systems (Kirkland, WA 98033, cat. N°: ACBRI 181). VEGF165 (Invitrogen) was only used as a positive control in 10 these experiments, otherwise tubulogenesis relied on endogenous VEGF produced by the culture. Assays were performed in a 96-well cell culture plate (Biologix). The basement membrane matrix Geltrex (Invitrogen) was thawed on ice overnight before use. 50 µl Geltrex was added to each well with a chilled pipette, then the plate was centrifuged at 2000 rpm for 10 min at 4 °C. Subsequently the matrix was let solidify in a humidified incubator at 37 °C for at least 30 minuntes. Before seeding, HRMEC cells were 15 treated with compounds (0.1 nM - 10 µM) in EBM-2 medium (Lonza) in the dark. After 5 minutes, 100 µl of suspension of treated cells was seeded into each Geltrex-coated well of the plate at a density of 103cells / well and then exposed to light treatment (cold white LED light) for 10 min at 37 °C and 5% CO2or kept in the dark (control plate) in the incubator during light treatment. Subsequently both the irradiated and the control plates were left in the incubator for 12 hours so that the tubulogenesis can proceed. Thereafter 20 cells were stained with Calcein AM at a concentration of 1.6 µM. Next, the plates were imaged using a Nikon Ti2 inverted microscope applying 4x and 10x objectives and a FITC filter set for Calcein AM. All images were analyzed using the NIS Elements (Nikon) software. A series of images were aqcuired spanning 120 µm range along the z axis and the built-in algorithm called Extended Depth of Field (EDF) projected structures to create one two-dimensional all-in-focus image. All EDF images were analyzed using the freely 25 customizable NIS-Elements General Analysis 3 module. We set up the experiment routine to segment and indentify tubular and nodular structures and extract total and individual tube lengths, tube number, node number and the number of meshes. In all the figures shown in the present patent, the number of meshes is indicated and the change of this particular parameter is shown upon changing the concentration of the inhibitor molecules. IC50 values for tubulogenesis experiments were calculated using such plots and the 30 GraphPad Prism software. INDUSTRIAL APPLICATION The pharmaceutical industry is the major field that can exploit the invention presented in this patent. Azidated molecules can be taken per os and can be targeted to the retina by natural photoactivation for any 35 therapeutic purpose. The present invention has embodiments that rely on blocking the signal transduction via the VEGFR2 receptor and can be targeted to the retina by the ambient light seen by the patient to be treated. Inhibition of VEGF signaling is currently the main treatment of DR. At present there are close to 500 million diabetic patients worldwide and their number do not stop increasing [Mansour et al., 2020]. Given its much P138182SG 102 earlier onset, as compared to AMD, DR is the most frequent reason why working adults show visual impairments in developed nations [Heng et al., 2012]. Out of the 93 million people diagnosed globally with DR, 17 million are in the proliferative stage where retinal neovascularization occurs, 21 million suffer from diabetic macular oedema, and 28 million have DR that threatens their eyesight [Heng et al., 2012]. 5 Nonetheless, AMD is a more frequent cause of blindness in the elderly population than DR, and currently used treatments remedying AMD patients also rely on the inhibition of VEGF signaling. This points to a further prominent industrial application of the prototype molecules of the present invention. Further therapeutic or diagnostic molecules acting on further ocular receptors or enzymes can be developed by capitalizing on the present invention and using already known retinal target molecules, or 10 even retinal target molecules that are to be discovered later. 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Claims

1. 106 CLAIMS Novel photoinducible kinase inhibitors for treating proliferative and vasoproliferative diseases CLAIMS 5 1. A compound for use in a method of treating a subject with a disease said compound comprising - a conjugated electron system, preferably a 2-oxo-indolin-3-ylidene moiety directly coupled to a pyrrol ring, or a 2-oxo-indolin-3-ylidene moiety directly coupled to a phenyl group, - an active agent moiety (highly preferably a compound having a sunitnib scaffold or vorolanib scaffold or a nintedanib scaffold), said moiety being a modulating entity, preferably a ligand or a substrate 10 of a biological target (preferably a receptor tyrosine kinase, more preferably FGFR, PDGFR or VEGFR ) and thereby being useful for treatment a disease, - an azide (N3) moiety comprising an azido group, wherein the π electrons of the azido group extend the said conjugated electron system , whereby the active agent moiety can be bound to the binding site of the biological target, the azide 15 moiety can be photoactivated to trigger N2 extrusion and radical generated by this process can become linked to the biological target via a covalent bond, whereby the compound inhibits said biological target in the subject to provide improved treatment for said subject as compared to the compound not linked covalently to the target 2. The compound for use according to claim 1 wherein said compound is 20 - for use in treating an ocular disease - can be photoactivated by natural light entering via the optical system of the eye - upon treatment is delivered into the site of treatment wherein its azido group is converted to a reactive radical upon exposure to ambient light and such exposure is an inseparable part of the treatment; preferably, wherein it is administered orally and / or formulated for oral administration and is 25 delivered into the eye wherein its azido group is converted to a reactive radical upon exposure to ambient light, or preferably wherein it is administered to treat a tumor, the azido group is converted into a reactive radical exclusively within the tumor by targeting the illumination onto the tumor or onto the location where malignuous cells are located, preferably within neovessels of the tumor, 30 preferably wherein it is administered to treat a tumor the said compound is not photoactivated in the healthy tissue of the subject.

