WO2020201610A1 - Spiro-heterocyclic compounds and method of preparation thereof - Google Patents

Spiro-heterocyclic compounds and method of preparation thereof Download PDF

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WO2020201610A1
WO2020201610A1 PCT/ES2020/070353 ES2020070353W WO2020201610A1 WO 2020201610 A1 WO2020201610 A1 WO 2020201610A1 ES 2020070353 W ES2020070353 W ES 2020070353W WO 2020201610 A1 WO2020201610 A1 WO 2020201610A1
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alkenyl
alkyl
aryl
heteroaryl
alkynyl
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PCT/ES2020/070353
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Spanish (es)
French (fr)
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José Antonio GARCÍA LÓPEZ
Hamid AZIZOLLAHI
Vaibhav Pravinchandra Mehta
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Universidad De Murcia
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Priority to ES202190006A priority Critical patent/ES2837132B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems

Definitions

  • the invention falls within the general field of chemistry, specifically in the field of processes for the synthesis of organic products with industrial applications.
  • Spirocyclic compounds are organic products that have two rings that are joined by a single carbon atom and can be classified according to the number of members that each of the rings consists of. This type of compound is of great interest due to its presence and use in natural products or drugs.
  • [Zheng, Y. et al. "The use of spirocyclic scaffolds in drug discover / ', Bioorganic & Medicinal Chemistry Letters 24 (2014) 3673-3682. B) Kotha, S. et al.” Design and synthesis of spirocycles "Eur. J. Org. Chem. 2017 , 5316-5342]
  • the applications, especially those of a pharmacological type, of the spirocyclic compounds depend to a great extent on the substitution patterns of the rings that make up the spirocyclic unit.
  • WO 2014060411 A1 (d) Stuart Cockerill et al. Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection. WO 2018025043 A1. (e) Ikeda, S. et al. Preparation of heterospirocyclic compounds as MAGL inhibitors for treatment of neurodegenerative diseases. WO 2017 171 100 A1. (f) Cook, B. N. et al. Preparation of bicyclic compounds as modulators of retinoid-related orphan receptor yt (RORyt orRORc). WO 2015035032 A1.
  • the present invention solves the problems described in the state of the art since it provides spirocyclic compounds where one of the rings is made up of a 2-methylene-cyclobutane unit, and the other ring of the spirocyclic system is of variable size (5, 6, or 7 members), contains heteroatoms in its chain and is fused with an aromatic group.
  • the synthesized spirocyclic compounds may contain highly relevant fragments due to their presence in products with pharmacological activity, such as oxoindole, indoline, dihydrobenzofuran, etc. nuclei.
  • the present invention refers to a spiro-heterocyclic compound of general formula (I), (hereinafter, compound of the present invention),
  • n is selected from 0, 1 and 2;
  • G is selected from C and N;
  • A is a heteroatom selected from O, S, N, NH and NRi, where Ri is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
  • B is selected from CH 2 and CO
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, CO2R2, NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R4, Rs, Re, R7 and Rs are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
  • aryl refers to a monocyclic, bicyclic, tricyclic or tetracyclic aromatic hydrocarbon that comprises an aromatic structure formed by between 6 and 16 carbon atoms.
  • alkenyl refers to radicals of hydrocarbon chains of 2 to 25 carbon atoms that contain one or more carbon-carbon double bonds.
  • alkyl refers to radicals of hydrocarbon chains, linear or branched, having from 1 to 16 carbon atoms
  • alkynyl refers to radicals of hydrocarbon chains of 2 to 25 carbon atoms containing one or more triple carbon-carbon bonds.
  • heteroaryl refers to five or more membered aromatic cyclic groups, containing a minimum of 4 carbon atoms, and having at least one heteroatom in at least one ring containing carbon atoms.
  • the present invention refers to the compound of the present invention, where:
  • n 0;
  • G is selected from C and N;
  • A is NRi, where Ri is selected from aryl, aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
  • the compound of the present invention comprises oxoindole and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises formula (la).
  • the present invention relates to the compound of the present invention, where
  • n 1;
  • G is selected from C and N;
  • A is O
  • B is CH2
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R 4 , R5, R 6, R 7 and Re are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
  • the compound of the present invention comprises isochroman and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises the formula (Ib).
  • the present invention refers to the compound of the present invention, where:
  • n 1;
  • G is selected from C and N;
  • A is O
  • B is CH 2 ;
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and OR 33 , where R 2 , R 3 , R 4 , R5, R 6, R 7 and Re are the same or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl. More particularly, the compound of the present invention comprises 2,3-dihydrobenzofuran and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises the formula (le).
  • the present invention refers to a process for the preparation of a compound of the present invention, (hereinafter process of the present invention) comprising:
  • n is selected from 0, 1 and 2;
  • X is a halogen
  • A is a heteroatom selected from O, S, N, NH, NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl; .
  • B is selected from CH2 and CO;
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
  • the catalyst formed by a metal of transition is a palladium catalyst, more in particular, the catalyst is a palladium salt.
  • the organic ligand is selected from monodentate phosphine and substituted N-heterocyclic carbon.
  • the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (lia) to give rise to the compound of general formula (la), according to scheme A,
  • n 0,
  • X is bromine
  • A is NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl, B is CO, and
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
  • the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (llb) to give rise to the compound of general formula (Ib), according to scheme B,
  • n 1;
  • X is bromine
  • A is O:
  • B is CH2
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs where R 2 , R 3 , R 4 , Rs, R 6 and R 7 are the same or different and selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl .
  • the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (lie) to give rise to the compound of general formula (le), according to scheme C,
  • X is bromine
  • A is O
  • R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R4, Rs, Re, R7 and Rs are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
  • the process of the present invention comprises a catalyst load of between 2-15 mol%.
  • the process of the present invention comprises an organic ligand load of between 3-25 mol%.
  • the process of the present invention is carried out at a temperature comprised between 70-150 ° C. Preferably between 80-120 ° C.
  • the synthesis method of spirocycles that include the 2-methylene-cyclobutane unit in their structure consists of a cascade reaction catalyzed by palladium in which it is key to use starting substrates that contain a 1,4-diene unit in the aliphatic chain and a catalytic system based on Pd (0).
  • the experimental procedure on which the synthesis method is based is the following: in a clean and dry Carius tube (or Schlenk flask), containing a magnetic stirring core, a pre-catalyst is added that generates Pd (0) in the medium of reaction, consisting of a salt of Pd (ll) (2.5-10 mol%), an organic ligand of the monodentate phosphine or carbene N- heterocyclic substituted NHCs (5-20 mol%, depending on the percentage of the Pd (ll) salt) and an inorganic base (1.5 equiv) sequentially.
  • the air in the flask is replaced by an inert atmosphere (nitrogen or argon).
  • the starting substrate [containing the 1,4-chain-linked diene fragment having an aromatic (or heteroaromatic) ring with a halogen (or pseudohalogen) substituent in position 2] (1 equivalent) is dissolved in dry toluene under nitrogen, and is added to the reaction mixture containing the rest of the reagents. Dry toluene is then added until the resulting concentration is 0.05 M in substrate. The mixture is heated to a minimum temperature of 80 ° C for 16 h. After cooling the mixture, the crude reaction is filtered and the solid is washed with an organic solvent that dissolves the organic product. The solvent in the filtrate is evaporated in vacuo and the resulting crude oil is purified by chromatography. In this way an organic compound is obtained that consists of a spirocyclic structure formed by a 2-methylene-cyclobutane fragment, and a 5, 6, or 7-membered ring.
  • the molar ratio of catalyst (Pd (OAc) 2 / ligand) that is added to the reaction mixture depends both on the starting substrate and on the reaction temperature at which one works.
  • the reaction takes place in good yield at 80 ° C, with a catalyst load of 2.5 mol% of Pd (OAc) 2 and 5 mol% of PPhb.
  • the reaction occurs in a single step by a cascade mechanism consisting of the following steps: a) oxidative addition of the C-X bond present in the starting product to Pd (0); b) double intramolecular carbopallation of the 1,4-diene fragment, and finally c) beta elimination of hydrogen.
  • the synthesis method of the present invention is general and applicable to various types of heterocyclic rings with different heteroatoms and ring sizes. Especially interesting is the application to amide-type substrates, which give rise to functionalized [4,5] -spirooxoindoles, compounds of great pharmaceutical importance.
  • the compounds obtained by applying this method present a series of novel aspects, among which it is worth highlighting: a)
  • the introduction of the alkenyl fragment may therefore be of interest in the screening processes for new drugs, and the synthesis of molecular libraries.
