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    • 专利摘要:
    Compounds for the treatment of HIV infection and other diseases caused by RNA viruses. The present invention is directed to the use of organic compounds for the treatment of infection caused by human immunodeficiency virus type 1 (HIV-1) as well as other diseases caused by RNA virus. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2736260A1
    申请号:ES201830637
    申请日:2018-06-25
    公开日:2019-12-27
    发明作者:Sala José Gallego；Martin Silvia Prado；Pertejo José Alcami
    申请人:Instituto de Salud Carlos III；Universidad Catolica de Valencia San Vicente Martir；
    IPC主号:
    专利说明:

    [0001]
    [0002] Compounds for the treatment of HIV infection and other diseases caused by RNA viruses
    [0003]
    [0004] Field of the Invention
    [0005] The present invention relates to the use of organic compounds for the treatment of infection caused by human immunodeficiency virus type 1 (HIV-1) as well as other diseases caused by RNA virus.
    [0006]
    [0007] Background of the invention
    [0008] According to the World Health Organization, at the end of 2016 there were more than 36 million people infected with HIV worldwide, and in that year there were 1.8 million new infections and 1 million related deaths due to diseases AIDS related.
    [0009]
    [0010] In recent years, antiretroviral therapy has decreased the incidence and mortality rates of the disease. The treatment is based on combinations of three or four drugs that inhibit protease, reverse transcriptase or virus integrase, or block their entry into the cell. However, this therapy does not eliminate the infection. The emergence of resistance and the lack of an effective vaccine further reinforce the need to identify new drugs that act on alternative targets of the virus. Therefore, today there is still a very important need to develop new therapies that eliminate HIV infection.
    [0011]
    [0012] RNA plays a central role in the functioning of living beings, and many human, bacterial and viral RNA molecules possess considerable therapeutic potential, which still remains unexploited. Two strategies are currently used to address this type of receptors. The first is based on the generation of antisense agents or RNAi, designed to mate with the target RNA and thus promote its degradation or block its translation. The second strategy consists in the synthesis of small organic molecules designed to specifically recognize the cavities formed by tertiary RNA structures and thus interfere with their function.
    [0013]
    [0014] Functional and structured RNA motifs are not easily accessible to antisense agents and have the advantage of strong sequence conservation and / or three-dimensional structure This factor is important for the development of anti-infectives, as it could result in a slower occurrence of resistance to drugs that act on these structures. However, except for various antibiotics that interact with bacterial ribosomal RNA sites, the development of new RNA-directed drugs has been hampered by the difficulties imposed by these structures, which have limited physicochemical diversity and are often flexible. For this strategy to succeed, it is imperative to identify new chemical skeletons and new mechanisms for specific recognition of structured RNA.
    [0015]
    [0016] The processes that contribute to the biogenesis and packaging of human immunodeficiency virus type 1 (HIV-1) RNA molecules are clearly unexplored from the pharmacological point of view. Activities such as transcription, cutting and splicing, nuclear export and packaging involve viral RNA domains and virus-encoded proteins with the potential to provide selectivity in relation to host components, but do not constitute the target of any of the antiretroviral drugs currently. marketed These agents block the first steps of the viral cycle, including the entry, retrotranscription and integration of the virus, as well as the generation of infectious virions through protease inhibition, but do not disrupt most post-virus integration activities. . The discovery and development of a drug directed at one or several steps of the biogenesis of HIV-1 RNA can provide new therapeutic opportunities to cure the disease and can also help alleviate the current problem of resistance to antiretroviral treatments.