3. The compound for use according to claim 1 or 2 wherein said compound is an aryl-azide compound, wherein the azido group forms a reactive radical upon illumination by light, preferentially a nitrene radical or a reactive cyclic ketene-imine, and such contact with ambient light is inseparable part of 35 the treatment 4. The compound for use according to any of claims 1 to 3 in treating the said subject suffering from an ocular disease that involves a targetable endogenous biomolecule (preferably a receptor or an enzyme), preferably an ocular disease where a targetable endogenous biomolecule is part of the pathomechanism; P138182SG 107 wherein preferably the ocular disease involves neovascularization and / or the ocular disease being selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), 5 - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), - retinal vein occlusion (RVO), - open angle glaucoma (OAG), 10 - angle closure glaucoma (ACG), - congenital glaucoma (CoG).

5. The compound for use according to any of claims 1 to 3 in reducing, arresting or blocking the growth of a localized tumor that is present in a subject, or reducing, arresting or blocking the spreading of tumor metastases within the body of a subject, 15 in a method comprising photoactivation of said compound at the tumor site.

6. The compound for use according to any of claims 1 to 5 wherein said compound is a VEGF PDGF or FGF signaling inhibitor, preferably a VEGF-receptor inhibitor, in particular a VEGFR inhibitor selected from the group consisting of VEGFR1, VEGFR2 and VEGFR3 inhibitors, preferentially a VEGFR2 inhibitor. 20 7. The compound for use according to any of claims 1 to 6, wherein the compound contains an indole-2-one moiety wherein the benzene ring of the indole-2-one is substituted with an azide moiety, and / or wherein the indole-2-one containing compound inhibits the a VEGF receptor, preferably an the VEGFR2 receptor. 25 8. The compound for use according to any of claims 1 to 7, wherein preferably the indole-2-one derivative VEGFR2 inhibitor has a general formula (X) wherein in the formula at least one of R2, R3, R4and R5is an azido group (N3); preferably at least one of R3and R4is an 30 azido group (N3); more preferably one of R3and R4is an azido group (N3); P138182SG 108 wherein any one of R2, R3, R4and R5which is different from an azido group, is selected independently from the group consisting of - H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, OEt, -NO2, -NH2, -NHMe, -COOH, -CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, , 5 - substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, , C1- C8 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl-heteroaryl, C1-C5 amide, a C1-C8 carbonyl, a C1-C8 carboxyl, a C2-C8 carboxylate ester said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, - NHMe, 10 - NR21R22, wherein R21and R22are, independently selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C8 alkyl and C1-C8 alkoxy, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, - NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R21and R22is H, Me or Et, 15 - SO2NR23R24, wherein R23and R24are, independently selected from H, substituted or unsubstituted C1-C8 alkyl, preferably C1-C4, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R23and R24is H, Me or Et; 20 -ureido, preferably aryl-ureido, or heteroaryl-ureido, preferably C1-C20 aryl-ureido, more preferably a phenyl-ureido optionally substituted with (preferably in para position) C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 carbonyl (preferably C2-C4 alkylcarbonyl, C3-C4 alkenylcarbony or C3-C4 alkynylcarbonyl), C1-C4 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl-heteroaryl, C1-C5 amide, C1-C6 carboxyl25 (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 alkenylcarboxyl, a C3-C6 alkynylcarboxyl), C2- C6 carboxylate ester, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, highly preferably (para-metoxy-phenyl)-ureido; R6is selected from H and an in vivo metabolizable (preferably an intracellularly metabolizable) moiety whereby the compound is a prodrug; and / or a moiety selected from the group consisting of the 30 following moieties: i) a substituted or unsubstituted C1-C4 alkyloxy group linked via a carbon to the nitrogene atom of the oxindole structure (in particular a C1-alcoxy, preferably a CH2-O- moiety) preferably acylated to be an ester by an -C(O)-R31group, wherein R31is selected from the group consisting of OR32, SR32, and N(R32)2; and 35 R31or R32is selected from the group consisting of -H, unsubstituted or substituted C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C4 alkenyl, in particular a C1-C6 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or P138182SG 109 a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1- C6 alkyl, C1-C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, 5 heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, said substituent of the C1-C4 alkyloxy group if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, and -NHMe, 10 wherein it is noted that esters can typically be cleaved by intracellular esterases that are not present in the extracellular space, ii) or R6is a C(O)-R33group forming an amide bond with the ring N, wherein R33group is selected from C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl, preferably a C1-C12 alkenyl, more preferably a C1-C8 or a 15 C1-C6 alkenyl, in particular a C1-C4 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, 20 carboxylalkyl or alkylamido group, wherein in a particular embodiment said R33group is selected from a C1-C8 alkyl, in particular a C1-C4 alkyl, wherein the said alkyl, has a substituent (is substituted by a group selected from) a 4-15 membered heterocyclyl, in a particularly preferred embodiment R6comprises a biotinyl group with or without a linker, iii) or R6in an alternative embodiment is selected from a substituted or unsubstituted C1-C4 25 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C8 alkylester, C3-C8 alkenylester or C3-C8 alkynylester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, - NHMe, iv) or R6an alternative embodiment is a substituted or unsubstituted C1-C4 alkyloxy group linked via the alkyloxy oxygen to the ring N forming an N-O bond, said substituent on the C1-C4 30 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety), if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- 15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, - OH, -SH, -OMe, -NO2, -NH2, and -NHMe, wherein R6is preferably H; 35 R7and R8are, independently, selected from the group consisting of H, a substituted or unsubstituted aryl, in particular a C6-C10aryl, a heteroaryl, in particular a 5 to 10 membered heteroaryl, C1-C5 amine, C1-C5 amide and C2-C6alkenyl, a C1-C6 carbonyl, a C1- C6 carboxyl, a C1-C6 carboxylate ester, wherein if any of R7and R8is substituted, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, P138182SG 110 with the proviso that at least one of R7and R8is different from H, preferably at least one, preferably one of R7and R8is selected from the group consisting of a substituted aryl, in particular a C6-C10 aryl, and a substituted heteroaryl, in particular a 5 to 10 membered heteroaryl and 5 preferably at least one of R7and R8is selected from a group having the formula A1 (A1.1), wherein in A1 (1) means the point of attachment to general formula (X) R14is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair10 of said C2-C3 alkenyl is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R14is selected from H and methyl, R15is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2- 15 C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15is selected from H and methyl, R16is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkenylcarbonyl, C1-C6 alkynylcarbonyl, C1-C6 alkylamide, C6-C10 aryl, C7-C12 20 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl-heteroaryl, C1-C5 amide, C1-C6 alkylcarboxyl, a C2-C6 alkenylcarboxyl, a C2- C6 alkynylcarboxyl, and a C2-C6 carboxylate ester said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, - NHMe, and a substituted amine or amide wherein preferably said amide is bound via the carbonyl to the pyrrole 25 ring thereby the π electrons of the oxo group forming part of the conjugated system of the pyrrole ring, said amine or amide substituent in R16being selected from - substituent 1 (S1) being a C1-C8 alkyl (preferably C1-C4 or C2-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 30 alkyl or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine), and a group as defined as substituent S2below, P138182SG 111 - substituent 2 (S2) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group having the formula X-R10wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, and R10is 5 selected from a 5 to 10 membered heterocycle or a C6-C10 aryl, optionally further substituted with 1 to 4 membered group selected from alkyl, alkenyl, amide, carboxyl alkylcarbonyl, alkoxy and halogenide, - substituent 3 (S3) being a polyether, preferably a polyethylene glycol, wherein the number ether - O- is 2 to 12, preferably 3 to 9, (or in an alternative embodiment R16is a group as defined for R1510 or a salt or solvate thereof - substituent 4 (S4) and substituent 5 (S5), together with the N atom to which they are attached form a 5 to 10 membered (preferably 5 to 6 membered) heterocycle optionally further containing 1 additional N heteroatom, said heterocycle may be substituted with a group having the formula X- R100wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl 15 and C2-C3 alkoxy), O, S, C1-C3 alkyl and C1-C3 alkenyl, and R100is selected from C1-C3 alkyl and OH, or. wherein (1) means the point of attachment to general formula (X) 20 R24 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24 is selected from H and methyl, (or in an alternative embodiment R24 is a group as defined for R26 below, provided that R26 is a 25 group as defined for R24 in the previous paragraph), R25 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15 is selected from H and methyl, 30 and R26 is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C6 P138182SG 112 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe,), and 5 a substituted amine or amide wherein preferably said amide is bound via the N to the aryl ring of R8, said amine or amide substituent in R26being selected from - substituent 6 (S6) being a C1-C8 alkyl (preferably C1-C4 or C1-C3 alkyl) preferably substituted with a substituent selected from 10 an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl and a group as defined as substituent S7below, - substituent 7 (S7) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably selected from 15 a 5 to 10 membered heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, in particular pyrrolidine, or piperazine, wherein said heterocycle being 20 optionally substituted with one or two C1-C4 or C1-C3 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C3 alkyl; R27is H.