  • Example 1 Preparation of spirocyclo la, containing the oxoindole and 2-methylene-cyclobutane fragments (GENERAL SCHEME A).
  • Example 3 Preparation of the spirocycle le, containing the fragments 2,3-dihydrobenzofuran and 2-methylene-cyclobutane (Scheme C).
  • Pd (OAc) 2 3.6 mg, 10 mol%)
  • PCy 3 9 mg, 20 mol%)
  • K2CO3 33 mg, 1.5 equiv
  • the corresponding starting 1,4-diene substrate, in this case lie, (45 mg, 0.16 mmol, 1 equivalent) was dissolved in 1 ml_ of dry toluene under nitrogen, and added to the reaction mixture containing the rest of reagents . Then 2 ml_ of dry toluene was added (the resulting concentration was 0.05 M in lie). The mixture was heated at 80 ° C for 16 h. After cooling the Carius tube, the crude was filtered and the solid was washed with dichloromethane (10 mL). The solvent in the filtrate was evaporated to dryness in vacuo and the resulting crude oil was purified by column chromatography using a petroleum ether / EtOAc gradient.

Abstract

The present invention relates to the spiro-heterocyclic compounds of general formula (I), wherein: n is selected from 0, 1 and 2; G is selected from C and N; A is a heteroatom selected from O, S, N, NH and NRi, wherein Ri is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl; B is selected from CH2 and CO; R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R2, NHR3, NR4, SR5, S(O)R6, S(O)2R7 and OR8, wherein R2, R3, R4, R5, R6, R7 and R8 are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl. The present invention also relates to the method for preparing said compounds and to the use thereof.

Description

COMPUESTOS ESPIRO-HETEROCÍCLICOS Y MÉTODO PARA SU PREPARACIÓN SPIRO-HETEROCYCLIC COMPOUNDS AND METHOD FOR THEIR PREPARATION
Sector de la técnica Technical sector
La invención se encuadra en el campo general de la química, en concreto en el campo de los procesos de síntesis de productos orgánicos con aplicaciones industriales. The invention falls within the general field of chemistry, specifically in the field of processes for the synthesis of organic products with industrial applications.
Antecedentes de la invención Background of the invention
Los compuestos espirocíclicos son productos orgánicos que poseen dos anillos que están unidos por un único átomo de carbono y se pueden clasificar según sea el número de miembros de que consta cada uno de los anillos. Este tipo de compuestos son de gran interés por su presencia y uso en productos naturales o fármacos. [Zheng, Y. et al. " The use of spirocyclic scaffolds in drug discover/', Bioorganic & Medicinal Chemistry Letters 24 (2014) 3673-3682. b) Kotha, S. et al. "Design and synthesis of spirocycles" Eur. J. Org. Chem. 2017, 5316-5342] Las aplicaciones, especialmente las de tipo farmacológico, de los compuestos espirocíclicos dependen en gran medida de los patrones de sustitución de los anillos que componen la unidad espirocíclica. Spirocyclic compounds are organic products that have two rings that are joined by a single carbon atom and can be classified according to the number of members that each of the rings consists of. This type of compound is of great interest due to its presence and use in natural products or drugs. [Zheng, Y. et al. "The use of spirocyclic scaffolds in drug discover / ', Bioorganic & Medicinal Chemistry Letters 24 (2014) 3673-3682. B) Kotha, S. et al." Design and synthesis of spirocycles "Eur. J. Org. Chem. 2017 , 5316-5342] The applications, especially those of a pharmacological type, of the spirocyclic compounds depend to a great extent on the substitution patterns of the rings that make up the spirocyclic unit.
Uno de los tipos de espirociclos que ha generado gran interés en la industria química y farmacéutica es aquel cuya estructura incluye un anillo de ciclobutano sustituido en su esqueleto espirocíclico. La inmensa mayoría de los métodos descritos en la bibliografía para sintetizar espirociclos con anillos de ciclobutano generan este tipo de anillos con sustituyentes alquílicos en las distintas posiciones del ciclo, pero no producen anillos de ciclobutano con sustituyentes de tipo alquenílico (dobles enlaces C=C). Estos métodos parten de sustratos que ya cuentan con el fragmento de ciclobutano sustituido [Carreira, E. M. and Fessard, T. C. Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities" Chem. Rev. 2014, 1 14, 8257-8322] Los métodos más importantes utilizados para construir compuestos espirocíclicos generando in situ el anillo de ciclobutano con sustituyentes alquílicos o arílicos (no alquenílicos) se pueden clasificar en: a) reacciones de alquilación de ciclos que contienen protones en posición alfa a un grupo carbonilo, por ejemplo, los que están en posición 3 de un núcleo de oxoindol, por reacción con 1 ,3-dibromopropano. [(a) Rangarajan, R. et al. PCT Int. Appl. 2013, 042035. (b) Griffiths-Jones, C. M. et al, PCT Int. Appl. 2012, 143726. (c) Cuvigny, T.; Hullot, P.; Mulot, P.; Larcheveque, M.; Normant, H., Can. J. Chem. 1979, 57, 1201] b) cicloadiciones de tipo [2+2] [(a) Wang, L.-X. et al. Asymmetric synthesis of 3,3'- spirooxindoles fused with cyclobutanes through organocatalytic formal [2 + 2] cycloadditions under H-bond-directing dienamine activation, Org. Lett. 2014, 16, 6436-6439. b) Halskov, K. S. et al. Organocatalytic enamine-activation of cyclopropanes for highly stereoselective formation of cyclobutanes, J. Am. Chem. Soc. 2015, 137, 1685 -1691. One of the types of spirocycles that has generated great interest in the chemical and pharmaceutical industry is one whose structure includes a substituted cyclobutane ring in its spirocyclic skeleton. The vast majority of the methods described in the literature to synthesize spirocycles with cyclobutane rings generate this type of rings with alkyl substituents at the different positions of the ring, but they do not produce cyclobutane rings with alkenyl-type substituents (C = C double bonds). . These methods start from substrates that already have the substituted cyclobutane fragment [Carreira, EM and Fessard, TC Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities "Chem. Rev. 2014, 1 14, 8257-8322]. The most important compounds used to construct spirocyclic compounds generating in situ the cyclobutane ring with alkyl or aryl substituents (not alkenyl) can be classified into: a) alkylation reactions of cycles containing protons in the alpha position to a carbonyl group, for example, the which are in position 3 of an oxoindole nucleus, by reaction with 1,3-dibromopropane. [(a) Rangarajan, R. et al. PCT Int. Appl. 2013, 042035. (b) Griffiths-Jones, CM et al, PCT Int. Appl. 2012, 143726. (c) Cuvigny, T .; Hullot, P .; Mulot, P .; Larcheveque, M .; Normant, H., Can. J. Chem. 1979, 57, 1201] b) [2 + 2] cycloadditions [(a) Wang, L.-X. et al. Asymmetric synthesis of 3,3'- spirooxindoles fused with cyclobutanes through organocatalytic formal [2 + 2] cycloadditions under H-bond-directing dienamine activation, Org. Lett. 2014, 16, 6436-6439. b) Halskov, KS et al. Organocatalytic enamine-activation of cyclopropanes for highly stereoselective formation of cyclobutanes, J. Am. Chem. Soc. 2015, 137, 1685-1691.
c) reacciones de carbo-boración intramolecular de ioduros alquílicos con un resto alqueno catalizada por cobre. [Royes, J. et al. Copper-catalyzed borylative ring closing C-C coupling toward spiro- and dispiroheterocycles, ACS Cata!. 2018, 8, 2833-2838] d) reacciones que implican activación C-H de árenos. [Lautens, M. et al. " Remóte C-H alkylation and C-C bond cleavage enabled by an in situ generated paiiadacycie" , Nat. Chem. 2017, 9, 361-368] c) intramolecular carbo-boration reactions of alkyl iodides with a copper-catalyzed alkene residue. [Royes, J. et al. Copper-catalyzed borylative ring closing C-C coupling toward spiro- and dispiroheterocycles, ACS Cata !. 2018, 8, 2833-2838] d) reactions involving C-H activation of arenes. [Lautens, M. et al. "Remóte C-H alkylation and C-C bond cleavage enabled by an in situ generated paiiadacycie", Nat. Chem. 2017, 9, 361-368]
Es importante remarcar que estos métodos en los que se genera el anillo de ciclobutano en la propia síntesis del compuesto espirocíclico, generan anillos de ciclobutano con sustituyentes alquílicos, no con sustituyentes que contienen dobles enlaces C=C. It is important to note that these methods in which the cyclobutane ring is generated in the synthesis of the spirocyclic compound itself, generate cyclobutane rings with alkyl substituents, not with substituents that contain C = C double bonds.
