Patent Description:
Hyperactivity of kinases occurs in many types of diseases and particularly in neurodegenerative diseases and cancer. Hyperphosphorylation of the TDP-<NUM> protein induces the formation of aggregates that have been detected in patients with amyotrophic lateral sclerosis or frontotemporal lobular degeneration. It has been detected that CDC7 kinase is responsible for the dual hyperphosphorylation of TDP-<NUM> in serines <NUM>/<NUM> in certain models, so the inhibition of CDC7 would be an interesting strategy to develop drugs for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or frontotemporal lobular degeneration (<NPL>). There are other neurological diseases also mediated by TDP-<NUM>, such as chronic traumatic encephalopathy and age-associated cognitive impairment (<NPL>; <NPL>;<NPL>).

Document <CIT> describes <NUM>,<NUM>-substituted purine derivatives that are useful for a number of therapeutic and cosmetic uses. Among the possible therapeutic uses, mention is made of the treatment of multiple sclerosis or as anti-neurodegenerative drugs.

Document <CIT> describes a series of compounds with an indazole structural nucleus that have the ability to inhibit CDC-<NUM> and that are useful for the treatment of a disease in which this kinase is involved, such as cancer.

In <NPL>et al. describe a study on the interaction of azaindole-derived compounds with the CDC-<NUM> and the possibility of using these compounds in cancer therapy.

Document <CIT> describes a family of pyrolpyrazines that are kinaseinhibitors such as CDC-<NUM> and their use for the treatment of kinase-associated diseases such as cancer. <NPL>, identifies one kinase, CDC7 (cell division cycle kinase <NUM>), responsible for pathological TDP-<NUM> phosphorylation in transgenic C. elegans and human cells.

The present invention provides a series of purine-derived compounds that are inhibitors of CDC-<NUM> and useful as potential drugs for diseases mediated by TDP-<NUM> proteinopathies, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

Therefore, in a first aspect, the present invention refers to a compound formula (I)
<CHM>
wherein:.

In a preferred aspect G is a phenyl and the compound of formula (I) is a compound formula (II):
<CHM>
wherein:.

The term "aryl", in the present invention, refers to single or multiple aromatic rings, which have between <NUM> and <NUM> carbon atoms in the part of the ring, such as, but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenantryl, fluorenyl or anthracyl Preferably the aryl group has <NUM> to <NUM> carbon atoms and more preferably the aryl group is a phenyl. The aryl groups can optionally be substituted in any of their positions by one or more substitutes or by two substitutes forming an aryl condensed cycle and are independently selected from among such as CF<NUM>, C<NUM>-C<NUM> alkyl, S-C<NUM>-C<NUM> alkyl, halogen, CN, O-C<NUM>-C<NUM> Alkyl, NO<NUM>, COO-C<NUM>-C<NUM> alkyl, NHCO-C<NUM>-C<NUM> alkyl, NH<NUM> and NH-C<NUM>-C<NUM> alkyl, and more preferably between CF<NUM>, C<NUM>-C<NUM>alkyl, halogen, CN and NO<NUM>.

The term "heteroaryl" refers to an aryl, as defined above, which contains at least one distinct carbon atom, such as S, N, or O, forming part of the aromatic ring. The heteroaryl groups can optionally be substituted in any of their positions by one or more substituents or by two substituents forming a heteroaryl condensed cycle and are independently selected among such as CF<NUM>, C<NUM>-C<NUM> alkyl, S-C<NUM>-C<NUM> alkyl, halogen, CN, O-C<NUM>-C<NUM> alkyl, NO<NUM>, COO-C<NUM>-C<NUM> alkyl, NHCO-C<NUM>-C<NUM> alkyl, NH<NUM> and NH-C<NUM>-C<NUM> alkyl, and more preferably between CF<NUM>, C<NUM>-C<NUM> alkyl, halogen, CN and NO<NUM>.