9. The compound for use according to any of claims 1 to 8 in treating the said subject suffering 25 from an ocular disease that involves a targetable endogenous biomolecule (preferably a receptor or an enzyme). preferably said ocular disease being selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative 30 diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), - retinal vein occlusion (RVO), - open angle glaucoma (OAG), - angle closure glaucoma (ACG), 35 - congenital glaucoma (CoG), 10. The compound for use according to any of claims 1 to 9 wherein said compound has general formula (I.3) P138182SG 113 wherein in the formula at least one of R2, R3, R4and R5is an azido group (N3); wherein any one of R2, R3, R4and R5which is different from an azido group, is defined in claim 8, 5 wherein preferably R2, R3, R4and R5, when being different from azido, are, independently, selected from a - H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2-CF3; preferably H, halogenide, pseudohalogenide, -OMe, -OH, -SH, -substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-10 C4 alkenylcarbonyl, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl- heteroaryl, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, - NO2, -NH2, -NHMe, - NR21R22, wherein R21and R22are, selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, said substituent, if any, 15 preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R21and R22is H, Me or Et, - SO2NR23R24, wherein R23and R24are, independently selected from H, substituted or unsubstituted C1-C4, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, - 20 NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R23and R24is H, Me or Et, -ureido, preferably aryl-ureido or heteroaryl-ureido, preferably phenyl-ureido optionally substituted with (preferably in para position) C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular C1-C2 alkoxy, 25 halogenide, methyl or unsubstituted, highly preferably (para-metoxy-phenyl)-ureido; R6is as define in claim 8, in particular in i) or in ii), R14is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halo, a C6-C10 aryl or a 5-10 membered heteroaryl, R1430 is preferably selected from H and methyl, P138182SG 114 R15is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair is conjugated with the π electron system of the pyrrole ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halo, a C6-C10 aryl or a 5-10 membered heteroaryl, R15is preferably selected from H and methyl, 5 R16is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkenylcarbonyl, C1-C4 alkynylcarbonyl, C1-C4 alkylamide, C1-C4 amide, C1-C4 alkylcarboxyl, a C2-C4 alkenylcarboxyl, a C2- C4 alkynylcarboxyl, and a C2-C4 carboxylate ester said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, - 10 NHMe, and preferably, a substituted amine or amide wherein preferably said amid is bound via the carbonyl to the pyrrole ring thereby the π electrons of the oxo group forming part of the conjugated system, said amine or amide substituent being selected from - substituent S1being a C1-C4 alkyl (preferably C1-C4 or C2-C3 alkyl) preferably substituted with 15 a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine), and a group as defined as substituent S2below, 20 - substituent S2being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group having the formula X-R10wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C1-C3 alkenyl and C1-C3 alkoxy), O, S, C1-C3 alkyl and C1-C3 alkenyl, and R10is selected from a 5 to 10 membered heterocycle or a C6-C10 aryl, optionally further substituted 25 with 1 to 4 membered group selected from alkyl, alkenyl, amide, carboxyl alkylcarbonyl, alkoxy and halogenide, - substituent S3being a polyether, preferably a polyethylene glycol, wherein the number ether -O- is 2 to 12, preferably 3 to 9, (or in an alternative embodiment R16is a group as defined for R15- substituent S4and substituent S5, together with the N atom to which they are attached form a 5 to 30 6 membered heterocycle, optionally further containing 1 additional N heteroatom, said heterocycle may be substituted with a group having the formula X-R100wherein X is selected from NH, NR11, R11being selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, and R100is selected from C1-C3 alkyl and OH; R7is H or a C1-C4 alkyl, a C6-C10 aryl or a 5 to 6 membered heterocycle, preferably heteroaryl, 35 H, amine, amide and C1-C3alkenyl, a C1-C4 alkylcarbonyl, C1-C4 alkenylcarbonyl, C1-C4 alkynylcarbonyl, a C1-C4 alkylcarboxyl, C1-C4 alkenylcarboxyl, C1-C4 alkynylcarboxyl or C1-C4 carboxylate ester, wherein if any of R7and R8is substituted, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, P138182SG 115 R17 is selected from H and optionally an in vivo metabolizable group whereby the compound is a prodrug; preferably an intracellularly metabolizable group; preferably R17, once present, is i) a substituted or unsubstituted C1-C4 alkyloxy group linked via a carbon to the nitrogene atom of the oxindole structure (in particular a C1-alcoxy, preferably a CH2-O- moiety) preferably 5 acylated to be an ester by an -C(O)-R41group, wherein R41is selected from the group consisting of OR42, SR42, and N(R42)2; and R41or R42is selected from the group consisting of -H, unsubstituted or substituted C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl preferably 10 a C1-C12 alkenyl, more preferably a C1-C8 or a C1-C4 alkenyl, in particular a C1-C6 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably a C1-C8 or a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1- C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a 