Los procesos descritos en la bibliografía para formar sistemas espirocíclicos que contengan específicamente un fragmento 2-metilen-ciclobutano son muy escasos. Para sistemas que contienen anillos aromáticos fusionados sólo existen casos muy particulares que dan lugar a estructuras de tipo fluoreno, y no son aplicables a otro tipo ciclos con mayor relevancia farmacéutica [(a) McGlinchey, M. J. et al. From alienes to tetracenes: a synthetic and structural study of silyl- and halo-alienes and their dimers. Eur. J. Org. Chem. 2007, 2611— 2622. (b) McGlinchey, M. J. et al. Syntheses, X-ray crystal structures and reactivity of fluorenylidene- and dibenzosuberenylidene-allenes: convenient precursors to dispirotetracenes, di-indenotetracenes and 2-phenyl-11b H-dibenz[cd,h]azulene. Org. Biomol. Chem. 2010, 8, 3997^010] The processes described in the literature to form spirocyclic systems that specifically contain a 2-methylene-cyclobutane fragment are very scarce. For systems containing fused aromatic rings, there are only very particular cases that give rise to structures of the fluorene type, and they are not applicable to other types of cycles with greater pharmaceutical relevance [(a) McGlinchey, M. J. et al. From alienes to tetracenes: a synthetic and structural study of silyl- and halo-alienes and their dimers. Eur. J. Org. Chem. 2007, 2611-2622. (B) McGlinchey, M. J. et al. Syntheses, X-ray crystal structures and reactivity of fluorenylidene- and dibenzosuberenylidene-allenes: convenient precursors to dispirotetracenes, di-indenotetracenes and 2-phenyl-11b H-dibenz [cd, h] azulene. Org. Biomol. Chem. 2010, 8, 3997 ^ 010]
Existen algunos sistemas policíclicos alifáticos, es decir no contienen anillos aromáticos u heteroaromáticos fusionados en su estructura, que presentan el fragmento 2-metilen- ciclobutano. Estos productos suelen generarse por reacciones de cicloadición [2+2], por ejemplo de cetonas a,b-insaturadas con alenos. [(a) Takatori, K. et al., Synthesis of methylenebicyclo[3.2. 1]octanol by a Sm(ll)-induced 1 ,2-rearrangement reaction with ring expansión of methylenebicyclo[4.2.0]octanone. Org. Lett. 2017, 19, 3763-3766. (b) Brown, M. K. et al. Synthesis of 1 ,3-substituted cyclobutanes by allenoate-alkene [2 +2] cycloaddition, J. Org. Chem. 2016, 81 , 8050-8060] También hay un ejemplo de síntesis de lactamas espirocíclicas alifáticas que contienen el fragmento 2-metilen-ciclobutano formados en un proceso de oxapaladación intramolecular. [Tsvelikhovsky D. et at. Cascade Pd(ll)-catalyzed Wacker lactonization-Heck reaction: rapid assembly of spiranoid lactones. Chem. Commun. 2016, 52, 3095-3098] There are some aliphatic polycyclic systems, that is, they do not contain fused aromatic or heteroaromatic rings in their structure, which present the 2-methylene-cyclobutane fragment. These products are usually generated by cycloaddition reactions [2 + 2], for example of a, b-unsaturated ketones with allenes. [(a) Takatori, K. et al., Synthesis of methylenebicyclo [3.2. 1] octanol by a Sm (ll) -induced 1, 2-rearrangement reaction with ring expansion of methylenebicyclo [4.2.0] octanone. Org. Lett. 2017, 19, 3763-3766. (b) Brown, MK et al. Synthesis of 1, 3-substituted cyclobutanes by allenoate-alkene [2 +2] cycloaddition, J. Org. Chem. 2016, 81, 8050-8060] There is also an example of the synthesis of aliphatic spirocyclic lactams containing the 2-methylene-cyclobutane fragment formed in an intramolecular oxapallation process. [Tsvelikhovsky D. et at. Cascade Pd (ll) -catalyzed Wacker lactonization-Heck reaction: rapid assembly of spiranoid lactones. Chem. Commun. 2016, 52, 3095-3098]
Hasta el momento, no existen en la bibliografía compuestos espiro-heterocíclicos cuya estructura esté formada por una unidad 2-metilen-ciclobutano, y un ciclo de tamaño variable que esté fusionado a un anillo aromático o heteroaromático, que no sea el núcleo de fluoreno. [McGlinchey, M. J. et al. From alienes to tetracenes: a synthetic and structural study of silyl- and halo-alienes and their dimers. Eur. J. Org. Chem. 2007, 2611-2622] Los métodos descritos en la bibliografía comentados anteriormente, bien describen compuestos espirocíclicos que contienen anillos aromáticos y un grupo ciclobutilo con sustituyentes alquílicos en su estructura, pero no sustituyentes alquenílicos (dobles enlaces C=C), o bien describen compuestos espirocíclios que contienen el fragmento 2-metilen-ciclobutano en compuestos alifáticos sin anillos aromáticos fusionados el otro anillo de la estructura espirocíclica. La presencia del fragmento C=CH2 exocíclico en el anillo de ciclobutano cambia las propiedades de los compuestos espirocíclicos respecto a estructuras análogas que no lo contienen, al tratarse de un fragmento que da mayor rigidez al anillo. So far, there are no spiro-heterocyclic compounds in the literature whose structure is formed by a 2-methylene-cyclobutane unit, and a ring of variable size that is fused to an aromatic or heteroaromatic ring, other than the fluorene nucleus. [McGlinchey, M. J. et al. From alienes to tetracenes: a synthetic and structural study of silyl- and halo-alienes and their dimers. Eur. J. Org. Chem. 2007, 2611-2622] The methods described in the literature discussed above either describe spirocyclic compounds that contain aromatic rings and a cyclobutyl group with alkyl substituents in their structure, but no alkenyl substituents (C = C double bonds), or else describe spirocyclic compounds that contain the 2-methylene-cyclobutane fragment in aliphatic compounds without aromatic rings fused to the other ring of the spirocyclic structure. The presence of the exocyclic C = CH2 fragment in the cyclobutane ring changes the properties of spirocyclic compounds with respect to analogous structures that do not contain it, as it is a fragment that gives greater rigidity to the ring.
La introducción de un fragmento C=CH2 en el anillo de ciclobutano de compuestos espirocíclios no es una transformación trivial, puesto que los métodos descritos anteriormente no son aplicables a la síntesis de este tipo de moléculas que contengan simultáneamente anillos aromáticos fusionados en uno de sus ciclos. Adicionalmente, los fragmentos C=CH2 pueden servir como un punto estratégico para realizar procesos de funcionalización a través de reacciones conocidas para este grupo funcional como por ejemplo epoxidación o acoplamiento cruzado con otros grupos funcionales. The introduction of a C = CH2 fragment into the cyclobutane ring of spirocyclic compounds is not a trivial transformation, since the methods described above are not applicable to the synthesis of this type of molecules that simultaneously contain fused aromatic rings in one of their cycles . Additionally, C = CH2 fragments can serve as a strategic point to carry out functionalization processes through known reactions for this functional group, such as epoxidation or cross-coupling with other functional groups.
Dada la gran relevancia que tienen los compuestos espirocíclicos conteniendo simultáneamente anillos fusionados con grupos aromáticos o heteroaromáticos y la unidad de ciclobutano sustituida y la dependencia de sus propiedades según sea el patrón de sustitución de estas unidades estructurales, resulta de enorme interés disponer de métodos que generen nuevos patrones de sustitución, como por ejemplo la introducción de fragmentos alquenílicos, que permitan obtener espirociclos con nuevas propiedades y aplicaciones, especialmente compuestos con aplicaciones farmacológicas. Given the great relevance of spirocyclic compounds containing simultaneously fused rings with aromatic or heteroaromatic groups and the substituted cyclobutane unit and the dependence of their properties depending on the substitution pattern of these structural units, it is of great interest to have methods that generate new substitution patterns, such as the introduction of alkenyl fragments, which allow obtaining spirocycles with new properties and applications, especially compounds with pharmacological applications.
