SRPK inhibitors

Abstract

The novel formula (I): A compound represented by JPEG2024528729000054.jpg5166, In the formula, W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m have the meaning according to the claims, said compounds are SRPK inhibitors and may be used inter alia for the treatment of hyperproliferative disorders.

Description

[Technical field]

[0001] FIELD OF THE PRESENT APPLICATION The present invention relates to a compound of formula (I): [ka] In the formula, W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m has the meaning according to the claim. The present invention relates to a compound represented by the formula (I) and / or its physiologically acceptable salts. The compound represented by the formula (I) can be used as a SRPK inhibitor. The subject of the present invention is also a pharmaceutical composition comprising the compound represented by the formula (I) and the use of the compound represented by the formula (I) for the treatment of hyperproliferative disorders. [Background technology]

[0002] background Protein kinases constitute a large family of structurally related enzymes that are responsible for regulating a wide variety of signaling processes within the cell (G Hardie & S Hanks 1995, The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Kinases may be divided into family categories according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (see, e.g., Hanks & Hunter, FASEB J 1995, 9: 576-596; Knighton et al., Science 1991, 253: 407-414; Hiles et al., Cell 1992, 70: 419-429; Kunz et al., Cell 1993, 73: 585-596; Garcia-Bustos et al., EMBO J 1994, 13: 2352-2361).

[0003] Protein kinases may be characterized by their mechanisms of regulation, including, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. Individual protein kinases may be regulated by more than one mechanism.

[0004] Kinases regulate many different cellular processes, including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, and other signaling processes; by adding phosphate groups to target proteins, these phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stress, etc. Suitable protein kinases are involved in activating or deactivating (either directly or indirectly) signaling pathways, e.g., metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Unregulated signaling due to defective regulation of protein phosphorylation is associated with numerous diseases, including, e.g., inflammation, cancer, allergy / asthma, and diseases of the immune system, central nervous system, and angiogenesis diseases and disorders.

[0005] Serine-arginine protein kinases (SRPKs) are a subfamily of serine-threonine kinases that phosphorylate serine at the serine-arginine dipeptide motif. SRPKs have been described to alter constitutive and alternative mRNA splicing and maturation as well as chromatin reorganization, cell cycle and p53 regulation in somatic and sperm cells (T Giannakouros, E Nikolakaki, I Mylonis, E Georgatsou, FEBS Journal 2011, 278: 570-586). SRPKs are associated with promoting cancer growth, so SRPK inhibition could be an effective treatment (IP Nikas, SC Themistocleous, SA Paschou, KI Tsamis, HS Ryu, Cells 2020, 9(1): 19; G Wang, W Sheng, X Shi, X Li, J Zhou, M Dong, The FEBS Journal 2019, 286: 1668-1682; T Arends, JM Taliaferro, E Petermann, JR Knapp, BO' Connor, RM Torres, JR Hagman, bioRxiv 759829). The best-characterized family members are SRPK1, SRPK2 and SRPK3.

[0006] A number of different small molecules with SRPK inhibitory activity have been described in the art. However, current SRPK inhibitors lack potency and / or selectivity (T Fukuhara, T Hosoya, S Shimizu, K Sumi, T Oshiro, Y Yoshinaka, M Suzuki, N Yamamoto, LA Herzenberg, LA Herzenberg, M Hagiwara, PNAS 2006, 103(30): 11329-11333; RP Siqueira et al., Eur J Med Chem 2017, 134: 97-109; J Batson et al., ACS Chem. Biol. 2017, 12(3): 825-832; JM Hatcher, Cell Chem Bio 2018, 25(4): 460-470). Specifically, SRPK inhibitors typically exhibit cross-reactivity to the structurally related CLK or DYRK proteins. Summary of the Invention

[0007] SUMMARY OF THE PRESENT APPLICATION The present invention had the problem of finding new compounds with valuable properties, especially those that can be used for the preparation of medicines. Surprisingly, it has been found that the compounds according to the invention and their salts have very valuable pharmacological properties while being well tolerated. In particular, they act as SRPK inhibitors. The present invention relates to compounds of formula (I): [ka] A compound represented by the formula: During the ceremony, W 1 , W 2 , W 3 , W 4 represent, independently of one another, N or CH; R 1 NYSO 2 Y or Y stands for; R 2 , R 4represents Y; R 3 represents Y or Hal; R 2 , R 3 Also together - (CY) 2 -or- (CR 7 )-(CY) 2 - also stands for; R 5 , R 6 represent, independently of one another, Hal, Y or Het; R 7 represents Y or =O; Y represents H or A; A represents unbranched or branched alkyl having 1 to 10 C atoms, in which 1 to 7 H atoms may be replaced, independently of one another, by Hal; Het represents an optionally substituted saturated, unsaturated or aromatic monocyclic 5-6-membered heterocycle having 2-5 C atoms and 1-3 N, O and / or S atoms; Hal represents F, Cl, Br or I; and m represents 0, 1, 2 or 3; Concerning the above compounds, and / or physiologically acceptable salts thereof; however [ka] is excluded. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description of the Invention Compounds in the sense of the present invention are defined to include the pharma- ceutical usable derivatives, as well as solvates, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, and mixtures thereof in any ratio.

[0009] The term "pharmaceutical usable derivatives" is taken to mean, for example, the salts of the compounds according to the invention and so-called prodrug compounds.

[0010] The term "solvates" of a compound is taken to mean adductions of inert solvent molecules onto the compound, which are formed due to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alkoxides. The invention also includes solvates of the salts of the compounds according to the invention.

[0011] The term "prodrug" is taken to mean a compound according to the invention that is modified, for example with alkyl or acyl groups, sugars or oligopeptides, and is rapidly cleaved in the organism to form an active compound according to the invention. They also include biodegradable polymer derivatives of the compounds according to the invention. In cases where the actual biologically active form is only released through metabolism, it is equally possible for the compounds of the invention to be in any desired prodrug form, for example, esters, carbonates, carbamates, ureas, amides or phosphates. Any compound (i.e., a compound of the invention) that can be converted in-vivo to provide biological activity is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known and described in the art. Furthermore, it is known that chemicals can be converted in the body into metabolites that, where appropriate, can also elicit the desired biological effect - even in a more pronounced form in some circumstances. Any biologically active compound that is converted in-vivo by a form of metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.

[0012] The compounds of the present invention may be present in the form of their double bond isomers as pure E or Z isomers, in the form of mixtures of their double bond isomers. If possible, the compounds of the present invention may be in the form of tautomers, such as keto-enol tautomers. All stereoisomers of the compounds of the present invention, either in mixtures or in pure or substantially pure form, are contemplated. The compounds of the present invention may have asymmetric centers at any of the carbon atoms. As a result, they may be present in the form of their racemates, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of their enantiomers and / or diastereomers. The mixtures may have any desired mixture ratio of stereoisomers. Thus, for example, the compounds of the present invention that have one or more centers of chirality and occur as racemates or as diastereomeric mixtures can be fractionated into their optically pure isomers, i.e., enantiomers or diastereomers, by known methods. Resolution of the compounds of the invention can occur by column separation on chiral or non-chiral phases, or by recrystallization, optionally from optically active solvents or with the use of optically active acids or bases, or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, followed by elimination of a radical.

[0013] The present invention also relates to the use of mixtures of compounds according to the invention, such as mixtures of the two diastereomers, for example in ratios of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of stereoisomeric compounds.

[0014] The nomenclature for defining the compounds, in particular the compounds according to the invention, as used herein, is based on the rules of the IUPAC organization for chemical compounds in general and organic compounds in particular. The terms indicated for the description of the compounds of the invention above always have the following meanings, unless otherwise indicated in the description or in the claims:

[0015] The term "unsubstituted" means that the corresponding radical, group, or moiety has no substituents.

[0016] The term "substituted" means that the corresponding radical, group, or moiety has one or more substituents. When a radical has multiple substituents and various substituent options are specified, the substituents are selected independently of each other and need not be the same. When a radical has more than one of a particular named substituent (e.g., Y 2 or YY), although occurrences of such substituents may be different from each other (e.g., methyl and ethyl). It should be consequently understood that multiple substitutions with any radical of the present invention may involve the same or different radicals. Thus, when individual radicals occur several times in a compound, the radicals apply independently of each other the indicated meanings. In case of multiple substitutions, the radicals can alternatively be designated as R', R'', R''', R'''', etc.