    [0017]
    [0018] Rev, a 116-amino acid protein encoded by virus that adopts a helix-turn-helix conformation, binds to the Rev response element (RRE), a 350 nucleotide structure present in semi-processed and unprocessed viral RNA transcripts. The formation of RRE-Rev ribonucleoprotein involves the association of several Rev monomers to RRE through a cooperative process that involves RNA-protein and protein-protein interactions. This process is triggered by a high affinity interaction between an internal loop located within subdomain IIB of the RRE and the RNA binding helix (hereinafter referred to as Rev34-50) of the first Rev monomer. Once formed, the RRE- complex Rev joins the Crm1 cell factor to induce nuclear export of semi-processed and unprocessed viral RNA molecules, an essential stage in the late phase of the virus cycle. Rev-mediated nuclear RNA export represents a potential target for anti-HIV-1 therapy.
    [0019] In this sense, small molecules have been found that act on the RRE-Rev interaction. For example, small molecules that mimic Rev34-50 with antiretrovial activity are described (Gonzalez-Bulnes et al., Angewandte Chemie-International Edition 52 (50) (2013) 13405-13409). It has also been described that clomiphene affects the formation of the RRE-Rev complex in vitro and exhibits ex vivo antiretroviral activity, through transcriptional blockade and inhibition of Rev function (S. Prado et al., Biochem Pharmacol 107 (2016) 14 -28).
    [0020]
    [0021] However, there is a need to develop new compounds to treat diseases caused by RNA viruses, in particular by HIV-1 virus, and especially compounds that act in the post-virus integration stages.
    [0022]
    [0023] Summary of the invention
    [0024] Researchers have found that compounds of formula (I), (II) and (III) are capable of inhibiting the RRE-Rev interaction, both the interaction of subdomain IIB of the RRE RNA with the RNA-binding helix of Rev and the complete RRE-Rev interaction. These compounds also have antiretroviral activity.
    [0025]
    [0026] Therefore, a first aspect of the invention relates to a compound of formula (I) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by viruses. RNA
    [0027]
    [0028] In a second aspect, the invention is directed to a compound of formula (II) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA viruses.
    [0029]
    [0030] In a third aspect, the invention is directed to a compound of formula (III) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA viruses.
    [0031]
    [0032] Another aspect of the invention relates to the use of a compound of formula (I), (II) or (III) as described herein, or a salt or solvate thereof, in the preparation of a medicament for prevention or treatment of infections caused by RNA viruses.
    [0033] Another aspect of the invention is directed to a method of prevention or treatment of infections caused by RNA viruses comprising administering a therapeutically effective amount of a compound of formula (I), (II) or (III) as described herein. document, or a salt or solvate thereof.
    [0034]
    [0035] In a further aspect, the invention is directed to a pharmaceutical composition comprising a compound of formula (I), (II) or (III) as described herein, or a salt or solvate thereof, for use. in the prevention or treatment of infections caused by RNA viruses.
    [0036]
    [0037] Description of the figures
    [0038] Figure 1 Chemical structure of compounds 1a , 2a and 2b .
    [0039] Figure 2 Inhibition of the IIBh-Rev34_50 interaction and the formation of the complete RRE-Rev complex by compounds 1a , 2a and 2b . (a) IIBh-Rev34-50 inhibition curves obtained with fluorescence anisotropy experiments. (b) Inhibition of the formation of the complete RRE-Rev complex analyzed by EMSA. In (a), the error bars represent the standard deviation of three independent experiments.
    [0040] Figure 3 Recognition of the IIBh RNA hairpin by compounds 1a , 2a and 2b . IIBh binding curves, obtained with experiments of fluorescence intensity in the absence (black circles) and presence of a 100-fold molar excess of unlabeled competitor RNA (tRNA; gray triangles) or unlabeled competitor double helix DNA (LTRd; gray inverted triangles). Error bars represent the standard deviations of two independent experiments.
    [0041] Figure 4 Cellular assays for compounds 1a , 2a and 2b . (a) Antiviral activity based on the concentration of the compound in HIV-1 cell infection experiments. Cellular toxicity (black squares) is also shown in the same graphs. (b) Inhibition of the post-HIV-1 integration stages: the cells were transfected with a DNA plasmid encoding a full length virus containing a luciferase reporter gene. In all cases, the results are expressed as percentage of luminescence (RLU), where 100% is the level of viral replication obtained in the presence of the vehicle used to dissolve the compounds.