Algunos ejemplos que ponen de relieve la gran relevancia de estos compuestos los encontramos en los siguientes documentos [(a) Ramizi, F. Sweis et al. "Discovery and development of pote nt and selective inhibitors of histone methyltransferase G9a." ACS Med. Chem. Lett. 2014, 5, 205-209. (b) Ravi Kotrabasaiah et al. Preparation of spirofcyclobutane- 1,3'-indolin]-2'-one derivatives as bromodomain inhibitors. WO 2016203112 A1. (c) Tahri, Abdellah et al. Preparation of indolylmethylspiropiperidinepyrrolopyridinone derivatives and analogs for use as RSV inhibitors. WO 2014060411 A1. (d) Stuart Cockerill et al. Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection. WO 2018025043 A1. (e) Ikeda, S. et al. Preparation of heterospirocyclic compounds as MAGL inhibitors for treatment of neurodegenerativo diseases. WO 2017171 100 A1. (f) Cook, B. N. et al. Preparation of bicyclic compounds as modulators of retinoid-related orphan receptor yt (RORyt orRORc). WO 2015035032 A1. Some examples that highlight the great relevance of these compounds are found in the following documents [(a) Ramizi, F. Sweis et al. "Discovery and development of pot nt and selective inhibitors of histone methyltransferase G9a." ACS Med. Chem. Lett. 2014, 5, 205-209. (b) Ravi Kotrabasaiah et al. Preparation of spirofcyclobutane- 1,3'-indolin] -2'-one derivatives as bromodomain inhibitors. WO 2016203112 A1. (c) Tahri, Abdellah et al. Preparation of indolylmethylspiropiperidinepyrrolopyridinone derivatives and analogs for use as RSV inhibitors. WO 2014060411 A1. (d) Stuart Cockerill et al. Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection. WO 2018025043 A1. (e) Ikeda, S. et al. Preparation of heterospirocyclic compounds as MAGL inhibitors for treatment of neurodegenerative diseases. WO 2017 171 100 A1. (f) Cook, B. N. et al. Preparation of bicyclic compounds as modulators of retinoid-related orphan receptor yt (RORyt orRORc). WO 2015035032 A1.
Las reacciones de carbopaladación intramolecular de alquenos son una herramienta que se ha aplicado a la obtención de diversas estructuras con sistemas cíclicos fusionados o espirocíclicos [(a) García-López, J. A. et al. Trapping sigma-alkyl-palladium(ll) intermediates with arynes encompassing intramolecular C-H activation: spirobiaryls through Pd-catalyzed cascade reactions. Angew. Chem., Int. Ed., 2016, 55, 14389. (b) García-López, J. A. et al. Synthesis of spiro-oxoindoles through Pd-catalyzed remóte C-H alkylation using alpha- diazocarbonyl compounds. Chem. Commun., 2017, 53, 2842] The intramolecular carbopallation reactions of alkenes are a tool that has been applied to obtain various structures with fused cyclic or spirocyclic systems [(a) García-López, J. A. et al. Trapping sigma-alkyl-palladium (ll) intermediates with arynes encompassing intramolecular C-H activation: spirobiaryls through Pd-catalyzed cascade reactions. Angew. Chem., Int. Ed., 2016, 55, 14389. (b) García-López, J. A. et al. Synthesis of spiro-oxoindoles through Pd-catalyzed remóte C-H alkylation using alpha-diazocarbonyl compounds. Chem. Commun., 2017, 53, 2842]
Existe pues la necesidad de proporcionar nuevos compuestos espirociclos con nuevas propiedades y aplicaciones, especialmente compuestos con aplicaciones farmacológicas. Breve descripción de la invención There is thus a need to provide new spirocycle compounds with new properties and applications, especially compounds with pharmacological applications. Brief description of the invention
La presente invención soluciona los problemas descritos en el estado de la técnica ya que proporciona compuestos espirocíclicos donde uno de los anillos está constituido por una unidad 2-metilen-ciclobutano, y el otro anillo del sistema espirocíclico es de tamaño variable (5, 6, o 7 miembros), contiene heteroátomos en su cadena y está fusionado con un grupo aromático. Así, por ejemplo, los compuestos espirocíclicos sintetizados pueden contener fragmentos de gran relevancia por su presencia en productos con actividad farmacológica, como son los núcleos de oxoindol, indolina, dihidrobenzofurano, etc. The present invention solves the problems described in the state of the art since it provides spirocyclic compounds where one of the rings is made up of a 2-methylene-cyclobutane unit, and the other ring of the spirocyclic system is of variable size (5, 6, or 7 members), contains heteroatoms in its chain and is fused with an aromatic group. Thus, for example, the synthesized spirocyclic compounds may contain highly relevant fragments due to their presence in products with pharmacological activity, such as oxoindole, indoline, dihydrobenzofuran, etc. nuclei.
Así pues, en un primer aspecto, la presente invención se refiere a un compuesto espiro- heterocíclico de fórmula general (I), (de aquí en adelante, compuesto de la presente invención), Thus, in a first aspect, the present invention refers to a spiro-heterocyclic compound of general formula (I), (hereinafter, compound of the present invention),
Figure imgf000007_0001
Figure imgf000007_0001
donde: where:
n es seleccionado de entre 0, 1 y 2; n is selected from 0, 1 and 2;
G es seleccionado de entre C y N; G is selected from C and N;
A es un heteroátomo seleccionado de entre O, S, N, NH y NRi, donde Ri es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; A is a heteroatom selected from O, S, N, NH and NRi, where Ri is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
B es seleccionado de entre CH2 y CO; B is selected from CH 2 and CO;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, CO2R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, CO2R2, NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R4, Rs, Re, R7 and Rs are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
En la presente invención por arilo se refiere un hidrocarburo aromático monociclico, biciclico, triciclico o tetracidico que comprende una estructura aromática formada por entre 6 y 16 átomos de carbono. En la presente invención por alquenilo se refiere a radicales de cadenas hidrocarbonadas de 2 a 25 átomos de carbono que contienen uno o más enlaces carbono-carbono dobles. In the present invention by aryl refers to a monocyclic, bicyclic, tricyclic or tetracyclic aromatic hydrocarbon that comprises an aromatic structure formed by between 6 and 16 carbon atoms. In the present invention by "alkenyl" refers to radicals of hydrocarbon chains of 2 to 25 carbon atoms that contain one or more carbon-carbon double bonds.
En la presente invención por alquilo se refiere a radicales de cadenas hidrocarbonadas, lineales o ramificadas, que tienen de 1 a 16 átomos de carbono, In the present invention by alkyl refers to radicals of hydrocarbon chains, linear or branched, having from 1 to 16 carbon atoms,
En la presente invención por alquinilo se refiere a radicales de cadenas hidrocarbonadas de 2 a 25 átomos de carbono que contienen uno o más enlaces carbono-carbono triples. In the present invention, by "alkynyl" refers to radicals of hydrocarbon chains of 2 to 25 carbon atoms containing one or more triple carbon-carbon bonds.
En la presente invención por heteroarilo se refiere a grupos cíclicos aromáticos de cinco o más miembros, que contienen un mínimo de 4 átomos de carbono, y que tienen al menos un heteroátomo en al menos un anillo que contiene átomos de carbono. In the present invention by "heteroaryl" refers to five or more membered aromatic cyclic groups, containing a minimum of 4 carbon atoms, and having at least one heteroatom in at least one ring containing carbon atoms.
En una realización más en particular, la presente invención se refiere al compuesto de la presente invención, donde: In a more particular embodiment, the present invention refers to the compound of the present invention, where:
n es 0; n is 0;
G es seleccionado de entre C y N; G is selected from C and N;
A es NRi, donde Ri es seleccionado de entre arilo arilo, alquilo, heteroarilo, alquenilo y alquinilo; A is NRi, where Ri is selected from aryl, aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
B es CO, y B is CO, and
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
Más en particular el compuesto de la presente invención comprende fragmentos oxoindol y 2- metilen-ciclobutano. Mas en particular, el compuesto de la presente invención comprende la fórmula (la). More in particular the compound of the present invention comprises oxoindole and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises formula (la).
Figure imgf000008_0001
En una realización más en particular, la presente invención se refiere al compuesto de la presente invención, donde
Figure imgf000008_0001
In a more particular embodiment, the present invention relates to the compound of the present invention, where
n es 1 ; n is 1;
G es seleccionado de entre C y N; G is selected from C and N;
A es O; A is O;
B es CH2; B is CH2;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, R5, R6, R7 y Re son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R 4 , R5, R 6, R 7 and Re are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
Más en particular, el compuesto de la presente invención comprende fragmentos isocromano y 2-metilen-ciclobutano. Más en particular, el compuesto de la presente invención comprende la fórmula (Ib). More in particular, the compound of the present invention comprises isochroman and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises the formula (Ib).