[0017] The term "alkyl" or "A" refers to an acyclic, saturated or unsaturated hydrocarbon radical, which may be branched or straight chain, and preferably has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e., C 1 ~C 10Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-di ... Methylbutyl, 1- or 2-ethylbutyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-icosanyl, and n-docosanyl.

[0018] In a preferred embodiment of the present invention, A represents an unbranched or branched alkyl having 1 to 10 C atoms, in which 1 to 7 H atoms may be replaced independently of one another by Hal. More preferably, A represents an unbranched or branched alkyl having 1 to 6 C atoms, in which 1 to 4 atoms may be replaced independently of one another by Hal. In the most preferred embodiment of the present invention, A represents an unbranched or branched alkyl having 1 to 4 C atoms, in which 1 to 3 H atoms may be replaced independently of one another by Hal. It is highly preferred that A represents an unbranched or branched alkyl having 1 to 4 C atoms, optionally in which 1 to 3 H atoms may be replaced independently of one another by F and / or Cl. Even more preferably, C 1-4 -alkyl. 1-4-Alkyl radicals are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, in particular methyl, ethyl, propyl or trifluoromethyl. 1-2 -alkyl. It should be understood that each A representation is independent of the other and is any radical in the present invention.

[0019] The term "heterocycle" or "heterocyclyl" for the purposes of the present invention refers to a monocyclic or polycyclic system of 3 to 14 ring atoms, preferably 4 to 10 ring atoms, more preferably 4 to 8 ring atoms, containing carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, which may be the same or different, especially nitrogen, oxygen and / or sulfur. The cyclic system may be saturated, mono- or poly-unsaturated, or aromatic. In the case of a cyclic system consisting of at least two rings, the rings may be fused or spiro or otherwise connected. Such heterocyclyl radicals may be linked via any ring member. The term "heterocyclyl" also encompasses systems in which the heterocycle is part of a bicyclic or polycyclic saturated, partially unsaturated and / or aromatic system, such as when the heterocycle is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group via any desired and possible ring member of the heterocyclyl radical as defined herein. The compounds of general formula (I) may be linked via any available ring member of the heterocyclyl radical. Examples of suitable heterocyclyl radicals are pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl, and dihydropyranyl.

[0020] The term "heteroaryl" for the purposes of the present invention refers to a 1-15 membered, preferably 1-9 membered, most preferably 5-, 6- or 7-membered, monocyclic or polycyclic aromatic hydrocarbon radical containing at least one, where appropriate 2, 3, 4 or 5, heteroatoms, preferably nitrogen, oxygen and / or sulfur, the heteroatoms being the same or different. Preferably, the number of nitrogen atoms is 0, 1, 2, 3 or 4, and that of oxygen and sulfur atoms is 0 or 1, independently of each other. The term "heteroaryl" also encompasses systems in which the aromatic ring is a partially bicyclic or polycyclic saturated, partially unsaturated and / or aromatic system, such as when the aromatic ring as defined herein is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group via any desired and possible ring member, such as a heteroaryl radical. The compounds of general formula (I) may be bonded via any possible heteroaryl radical. Examples of suitable heteroaryls are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl, indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl, and acridinyl.

[0021] Heteroaryl in the category "Het" preferably denotes an optionally substituted, saturated, unsaturated or aromatic monocyclic 5-6 membered heterocycle having 2-5 C atoms and 1-3 N, O and / or S atoms. For example, Het is A, Hal, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, S.O. 2 NYY, NYSO 2 Y, NYY, NO 2, OCN, SCN and SH. In a more preferred embodiment of the invention, Het represents an unsaturated or aromatic monocyclic 5-6 membered heterocycle having 2-5 C atoms and 1-2 N atoms, which may be substituted by A or Hal. Most preferred is that Het represents an unsaturated monocyclic 5 membered heterocycle having 3-4 C atoms and 1-2 N atoms, which may be monosubstituted by A. Highly preferred is that Het represents 1-methylpyrazole.

[0022] For the purposes of the present invention, the terms "halogen", "halogen atom", "halogen substituent" or "Hal" refer to one or, where appropriate, multiple fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro), or iodine (I, iodo) atoms. The designations "dihalogen", "trihalogen" and "perhalogen" refer to two, three and four substituents, respectively, each of which may be independently selected from the group consisting of fluorine, chlorine, bromine, and iodine. Halogen preferably means a fluorine (F), chlorine (Cl), or bromine (Br) atom. In particular, when halogen is an alkyl (haloalkyl) or alkoxy group (e.g. CF 3 and CF 3 When substituted on aryl, fluoro and chloro are more preferred. Most preferably, Hal represents Cl. It should be understood that each representation of Hal is independent of each other in any radical of the present invention.

[0023] In the present invention, W 1 , W 2 , W 3 , W 4 represent, independently of each other, N or CH. In one embodiment of the invention, W 1 , W 2 , W 3 , W 4 are each independently N or CH, with the proviso that W 3 Or W 4 At least one of W represents N. In other words, 3 Or W 4represents N while each other radical represents N or CH.

[0024] In a preferred embodiment of the present invention, W 2 In a preferred embodiment of the present invention, W 1 represents N. In a preferred embodiment of the present invention, W 3 represents N. In a preferred embodiment of the present invention, W 4 represents N.

[0025] In a preferred embodiment of the present invention, W 1 , W 3 and / or W 4 represents N. In a more preferred embodiment of the present invention, W 1 represents N. In the most preferred embodiment of the present invention, W 1 and W 3 represents N. In a highly preferred embodiment of the present invention, W 1 , W 3 and W 4 represents N.

[0026] In a more preferred embodiment of the present invention, W 2 , CH, and / or W 1 W stands for 3 and / or W 4 represents N. In the most preferred embodiment of the present invention, W 2 represents CH, and W 1 represents N. In a highly preferred embodiment of the present invention, W 2 represents CH, and W 1 and W 3 represents N. In a particularly highly preferred embodiment of the present invention, W 2 represents CH, and W 1 , W 3 and W 4 represents N.

[0027] R according to the present invention 1 Radicals are NYSO 2 Represents Y or Y. NASO 2A or H is R according to the present invention. 1 is a preferred embodiment of the radical. More preferably, R 1 is NASO 2 The answer is A.

[0028] R according to the present invention 2 , R 4 The radical represents Y. H is preferred in R according to the present invention. 2 It is a preferred embodiment of the radical H. 4 This is a preferred embodiment of the radical.

[0029] R according to the present invention 3 The radical represents Y or Hal. H or Hal is R 3 is a preferred embodiment of the radical. More preferably, R 3 is H. In another preferred embodiment of the present invention, R 2 , R 3 and / or R 4 represents H.

[0030] In another aspect of the invention, R 2 , R 3 The radicals also combine together to form -(CY) 2 -or- (CR 7 )-(CY) 2 - is also represented. Preferably, R 2 , R 3 Together - (CY) 2 -or- (CR 7 )-(CY) 2 -, but W 4 represents N. More preferably, R 2 , R 3 Together - (CY) 2 -, most preferably -(CA) 2 -, highly preferably in each case W 4 represents N. In other words, it is highly preferred that R 2 , R 3 Together - (CY) 2 -, but W4 represents N.

[0031] R according to the present invention 5 , R 6 The radicals, independently of one another, represent Hal, Y or Het. Hal or A is indicative of R according to the invention. 5 is a preferred embodiment of the radical. More preferably, R 5 is Hal. Hal or A is R according to the present invention. 6 is a preferred embodiment of the radical. More preferably, R 6 is Hal.

[0032] R according to the present invention 7 The radical represents Y or =O. =O is an essential component of R according to the present invention. 7 This is a preferred embodiment of the radical. The m index according to the present invention represents 0, 1, 2 or 3, preferably 0 or 1, more preferably 0. R according to the present invention 5 , R 6 In another preferred embodiment the radicals, independently of one another, represent Hal or A and / or m represents 0 or 1. In aspects of the invention, Y represents H or A. It is understood that each representation of Y is independent of each other in any radical of the invention.