The term "alkyl" refers, in this invention, to saturated, linear or branched hydrocarbon chains, having from <NUM> to <NUM> carbon atoms, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc. Preferably the alkyl group has between <NUM> and <NUM> carbon atoms and more the alkyl group has between <NUM> and <NUM> carbon atoms. Alkyl groups may optionally be replaced by one or more substitutes such as CF<NUM>, C<NUM>-C<NUM> alkyl, S-C<NUM>-C<NUM>alkyl, halogen, CN, O-C<NUM>-C<NUM>alkyl, NO<NUM>, COO-C<NUM>-C<NUM>alkyl, NHCO-C<NUM>-C<NUM>alkyl, NH<NUM> and NH-C<NUM>-C<NUM>alkyl, and more preferably between CF<NUM>, halogen, CN and NO<NUM>.

"Halogen" in this invention means an atom of bromine, chlorine, iodine or fluorine, preferably bromine, chlorine or iodine.

In a preferred realization of the compounds of formula (II), R<NUM> to R<NUM> are selected independently of between H, CF<NUM>, halogen, C<NUM>-C<NUM> alkyl, CN, NO<NUM> or two of the radicals R<NUM> to R<NUM> form a cycle condensed to phenyl.

More preferably R<NUM> is H and even more preferably at least one of R<NUM>, R<NUM>, R<NUM> or R<NUM> is Cl, Br, I, methyl, CF<NUM>, CN or NO<NUM>, more preferably at least one of R<NUM>, R<NUM>, R<NUM> or R<NUM> is Cl, Br, I, CF<NUM>, CN or NO<NUM>.

More preferably R<NUM> is H and even more preferably two of the radicals R<NUM> to R<NUM> form a cycle condensed to phenyl, more preferably R<NUM> and R<NUM> form a cycle condensed to phenyl, even more preferably forming a naphthyl.

In another preferred performance, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are H.

In a more preferred realization the compound formula (I) or (II) is selected from among:.

The TDP-<NUM> related disease is a neurological or neurodegenerative disease selected from amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, chronic traumatic encephalopathy and age-associated cognitive impairment. Preferably the disease is selected between amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease and age-associated cognitive impairment, even more preferably the disease is amyotrophic lateral sclerosis.

Another aspect of the invention concerns a compound, henceforth composed of the second aspect of the invention, which is selected from among:.

Also disclosed is a pharmaceutical composition comprising at least one compound of the second aspect of the invention together with a pharmaceutically acceptable vehicle and may optionally comprise another active ingredient.

Also disclosed is the use of a compound of the second aspect of the invention for the manufacture of a medicament.

All compounds described in the invention can be in crystalline form as free compounds.

For application in therapy, the compounds of formula (I), (II) or the compounds of the second aspect of the present invention, their salts, will be found preferably, in a pharmaceutically acceptable or substantially pure form, that is to say, that it has a level of pharmaceutically acceptable purity excluding normal pharmaceutical additives such as thinners and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably above <NUM>%, most preferably above <NUM>%, and even more preferably above <NUM>%. In a preferred realization, they are greater than <NUM>% of compound formula (I), (II) or compounds of the second aspect of the present invention, or of its salts, solvates or isomers.

In another respect, the present invention refers to pharmaceutical compositions comprising at least one compound of the invention, a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient or vehicle, for administration to a patient for use as claimed.

In a preferred formulation, the pharmaceutical composition also includes another active ingredient.

The pharmaceutically acceptable adjuvants and vehicles that may be used in such compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the development of therapeutic compositions.

In the sense used in this description, the term "therapeutically effective quantity" refers to the quantity of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of the compounds themselves, including age, the state of the patient, the severity of the alteration or disorder, and the route and frequency of administration.

The compounds described in the present invention, their salts as well as the pharmaceutical compositions containing them may be used together with other drugs, or additional active ingredients, to provide a combination therapy. Such additional drugs may be part of the same pharmaceutical composition or, alternatively, may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), preferably a compound of formula (II), or a salt or solvent thereof.