Figure imgf000009_0001
Figure imgf000009_0001
En una realización más en particular, la presente invención se refiere al compuesto de la presente invención, donde: In a more particular embodiment, the present invention refers to the compound of the present invention, where:
n es 1 ; n is 1;
G es seleccionado de entre C y N; G is selected from C and N;
A es O; A is O;
B es CH2; B is CH 2 ;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7 y OR33, donde R2, R3, R4, R5, R6, R7 y Re son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. Más en particular, el compuesto de la presente invención comprende fragmentos 2,3- dihidrobenzofurano y 2-metilen-ciclobutano. Más en particular, el compuesto de la presente invención comprende la fórmula (le). R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and OR 33 , where R 2 , R 3 , R 4 , R5, R 6, R 7 and Re are the same or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl. More particularly, the compound of the present invention comprises 2,3-dihydrobenzofuran and 2-methylene-cyclobutane fragments. More in particular, the compound of the present invention comprises the formula (le).
Figure imgf000010_0001
Figure imgf000010_0001
En otro aspecto, la presente invención se refiere a un procedimiento para la preparación de un compuesto de la presente invención, (de aquí en adelante procedimiento de la presente invención) que comprende: In another aspect, the present invention refers to a process for the preparation of a compound of the present invention, (hereinafter process of the present invention) comprising:
a) carbometalación intramolecular del compuesto de fórmula general (II) para dar lugar al compuesto de fórmula general (I) en presencia de un catalizador conformado por un metal de transición, un ligando orgánico y una base inorgánica, según el esquema general 1 : a) intramolecular carbometallation of the compound of general formula (II) to give rise to the compound of general formula (I) in the presence of a catalyst made up of a transition metal, an organic ligand and an inorganic base, according to general scheme 1:
Figure imgf000010_0002
Figure imgf000010_0002
Esquema general 1 : Procedimiento de síntesis del compuesto de fórmula general (I) a partir del compuesto de fórmula general (II), donde: General scheme 1: Synthesis procedure of the compound of general formula (I) from the compound of general formula (II), where:
n es seleccionado de entre 0, 1 y 2; n is selected from 0, 1 and 2;
X es un halógeno; X is a halogen;
A es un heteroátomo seleccionado de entre O, S, N, NH, NR1 , donde R1 es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; . A is a heteroatom selected from O, S, N, NH, NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl; .
B es seleccionado de entre CH2 y CO; B is selected from CH2 and CO;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
En una realización más en particular, donde el catalizador conformado por un metal de transición es un catalizador de paladio, más en particular, el catalizador es una sal de paladio. In a more particular embodiment, where the catalyst formed by a metal of transition is a palladium catalyst, more in particular, the catalyst is a palladium salt.
En una realización más en particular, el ligando orgánico es seleccionado de entre fosfina monodentada y carbono N-heterocíclico sustituido. In a more particular embodiment, the organic ligand is selected from monodentate phosphine and substituted N-heterocyclic carbon.
En una realización más en particular, el procedimiento de la presente invención consta de una carbopaladación intramolecular del compuesto de fórmula general (lia) para dar lugar al compuesto de fórmula general (la), según el esquema A, In a more particular embodiment, the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (lia) to give rise to the compound of general formula (la), according to scheme A,
Figure imgf000011_0001
Figure imgf000011_0001
Esquema A: Procedimiento de síntesis del compuesto de fórmula general (la) a partir del compuesto de fórmula general (lia), donde Scheme A: Procedure for the synthesis of the compound of general formula (la) from the compound of general formula (lia), where
n es 0, n is 0,
X es bromo, X is bromine,
A es NR1 , donde R1 es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo, B es CO, y A is NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl, B is CO, and
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
En otra realización más en particular, el procedimiento de la presente invención consta de una carbopaladación intramolecular del compuesto de fórmula general (llb) para dar lugar al compuesto de fórmula general (Ib), según el esquema B, In another more particular embodiment, the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (llb) to give rise to the compound of general formula (Ib), according to scheme B,
Figure imgf000012_0001
Figure imgf000012_0001
Esquema B: Procedimiento de síntesis del compuesto de fórmula general (Ib) a partir del compuesto de fórmula general (llb), donde: Scheme B: Procedure for synthesis of the compound of general formula (Ib) from the compound of general formula (llb), where:
n es 1 ; n is 1;
X es bromo; X is bromine;
A es O: A is O:
B es CH2; B is CH2;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs donde R2, R3, R4, Rs, R6 y R7 son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs where R 2 , R 3 , R 4 , Rs, R 6 and R 7 are the same or different and selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl .
En otra realización más en particular, el procedimiento de la presente invención consta de una carbopaladación intramolecular del compuesto de fórmula general (lie) para dar lugar al compuesto de fórmula general (le), según el esquema C, In another more specific embodiment, the process of the present invention consists of an intramolecular carbopallation of the compound of general formula (lie) to give rise to the compound of general formula (le), according to scheme C,
Figure imgf000012_0002
Figure imgf000012_0002
Esquema C: Procedimiento de síntesis del compuesto de fórmula general (le) a partir del compuesto de fórmula general (lie), donde: n es 0; Scheme C: Procedure for the synthesis of the compound of general formula (le) from the compound of general formula (lie), where: n is 0;
X es bromo; X is bromine;
A es O; A is O;
B es CH2, B is CH2,
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R3, R4, Rs, Re, R7 and Rs are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
En otra realización más en particular el procedimiento de la presente invención comprende una carga de catalizador de entre 2-15 mol %. In another more particular embodiment, the process of the present invention comprises a catalyst load of between 2-15 mol%.
En otra realización más en particular, el procedimiento de la presente invención comprende una carga de ligando orgánico de entre 3-25 mol %. In another more particular embodiment, the process of the present invention comprises an organic ligand load of between 3-25 mol%.
En otra realización más en particular, el procedimiento de la presente invención se realiza a una temperatura comprendida entre 70-150°C. Preferentemente entre 80-120°C. In another more particular embodiment, the process of the present invention is carried out at a temperature comprised between 70-150 ° C. Preferably between 80-120 ° C.
Descripción detallada de la invención Detailed description of the invention
El método de síntesis de los espirociclos que incluyen la unidad 2-metilen-ciclobutano en su estructura consiste en una reacción en cascada catalizada por paladio en la que resulta clave utilizar sustratos de partida que contienen una unidad 1 ,4-dieno en la cadena alifática y un sistema catalítico basado en Pd(0). The synthesis method of spirocycles that include the 2-methylene-cyclobutane unit in their structure consists of a cascade reaction catalyzed by palladium in which it is key to use starting substrates that contain a 1,4-diene unit in the aliphatic chain and a catalytic system based on Pd (0).
El procedimiento experimental en el que se basa el método de síntesis es el siguiente: en un tubo Carius (o matraz Schlenk) limpio y seco, conteniendo un núcleo de agitación magnético, se añade un precatalizador que genere Pd(0) en el medio de reacción, consistente en una sal de Pd(ll) (2.5-10 mol%), un ligando orgánico de tipo fosfina monodentada o carbeno N- heterocíclico sustituido NHCs (5-20 mol%, según sea el porcentaje de la sal de Pd(ll)) y una base inorgánica (1.5 equiv) secuencialmente. El aire del matraz se reemplaza por una atmósfera inerte (nitrógeno o argón). El sustrato de partida [conteniendo el fragmento 1 ,4- dieno enlazado a una cadena que tienen un anillo aromático (o heteroaromático) con un sustituyente halógeno (o pseudohalógeno) en posición 2] (1 equivalente) se disuelve en tolueno seco bajo nitrógeno, y se añade a la mezcla de reacción conteniendo el resto de reactivos. A continuación, se añade tolueno seco hasta que la concentración resultante sea de 0.05 M en sustrato. La mezcla se calienta a una temperatura mínima de 80 °C durante 16 h. Tras enfriar la mezcla, el crudo de reacción se filtra y el sólido se lava con disolvente orgánico que disuelva que el producto orgánico. El disolvente del filtrado se evapora a vacío y el aceite crudo resultante se purifica por cromatografía. De esta forma se obtiene un compuesto orgánico que consta de una estructura espirocíclica formada por un fragmento 2- metilen-ciclobutano, y un anillo de 5, 6, o 7 miembros. The experimental procedure on which the synthesis method is based is the following: in a clean and dry Carius tube (or Schlenk flask), containing a magnetic stirring core, a pre-catalyst is added that generates Pd (0) in the medium of reaction, consisting of a salt of Pd (ll) (2.5-10 mol%), an organic ligand of the monodentate phosphine or carbene N- heterocyclic substituted NHCs (5-20 mol%, depending on the percentage of the Pd (ll) salt) and an inorganic base (1.5 equiv) sequentially. The air in the flask is replaced by an inert atmosphere (nitrogen or argon). The starting substrate [containing the 1,4-chain-linked diene fragment having an aromatic (or heteroaromatic) ring with a halogen (or pseudohalogen) substituent in position 2] (1 equivalent) is dissolved in dry toluene under nitrogen, and is added to the reaction mixture containing the rest of the reagents. Dry toluene is then added until the resulting concentration is 0.05 M in substrate. The mixture is heated to a minimum temperature of 80 ° C for 16 h. After cooling the mixture, the crude reaction is filtered and the solid is washed with an organic solvent that dissolves the organic product. The solvent in the filtrate is evaporated in vacuo and the resulting crude oil is purified by chromatography. In this way an organic compound is obtained that consists of a spirocyclic structure formed by a 2-methylene-cyclobutane fragment, and a 5, 6, or 7-membered ring.