    [0042] Figure 5 Effect of compound 1a in the processing of HIV-1 RNA. Processed, semi-processed and fully processed HIV-1 RNA transcripts were quantified by RT-qPCR after RNA isolation from cells transfected with an HIV-1 plasmid pNL4.3 and treated with the inhibitor. The results are expressed as relative amount of RNA (RQ), using untreated cells. as a reference (RQ = 1).
    [0043]
    [0044] Detailed description of the invention
    [0045] The term "halogen" refers to bromine, chlorine, iodine or fluorine.
    [0046]
    [0047] The term "alkyl" refers to a linear or branched alkane derivative containing from 1 to 6 ("C 1 -C 6 alkyl"), preferably from 1 to 3 ("C 1 -C 3 alkyl"), carbon atoms and which is attached to the rest of the molecule through a single bond Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl.
    [0048]
    [0049] The term "cycloalkyl" refers to a cycloalkane derivative containing from 3 to 7 ("C 3 -C7 cycloalkyl"), preferably from 3 to 6 ("C 3 -C6 cycloalkyl"), carbon atoms. Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
    [0050]
    [0051] The term "haloalkyl" refers to an alkyl group as defined above where at least one of the hydrogen atoms has been replaced by a halogen group, for example, CF 3 , CCh, CHF 2 , CF 2 CF 3 , etc. .
    [0052]
    [0053] The term "aryl" refers to an aromatic group having between 6 and 12, preferably between 6 and 1 0 carbon atoms, comprising 1 or 2 aromatic nuclei fused together. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl , phenanthryl, etc.
    [0054]
    [0055] The term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above, such as (C 6 -C 12 ) aryl (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl (C 1 -C 6) alkyl and (C 6 -C 10 ) aryl (C 1 -C 3 ) alkyl Examples of these groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc.
    [0056]
    [0057] The term "heterocyclyl" refers to a monocyclic, bicyclic or tricyclic system that may be completely or partially saturated or aromatic ("heteroaryl") containing 5 to 15, preferably 5 to 10, more preferably 5 or 6 , ring atoms containing one or more, specifically one, two, three or four ring heteroatoms independently selected from N, O and S, and the remaining ring atoms being carbon.
    [0058] The groups mentioned above may be optionally substituted in one or more positions available with one or more suitable groups such as OR, SR, SOR, SO 2 R, OSO 2 R, SO 3 R, NO 2 , N (R) 2 , N (R) COR, N (R) SO 2 R, CN, halogen, COR, CO 2 R, OCOR, OCO2R, OCON (R) 2, CON (R) 2, C1-C6 alkyl, C2-C6 alkenyl, alkynyl C2-C6, C6-C14 aryl and 5-10 membered heterocyclyl, wherein each of the R groups is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C14 aryl, and 5-10 membered heterocyclyl.
    [0059]
    [0060] The invention also provides "salts" of the compounds described in the present description. By way of illustration, said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the original compounds containing a basic or acidic moiety by means of conventional chemical procedures known in the art Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two.The illustrative examples of said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, perchlorate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, t artrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, triethanolamine, glutamine, basic salts of amino acids, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts. In a particular embodiment, the salt is an acid addition salt.
    [0061]
    [0062] Likewise, the compounds described in the present description can be obtained both as free compounds or as solvates (for example, hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. Solvation methods are generally known in the state of the art.
    [0063]
    [0064] As used herein, the term "pharmaceutical composition" refers to a formulation that has been adapted to administer a predetermined dose of one. or several therapeutic agents useful to a cell, a group of cells, an organ, a tissue or an organism.