15 substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, said substituent of the C1-C4 alkyloxy group if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, 20 and -NHMe, ii) or R17is a or a C(O)-R33group forming an amide bond with the ring N, wherein R33group is selected from C1-C30 alkyl, preferably a C1-C12 alkyl, more preferably a C1-C8 or a C1-C6 alkyl, in particular a C1-C4 alkyl, C2-C30 alkenyl, preferably a C1-C12 alkenyl, more preferably a C1-C8 or a C1- C6 alkenyl, in particular a C1-C4 alkenyl, C2-C30 alkynyl, preferably a C1-C12 alkynyl, more preferably 25 a C1-C8 or a C1-C6 alkynyl, in particular a C1-C4 alkynyl; C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkyl amido and phosphate group; or wherein the said alkyl, alkenyl or alkyl group has a substitutent (is substituted) by said cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxylalkyl, carboxylalkyl or alkylamido group, wherein in a particular embodiment said R33group is selected from a C1-C8 alkyl, in particular a C1-C4 alkyl, 30 wherein the said alkyl, has a substituent (is substituted by a group selected from) a 4-15 membered heterocyclyl, in a particularly preferred embodiment R17comprises a biotinyl group with or without a linker, iii) or in an alternative embodiment R17is selected from a substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C8 alkylester, C3-C8 alkenylester or C3-C8 alkynylester, said35 substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, - NHMe, iv) or R17is a substituted or unsubstituted C1-C4 alkyloxy group linked via the alkyloxy oxygen to the ring N forming an N-O bond, said substituent on the C1-C4 alkyloxy group (in particular a C1-alcoxy, preferably a CH2-O- moiety), if any, being selected from the group consisting of H, C1-C6 alkyl, C2-C6 P138182SG 116 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl; as well as halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, and -NHMe; in particular as defined in i) or in ii). 5 11. The compound for use according claim 10, wherein said compound has general formula (II) wherein at least one of R2, R3, R4 and R5 is an azido group (N3); wherein any of R2, R3, R4 and R5 which is different from an azido group, is selected from the group 10 as defined in claim 8, preferably as defined in claim 10, or more preferably is selected from -H, Me, halogenide, pseudohalogenide, -OH, -SH, -Ome, -Oet, -NO2, -NH2, -NHMe, -COOH, CONH2 -CF3; preferably H, halogenide, pseudohalogenide, -Ome, -OH, -SH, preferably -H, halogenide, pseudohalogenide, -Ome, -OH, -SH, in particular H or halogenide, -substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 15 alkylcarbonyl, C1-C4 alkenylcarbonyl, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered alkyl-heteroaryl, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, preferably H and halogenide,-NR21R22, wherein R21 and R22 are, selected from H, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, substituted or unsubstituted C1-C3 alkyl and C1-C3 alkoxy, said substituent, if any, preferably being selected20 from halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, preferably -OH, -Ome, - NH2, -NHMe and halogenide, more preferably halogenide, wherein preferably at least one of R21 and R22 is H, Me or Et, preferably H or Me, - SO2NR23R24, wherein R23 and R24 are, independently selected from H, substituted or unsubstituted C1-C4, C6 aryl, C7-C8 alkylaryl (aralkyl), 5 to 6 membered heteroaryl, 6-8 membered 25 alkyl-heteroaryl, said substituent, if any, preferably being selected from halogenide, pseudohalogenide, - OH, -SH, -Ome, -NO2, -NH2, -NHMe, more preferably halogenide, wherein preferably at least one of R23 and R24 is H, Me or Et, - phenyl-ureido optionally substituted in para position with C1-C3 alkyl, C2-C4 alkenyl, C2- 30 C4 alkynyl, C1-C4 alkoxy, halogenide, pseudohalogenide, -OH, -SH, -Ome, -NO2, -NH2, -NHMe, in P138182SG 117 particular C1-C2 alkoxy, halogenide, methyl or unsubstituted, highly preferably (para-metoxy- phenyl)-ureido; wherein R6and R17are as defined above, preferably R6being a metabolizable group or H, preferably H and preferably R17being H, 5 wherein R14, R15and R7is as defined in claim 8, preferably as defined claim 10, more preferably R12and R13are independently selected from H, C1-C8 alkyl, preferably C1-C4 or C2-C3 alkyl, preferably substituted with a substituent selected from one or two C1-C4 or C2-C3 alkyl, N(C1-C3alkyl)2or a polyether, preferably a polyethylene glycol, wherein the number ether -O- is 2 to 12, preferably 3 to 9, optionally a cyclic polyether forming a tertiary amine, wherein optionally R15and R13or R14, together with 10 the backbone atoms, form a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered, in particular a 6 membered heterocycle or a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, preferablypyrrolidine, that is optionally substituted with -C(O)N(C1-C3alkyl)2; or R12and R13together with the N atom to which they are attached form a 5 to 6 membered 15 heterocycle, optionally further containing 1 additional N heteroatom, preferably pyrrolidine or piperazine, said heterocycle may be substituted with hidroxy-C1-C3 alkyl or N(C1-C3alkyl)2or amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl or a group as defined as substituent S3below, optionally a cyclic polyether forming a tertiary amine, (i.e. said amine being a secondary or tertiary amine). 20 12. The compound for use according to any of claims 10 to 11 for use in the treatment of a disease as defined in claim 9.