In another particular development, this therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which such composition shall be formulated in the pharmaceutical form appropriate to the chosen route of administration. In a particular realization, the administration of the therapeutic composition provided by this invention is done orally, topically, rectally or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.).

In a preferred realization of the present invention, pharmaceutical compositions are suitable for oral administration, in solid or liquid form. Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, such as aggregating agents (e.g. syrup, acacia, gelatine, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (e.g. starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.

The compositions for oral administration can be prepared by the conventional methods of Galenic Pharmacy, as mixture and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.

Pharmaceutical compositions can be adapted for parenteral administration, such as sterile solutions, suspensions, or freeze-dried products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, may be used.

The above mentioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.

The administration of the compounds or compositions of this invention can be performed by any appropriate method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.

The amount of a compound administered from the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example <NUM>, <NUM>, <NUM> or <NUM> times a day, with a total dose between <NUM> and <NUM>/Kg/day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.

The compounds and compositions of the present invention may be used together with other drugs in combination therapies. Other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.

The use of the compounds of the invention is compatible with their use in protocols in which the compounds of the formula (I), or their mixtures are used by themselves or in combinations with other treatments or any medical procedure.

Throughout the description and claims the word "comprise" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For experts in the field, other objects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration only.

There follow illustrations of the invention by means of assays made by the inventors, which show the effectiveness of the product of the invention.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-(chloromethyl)naphthalene (<NUM>, <NUM> mmol) and stir overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. Product <NUM> is thus obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM>(1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM>(1C), <NUM>(1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). HPLC: Purity > <NUM>%, r. MS (ES): m/z <NUM> [M+<NUM>]. Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-(bromomethyl)benzonitrile (<NUM>, <NUM> mmol) and stir overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. It is not necessary to purify by means of a chromatographic column. In this way, product <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (1C), <NUM> (1C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>]. Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-chlorobenzene bromide (<NUM>, <NUM> mmol) is added and agitated overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way, the product <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (1C), <NUM> (2C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>], <NUM> [M+<NUM>]. Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>ClN<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

Dissolve <NUM>-chlorobenzyl alcohol (<NUM>, <NUM> mmol) in NaOH (<NUM>, <NUM> mmol) and heat until NaOH is dissolved. Cool the solution, add <NUM>-chloro-<NUM>-purine (<NUM>, <NUM> mmol) and heat to <NUM> for <NUM> day. Et<NUM>O (<NUM>) is added and extracted twice with an aqueous solution of NaOH <NUM>% (<NUM>). The aqueous phases are joined, washed with toluene and, after eliminating toluene, neutralised with <NUM>% HCl up to pH <NUM>-<NUM>. The solution is cooled in an ice bath and the precipitate obtained is collected by filtration. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way, the product <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM>. ,<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>ClN<NUM>O) Calculated: C <NUM>%, H <NUM>%, N <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-(trifluoromethyl)benzyl bromide (<NUM>, <NUM> mmol) is added and agitated overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. This produces product <NUM> in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (c, J = <NUM>, 1C), <NUM> (c, J = <NUM>, 1C), <NUM> (m, 1C), <NUM> (c, J = <NUM>, 1C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>], Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>F<NUM>N<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-chlorobenzyl bromide (<NUM>, <NUM> mmol) is added and agitated overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way the product <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>], <NUM> [M+<NUM>], Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>ClN<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-iodobenzyl bromide (<NUM>, <NUM> mmol) and stir for <NUM> hours at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. It is not necessary to purify by means of a chromatographic column. In this way, the product <NUM> is obtained in the form of a pale yellow solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>IN<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-nitrobenzyl bromide (<NUM>, <NUM> mmol) is added and agitated for <NUM> hours at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. It is not necessary to purify by means of a chromatographic column. In this way the product <NUM> is obtained in the form of a pale yellow solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>O<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol)are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-bromobenzyl bromide (<NUM>, <NUM> mmol) is added and agitated for <NUM> hours at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. It is not necessary to purify by means of a chromatographic column. In this way the product <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>BrN<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. <NUM>-chlorobenzyl bromide (<NUM>, <NUM> mmol) is added and agitated overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way the compound <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>], <NUM> [M+<NUM>], Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>ClN<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add ethyl <NUM>-(chloromethyl)benzoate (<NUM>, <NUM> mmol) and stir overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. Crude oil is purified by recrystallization in EtOH. In this way the compound <NUM> is obtained in the form of a white solid (<NUM>, <NUM>%). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM>(1C), <NUM> (1C), <NUM> (1C), <NUM>(1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> -<NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>O<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-acetamidobenzyl chloride (<NUM>, <NUM> mmol) and agitate for <NUM> <NUM> at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way, compound <NUM> is obtained in the form of a pale yellow solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C) <NUM> (2C), <NUM> (2C), <NUM> (1C), <NUM> (1C). HPLC: Purity > <NUM>%, r. MS (ES): m/z <NUM> [M+<NUM>]. Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>OS) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-cyanobenzyl bromide (<NUM>, <NUM> mmol) and agitate for <NUM> hours at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way the compound <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (2C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>S) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