    [0065]
    [0066] The compounds of the invention are administered in a therapeutically effective amount. A "therapeutically effective amount" is understood as an amount that can provide a therapeutic effect and that can be determined by one skilled in the art by commonly used means. The effective amount will vary with the particular disorder being treated, age and physical condition. of the subject being treated, the intensity of the disorder, the duration of treatment, the nature of simultaneous or combination therapy (if any), the specific route of administration and similar factors within the knowledge and experience of the healthcare professional. Those skilled in the art will appreciate that dosages can also be determined with the guidelines of Goodman and Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711 and of Goodman and Goldman's The Pharmacological Basis of Therapeutics, Tenth Edition (2001), Appendix II, pages 475 493.
    [0067]
    [0068] The pharmaceutical compositions of the invention may include at least one pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means a filler, diluent, encapsulation material or adjuvant of solid, semi-solid or liquid, inert, non-toxic formulation of any kind that is acceptable to the patient from a pharmacological / toxicological point of view and for the manufacturing pharmaceutical chemist from a physical / chemical point of view regarding the composition, formulation, stability, acceptance by the patient and bioavailability Remington's Pharmaceutical Sciences Ed. by Gennaro, Mack Publishing, Easton, Pa., 1995 describes various vehicles used in the formulation of pharmaceutical compositions and known techniques for the preparation thereof Pharmaceutical compositions of the invention include any solid composition (tablets, pills, capsules, granules, etc.), semi- solid (creams, ointments, etc.) or liquid (solution, suspension or emulsion).
    [0069]
    [0070] The compounds and pharmaceutical compositions of this invention can be administered to a patient by any means known in the art including oral and parenteral routes.
    [0071]
    [0072] As used herein, the terms "treat" and "treatment" they include but are not limited to, reduce, suppress, inhibit, alleviate or affect the progression, severity and / or extent of a state, the possibility of resurgence or return of a disease after a remission. In one embodiment, treating may include directly affecting or curing, suppressing, inhibiting, reducing the intensity of, delaying the onset of, reducing the symptoms associated with an infection, or a combination thereof. In another embodiment, treating includes delaying progression, accelerating remission, inducing remission, increasing remission, accelerating recovery, increasing the effectiveness of or decreasing resistance to alternative treatments, or a combination thereof.
    [0073]
    [0074] The terms "prevent" and "prevention", as used herein, include but are not limited to, delay the onset of symptoms, prevent infection by a virus, prevent relapse of a disease, decrease the number or the frequency of relapse episodes, increase latency between symptomatic episodes, or a combination thereof.
    [0075]
    [0076] Compounds of formula (I)
    [0077] In a first aspect the invention relates to a compound of formula (I)
    [0078]
    [0079]
    [0080]
    [0081] or a salt or solvate thereof, where
    [0082] - R1 and R2 are independently selected from H, halogen, OR ', OC (O) R', C (O) R ', C (O) OR', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl , C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl, wherein R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1- haloalkyl 6, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl; or
    [0083] R1 and R2 form, together with the carbon atom to which they are attached, a 5-membered carbocycle or heterocycle;
    [0084] - each R3 and R4 is independently selected from halogen, OC (O) R ', SOR', SO2R ', C (O) R', C (O) OR ', CN, NO2, C1-6 alkyl, C3 cycloalkyl- 7, C1-6 haloalkyl, C6-12 aryl, (C6_12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl and a group of formula (A), where R 'is independently selected from H, alkyl C1-6, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl; or two adjacent R3 or R4 groups form a benzene ring;
    [0085] - R5 is selected from H, halogen, OC (O) R ', SOR', SO 2 R ', C (O) R', C (O) OR ', CN, NO 2 , C1-6 alkyl, C3 cycloalkyl -7, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl and a group of formula (A), where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl; - R6 is selected from H, halogen, OC (O) R ', SOR', SO 2 R ', C (O) R', C (O) OR ', CN, NO 2 , C1-6 alkyl, C3 cycloalkyl -7, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl and a group of formula (A), where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl; - n represents 0, 1, 2, 3, or 4; Y
    [0086] - m represents 0, 1,2, 3, or 4;
    [0087] where at least one of R3, R4, R5 and R6 is a group of formula (A)
    [0088]
    [0089]
    [0090]
    [0091] where
    [0092] - Z is selected from 5-10 membered heterocyclyl, O, S and NR ', where R' represents H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12 ) (C1.6) alkyl or 5-10 membered heterocyclyl;
    [0093] - each Ra and Rb is independently selected from H, halogen, OR ', OC (O) R', NR'2, C (O) R ', C (O) OR', CN, NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, haloalkyl C1-6, C6-12 aryl, (C6.12) aryl (C1.