13. The compound for use according to any of claims 10 to 11 for use in the treatment of an ocular 25 disease selected from the group consisting of - macular degeneration, in particular age-related macular degeneration (AMD), - retinopathies, in particular diabetic retinopathies, proliferative retinopathies, e.g proliferative diabetic retinopathy (PDR), - macular oedema, in particular diabetic macular oedema (DME), 30 - retinal vein occlusion (RVO), - open angle glaucoma (OAG), - angle closure glaucoma (ACG), - congenital glaucoma (CoG), and - any other disease where ocular neovascularization is part of the pathomechanism. 35 14. The compound for use according to any of claims 1 to 13, said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1), (VIII.1), (IX.1) and (X.1): P138182SG 119 or said compound having general formula selected from the group consisting of general formulae (V), (VI), (VII), (VIII), (IX) and (X): 5 (VI) P138182SG 120 wherein R1 is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or alternatively an azido group connected to carbon 6 of the indole-2-one moiety, and 5 R4 is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2 -CF3; preferably H, halogenide, pseudohalogenide, -OMe, - OH, -SH, in particular halogenide, highly preferably F or Cl wherein R6 group on the nitrogen atom of the indoline-2-one moiety, if present, is as defined in claim 8, 10 or 11. 10 15. The compound for use according to any of claims 1 to 9, wherein the compound having general formula (I.4) or (I.5) preferably a compound for use according to any of paragraphs 1 to 9, in particular paragraphs 1, 2, 3, 4, 5 or 9, P138182SG 121 1.5) wherein R2, R3, R4, R5 and R7 are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), 5 (I.3) or (I.3.1) R24 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24 is selected from H and methyl, 10 (or in an alternative embodiment R24is a group as defined for R26below, provided that R26is a group as defined for R24in the previous paragraph), R25 is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 15 membered heteroaryl, preferably R15 is selected from H and methyl, and R26is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C620 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- P138182SG 122 heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe,) and a substituted amine or amide wherein preferably said amide is bound via the N to the aryl ring of 5 R8, said amine or amide substituent in R26being selected from - substituent 6 (S6) being a C1-C8 alkyl (preferably C1-C4 or C1-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 10 alkyl and a group as defined as substituent S7below, - substituent 7 (S7) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably selected from a 5 to 10 membered heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally 15 substituted with a group selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, , preferably pyrrolidine, or piperazine, wherein said heterocycle being optionally substituted with one or two C1-C4 or C1-C3 alkyl, 20 preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C3 alkyl; R27is H.