[0033] Consequently, the subject of the present invention relates to compounds represented by formula (I), in which at least one of the above-identified radicals has any meaning, and in particular realizes any aspect or preferred embodiment as described above. Any radical not expressly specified in the context of any aspect or embodiment of formula (I), its subformulas, or other radicals thereto, are to be interpreted as meaning any respective representation according to formula (I) disclosed herein below to solve the problem of the present invention. It is to be understood that any aspect of a radical may be combined with any aspect of one or more other radicals, including but not limited to any preferred embodiment.

[0034] In another preferred embodiment of the invention, the compound of sub-formula (IA) [ka] During the ceremony, R 5 , R 6 represent, independently of one another, Hal or A, and W 3 , R 2 , R 3 , R 4 and A has the meaning as defined above; and / or any physiologically acceptable salt thereof.

[0035] The prior teachings herein on compounds of formula (I), including any radical definitions and preferred embodiments thereof, where appropriate, are valid and applicable without limitation to compounds and physiologically acceptable salts according to sub-formula (IA).

[0036] Highly preferred embodiments are those compounds of formula (I) and (IA) as listed below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] and / or a physiologically acceptable salt thereof.

[0037] The compounds according to formula (I) and the starting materials for their preparation, respectively, are prepared according to known methods, i.e. under reaction conditions known and suitable for the reactions, as described in the literature (e.g. in standard texts such as Houben-Weyl, Methods of Organic Chemistry).

[0038] Use can be made by variants which are known per se but are not mentioned in more detail here. If desired, the starting materials can also be formed in-situ by leaving them in an unseparated state in the crude reaction mixture but immediately converting them further into the compounds according to the invention. It is also possible to carry out the reaction in stages.

[0039] The reaction is generally accomplished in an inert solvent. Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid, acetic acid, or trifluoroacetic acid (TFA); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents. Specific preferences are DMF, TFA, H 2 O, THF, tert.-butanol, tert.-amyl alcohol, triethylamine, or dioxane.

[0040] Depending on the conditions used, the reaction time is between 2-3 minutes and 14 days, and the reaction temperature is between about -30°C and 140°C, usually between -10°C and 130°C, preferably between 0°C and 100°C.

[0041] The present invention also includes the steps of: (a) A compound represented by formula (II): [ka] In the formula, R 4 , R 5 , R 6 and m has the meaning as defined above. and Compounds represented by formula (III): [ka] During the ceremony, R 8 represents CN, COOH or Hal; and W 1 , W 2 , W 3 , W 4 , R 1 , R 2 and R 3 has the meaning as defined above, React with Compounds represented by formula (I): [ka] In the formula, W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m has the meaning defined above; It produces and optionally (b) converting the base or acid of a compound of formula (I) into a salt thereof; The present invention relates to a process for producing a compound represented by formula (I), comprising:

[0042] The compound of formula (I) is accessible via the above route. The starting materials, including the compounds of formula (II) and (III), are known to those skilled in the art or are easily prepared by known methods. As a result, any of the compounds of formula (II) and (III) can be purified, provided as intermediate products, and used as starting materials for the preparation of the compound of formula (I).

[0043] In the final step of the above process, the salt of the compound according to formula (I) is optionally provided.The compounds according to the present invention can be used in their final non-salt form.On the other hand, the present invention also includes the use of these compounds in the form of pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.

[0044] The pharmaceutically acceptable salt form of the compound according to the present invention is prepared by conventional methods for the most part.When the compound according to the present invention contains a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to produce the corresponding base addition salt.Such bases are, for example, alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.The aluminum salt of the compound according to the present invention is also included. In most cases of the compounds according to the invention, acid addition salts are preferably formed by treating these compounds with pharma- ceutically acceptable organic and inorganic acids, for example hydrogen halides such as hydrogen chloride, hydrogen bromide, or hydrogen iodide; other mineral acids such as sulfates, nitrates, or phosphates, and the like, and the corresponding salts thereof; and alkyl- and arylsulfonates, such as ethanesulfonate, toluenesulfonate, and benzenesulfonate; and other organic acids, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like, and the corresponding salts thereof.Consequently, pharma- ceutically acceptable acid addition salts of the compounds according to the invention include the following: acetate, adipate, alginate, alginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, Hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, and phthalate, but this does not represent a limitation.

[0045] In the above, the expressions "pharmaceutical acceptable salt" and "physiologically acceptable salt", which are used interchangeably in this specification, can be taken to mean the active ingredient, including the compound according to the present invention, in one of its salt forms, especially when this salt form gives the active ingredient improved pharmacokinetic properties compared to the free form of the active ingredient or any other salt form of the active ingredient previously used.The pharmaceutical acceptable salt form of the active ingredient can also provide the active ingredient with desired pharmacokinetic properties that it did not have before for the first time, and even have a positive effect on the pharmacodynamics of this active ingredient in terms of its therapeutic effectiveness in the body.

[0046] A subject of the present invention is also the use of compounds according to formula (I) and / or their physiologically acceptable salts for modulating, and preferably inhibiting, SRPK activity.

[0047] The term "modulation" refers to any change in SRPK-mediated signal transduction based on the action of a particular compound of the invention that can interact with a SRPK target in a manner that allows for recognition, binding, and inhibition.

[0048] The term "inhibition" refers to any reduction in SRPK activity based on the action of a particular compound of formula (I) that can interact with the target SRPK in such a way as to allow recognition, binding and blocking. The compound is characterized by a clear affinity for SRPK, which ensures reliable binding and blocking of SRPK activity. Preferably, the compound is specific for SRPK to ensure exclusive and directed recognition of the SRPK target. In an embodiment of the present invention, the compound of formula (I) is bispecific to ensure exclusive and directed recognition of two targets selected from the group of SRPK1, SRPK2 and SRPK3. In another embodiment of the present invention, the compound of formula (I) is trispecific to ensure exclusive and directed recognition of the targets SRPK1, SRPK2 and SRPK3. In another embodiment of the present invention, the compound of formula (I) and / or its physiologically acceptable salt is a SRPK inhibitor that does not show cross-reactivity with CLK proteins and / or DYRK proteins.

[0049] In the context of the present invention, the term "recognition" refers to any type of interaction between a specific compound and a target, particularly, but not limited to, covalent or non-covalent binding or association, such as covalent bonds, hydrophobic / hydrophilic interactions, van der Waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions, etc. Such associations may also encompass the presence of other molecules, such as peptides, proteins, or nucleotide sequences. The interaction is characterized by high affinity, high selectivity, and minimal or no cross-reactivity to other target molecules, to eliminate unhealthy and harmful effects on the treated subject.

[0050] A preferred subject of the present invention relates to a method for inhibiting SRPK, in which a system capable of expressing, preferably expressing, SRPK is contacted with at least one compound of formula (I) according to the present invention and / or its physiologically acceptable salt under conditions such that said SRPK is inhibited. In the scope of the present invention, a cell system is preferred. A cell system is defined as any object, provided that the object consists of cells. Thus, a cell system may be selected from the group of a single cell, a cell culture, a tissue, an organ, and an animal. The method for inhibiting SRPK is preferably carried out in-vitro. The preceding teachings of the present specification on the compound of formula (I), including all its preferred embodiments, are valid and applicable without limitation to the compound according to formula (I) and its salts when used in a method for inhibiting SRPK.

[0051] The compounds according to the invention preferably exhibit advantageous biological activity, which is easily demonstrated in cell culture-based assays, such as those described herein or in the prior art. In such assays, the compounds according to the invention preferably exhibit and cause an inhibitory effect. The compounds of the invention have IC values ​​in the range of 1 nM to 25 μM. 50 The compounds of the present invention have IC 50It is preferred that the activity expressed on a scale is below 2.5 μM, preferably below 1 μM, more preferably below 0.5 μM, most preferably below 0.05 μM.

[0052] The method of the present invention can be carried out in-vitro or in-vivo. The sensitivity of a particular cell to treatment with a compound according to the present invention can be determined in particular by in-vitro testing, whether during research or during clinical application. Typically, a culture of cells is combined with a compound according to the present invention at various concentrations for a period sufficient for the active agent to modulate SRPK activity, usually between about 1 hour and 1 week. In-vitro treatment is accomplished using cultured cells from a biopsy sample or a cell line. In a preferred aspect of the present invention, follicular cells are stimulated for maturation. Viable cells remaining after treatment are counted and further processed.

[0053] The host or patient may belong to any mammalian species, such as primates, particularly humans; rodents, including mice, rats, hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations and provide models for the treatment of human diseases.