    [0094] 6) and 5-10 membered heterocyclyl;
    [0095] - Y is selected from H, OR ', OC (O) R', NR ' 2 , NR' 3 , C (O) R ', C (O) OR', OC (O) NR ' 2 , C (O ) NR'2, SR ', SOR', SO2R ', C3-7 cycloalkyl, C6-12 aryl and 5-10 membered heterocyclyl, where each R' is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl , C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.6) alkyl and 5-10 membered heterocyclyl;
    [0096] - p represents 0, 1,2, 3, 4, 5 or 6; Y
    [0097] - q represents 0, 1, 2 or 3;
    [0098] for use in the prevention or treatment of infections caused by RNA viruses.
    [0099] Preferably, the compound of formula (I) is a compound of formula (I ’)
    [0100]
    [0101]
    [0102]
    [0103] or a salt or solvate thereof, where n, m, R3, R4, R5 and R6 are as defined above, and
    [0104] - X is selected from O, S, NR7 and C (R8) (R9), where
    [0105] R7 is selected from H, C (O) R ', C (O) OR', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1. 6) and optionally substituted 5-10 membered heterocyclyl, wherein R 'is independently selected from Ci-6 alkyl, C 3-7 cycloalkyl, Ci-6 haloalkyl, C 6-12 aryl, aryl (C 6 -i 2 ) alkyl (Ci- 6 ) and 5-10 membered heterocyclyl;
    [0106] R8 and R9 are independently selected from H, halogen, OR ', OC (O) R', C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, aryl (C 6 - 2 ) (Ci- 6 ) alkyl and optionally substituted 5-10 membered heterocyclyl, wherein R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl ( C6-12) (C1-6) alkyl and 5-10 membered heterocyclyl; or
    [0107] R8 and R9 form, together with the carbon atom to which they are attached, a group C = O.
    [0108]
    [0109] More preferably, the compound of formula (I) is a compound of formula (I ’’)
    [0110]
    [0111]
    [0112]
    [0113] or a salt or solvate thereof, where n, m, R3, R4, R5, R6, R8 and R9 are as defined above.
    [0114]
    [0115] The following particular and preferred embodiments apply to the compounds of formula (I), (I ') and (I'').
    [0116] In a particular embodiment,
    [0117] - R1 and R2 are independently selected from H, halogen, OR ', OC (O) R', C (O) R ', C (O) OR', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl , C6.12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1- haloalkyl 6, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl; or
    [0118] R1 and R2 form, together with the carbon atom to which they are attached, a 5-membered carbocycle or heterocycle;
    [0119] - each R3 and R4 is independently selected from halogen, OR ', OC (O) R', SR ', SOR', SO 2 R ', NR' 2 , C (O) R ', C (O) OR', CN, NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C6-12 aryl, C 1-12 aryl (C 1-6) alkyl and optionally substituted 5-10 membered heterocyclyl, where R 'is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and 5-10 membered heterocyclyl; or two adjacent R3 or R4 groups form a benzene ring;
    [0120] - R5 is selected from H, halogen, OC (O) R ', SOR', SO 2 R ', C (O) R', C (O) OR ', CN, NO 2 , C1-6 alkyl, C3 cycloalkyl -7, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.6) alkyl and optionally substituted 5-10 membered heterocyclyl and a group of formula (A), where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.6) alkyl and 5-10 membered heterocyclyl; - R6 is selected from H, halogen, OR ', OC (O) R', SR ', SOR', SO 2 R ', NR' 2 , C (O) R ', C (O) OR', CN, NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl, where R 'is independently selected H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.6) alkyl and 5-10 membered heterocyclyl;
    [0121] - n represents 0, 1, 2, 3, or 4; Y
    [0122] - m represents 0, 1,2, 3, or 4.