16. The compound for use according to claim 15, wherein the compound has general formula (II.4), 25 wherein R2, R3, R4, R5and R7are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), (I.3) or (I.3.1), preferably R7 is phenyl R24 and R25 are, independently, selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl P138182SG 123 ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24is selected from H and methyl, R28and R29are, independently, R28and R29is independently selected from H, C1-C4 or C2-C3 alkyl, preferably substituted with a 5 substituent selected from one or two C1-C4 or C2-C3 alkyl, or a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, , preferably pyrrolidine, that is optionally substituted with a C1-C4 or C2-C3 alkyl or R28and R29together with the N atom to which they are attached form a 5 to 6 membered heterocycle, optionally further containing 1 additional N heteroatom, , preferably pyrrolidine or piperazine, 10 said heterocycle may be substituted with a C1-C4 or C1-C3 alkyl, preferably R28and R29together with the N atom to which they are attached form a piperazine, wherein said piperazine may be substituted with a C1-C4 or C1-C3 alkyl or C1-C2 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C2 alkyl; 15 R27is H.

17. The compound for use according to any of claims 1 to 13 or 15 to 16, said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1) (VIII.1), (IX.1), (X.1) (V), (VI), (VII), (VIII), (IX) and (XI): 20 wherein R1is connected to carbon 4, 6 or 7 of the indole-2-one moiety or alternatively connected to carbon 6 of the indole-2-one moiety and is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular H and halogenide, highly preferably F or Cl and R4is an azido group, 25 wherein group on the nitrogen atom of the indoline-2-one moiety, if present, is as defined in claim 8, 10 or 11.