Dissolve <NUM>-bromobenzyl alcohol (<NUM>, <NUM> mmol) and NaOH (<NUM>, <NUM> mmol) in a little MeOH (<NUM>). The reaction mixture is kept in agitation until the NaOH is dissolved. Add <NUM>-chloro-<NUM>-purine (<NUM>, <NUM> mmol) and heat to (<NUM>) for <NUM>. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is then dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way the compound <NUM> is obtained in the form of beige solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM>(1C), <NUM> (2C), <NUM> (2C), <NUM> (1C), <NUM> (1C), <NUM> (1C). Melting point °C. Elemental analysis (C<NUM>H<NUM>BrN<NUM>O) Calculated: C <NUM>%, H <NUM>%, N <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%.

<NUM>-mercaptopurine monohydrate (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) are dissolved in DMF (<NUM>). Keep the reaction mixture in agitation for <NUM> at room temperature. Add <NUM>-(methylthio)benzyl bromide (<NUM>, <NUM> mmol) and stir overnight at room temperature. The solvent is evaporated at reduced pressure and AcOEt (<NUM>) is added. The organic phase is washed with distilled water (<NUM> x <NUM>) adding a little NaCl. It is dried on anhydrous Mg<NUM>SO<NUM>, filtered and concentrated to dryness. The crude compound is purified by chromatographic column using CH<NUM>Cl<NUM>/MeOH (<NUM>:<NUM>) as eluent. In this way, compound <NUM> is obtained in the form of a white solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). <NUM>C-NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (1C), <NUM> (2C), <NUM> (2C), <NUM> (1C), <NUM> (1C). MS (ES): m/z <NUM> [M+<NUM>], Melting point <NUM> - <NUM>. Elemental analysis (C<NUM>H<NUM>N<NUM>S2) Calculated: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%. Found: C <NUM>%, H <NUM>%, N <NUM>%, S <NUM>%.

The method used is a non-radioactive enzyme inhibition assay using human recombinant CDC7. It is based on luminometric quantification of inhibition using the ADP-Glo™ Kinase Kit. In this test the luminescent signal correlates positively with the amount of adenosine diphosphate (ADP) and the activity of the kinase. All compounds were evaluated at a fixed concentration of <NUM>). For compounds with an inhibition percentage greater than <NUM>%, a dose-response study is carried out to determine their Cl<NUM> value (concentration of a compound capable of inhibiting CDC7 function by <NUM>%).