[0054] To identify signal transduction pathways and detect interactions between various signal transduction pathways, various scientists have developed suitable models and model systems, such as cell culture models and transgenic animal models. To determine a stage in the signal transduction cascade, interacting compounds can be used to modulate the signal. The compounds according to the present invention can also be used as reagents to study SRPK-dependent signal transduction pathways in animal and / or cell culture models or in clinical diseases described in this application.

[0055] The use according to the previous paragraph of this specification can be carried out either in-vitro or in-vivo models. The modulation can be monitored by the techniques described herein. The in-vitro use is preferably applied to human samples suffering from hyperproliferative disorders. The testing of several specific compounds and / or their derivatives allows the selection of the best suitable active ingredient for the treatment of human subjects. The in-vivo dosage rate of the selected derivative is advantageously pre-adjusted to the SRPK sensitivity and / or disease severity of each subject with respect to the in-vitro data. Thus, the therapeutic efficacy is unexpectedly enhanced. Moreover, the subsequent teachings of this specification on the use of the compounds according to formula (I) and their pharmacopoeiaacceptable salts for the production of medicaments for preventive or therapeutic treatment and / or monitoring are considered to be valid and applicable without limitation to the use of the compounds for the modulation of SRPK activity, if appropriate.

[0056] As a result, the compounds according to the invention are useful for the prevention and / or treatment of diseases that depend on said signaling pathways, by interacting with one or more of said signaling pathways. The invention therefore relates to the compounds according to the invention as modulators, preferably inhibitors, of the signaling pathways described herein. In particular, the invention relates to the use of the compounds according to the invention for the preparation of medicaments for the treatment of hyperproliferative disorders associated with the enhancement of SRPK, as well as diseases modulated by the SRPK cascade in mammals, or disorders mediated by hyperproliferation, such as cancer and inflammation.

[0057] The present invention furthermore relates to a medicament comprising at least one compound according to the invention and / or its pharma- ceutically usable derivatives, salts, solvates and stereoisomers, as well as mixtures thereof in any ratio.Preferably, the present invention relates to a medicament comprising at least one compound according to the invention and / or its physiologically acceptable salts.

[0058] A "medicinal product" in the sense of the present invention is any agent in the pharmaceutical field, which comprises one or more compounds of formula (I) or preparations thereof (e.g. pharmaceutical compositions or pharmaceutical formulations) that can be used in the prophylaxis, treatment, follow-up or aftercare of patients suffering from a disease associated with SRPK activity in such a way that a pathogenic modification of the overall condition or of the condition of a specific area of ​​the organism can be established, at least temporarily.

[0059] The present invention also relates to pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) according to the invention and / or its physiologically acceptable salts, together with pharma- ceutically tolerable adjuvants and / or excipients. It should be understood that the compound of the invention is provided in an effective amount.

[0060] "Adjuvants" in the sense of the present invention refers to any substance that enables, intensifies or modifies a specific response to the active ingredient of the invention when administered simultaneously, contemporarily or sequentially. Known adjuvants for injections are, for example, aluminum compositions such as aluminum hydroxide or aluminum phosphate; saponins such as QS21, muramyl dipeptide or muramyl tripeptide; proteins such as gamma-interferon or TNF; M59, squalene or polyols.

[0061] Furthermore, the active ingredient can be administered alone or in combination with other treatments. Synergistic effects can be achieved by using multiple compounds in a pharmaceutical composition, i.e., by combining a compound of formula (I) with at least another agent as an active ingredient, either another compound of formula (I) or a compound of a different structural scaffold. The active ingredients can be used simultaneously or sequentially. The present invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell proliferation or cancer in a mammal, comprising an amount of a compound of the present invention, or a pharma-ceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of another anti-cancer therapeutic agent, wherein the amount of the compound, salt, solvate or prodrug, and the amount of the chemotherapeutic agent are together effective in inhibiting abnormal cell proliferation or cancer. The compounds of the present invention are suitable for combination with known anti-cancer agents.

[0062] Currently, many cancer therapeutics are known in the art.In a preferred embodiment, the other active pharmaceutical ingredient is an anti-cancer therapeutic that is a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.In another preferred embodiment of the present invention, the anti-cancer therapeutic is an antibody selected from the group consisting of bevacizumab, CD40-specific antibodies, chTNT-1 / B, denosumab, zanolimumab, IGF1R-specific antibodies, lintuzumab, elecolomab, WX G250, rituximab, ticilimumab, trastuzumab, and cetuximab. In yet another preferred embodiment of the invention, the anti-cancer therapeutic agent is an inhibitor of another protein kinase, such as, for example, Akt, Axl, dyrk2, efa2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt-3, PDK1, Erk, etc. Additional anti-cancer agents are known to those of skill in the art and are useful with the compounds of the invention.

[0063] The present invention also relates to a set (kit) consisting of separate packs of an effective amount of the compound according to the invention and / or its pharma- ceutically acceptable salts, derivatives, solvates and stereoisomers (including mixtures thereof in all ratios) and an effective amount of further medicament active ingredients. The set comprises suitable containers such as boxes, individual bottles, bags or ampoules. The set comprises, for example, separate ampoules, each of which contains an effective amount of the compound according to the invention and / or its pharma- ceutically acceptable salts, derivatives, solvates and stereoisomers (including mixtures thereof in all ratios) and an effective amount of further medicament active ingredients in dissolved or lyophilized form.

[0064] Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal). Such formulations can be prepared, for example, by combining the active ingredient with excipients or adjuvants, by any process known in the pharmaceutical art.

[0065] The pharmaceutical composition of the present invention is prepared in a known manner with suitable dosages using common solid or liquid carriers, diluents and / or additives, and common adjuvants for pharmaceutical design. The amount of excipients combined with active ingredients to produce a single dosage form varies depending on the host treated and the mode of administration. Suitable excipients include organic or inorganic substances that are suitable for different administration routes, such as enteral (e.g. oral), parenteral or topical application, and do not react with the compound of formula (I) or its salts. Examples of suitable excipients are water, vegetable oils, benzyl alcohol, alkylene glycol, polyethylene glycol, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc, and petrolatum.

[0066] Pharmaceutical formulations adapted for oral administration may be administered as discrete units, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0067] Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes that make the preparation isotonic with the blood of the treated recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending media and thickening agents. The preparations may be administered in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a lyophilized (lyophilized) state, so that only the addition of a sterile carrier liquid, for example water for injection, is required immediately before use. Recipe-prepared injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0068] It goes without saying that in addition to the ingredients specifically mentioned above, the formulations may also contain other agents customary in the art with respect to the particular type of formulation; thus, for example, formulations suitable for oral administration may contain flavors.

[0069] In a preferred embodiment of the present invention, pharmaceutical composition is adapted for oral administration.Preparation can be sterilized and / or can contain auxiliary agents, such as carrier proteins (for example, serum albumin), lubricants, preservatives, stabilizers, fillers, chelating agents, antioxidants, solvents, binders, suspending agents, wetting agents, emulsifiers, salts (to affect osmotic pressure), buffer substances, colorants, flavoring agents, and one or more additional active substances, such as one or more vitamins.Additives are well known in the art, and they are used in various formulations.

[0070] The present invention also relates to a pharmaceutical composition comprising, as an active pharmaceutical ingredient, at least one compound of formula (I) according to the invention and / or its physiologically acceptable salt, together with pharma- ceutically tolerable adjuvants, optionally in combination with at least another active pharmaceutical ingredient. Both active pharmaceutical ingredients are preferably provided in effective amounts. The teachings herein above on the route of administration or on the combination product are valid and applicable without restriction to the combination of both features, if appropriate.

[0071] The terms "effective amount" or "effective amount" or "dose" are used interchangeably herein and refer to an amount of a pharmaceutical compound that has a prophylactically or therapeutically relevant effect in a disease or pathological condition, i.e., that elicits a biological or medical response in a tissue, system, animal or human as is sought or desired, e.g., by a researcher or physician.

[0072] A "prophylactic effect" reduces the likelihood of disease onset or prevents disease onset. A "therapeutically relevant effect" alleviates to some extent one or more symptoms of a disease, or partially or completely restores one or more physiological or biochemical parameters associated with or causing a disease or pathological condition to normal. In addition, the expression "therapeutically effective amount" refers to an amount that has the following causal relationship: improved treatment, cure, prevention or elimination of a disease, syndrome, condition, complaint, disorder or side effect, or a reduction in the progression of a disease, complaint or disorder, compared to a corresponding subject that has not been administered this amount. The expression "therapeutically effective amount" also covers an amount that is effective for enhancing normal physiological function.