18. The compound for use according to any of claims 1 to 13 or claim 17, and selected from the following compounds: Ex.1) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 30 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1028) Ex.2) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1052) Ex.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1013) 35 Ex.4) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1089) Ex.5) ethyl 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1056) P138182SG 124 Ex.6) 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1091) Ex.7) 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1093) 5 Ex.8) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethylcarbamoyl )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1088) Ex.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1114) Ex.10.) Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- 10 pyrrole-3-carboxylate (EYE1063) Ex.11) 5-[(Z)-(6-azido-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1087) Ex.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1116) 15 Ex.13) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1118) Ex.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1112) Ex.15) (3Z)-6-azido-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- 20 yl]methylene]indolin-2-one (EYE1068) Ex.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one (EYE1094) Ex.17) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1090). 25 19. The compound for use according to any of claims 1 to 8 or claim 15 to 16, wherein said compound is Ex.18) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (EYE1309). 30 20. The compound for use according to any of claims 1 to 19, said compound binding to the biological target (preferably a receptor or an enzyme) in an assay, preferably in vitro.

21. The compound for use according to any of claims 8 to 19, said compound inhibiting VEGFR, PDGFR or FGFR in a VEGFR2, PDGFR or FGFR inhibition assay, preferably in vitro.

22. A pharmaceutical composition for ophthalmic use, preferably for use in a disease as defined in 35 any of claims 8 to 9, preferably claim 9, said pharmaceutical composition comprising a compound as defined in any of claims 1 to 19, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22, which is an oral pharmaceutical composition for ophthalmic use, wherein said composition is formulated to protect the compound from P138182SG 125 light and / or to prevent light-induced excitation, unwanted photoactivation or decomposition of the azido group.

24. The pharmaceutical composition according to claim 22, which is an eye-drop formulation for ophthalmic use, wherein said composition is formulated to protect the compound from light and / or to 5 prevent light-induced excitation, unwanted photoactivation or decomposition of the azido group.

25. A compound having general formula (I.1) or (I.3.1) preferably, where appropriate, as defined in claim 11. 10 26. The compound according claim 25, wherein said compound has general formula (II) wherein R2, R3, R4, R5R7, R12, R13, R14, R15and R16are as defined in claim 11.

27. The compound according to any of claims 25 to 26, said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1), (VIII.1), (IX.1) and (X.1): P138182SG 127 said compound having general formula selected from the group consisting of general formulae (V), (VI), (VII), (VIII),: 5 P138182SG 128 wherein R1 is an azido group connected to carbon 4, 6 or 7 of the indole-2-one moiety or 5 alternatively an azido group connected to carbon 6 of the indole-2-one moiety, and R4 is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -OEt, -NO2, -NH2, -NHMe, -COOH, CONH2 -CF3; preferably H, halogenide, pseudohalogenide, -OMe, - OH, -SH, in particular halogenide, highly preferably F or Cl, wherein R6 group on the nitrogen atom of the indoline-2-one moiety, if present, is as defined in claim 8. 10 28. A the compound having general formula (I.4) or (I.5), P138182SG 129 wherein R2, R3, R4, R5 and R7 are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), (I.3) or (I.3.1) R24is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair 5 of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24is selected from H and methyl, (or in an alternative embodiment R24is a group as defined for R26below, provided that R26is a group as defined for R24in the previous paragraph), 10 R25is selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2- C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R15is selected from H and methyl, and 15 R26is selected from H, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 carbonyl (preferably C2-C6 alkylcarbonyl, C3-C6 alkenylcarbony or C3-C6 alkynylcarbonyl), C1-C6 alkylamide, C6-C10 aryl, C7-C12 alkylaryl (aralkyl), 5 to 10 membered heteroaryl, 6-12 membered alkyl- heteroaryl, C1-C5 alkylamide, C1-C6 carboxyl (preferably carboxyl, C2-C6 alkylcarboxyl, a C3-C6 20 alkenylcarboxyl, a C3-C6 alkynylcarboxyl) and a C2-C6 carboxylate ester, said substituent, if any, being selected from halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe,) and a substituted amine or amide wherein preferably said amide is bound via the N to the aryl ring of R8, said amine or amide substituent in R26being selected from 25 - substituent 6 (S6) being a C1-C8 alkyl (preferably C1-C4 or C1-C3 alkyl) preferably substituted with a substituent selected from an amine; said amine being optionally substituted with one or two C1-C4 or C2-C3 alkyl and a group as defined as substituent S7below, 30 - substituent 7 (S7) being a 5 to 10 membered (preferably 5 to 6 membered) heterocycle, preferably selected from a 5 to 10 membered heteroaryl and a C6-C10 aryl, said heterocycle or aryl being optionally substituted with a group selected from C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkoxy), O, S, C1-C3 alkyl and C2-C3 alkenyl, 35 a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, , preferably pyrrolidine, or piperazine, wherein said heterocycle being optionally substituted with one or two C1-C4 or C1-C3 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C3 alkyl; R27is H. 40 P138182SG 130 29. The compound according to claim 28, wherein the compound has general formula (II.4), wherein R2, R3, R4, R5and R7are as defined above for any of formulae (X.1), (I.1), (I.1.1), (I.2), (I.2.1), 5 (I.3) or (I.3.1), preferably R7is phenyl R24 and R25 are, independently, selected from H and a C1-C3 alkyl or C2-C3 alkenyl preferably wherein the π electron pair of said C2-C3 alkenyl is conjugated with the π electron system of the phenyl ring, said C1-C3 alkyl or C2-C3 alkenyl being optionally substituted with a group selected from a halogenide, a C6-C10 aryl or a 5-10 membered heteroaryl, preferably R24 is selected from H and methyl, 10 R28 and R29 are, independently, R28 and R29 is independently selected from H, C1-C4 or C2-C3 alkyl, preferably substituted with a substituent selected from one or two C1-C4 or C2-C3 alkyl, or a 5 to 8 membered heterocycle, preferably a 5 or 6 to 7 membered, preferably a 5 or 6 membered heterocycle, , preferably pyrrolidine, that is optionally substituted with a C1-C4 or C2-C3 alkyl or 15 R28 and R29 together with the N atom to which they are attached form a 5 to 6 membered heterocycle, optionally further containing 1 additional N heteroatom, , preferably pyrrolidine or piperazine, said heterocycle may be substituted with a C1-C4 or C1-C3 alkyl, preferably R28 and R29 together with the N atom to which they are attached form a piperazine, wherein said 20 piperazine may be substituted with a C1-C4 or C1-C3 alkyl or C1-C2 alkyl, preferably a piperazine being N-substituted with a C1-C4 or preferably a C1-C2 alkyl; R27 is H.