CDC7 enzyme inhibition studies were conducted using the promega kit: ADP-Glo™ Kinase Assay + CDC7/DBF4 Kinase Enzyme System (Catalogue No. V5089). ATP and other reagents were purchased in Sigma-Aldrich (St. Louis, MO). The trials were performed in a buffer solution using <NUM>-well plates. The compound to be tested (<NUM>µL, <NUM>µL) dissolved in DMSO <NUM> %) was added to each well followed by the enzyme (<NUM>µL, <NUM> ng/well), ATP (<NUM>µL, final concentration in well <NUM>) and PDKtidE (<NUM>µL, <NUM>µg/well). It was then incubated for <NUM> minutes at room temperature and the reagent ADP-GIoTM (<NUM>µL) was added and incubated again for <NUM> at room temperature. After incubation, the kinase detection agent (<NUM>µL) was added and incubated for <NUM> at room temperature. Finally, the luminescence (integration time of <NUM> - <NUM> sec) was measured using a POLARstar Optima multimode reader polarimeter. Inhibition activities were calculated as a function of maximum activity, measured in the absence of inhibitor. The inhibition values determined for prepared compounds are listed in Table <NUM>.

The LanthaScreen Eu kinases inhibition assay uses an Alexa marker Fluor™ that binds to a kinase and is detected by the addition of an Eu-marked antibody. The binding of the marker and the antibody to the kinase results in a high degree of FRET, while the displacement of the marker by an inhibitor results in a loss of FRET. Unlike many other kinase activity tests, this is a simple mix and read test, with no developmental stages. This test method has been developed by Life Technologies and identifies competitive ATP kinase inhibitors, making them suitable for the detection of any compound that binds to the ATP site.

The compounds are evaluated at <NUM>% DMSO (final) in the well. A mixture of human recombinant CDC7/DBF4 (<NUM>), Eu-antiGST antibody (<NUM>) and AlexaFluor marker (<NUM>) has been used in a buffer of <NUM> HEPES pH <NUM>, <NUM>% BRIJ-<NUM>, <NUM> MgCl2, <NUM> EGTA in white plates of <NUM> wells, low volume, coded (Greiner cat. #<NUM>), <NUM> nL (<NUM> x <NUM>% DMSO compound), <NUM>µL (buffer with CDC7/DBF4), <NUM>µL (antibody), <NUM>µL (marker) are added. Agitate <NUM> and incubate at room temperature for <NUM>. Then measure the fluorescence in the plate reader and analyze the data (Table <NUM>).

An essential requirement for drugs for the treatment of neurodegenerative diseases is the ability to cross the blood-brain barrier (BBB), as otherwise they could not act on the target of interest. Therefore, for compounds that are not permeable or located in the area of uncertainty, it may be necessary to properly convey a pharmaceutical formulation through methods known to an expert in the field, such as encapsulation. This capability can be predicted in vitro using a method known by the acronym PAMPA (Parallel Artificial Membrane Permeability Assay) described by Di et al (<NPL>) and which has subsequently been fine-tuned in our research group. This method allows predicting the effective permeability through artificial membranes by means of a passive diffusion process.

First of all, it is necessary to validate the method, for which <NUM> commercial compounds are used whose penetration capacity in the central nervous system (CNS) is known and which are to be specified below, obtaining in this case a good linear correlation between the experimental permeability values (Pe) and those described (<FIG>). This correlation line obtained following the pattern described in the bibliography allows establishing the limits to predict whether or not a compound can cross the blood-brain barrier. Thus, a compound is considered BBB permeable (SNC+) if it has a permeability > <NUM> × <NUM>-<NUM> cm-s-<NUM>.

For the procedure, between <NUM>-<NUM> of caffeine, desipramine, enoxacin, hydrocortisone, ofloxacin, piroxicam and testosterone, <NUM> of promazine and <NUM> of atenolol and verapamil were taken and dissolved in EtOH (<NUM>µL). <NUM>µL of these solutions were taken and EtOH (<NUM>µL) and phosphate buffer (PBS) pH = <NUM> (<NUM>µL) were added in order to achieve a final EtOH concentration of <NUM>% v/v in solution. Finally, the dissolutions were filtered.

On the other hand, a PBS/EtOH solution (<NUM>:<NUM>) was added to each well of the acceptance plate (<NUM>µL). The donor plate was impregnated with a porcine brain lipid solution (<NUM>µL) dissolved in dodecane (<NUM> mL-<NUM>). After <NUM>, dissolution of each compound was added to this plate (<NUM>µL).