[0073] Each dose or dosage range for administering the pharmaceutical composition according to the present invention is sufficiently high to achieve the desired preventive or therapeutic effect of reducing the symptoms of the above-identified diseases, such as cancer and inflammation.It will be understood that the specific dose level, frequency of administration and duration of administration for any particular human will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time and route of administration, excretion rate, drug combination, and the severity of the specific disease to which the specific treatment is applied.Using well-known means and methods, the exact dose can be determined by those skilled in the art as a matter of routine experimentation.The preceding teachings of this specification are valid and applicable without limitation to pharmaceutical compositions containing compounds represented by formula (I), where appropriate.

[0074] The pharmaceutical preparations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. The concentration of the prophylactic or therapeutic active ingredient in the preparation may vary in the range of about 0.1-100 wt%. Preferably, the compound of formula (I) or its pharma- ceutically acceptable salt is administered in a dose of about 0.5-1000 mg per dosage unit, more preferably between 1 mg and 700 mg, most preferably between 5 mg and 100 mg. Generally, such a dosage range is appropriate for the total daily dosage. In other words, the daily dose is preferably between about 0.02 mg / kg body weight and 100 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, as already described herein (for example, depending on the condition to be treated, the method of administration, and the age, weight, and condition of the patient). Preferred dosage unit formulations are those containing a daily dose or partial dose of the active ingredient, or a corresponding fraction thereof, as indicated above. Furthermore, pharmaceutical formulations of this type can be prepared using processes generally known in the pharmaceutical art.

[0075] Although the therapeutically effective amount of the compound according to the invention must ultimately be determined by the treating physician or veterinarian by considering many factors (e.g. age and weight of the animal, the exact condition requiring treatment, the severity of the condition, the nature of the formulation and the method of administration), an effective amount of the compound according to the invention for the treatment of neoplastic growths, such as colon cancer or breast cancer, is generally in the range of 0.1-100 mg / kg of body weight of the recipient (mammal) per day, and more particularly typically in the range of 1-10 mg / kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 mg and 700 mg, which amount can be administered as a single dose per day or as a series of partial doses (e.g. 2, 3, 4, 5 or 6 times, etc.) most often per day, so that the total daily dose is the same. The effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a fraction of the effective amount of the compound according to the invention itself. Similar doses can be presumed to be suitable for the treatment of the other conditions mentioned above.

[0076] The pharmaceutical composition of the present invention can be employed as a medicament in human and veterinary medicine. The compounds of formula (I) and / or their physiological salts according to the present invention are suitable for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated and / or propagated by SRPK activity. The diseases are preferably selected from the group of hyperproliferative disorders, cancer, metastasis, tumors, angiogenic disorders, tumor angiogenesis, benign hyperplasia, hemangiomas, gliomas, melanomas, Kaposi's sarcoma, angiogenesis or angiogenesis-related prostate diseases, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma and age-related macular degeneration. It should be understood that a host of compounds are included within the scope of protection according to the present invention.

[0077] Particular preference is given to the treatment of cancers such as brain, lung, colon, epidermoid, squamous, bladder, stomach, pancreas, breast, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, uterine, rectal, esophageal, testicular, gynecological or thyroid cancer, or melanoma; hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic myeloid leukemia or myeloid cell leukemia; glioma; Kaposi's sarcoma; or any other type of solid or liquid tumor. More preferably, the cancer to be treated is selected from breast, colorectal, lung, prostate or pancreatic cancer, or glioblastoma.

[0078] Further preference is given to the treatment of diseases associated with vasculogenesis or angiogenesis in mammals, which comprises administering a therapeutically effective amount of the compound of the present invention or a pharma-ceutically acceptable salt prodrug or hydrate thereof and a pharma-ceutically acceptable carrier. In one embodiment, the compound or pharmaceutical composition of the present invention is for treating a disease selected from the group consisting of tumor angiogenesis; chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, or atherosclerosis; skin diseases such as psoriasis, eczema, or scleroderma; metabolic diseases such as diabetes, obesity, metabolic syndrome, insulin resistance, hyperglycemia, hyperaminoacidemia, hyperlipidemia, diabetic retinopathy, or retinopathy of prematurity; and age-related macular degeneration.

[0079] The present invention also relates to the use of the compound represented by formula (I) and / or its physiologically acceptable salt for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated and / or propagated by SRPK activity. Furthermore, the present invention relates to the use of the compound represented by formula (I) and / or its physiologically acceptable salt for the production of a medicament for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated and / or propagated by SRPK activity. The compound represented by formula (I) and / or its physiologically acceptable salt can further be employed as an intermediate for the preparation of further medicament active ingredients. The pharmaceutical preparation is preferably prepared in a non-chemical manner, for example, by combining the active ingredient with at least one solid, liquid and / or semi-liquid carrier or excipient, and optionally with one or more other active substances in a suitable dosage form.

[0080] Another subject of the present invention relates to compounds of formula (I) according to the present invention and / or physiologically acceptable salts thereof for use in the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated and / or propagated by SRPK activity. Another preferred subject of the present invention relates to compounds of formula (I) according to the present invention and / or physiologically acceptable salts thereof for use in the preventive or therapeutic treatment and / or monitoring of hyperproliferative disorders. The preceding teachings of the present specification on compounds of formula (I), including any preferred embodiments thereof, are valid and applicable without limitation to compounds according to formula (I) and their salts for use in the preventive or therapeutic treatment and / or monitoring of hyperproliferative disorders.

[0081] The compound of formula (I) according to the present invention can be administered once or several times before or after the onset of the disease to act as a treatment. The above compounds and medical products of the use of the present invention are particularly used for therapeutic treatment. The therapeutically relevant effect is to alleviate to some extent one or more symptoms of the disease, or to partially or completely return to normal one or more physiological or biochemical parameters related to or caused by the disease or pathological condition. Monitoring is considered as a kind of treatment, provided that the compound is administered at a defined interval, for example, to boost the response and completely eradicate the pathogen and / or the symptoms of the disease. Either the same compound or different compounds can be applied. The pharmaceutical of the present invention can also be used to reduce the possibility of the onset of the disease, or to prevent the onset of the disease related to SRPK activity in advance, or to treat the symptoms that occur and continue. The disorder related to the present invention is preferably a hyperproliferative disorder.

[0082] A prophylactic treatment within the meaning of the present invention is appropriate when the subject has the prerequisites for the above identified physiological or pathological conditions, such as a familial predisposition, a genetic defect, a previously suffered disease, etc.

[0083] Another object of the present invention is to provide a method for treating diseases caused, mediated and / or propagated by SRPK activity, wherein at least one compound of formula (I) according to the present invention and / or its physiologically acceptable salt is administered to a mammalian subject in need of such treatment. Another preferred object of the present invention is to provide a method for treating hyperproliferative disorders, wherein at least one compound of formula (I) according to the present invention and / or its physiologically acceptable salt is administered to a mammalian subject in need of such treatment. The compound is preferably provided in an effective amount as defined above. A preferred treatment is oral administration.

[0084] In another preferred aspect, a method of treating cancer in a mammal comprises administering to the mammal an amount of a compound of the present invention in combination with radiation therapy, wherein the amount of the compound is administered in combination with radiation therapy effective in treating cancer in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The amount and administration of the compound of the present invention in this combination therapy can be determined according to the means for ascertaining the effective amount, dose and route of the compound as described herein. It is believed that the compound of the present invention can make non-normal cells more sensitive to treatment with radiation, for the purpose of killing such cells and / or inhibiting the proliferation of such cells. Consequently, the present invention relates to a method of sensitizing non-normal cells of a mammal to treatment with radiation, comprising administering to the mammal an amount of a compound of the present invention in an amount effective to sensitize non-normal cells to treatment with radiation.

[0085] It is yet another aspect of the present invention to provide a method of inhibiting abnormal cell proliferation in a mammal comprising an amount of a compound of the present invention or an isotopically labeled derivative thereof and an amount of one or more agents selected from an antiangiogenic agent, a signal transduction inhibitor, and an antiproliferative agent.