La proporción molar de catalizador (Pd(OAc)2/ligando) que se añade a la mezcla de reacción depende tanto del sustrato de partida como de la temperatura de reacción a la que se trabaje. Así por ejemplo, para sustratos de tipo N-2-haloaril-amida conteniendo la unidad 1 ,4-dieno (Figura 4), la reacción tiene lugar en buen rendimiento a 80 °C, con una carga de catalizador del 2.5 mol% de Pd(OAc)2 y 5 mol% de PPhb. Para sustratos de tipo 2-haloaril éter conteniendo la unidad 1 ,4-dieno (Figura 6), la reacción se completa con una carga de catalizador del 10 mol% de Pd(OAc)2 y 20 mol% de PCy3 a 80 °C, pero si se trabaja a una temperatura mayor (120 °C) se puede bajar al 5 mol% de Pd(OAc)2 y 10 mol% de PCy3 para que la reacción proceda en buen rendimiento. The molar ratio of catalyst (Pd (OAc) 2 / ligand) that is added to the reaction mixture depends both on the starting substrate and on the reaction temperature at which one works. Thus, for example, for N-2-haloaryl-amide type substrates containing the 1,4-diene unit (Figure 4), the reaction takes place in good yield at 80 ° C, with a catalyst load of 2.5 mol% of Pd (OAc) 2 and 5 mol% of PPhb. For 2-haloaryl ether type substrates containing the 1,4-diene unit (Figure 6), the reaction is completed with a catalyst load of 10 mol% of Pd (OAc) 2 and 20 mol% of PCy3 at 80 ° C , but if you work at a higher temperature (120 ° C) it can be lowered to 5 mol% of Pd (OAc) 2 and 10 mol% of PCy3 so that the reaction proceeds in good yield.
La reacción ocurre en un solo paso por un mecanismo en cascada consistente en los siguientes pasos: a) adición oxidante del enlace C-X presente en el producto de partida a Pd(0); b) doble carbopaladación intramolecular del fragmento 1 ,4-dieno, y finalmente c) eliminación beta de hidrogeno. The reaction occurs in a single step by a cascade mechanism consisting of the following steps: a) oxidative addition of the C-X bond present in the starting product to Pd (0); b) double intramolecular carbopallation of the 1,4-diene fragment, and finally c) beta elimination of hydrogen.
El método de síntesis de la presente invención es general y aplicable a varios tipos de anillos heterocíclicos con distintos heteroátomos y tamaños de ciclo. Es especialmente interesante la aplicación a sustratos tipo amida, que dan lugar a [4,5]-espirooxoindoles funcionalizados, unos compuestos de gran importancia farmacéutica. Los compuestos obtenidos mediante la aplicación de este método presentan una serie de aspectos novedosos, entre los que cabe destacar: a) Los espirociclos sintetizados presentan un doble enlace C=C exocíclico en la posición 2 respecto al carbono espirocíclico. Estas estructuras pueden presentar propiedades intrínsecas distintas a las estructuras en las que existe un simple anillo de ciclobutano. La presencia del fragmento C=CH2 exocíclico cambia las propiedades de los compuestos espirocíclicos respecto a estructuras análogas que no lo contienen. La introducción del fragmento alquenílico puede por tanto ser de interés en los procesos de screening de nuevos fármacos, y la síntesis de librerías moleculares. b) Adicionalmente, el doble enlace C=C exocíclico podría funcionalizarse posteriormente, dando lugar a una mayor complejidad estructural de estos compuestos. Es decir, los espirociclos sintetizados pueden a su vez utilizarse como productos de partida para preparar otras familias de compuestos al contar con un fragmento alquenilo. The synthesis method of the present invention is general and applicable to various types of heterocyclic rings with different heteroatoms and ring sizes. Especially interesting is the application to amide-type substrates, which give rise to functionalized [4,5] -spirooxoindoles, compounds of great pharmaceutical importance. The compounds obtained by applying this method present a series of novel aspects, among which it is worth highlighting: a) The synthesized spirocycles have an exocyclic C = C double bond in position 2 with respect to the spirocyclic carbon. These structures may have different intrinsic properties than structures in which there is a single cyclobutane ring. The presence of the exocyclic C = CH2 fragment changes the properties of spirocyclic compounds with respect to analogous structures that do not contain it. The introduction of the alkenyl fragment may therefore be of interest in the screening processes for new drugs, and the synthesis of molecular libraries. b) Additionally, the exocyclic C = C double bond could be subsequently functionalized, giving rise to a greater structural complexity of these compounds. That is, the synthesized spirocycles can in turn be used as starting products to prepare other families of compounds by having an alkenyl fragment.
Ejemplo 1. Preparación del espirociclo la, conteniendo los fragmentos oxoindol y 2-metilen- ciclobutano (ESQUEMA GENERAL A). Example 1. Preparation of spirocyclo la, containing the oxoindole and 2-methylene-cyclobutane fragments (GENERAL SCHEME A).
En un tubo Carius limpio y seco, conteniendo un núcleo de agitación magnético, se añadió Pd(OAc)2 (4 mg, 2.5 mol%), PPh3 (9 mg, 5 mol%) y K2CO3 (140 mg, 1.5 equiv) secuencialmente. El tubo fue cerrado y se realizaron tres ciclos vacío/nitrógeno para reemplazar el aire de su interior por nitrógeno. El sustrato 1 ,4-dieno de partida correspondiente, en este caso lia, (196 mg, 0.7 mmol, 1 equivalente) se disolvió en 1 mL de tolueno seco bajo nitrógeno, y se añadió a la mezcla de reacción conteniendo el resto de reactivos. A continuación, se añadieron 13 mL de tolueno seco (la concentración resultante fue de 0.05 M en lia. La mezcla se calentó a 80 °C durante 16 h. Tras enfriar el tubo Carius, el crudo se filtró y el sólido se lavó con diclorometano (10 mL). El disolvente del filtrado se evaporó a sequedad a vacío y el aceite crudo resultante se purificó por cromatografía en columna utilizando un gradiente de éter de petróleo/EtOAc en relación en volumen 10: 1 a 5:1. In a clean and dry Carius tube, containing a magnetic stirring core, add Pd (OAc) 2 (4 mg, 2.5 mol%), PPh 3 (9 mg, 5 mol%) and K2CO3 (140 mg, 1.5 equiv) sequentially. The tube was closed and three vacuum / nitrogen cycles were performed to replace the air inside with nitrogen. The corresponding starting 1,4-diene substrate, in this case lia, (196 mg, 0.7 mmol, 1 equivalent) was dissolved in 1 mL of dry toluene under nitrogen, and added to the reaction mixture containing the rest of reagents . Subsequently, 13 mL of dry toluene were added (the resulting concentration was 0.05 M in lia. The mixture was heated at 80 ° C for 16 h. After cooling the Carius tube, the crude was filtered and the solid was washed with dichloromethane (10 mL) The solvent in the filtrate was evaporated to dryness in vacuo and the resulting crude oil was purified by column chromatography using a gradient of petroleum ether / EtOAc in volume ratio 10: 1 to 5: 1.