30. The compound according to any of claims 25 to 27 said compound having general formula selected from the group consisting of general formulae (V.1), (VI.1), (VII.1) (VIII.1), (IX.1), (X.1) (V), 25 (VI), (VII), (VIII), (IX) and (X): wherein R1 is connected to carbon 4, 6 or 7 of the indole-2-one moiety or alternatively connected to carbon 6 of the indole-2-one moiety and is selected from the group consisting of H, Me, halogenide, pseudohalogenide, -OH, -SH, -OMe, -NO2, -NH2, -NHMe, in particular H and halogenide, highly preferably F or Cl and 30 R4 is an azido group, P138182SG 131 wherein R6group on the nitrogen atom of the indoline-2-one moiety, if present, is as defined in claim 8.

31. The compound according to any one of claims 25 to 27, and selected from the following compounds: 5 Ex.1) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1028) Ex.2) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1052) Ex.3) 5-[(Z)-(4-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2(diethylamino)ethyl]- 10 2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1013) Ex.4) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1089) Ex.5) ethyl 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1056) 15 Ex.6) 5-[(Z)-(5-azido-6-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1091) Ex.7) 5-[(Z)-(5-azido-6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1093) Ex.8) 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- 20 (dimethylcarbamoyl )pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1088) Ex.9) 5-[(Z)-(5-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1-(dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1114) Ex.10.) Ethyl 5-[(Z)-(6-azido-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H- pyrrole-3-carboxylate (EYE1063) 25 Ex.11) 5-[(Z)-(6-azido-5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1087) Ex.12) 5-[(Z)-(6-azido-5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1116) Ex.13) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(3S)-1- 30 (dimethyl carbamoyl)pyrrolidin-3-yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1118) Ex.14) 5-[(Z)-(7-azido-5-fluoro-2-oxo-indolin-3-ylidene)methyl]-N-(2-diethylaminoethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (EYE1112) Ex.15) (3Z)-6-azido-3-[[4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2- yl]methylene]indolin-2-one (EYE1068) 35 Ex.16) (3Z)-5-azido-6-chloro-3-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-3,5- dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one (EYE1094) Ex.17) 5-[(Z)-(5-azido-6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (EYE1090) P138182SG 132 32. The compound according to claim 29, said compound being Ex.18) N-[4-[[(Z)-(5-azido-6-chloro-2-oxo-indolin-3-ylidene)-phenyl-methyl]amino]phenyl]-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (EYE1309) 5 33. Use of compound as defined in any of claims 1 to 32, preferably a compound as defined in any of claims 8 to 19 in an in vitro assay for testing of binding of said compound to its biological target, preferably a receptor or an enzyme, preferably of a compound described in any of claims 8 to 16 in a VEGFR, PDGFR or FGFR inhibition test.

34. Use of compound as defined in any of claims 1 to 32, preferably a compound as defined in any 10 of claims 8 to 19 in an in vitro assay for testing of binding of said compound to its biological target, preferably a receptor or an enzyme, preferably of a compound described in any of claims 8 to 16 in an inhibition test specific for VEGFR2. P138182SG

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