[0086] The preceding teachings of the present invention and its embodiments are valid and applicable without limitation to methods of treatment, where appropriate.

[0087] In the scope of the present invention, a novel SRPK inhibitory compound represented by formula (I) is provided for the first time. The present invention includes the use of the compound of formula (I) in regulating, modulating and / or inhibiting SRPK. The compound of the present invention can be advantageously applied as a research tool, for diagnosis, and / or in the treatment of any disorder that is responsive to SRPK signaling and inhibition.

[0088] For example, the compounds of the present invention are useful in vitro as unique tools for understanding the biological role of SRPKs, including the evaluation of the many factors that may affect and be affected by the production of SRPKs. The compounds of the present invention are also useful in the development of other compounds that interact with SRPKs because they provide important structure-activity relationship (SAR) information that facilitates their development.

[0089] The compounds of the present invention are potent, selective and orally bioavailable SRPK inhibitors, which address the unmet medical needs of a number of conditions, especially cancer and inflammation, the progressive features of disease.The medicaments and pharmaceutical compositions containing said compounds, and the use of said compounds for treating SRPK-mediated pathologies, are promising and novel approaches for a wide range of treatments, causing direct and immediate improvement of health conditions, whether in humans or animals.This effect, alone or in combination with other treatments, is particularly beneficial for effectively fighting against proliferative disorders.

[0090] Due to the surprising and obvious inhibitory activity against SRPK, the compounds of the present invention can be advantageously administered at lower doses compared to other less potent or less selective inhibitors of the prior art, while still achieving equivalent or even superior desired biological effects.In addition, such dose reduction advantageously causes less or no medical adverse effects.In addition, the compounds of formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and / or metabolites are characterized by high specificity and stability, low production costs and convenient handling.These characteristics are the basis for reproducible action, including lack of cross-reactivity, and the basis for reliable and safe interaction with target structures.

[0091] All documents cited herein are incorporated by reference in the present disclosure. It should be understood that the present invention is not limited to the specific compounds, pharmaceutical compositions, uses, and methods described herein. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the appended claims. As used herein, including the appended claims, singular terms such as "a", "an", and "the" include the corresponding plural referents unless the context clearly dictates otherwise. Thus, by way of example, reference to a "compound" includes single or multiple different compounds, and reference to a "method" includes reference to equivalent steps and methods known to those skilled in the art, and the like. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0092] The techniques essential to the present invention are described in detail in the specification. Other techniques not described in detail correspond to standard methods well known to those skilled in the art, or the techniques are described in detail in cited documents, patent applications, or standard documents. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of the present invention, but the following are suitable examples. The following examples are provided by way of illustration and not by way of limitation. Standard reagents and buffers free of contaminating activity (where practical) are used within the examples. The examples are not to be construed as being limited to the combination of features specifically illustrated, but the exemplified features may be recombined without restriction, provided that the technical problem of the present invention is solved. Similarly, any feature of any claim may be combined with the features of one or more other claims.

[0093] In the following examples, "conventional work-up" means that water is added if necessary, the pH is adjusted if necessary to a value between 2 and 10 depending on the composition of the final product, the mixture is extracted with ethyl acetate (EA) or dichloromethane (DCM), the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel or C-18, and / or crystallization.

[0094] Some abbreviations that may appear in this application are as follows: CAN Acetonitrile AcOH Acetic acid aq water-based API Active Pharmaceutical Ingredient CDCl 3 Deuterated chloroform CD 3 OD Deuterated Methanol c-hex cyclohexane DCC Dicyclohexyl carbodiimide DCM Dichloromethane DIC Diisopropylcarbodiimide DIEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sulfoxide EDC 1-(3-Dimethyl-amino-propyl)-3-ethylcarbodiimide Equivalent ESI Electrospray Ionization Et 2 O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol g grams h time HATU Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate HPLC High Performance Liquid Chromatography i-PrOH 2-Propanol K 2 CO 3 Potassium carbonate L Liter LC Liquid Chromatography MeOH Methanol mg milligram MgSO 4 Magnesium sulfate MHz Megahertz min mL Milliliters mm millimeters mm millimolar mmol mp Melting point MS mass spectrometry MTBE Methyl tert-butyl ether NaBH 4 Sodium borohydride NaHCO 3 Sodium bicarbonate NMM N-Methylmorpholine NMR nuclear magnetic resonance PE Petroleum Ether PyBOP Benzotriazol-1-yl-oxy-tris-pyrrolidine o-phosphonium hexafluorophosphate Rt residence time RT room temperature SPE solid phase extraction TBTU 2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uromium tetrafluoroborate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography UV ultraviolet light WL wavelength μL microliter

[0095] 1H NMR was recorded on a Bruker DPX-300, DRX-400, AVII-400 or 500 MHz spectrometer using the residual signal of the deuterated solvent as an internal reference. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ=2.49 ppm for 1H NMR in DMSO-d6). 1H NMR data were reported as chemical shifts (multiplicity, coupling constants, and number of hydrogens). Multiplicities were abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

[0096] LC-MS methods [Table 2-1] [Table 2-2]

[0097] Example 1-A: General Procedure (GP) GP A: To a stirred solution of the corresponding aryl chloride or aryl fluoride (1.00 equiv) and sulfonamide or amine (1.50 equiv) in solvent (39.68 equiv) was added base (2.00 equiv). The resulting mixture was stirred overnight under nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0098] GP B: The corresponding nitrile (1.00 equiv) was reacted with NH 3 (g) and MeOH (52.17 equiv) were dissolved. The resulting mixture was stirred at 25° C. under a hydrogen atmosphere (balloon) for 16 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give the desired product.

[0099] GP C: To a stirred mixture of aryl halide (1.00 equiv) and amine or sulfonamide (0.90 g, 6.942 mmol, 1.25 equiv, 95%) in solvent (35.00 equiv) was added base (1.50 equiv), ligand (0.10 equiv), Pd source (0.05 equiv). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with ethyl acetate (100 mL). The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep HPLC to give the desired product.

[0100] GP D: EtOH (58.83 equiv) / H 2 To a stirred solution of the corresponding carbonitrile (1.00 equiv) in O (126.48 equiv) was added NaOH (2.00 equiv). The resulting mixture was stirred at 80° C. for 2 h. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product.

[0101] GP E: To a stirred solution of the corresponding pyrrole (1.00 equiv) in DMSO (106.07 equiv) was added NaH (1.20 equiv) in portions at room temperature. The resulting mixture was stirred for 30 min under nitrogen atmosphere. To the above mixture was added the corresponding allyl chloride (1.50 equiv) at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction was quenched by the addition of water at 0° C. The resulting mixture was diluted with EA. The resulting mixture was diluted with H 2 O and brine. 2 SO 4After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-TL to give the desired product.

[0102] GP F: A round bottom flask was charged with the corresponding nitro compound (1.00 equiv), methanol (99.10 equiv) and Pt / C (0.01 equiv) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the desired product.

[0103] GP G: To a stirred mixture of the corresponding carboxylate (1.00 equiv) in THF (74.79 equiv) was added LiAlH4 (1.50 equiv) in portions at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was stirred at 0° C. with Na 2 SO 4* 10H 2 The mixture was quenched by the addition of O. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeOH. The precipitated solid was collected by filtration to give the desired product.

[0104] List of intermediates and starting materials (CAS# are commercially available) that can be obtained by reference or following General Procedures (GP). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7]

[0105] Example 1-B: Synthesis of intermediate N-[3-(chloromethyl)pyridin-2-yl]-N-ethylmethanesulfonamide (I.HOL) [ka] To a stirred solution of N-ethyl-N-[3-(hydroxymethyl)pyridin-2-yl]methanesulfonamide (I.APU, 270 mg, 0.934 mmol, 1.00 equiv, 79.7%) in tetrahydrofuran (25 mL), was added SOCl 2 (5.00 mL) was added at room temperature. The resulting mixture was stirred at 60° C. for 1 h under nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with EA. The residue was diluted with saturated Na 2 CO 3 (aq.) to pH 9. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TL (PE / EtOAc 2:1) to give N-[3-(chloromethyl)pyridin-2-yl]-N-ethylmethanesulfonamide (I.HOL, 220 mg, 94.65%) as a white solid.