Rendimiento del producto la aislado: 120 mg, 0.6 mmol, 86%. Aceite amarillo. 1 H NMR (300 MHz, Chloroform-d) d 7.48 (ddd, J = 7.4, 1.3, 0.6 Hz, 1 H), 7.27 (td, J = 7.7, 1.3 Hz, 1 H), 7.08 (td, J = 7.5, 1.0 Hz, 1 H), 6.81 (dt, J = 7.7, 0.7 Hz, 1 H), 5.01 (m, 2H), 3.51 - 3.31 (m, 2H), 3.21 (s, 3H), 3.01 - 2.86 (m, 2H). 13C NMR (75 MHz, chloroform-d) d 179.24 (s, Cq), 143.05 (s, Cq), 142.00 (s, Cq), 133.93 (s, Cq), 127.91 (s, CH), 122.63 (s, CH), 121.79 (s, CH), 107.68 (s, CH), 107.57 (s, CH2), 43.30 (s, Cq) 41.91 (s, CH2), 26.20 (s, CH3). HMRS (+ESI) calculado para C13H14NO [M+H]+ 200.107, valor encontrado experimentalmente 199.0997. Yield of the isolated product: 120 mg, 0.6 mmol, 86%. Yellow oil. 1 H NMR (300 MHz, Chloroform-d) d 7.48 (ddd, J = 7.4, 1.3, 0.6 Hz, 1 H), 7.27 (td, J = 7.7, 1.3 Hz, 1 H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (dt, J = 7.7, 0.7 Hz, 1H), 5.01 (m, 2H), 3.51 - 3.31 (m, 2H), 3.21 (s, 3H), 3.01 - 2.86 (m, 2H) . 13C NMR (75 MHz, chloroform-d) d 179.24 (s, Cq), 143.05 (s, Cq), 142.00 (s, Cq), 133.93 (s, Cq), 127.91 (s, CH), 122.63 (s, CH), 121.79 (s, CH), 107.68 (s, CH), 107.57 (s, CH2), 43.30 (s, Cq), 41.91 (s, CH2), 26.20 (s, CH3). HMRS (+ ESI) calculated for C13H14NO [M + H] + 200.107, experimentally found value 199.0997.
Ejemplo 2. Preparación del espirociclo Ib, conteniendo los fragmentos isocromano y 2- metilen-ciclobutano (Esquema B). Example 2. Preparation of Spirocycle Ib, containing isochroman and 2-methylene-cyclobutane fragments (Scheme B).
En un tubo Carius limpio y seco, conteniendo un núcleo de agitación magnético, se añadió Pd(OAc)2 (4.4 mg, 10 mol%), PCy3 (12 mg, 20 mol%) y K2CO3 (42 mg, 1.5 equiv) secuencialmente. El tubo fue cerrado y se realizaron tres ciclos vacío/nitrógeno para reemplazar el aire de su interior por nitrógeno. El sustrato 1 ,4-dieno de partida correspondiente, en este caso llb, (53 mg, 0.2 mmol, 1 equivalente) se disolvió en 1 ml_ de tolueno seco bajo nitrógeno, y se añadió a la mezcla de reacción conteniendo el resto de reactivos. A continuación, se añadieron 3 ml_ de tolueno seco (la concentración resultante fue de 0.05 M en llb). La mezcla se calentó a 80 °C durante 16 h. Tras enfriar el tubo Carius, el crudo se filtró y el sólido se lavó con diclorometano (10 mL). El disolvente del filtrado se evaporó a sequedad a vacío y el aceite crudo resultante se purificó por cromatografía en columna utilizando un gradiente de etér de petróleo/EtOAc In a clean and dry Carius tube, containing a magnetic stirring core, added Pd (OAc) 2 (4.4 mg, 10 mol%), PCy 3 (12 mg, 20 mol%) and K2CO3 (42 mg, 1.5 equiv) sequentially. The tube was closed and three vacuum / nitrogen cycles were performed to replace the air inside with nitrogen. The corresponding starting 1,4-diene substrate, in this case llb, (53 mg, 0.2 mmol, 1 equivalent) was dissolved in 1 ml_ of dry toluene under nitrogen, and added to the reaction mixture containing the rest of the reagents . Then, 3 ml_ of dry toluene was added (the resulting concentration was 0.05 M in llb). The mixture was heated at 80 ° C for 16 h. After cooling the Carius tube, the crude was filtered and the solid was washed with dichloromethane (10 mL). The solvent in the filtrate was evaporated to dryness in vacuo and the resulting crude oil was purified by column chromatography using a petroleum ether / EtOAc gradient.
Rendimiento del espirociclo Ib aislado: 20 mg, 0.106 mmol, 53%. Aceite amarillo. 1H NMR (300 MHz, Chloroform-d) d 7.57 (dd, J = 7.8, 1.3 Hz, 1 H), 7.31 - 7.23 (m, 1 H), 7.17 (td, J = 7.4, 1.3 Hz, 1 H), 6.96 (m, 1 H), 4.97 (m, 2H), 4.81 (d, J = 0.9 Hz, 2H), 3.89 (s, 2H), 3.05 - 2.94 (m, 2H), 2.83 - 2.72 (m, 2H). 13C NMR (75 MHz, Chloroform-d) d 143.87 (s, Cq), 140.44 (s, Cq), 133.84 (s, Cq), 127.14 (s, CH), 126.11 (s, CH), 125.42 (s, CH), 123.81 (s, CH), 108.23 (s, CH2), 74.58 (s, CH2), 68.86 (s, CH2), 43.47 (s, Cq). HMRS (+APCI) calculado para C13H15O [M+H]+ 187.11 17, valor encontrado experimentalmente 187.1 115. Yield of isolated Spirocycle Ib: 20mg, 0.106mmol, 53%. Yellow oil. 1 H NMR (300 MHz, Chloroform-d) d 7.57 (dd, J = 7.8, 1.3 Hz, 1 H), 7.31 - 7.23 (m, 1 H), 7.17 (td, J = 7.4, 1.3 Hz, 1 H ), 6.96 (m, 1H), 4.97 (m, 2H), 4.81 (d, J = 0.9Hz, 2H), 3.89 (s, 2H), 3.05-2.94 (m, 2H), 2.83-2.72 (m , 2H). 13 C NMR (75 MHz, Chloroform-d) d 143.87 (s, Cq), 140.44 (s, Cq), 133.84 (s, Cq), 127.14 (s, CH), 126.11 (s, CH), 125.42 (s , CH), 123.81 (s, CH), 108.23 (s, CH 2 ), 74.58 (s, CH 2 ), 68.86 (s, CH 2 ), 43.47 (s, Cq). HMRS (+ APCI) calculated for C13H15O [M + H] + 187.11 17, experimentally found value 187.1 115.
Ejemplo 3. Preparación del espirociclo le, conteniendo los fragmentos 2,3-dihidrobenzofurano y 2-metilen-ciclobutano (Esquema C). En un tubo Carius limpio y seco, conteniendo un núcleo de agitación magnético, se añadió Pd(OAc)2 (3.6 mg, 10 mol%), PCy3 (9 mg, 20 mol%) y K2CO3 (33 mg, 1.5 equiv) secuencialmente. El tubo fue cerrado y se realizaron tres ciclos vacío/nitrógeno para reemplazar el aire de su interior por nitrógeno. El sustrato 1 ,4-dieno de partida correspondiente, en este caso lie, (45 mg, 0.16 mmol, 1 equivalente) se disolvió en 1 ml_ de tolueno seco bajo nitrógeno, y se añadió a la mezcla de reacción conteniendo el resto de reactivos. A continuación, se añadieron 2 ml_ de tolueno seco (la concentración resultante fue de 0.05 M en lie). La mezcla se calentó a 80 °C durante 16 h. Tras enfriar el tubo Carius, el crudo se filtró y el sólido se lavó con diclorometano (10 mL). El disolvente del filtrado se evaporó a sequedad a vacío y el aceite crudo resultante se purificó por cromatografía en columna utilizando un gradiente de etér de petróleo/EtOAc. Example 3. Preparation of the spirocycle le, containing the fragments 2,3-dihydrobenzofuran and 2-methylene-cyclobutane (Scheme C). In a clean and dry Carius tube, containing a magnetic stirring core, Pd (OAc) 2 (3.6 mg, 10 mol%), PCy 3 (9 mg, 20 mol%) and K2CO3 (33 mg, 1.5 equiv) were added. sequentially. The tube was closed and three vacuum / nitrogen cycles were performed to replace the air inside with nitrogen. The corresponding starting 1,4-diene substrate, in this case lie, (45 mg, 0.16 mmol, 1 equivalent) was dissolved in 1 ml_ of dry toluene under nitrogen, and added to the reaction mixture containing the rest of reagents . Then 2 ml_ of dry toluene was added (the resulting concentration was 0.05 M in lie). The mixture was heated at 80 ° C for 16 h. After cooling the Carius tube, the crude was filtered and the solid was washed with dichloromethane (10 mL). The solvent in the filtrate was evaporated to dryness in vacuo and the resulting crude oil was purified by column chromatography using a petroleum ether / EtOAc gradient.