Of the compounds <NUM> to <NUM> evaluated, <NUM>-<NUM> were taken and dissolved in EtOH (<NUM>µL) and phosphate buffer (PBS) pH = <NUM> (<NUM>µL), filtered and added to the donor plate. With these solutions, the wavelengths at which the compounds absorb are determined and the initial absorbance levels at these wavelengths are measured using a UV absorbance reader. Each sample was analyzed from two to five wavelengths, in three wells and in two independent experiments.

The donor plate was then deposited on the acceptor forming a kind of "sandwich" and incubated for <NUM> hours and <NUM> minutes at <NUM>. In this way, the compounds will pass from the donor plate to the acceptor plate through the porcine brain lipid by passive diffusion. After that time, the donor plate is carefully removed and the concentration and final absorbance of both commercial and synthesized compounds is determined. The results obtained are expressed as the mean of the measurements [standard deviation (SD)] of the different experiments carried out and are shown in table <NUM>.

The human neuroblastoma cell line SH-SY5Y was cultured at <NUM> with <NUM>%CO<NUM> in DMEN medium (Dulbecco's Modified Eagle Medium) enriched with L-glutamine (<NUM>), <NUM>% non-essential amino acids, <NUM>% Penicillin/Estreptomycin and <NUM>% fetal bobin serum. In the semiconfluence state, the cells were treated with CDC7 inhibitors (compounds <NUM> and <NUM>) at different concentrations for <NUM> hours post-addition of the causative agent of TPD-<NUM> phosphorylation; ethacrynic acid (<NUM>) (Sigma). After <NUM> hours, cell viability was evaluated with MTT ([<NUM>-(<NUM>,<NUM>-dimethylthiazol-<NUM>-yl)-<NUM>,<NUM>-diphenyltetrazolium bromide) following a described procedure (<NPL>) and levels of western blot phosphorylated TDP-<NUM> (<FIG>).

To evaluate the levels of TDP-<NUM> phosphorylated in the presence of CDC7 inhibitors (compounds <NUM> and <NUM>), the cells after <NUM> of incubation with ethacrylic acid were washed with PBS and then cold lysed with lysis buffer (<NUM> Tris pH <NUM>, <NUM> NaCl, <NUM> NaF, <NUM>% Nonidet P-<NUM> and Protease and phosphatase inhibitors (Roche)). The collected cell extracts were centrifuged for <NUM> minutes at <NUM>,<NUM> rpm. Protein quantification was performed with the Pierce BCA protein assay kit (Thermo Scientific). <NUM>µg of protein were loaded into the polyacrylamide gel with SDS and subsequently transferred to a polyvinylidene fluoride (PVDF) membrane (Millipore). The membrane was blocked with <NUM>% bovine serum albumin (Sigma), and incubated for <NUM> hours with the following primary antibody concentrations (anti-human phosphorus (S409/<NUM>)-TDP-<NUM> (<NUM>:<NUM>) (<NUM>-1AP, Proteintech); α-tubulin (<NUM>:<NUM>,<NUM>) (sc-<NUM>, Santa Cruz Biotechnologies).

Claim 1:
Compound of formula (I)
<CHM>
wherein:
G is an aryl group, optionally substituted by at least one substituent selected from CF<NUM>, C<NUM>-C<NUM> alkyl, S-C<NUM>-C<NUM> Alkyl, halogen, CN, O-C<NUM>-C<NUM> Alkyl, NO<NUM>, COO-C<NUM>-C<NUM> Alkyl, NHCO-C<NUM>-C<NUM>Alkyl, NH<NUM> and NH-C<NUM>-C<NUM> Alkyl, or optionally substituted by two substituents forming an aryl condensed cycle.
Z is selected from O or S;
or any of its pharmaceutically acceptable salts, for use in treatment and/or prevention of pathologies related to the protein TDP-<NUM>, wherein the TDP-<NUM> related pathology is a neurological disease selected from amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, age-associated cognitive impairment, and chronic traumatic encephalopathy.