[0106] Example 1-C: Synthesis of intermediate 4-tert-butyl-5-fluorobenzene-1,2-diamine (I.HMD) [ka] Step 1: N-(5-tert-butyl-4-fluoro-2-nitrophenyl)pyrimidin-2-amine To a stirred solution of N-(3-tert-butyl-4-fluorophenyl)pyrimidin-2-amine (I.RYP, 1.00 equiv), silver nitrite (2 equiv), potassium peroxydisulfate (2 equiv) and AcOH (3 equiv) in DCE (97.85 equiv), Pd(AcO) 2 (0.1 equiv) was added at room temperature. The resulting mixture was diluted with O 2 The mixture was stirred under atmosphere at 80° C. overnight. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H 2 The mixture was diluted with 200 mL of ethyl acetate and extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-(5-tert-butyl-4-fluoro-2-nitrophenyl)pyrimidin-2-amine as a yellow solid.

[0107] Step 2: 5-tert-butyl-4-fluoro-N1-(1,2,3,4-tetrahydropyrimidin-2-yl)benzene-1,2-diamine To a stirred solution of N-(5-tert-butyl-4-fluoro-2-nitrophenyl)pyrimidin-2-amine (1.00 equiv) and HCl (2M) (3 equiv) in i-PrOH (30 V equiv) was added Pd / C (0.14 equiv). The resulting mixture was stirred at 50° C. under a hydrogen atmosphere overnight. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-4-fluoro-N1-(1,2,3,4-tetrahydropyrimidin-2-yl)benzene-1,2-diamine (250 mg, 88.27%) as a bright yellow solid.

[0108] Step 3: 4-tert-butyl-5-fluorobenzene-1,2-diamine (I.HMD) To 5-tert-butyl-4-fluoro-N1-(pyrimidin-2-yl)benzene-1,2-diamine (I.XTV, 1.00 equiv) was added HCl (40.20 equiv). The final reaction mixture was irradiated with microwave radiation at 150° C. for 60 min. The mixture was basified to pH 10 with NaOH (30%). The resulting mixture was extracted with EtOEt and washed with anhydrous Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TL to give 4-tert-butyl-5-fluorobenzene-1,2-diamine (I.HMD, 170 mg, 37.47%) as a brown solid.

[0109] Example 1-D: Intermediate 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (I.EYP) [ka] 7-Bromo-1H-1,6-naphthyridin-2-one (I.YLW, 1.90 g, 7.083 mmol, 1.00 equiv, 83.9%) and Zn(CN) in DMF (30.00 mL) 2 To a stirred solution of 2.70 g, 21.840 mmol, 3.08 equiv, 95%) Pd(PPh3) 4 (1.80 g, 1.402 mmol, 0.20 equiv, 90%) was added. The resulting mixture was stirred at 115° C. overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H 2 The mixture was diluted with 200 mL of 1H2O (30 mL) and extracted with EtOAc (5x30 mL). The combined organic layers were washed with brine (1x30 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (10 mL). This resulted in 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (I.EYP, 950 mg, 50.07%) as a light yellow solid.

[0110] Example 1-E: Synthesis of intermediate 5-chloro-2-(4-chloropyrimidin-2-yl)-1H-indole (I.QXU) [ka] Step 1: tert-Butyl 5-chloro-2-(4-methoxypyrimidin-2-yl)-1H-indole-1-carboxylate THF (15.00 mL, 208.044 mmol, 57.60 equiv, 100%) and H 2 To a solution of (tert-butoxycarbonyl)-5-chloroindol-2-ylboronic acid (I.MUM, 1.00 g, 3.21 mmol, 1.00 equiv, 95%) and 2-chloro-4-methoxypyrimidine (CAS#: 22536-63-6, 0.98 g, 6.440 mmol, 2.00 equiv, 95%) in 2O (1.50 mL, 83.257 mmol, 25.90 equiv, 100%), 2 CO 3 (0.94 g, 6.461 mmol, 2.01 equiv, 95%) and Pd(PPh 3 ) 4 (0.39 g, 0.321 mmol, 0.10 equiv, 95%) was added. After stirring at 70° C. for 16 h under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by Prep-TL eluting with PE / EtOAc (5:1) to give tert-butyl 5-chloro-2-(4-methoxypyrimidin-2-yl)indole-1-carboxylate (1.1 g, 90.35%) as a yellow solid.

[0111] Step 2: 2-(5-chloro-1H-indol-2-yl)pyrimidin-4-ol To a stirred solution of tert-butyl 5-chloro-2-(4-methoxypyrimidin-2-yl)indole-1-carboxylate (500.00 mg, 1.320 mmol, 1.00 equiv, 95%) in MeCN (10.00 mL, 243.592 mmol, 144.11 equiv, 100%), KI (1153.41 mg, 6.601 mmol, 5.00 equiv, 95%), TMSI (1390.27 mg, 6.601 mmol, 5.00 equiv, 95%) were added in portions at room temperature. The resulting mixture was stirred at 80° C. for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-(5-chloro-1H-indol-2-yl)pyrimidin-4-ol (300 mg, 82.23%) as a yellow solid.

[0112] Step 3: 5-Chloro-2-(4-chloropyrimidin-2-yl)-1H-indole (I.QXU) To a stirred solution of 2-(5-chloro-1H-indol-2-yl)pyrimidin-4-ol (I.STV, 200.00 mg, 0.724 mmol, 1.00 equiv, 88.9%) in tetrahydrofuran (25 mL), POCl 3 (3.00 mL, 19.565 mmol, 44.47 equiv, 100%) was added at room temperature. The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction was cooled to room temperature with saturated NaHCO 3 The mixture was quenched at room temperature by the addition of aq. (50 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated in vacuo to give 5-chloro-2-(4-chloropyrimidin-2-yl)-1H-indole (I.QXU, 200 mg, 83.39%) as a yellow solid.

[0113] Example 1-F: Intermediate N-{3-[(5-bromo-2-cyano-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (I.GER) [ka] To a solution of I.CAL (1.00 equiv) in acetonitrile (10.00V equiv) was added 1-bromo-pyrrolidine-2,5-dione (1.00 equiv) at -10°C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and washed with brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the product.

[0114] Example 2-A: Synthesis of 2-(5-chloro-1H-benzo[d]imidazol-2-yl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine [ka] POCl 3 To a stirred solution of 4-[(pyridin-3-ylmethyl)amino]pyrimidine-2-carboxylic acid (I.PPX, 1.0 equiv) in (95.51 equiv) was added 4-chloro-1,2-benzenediamine (I.GOL, 1.0 equiv). The resulting mixture was stirred for 16 h at 80 °C under a nitrogen atmosphere. The reaction was concentrated with saturated aqueous NaHCO 3 The resulting mixture was quenched with EtOAc. The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by Prep-HPLC. LC-MS: rt = 0.90 min.; Method: LC-MS A

[0115] The following compounds were prepared as described for Exemplary Compound A1 above. [Table 4]

[0116] Example 2-B: Synthesis of N-methyl-N-(3-(((2-(6-methyl-1H-benzo[d]imidazol-2-yl)pyrimidin-4-yl)amino)methyl)pyridin-2-yl)methanesulfonamide [ka] A mixture of 3,4-diaminotoluene (I.PXR, 1.0 equiv) and N-(3-[[(2-cyanopyrimidin-4-yl)amino]methyl]pyridin-2-yl)-N-methylmethanesulfonamide (I.CAL, 1 equiv) was stirred at 160° C. for 2 h under an argon atmosphere. The residue was purified by reverse flash chromatography. The crude product was purified by preparative HPLC to give the desired product.