Rendimiento del producto le aislado: 17 mg, 0.085 mmol, 53%. Aceite amarillo. 1 H NMR (300 MHz, Chloroform-d) d 6.92 (dd, J = 2.0, 1.2 Hz, 1 H), 6.74 - 6.63 (m, 2H), 5.05 - 4.83 (m, 2H), 4.54 (s, 2H), 3.78 (s, 3H), 3.11 - 3.01 (m, 2H), 3.00 - 2.90 (m, 2H). 13C NMR (75 MHz, Chloroform-d) d 154.58Yield of the isolated product: 17 mg, 0.085 mmol, 53%. Yellow oil. 1 H NMR (300 MHz, Chloroform-d) d 6.92 (dd, J = 2.0, 1.2 Hz, 1 H), 6.74 - 6.63 (m, 2H), 5.05 - 4.83 (m, 2H), 4.54 (s, 2H ), 3.78 (s, 3H), 3.11-3.01 (m, 2H), 3.00-2.90 (m, 2H). 13 C NMR (75 MHz, Chloroform-d) d 154.58
(s, Cq), 153.58 (s, Cq), 142.67 (s, Cq), 135.31 (s, Cq), 113.29 (s, CH), 109.27 (s, CH), 108.36 (s, CH), 107.59 (s, CH2), 83.70 (s, CH2), 56.06 (s, CH3), 45.24 (s, CH2), 43.61 (s, Cq). HMRS (+APCI) calculado para Ci3His02 [M+H]+ 203.1067, valor encontrado experimental mente 203.1062. (s, Cq), 153.58 (s, Cq), 142.67 (s, Cq), 135.31 (s, Cq), 113.29 (s, CH), 109.27 (s, CH), 108.36 (s, CH), 107.59 ( s, CH 2 ), 83.70 (s, CH 2 ), 56.06 (s, CH 3 ), 45.24 (s, CH 2 ), 43.61 (s, Cq). HMRS (+ APCI) calculated for Ci 3 His0 2 [M + H] + 203.1067, value found experimentally 203.1062.

Claims

REIVINDICACIONES
1. Compuesto espiro-heterocíclico de fórmula general I 1. Spiro-heterocyclic compound of general formula I
Figure imgf000018_0001
Figure imgf000018_0001
donde: where:
n es seleccionado de entre 0, 1 y 2; n is selected from 0, 1 and 2;
G es seleccionado de entre C y N; G is selected from C and N;
A es un heteroátomo seleccionado de entre O, S, N, NH y NRi, donde Ri es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; A is a heteroatom selected from O, S, N, NH and NRi, where Ri is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
B es seleccionado de entre CH2 y CO; B is selected from CH2 and CO;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7, y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 , and ORs, where R 2, R3, R4, Rs, Re, R7 and Rs are identical or different and is selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
2. Compuesto según la reivindicación 1 , donde: 2. Compound according to claim 1, where:
n es 0; n is 0;
G es seleccionado de entre C y N; G is selected from C and N;
A es NR1, donde R1 es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; B es CO, y A is NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl; B is CO, and
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)R6, S(0)2R7 y OR8, donde R2, R3, R4, R5, Re, R7 y R8 son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from among hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR 5 , S (0) R 6 , S (0) 2R 7 and OR 8 , where R 2 , R 3 , R 4 , R 5 , Re , R 7, and R 8 are the same or different and selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
3. Compuesto según la reivindicación 1 , donde: 3. Compound according to claim 1, where:
n es 1 ; n is 1;
G es seleccionado de entre C y N; G is selected from C and N;
A es O; A is O;
B es CH2; B is CH2;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Rs, S(0)2R7 y ORs, donde R2, R3, R4, R5, R6, R7 y Re son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Rs, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , R5, R 6, R 7 and Re are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
4. Compuesto según la reivindicación 1 , donde: 4. Compound according to claim 1, where:
n es 0; n is 0;
G es seleccionado de entre C y N; G is selected from C and N;
A es O; A is O;
B es CH2; B is CH2;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)Re, S(0)2R7, ORs, donde R2, R3, R4, R5, R6, R7 y Re son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR5, S (0) Re, S (0) 2R 7 , ORs, where R 2 , R3, R 4 , R5, R 6, R 7 and Re are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
5. Procedimiento para la preparación de un compuesto espiro-herocíclico de fórmula general (I), según cualquiera de las reivindicaciones 1-4 que comprende: 5. Process for the preparation of a spiro-herocyclic compound of general formula (I), according to any of claims 1-4 comprising:
a) carbometalaciónintramolecular del compuesto de fórmula general (II) para dar lugar al compuesto de fórmula general (I) en presencia de un catalizador conformado por un metal de transición, un ligando orgánico y una base inorgánica: a) intramolecular carbometalation of the compound of general formula (II) to give rise to the compound of general formula (I) in the presence of a catalyst made up of a transition metal, an organic ligand and an inorganic base:
Figure imgf000020_0001
Figure imgf000020_0001
donde where
n es seleccionado de entre 0, 1 y 2; n is selected from 0, 1 and 2;
X es un halógeno; X is a halogen;
A es un heteroátomo seleccionado de entre O, S, N, NH y NR1 , donde R1 es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; A is a heteroatom selected from O, S, N, NH, and NR1, where R1 is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl;
B es seleccionado de entre CH2 y CO; B is selected from CH 2 and CO;
R es seleccionado de entre Hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Re, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from among Hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Re, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
6. Procedimiento según la reivindicación 5, donde el catalizador conformado por un metal de transición es un catalizador de paladio. 6. Process according to claim 5, wherein the catalyst formed by a transition metal is a palladium catalyst.
7. Procedimiento según cualquiera de las reivindicaciones 5-6, donde el ligando orgánico es seleccionado de entre fosfina monodentada y carbono N-heterocíclico sustituido. 7. Process according to any of claims 5-6, wherein the organic ligand is selected from monodentate phosphine and substituted N-heterocyclic carbon.
8. Procedimiento según cualquiera de las reivindicaciones 5-7, donde: 8. Process according to any of claims 5-7, where:
n es 0; n is 0;
X es bromo; X is bromine;
A es NRi, donde Ri es seleccionado de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo; B es CO, y A is NRi, where Ri is selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl; B is CO, and
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Rs, S(0)2R7 y ORs, donde R2, R3, R4, Rs, Re, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from among hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Rs, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , Rs, Re, R 7 and Rs are the same or different and are selected from aryl, alkyl, heteroaryl, alkenyl and alkynyl.
9. Procedimiento según cualquiera de las reivindicaciones 5-7, donde: 9. Process according to any of claims 5-7, where:
n es 1 ; n is 1;
X es bromo; X is bromine;
A es O: A is O:
B es CH2; B is CH2;
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SR5, S(0)R6, S(0)2R7 y OR8, donde R2, R3, R4, R5, Re, R7 y R8 son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from among hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SR 5 , S (0) R 6 , S (0) 2R 7 and OR 8 , where R 2 , R 3 , R 4 , R 5 , Re , R 7, and R 8 are the same or different and selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
10. Procedimiento según cualquiera de las reivindicaciones 5-7, donde: 10. Process according to any of claims 5-7, where:
n es 0; n is 0;
X es bromo; X is bromine;
A es O; A is O;
B es CH2, B is CH 2 ,
R es seleccionado de entre hidrógeno, arilo, alquilo, heteroarilo, alquenilo y alquinilo, halógeno, CN, C02R2, NHR3, NR4, SRs, S(0)Rs, S(0)2R7 y ORs, donde R2, R3, R4, R5, Rs, R7 y Rs son iguales o diferentes y se selecciona de entre arilo, alquilo, heteroarilo, alquenilo y alquinilo. R is selected from among hydrogen, aryl, alkyl, heteroaryl, alkenyl and alkynyl, halogen, CN, C02R 2 , NHR 3 , NR 4 , SRs, S (0) Rs, S (0) 2R 7 and ORs, where R 2 , R 3 , R 4 , R 5 , Rs , R 7 and Rs are the same or different and selected from aryl, alkyl, heteroaryl, alkenyl, and alkynyl.
11. Uso del compuesto de fórmula general (I) según cualquiera de las reivindicaciones 1-4, para el cribado y evaluación de fármacos. 11. Use of the compound of general formula (I) according to any of claims 1-4, for drug screening and evaluation.
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WO2015092118A1 (en) * 2013-12-17 2015-06-25 Orion Corporation Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors
WO2016203112A1 (en) * 2015-06-16 2016-12-22 Orion Corporation Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors

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WO2015092118A1 (en) * 2013-12-17 2015-06-25 Orion Corporation Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors
WO2016203112A1 (en) * 2015-06-16 2016-12-22 Orion Corporation Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors

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