[0117] The following compounds were prepared as described for Exemplary Compound B1 above. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0118] Example 2-E: Synthesis of N-(3-{[5-bromo-2-(5-chloro-1H-benzimidazol-2-yl)-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide (E1) [ka] To a solution of I.GER (1.00 equiv) in methanol (20.00 equiv), sodium methoxide (25% w / v in methanol) (2.00 equiv) and I.GOL (1.00 equiv) were added at room temperature and the reaction mass was stirred at 60° C. for 3 h. After completion of the reaction as evidenced by TLC, the reaction mixture was evaporated under vacuum and diluted with H 2 The mixture was quenched with 200 mL of ethyl acetate and extracted with ethyl acetate. The organic layer was separated and washed with Na 2 SO 4 The mixture was dried using hexanes and filtered. The filtrate was concentrated under vacuum and the crude reaction mixture was purified using silica gel column chromatography to give N-(3-{[5-bromo-2-(5-chloro-1H-benzimidazol-2-yl)-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide as a white yellow powder. LC-MS: rt: 3,47 min; Method: LC-MS H. 1 H NMR: 400 MHz, DMSO-d6: 13.00-12.39 (m,1H),9.52(s,1H),8.42-8.410(m,1H),8.32-8.26(m,J = 6.00 Hz,1H),7.87-7.85 (m,1H),6.51-6.49(d,J = 8.68 Hz,1H),7.23 (s,1H),7.40-7.37 (m,1H),7.29-7.26 (m,1H),4.90-4.88 (m,2H),3.43 (s,3H),3.16 (s,3H).

[0119] Example 3: Biochemical assays to evaluate SRPK1, SRPK2 and SRPK3 inhibition Buffer conditions 20 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1mM EGTA, 0.01% Brij35, 0.02mg / ml BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO Reaction procedure The indicated substrate was prepared in freshly prepared reaction buffer. The required cofactors were added to the above substrate solution. The indicated kinase was delivered to the substrate solution and mixed gently. Compounds in DMSO were delivered into the kinase reaction mixture using acoustic techniques (Echo550). 33 P-ATP (final specific activity 0.01 μCi / μl) was delivered into the reaction mixture to initiate the reaction. The kinase reaction was incubated at room temperature for 120 min. The reaction was spotted onto P81 ion exchange paper (Whatman # 3698-915). The filter was washed extensively in 0.75% phosphoric acid. The radioactive phosphorylated substrate remaining on the filter paper was measured.

[0120] Data analysis Kinase activity data were expressed as the percentage of remaining kinase activity in the test samples compared to the vehicle (dimethylsulfoxide) reaction. To pass QC, all DMSO control values ​​had a coefficient of variation less than 10% of the IC of the internal control. 50 The value must be within three times the average value over the past six months. 50 Values ​​and curve fits were obtained using Prism4 software (GraphPad). The equation used to fit the curve was:

number

[0121] Substrate and cofactor information [Table 6] [Table 7] Compound Inhibition (IC 50 ) is given below: (A<50nM, 50≦B<500nM, and 500≦C<2500nM)

[0122] Example 4: Pharmaceutical Preparation (A) Injection vials: A solution of 100 g of an API according to the present invention and 5 g of disodium hydrogen phosphate in 3 liters of double distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions, and sealed under sterile conditions. Each injection vial contained 5 mg of API.

[0123] (B) Suppositories: A mixture of 20 g of an API according to the present invention was dissolved with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds, and allowed to cool. Each suppository contained 20 mg of API.

[0124] (C) Solution: 1 g of an API according to the present invention in 940 ml of double distilled water, NaH 2 PO 4 2H 2 O 9.38g, Na 2 HPO 4 12H 2 A solution was prepared from 28.48 g of O and 0.1 g of benzalkonium chloride. The pH was adjusted to 6.8 and the solution was made up to 1 liter and sterilized by irradiation. This solution could be used in the form of eye drops.

[0125] (D) Ointment: 500 mg of an API according to the present invention was mixed with 99.5 g of petrolatum under aseptic conditions.

[0126] (E) Tablets: A mixture of 1 kg of API according to the present invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was pressed to form tablets, each tablet containing 10 mg of API.

[0127] (F) Coated Tablets: Tablets were pressed similarly to the examples and subsequently coated in a conventional manner with coatings of sucrose, potato starch, talc, tragacanth, and dyes.

[0128] (G) Capsules: 2 kg of the API according to the present invention was incorporated into hard gelatin capsules in a conventional manner such that each capsule contained 20 mg of API.

[0129] (H) Ampoules: A solution of 1 kg of the API according to the invention in 60 L of double distilled water was sterilized, filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contained 10 mg of active ingredient.

[0130] (I) Inhalation spray: 14 g of the API according to the invention was dissolved in an isotonic NaCl solution and the solution was transferred into a commercially available spray container with a pump mechanism. The solution could be sprayed into the mouth or nose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14 mg.

Claims

1. Compound of formula (I): 【Chemical 1】 which is a compound represented by wherein W 1 、W 2 、W 3 、W 4 each independently represents N or CH; R 1 represents NYSO 2 Y or represents Y; R 2 and R 4 represent Y; R 3 represents Y or Hal; R 2 、R 3 also represents, together with -(CY) 2 - or -(CR 7 )-(CY) 2 - also; R 5 and R 6 each independently represent Hal, Y or Het; R 7 represents Y or =O; Y represents H or A; A represents unbranched or branched alkyl having 1 to 10 C atoms, wherein 1 to 7 H atoms can be independently replaced by Hal; Het represents a saturated, unsaturated or aromatic monocyclic 5- to 6-membered heterocycle having optionally substituted 2 to 5 C atoms and 1 to 3 N, O and / or S atoms; Hal represents F, Cl, Br or I; and m represents 0, 1, 2 or 3; said compound, and / or its physiologically acceptable salts; provided that [Chemical 2] is excluded.

2. W 2 represents CH, and W 1 , W 3 and / or W 4 The compound according to claim 1, wherein W, 1 , and / or 3 represents N.

3. R 1 represents NASO 2 and denotes A A compound according to claim 1 or 2.

4. R 2 、R 3 and / or R 4 represents H, or R 2 and R 3 together represent -(CY) 2 -, provided that W 4 represents N, the compound according to claim 1 or 2.

5. R 5 and R 6 each independently represent Hal or A, and / or wherein m represents 0 or 1, A compound according to claim 1 or 2.

6. Sub-formula (I-A): 【Chemical Formula 3】 having wherein R 5 、R 6 each independently represents Hal or A, and W 3 、R 2 、R 3 、R 4 and A have the meanings as defined in claim 1, A compound according to claim 1 or 2.

7. The following: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 A compound according to claim 1 or 2, and / or its physiologically acceptable salts, selected from the group of

8. A process for producing a compound represented by formula (I), comprising the following steps: (a) A compound represented by formula (II): [Chemical Formula 4] wherein R 4 , R 5 , R 6 and m have the meanings as defined in claim 1, and a compound represented by formula (III): [Chemical Formula 5] wherein R 8 represents CN, COOH or Hal; and W 1 and W 2 and W 3 and W 4 and R 1 and R 2 and R 3 have the meanings as defined in claim 1, reacting them to produce a compound represented by formula (I): 【Chemical Formula 6】 wherein, W 1 、W 2 、W 3 、W 4 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and m have the meanings as defined in claim 1; and optionally (b) converting the base or acid of the compound represented by formula (I) into its salt The above process.

9. A medicament comprising at least one compound according to claim 1 or 2 and / or its physiologically acceptable salts.

10. A pharmaceutical composition comprising at least one compound according to claim 1 or 2 and / or its physiologically acceptable salts as an active ingredient, together with a pharmaceutically acceptable excipient and optionally in combination with one or more further active ingredients.

11. A compound according to claim 1 or 2 and / or its physiologically acceptable salts for use in the prophylactic or therapeutic treatment and / or monitoring of diseases caused by, mediated by, and / or propagated by SRPK activity.

12. Use of a compound according to claim 1 or 2 and / or its physiologically acceptable salts for the preparation of a medicament for the prophylactic or therapeutic treatment and / or monitoring of diseases caused by, mediated by, and / or propagated by SRPK activity.

13. ​ A method for treating a disease caused by, mediated by, and / or propagated by SRPK activity, wherein the compound according to at least one of claims 1 or 2 and / or a physiologically acceptable salt thereof is administered to a mammal in need of such treatment, said method.

14. The method according to claim 13, wherein the disease is selected from the group consisting of proliferative disorders, cancer, metastasis, tumors, angiogenesis disorders, tumor angiogenesis, benign hyperplasia, hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseases associated with vasculogenesis or angiogenesis, inflammation, pancreatitis, retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes, pain, restenosis, psoriasis, eczema, scleroderma, and age-related macular degeneration.

15. A method for inhibiting SRPK, wherein a system expressing SRPK is contacted with the compound according to at least one of claims 1 or 2 and / or a physiologically acceptable salt thereof under conditions such that SRPK is inhibited, said method.

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