    [0123]
    [0124] In a preferred embodiment, in the group of formula (A):
    [0125] - Z is selected from 5-10 membered heterocyclyl, O, S and NR ', where R' represents H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-12) alkyl. 6) or 5-10 membered heterocyclyl;
    [0126] - each Ra and Rb is independently selected from H, halogen, OH, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) alkyl (C1.6) and heterocyclyl of 5 to 10 members;
    [0127] - Y is selected from NR ' 2 , NR' 3 , OR ', OC (O) NR' 2 , C (O) NR ' 2 and heterocyclyl from 5 to 10 members, where each R 'is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and 5-10 heterocyclyl members;
    [0128] - p represents 0, 1,2, 3, 4, 5 or 6; Y
    [0129] - q represents 0, 1, 2 or 3.
    [0130]
    [0131] In a preferred embodiment, in the group of formula (A) q is 0. In another embodiment each Ra and Rb is independently selected from H, OH and C1-6 alkyl, more preferably they are H. In a particular embodiment, q is 0 and Ra and Rb are independently selected from H, OH and C1-6 alkyl. Preferably, q is 0 and Ra and Rb are H.
    [0132]
    [0133] In a preferred embodiment, in the group of formula (A):
    [0134] - Z is selected from 5 or 6 membered heterocyclyl, O and NR ', where R' represents H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl or 5-10 membered heterocyclyl;
    [0135] - each Ra and Rb is independently selected from H, OH and C1-6 alkyl;
    [0136] - Y is selected from NR'2 and 5-10 membered heterocyclyl, where each R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6- 12) C1-6 alkyl and 5-10 membered heterocyclyl;
    [0137] - p represents 0, 1, 2, 3, 4, 5 or 6; Y
    [0138] - q represents 0.
    [0139]
    [0140] Preferably, in the group of formula (A) p is selected from 1, 2, 3, 4, 5 or 6, more preferably from 1.2, 3 or 4.
    [0141] Preferably, the groups C1-6 alkyl, C3-7 cycloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and optionally substituted 5-10 membered heterocyclyl may be substituted by halogen, OR '' , OC (O) R '', SR '', SOR '', SO 2 R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , alkyl C1-6, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl.
    [0142]
    [0143] In one embodiment of the invention, R5 is selected from a group of formula (A), C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, C6-12 aryl (C1-6) alkyl ), 5 to 10 optionally substituted heterocyclyl, OC (O) R ', SOR', SO2R ', C (O) R', C (O) OR ', where R' is independently selected from C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 heterocyclyl.
    [0144] Preferably, the groups C1-6 alkyl, C3-7 cycloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-10 membered heterocyclyl in R5 may be optionally substituted by halogen, OR '' , OC (O) R '', SR '', SOR '', SO 2 R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , alkyl C1-6, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl.
    [0145]
    [0146] Preferably, R5 is a group of formula (A) as defined above.
    [0147]
    [0148] In one embodiment, R6 is selected from H, halogen, OH, OR ', NR'2, C1-6 alkyl and haloalkyl, where each R' is independently selected from C1-6 alkyl and C1-6 haloalkyl. Preferably, R6 is H.
    [0149]
    [0150] In one embodiment, each R3 and R4 is independently selected from halogen, OH, OR ', NR'2, C1-6 alkyl and haloalkyl, where each R' is independently selected from C1-6 alkyl and C1-6 haloalkyl; or two adjacent R3 or R4 groups form a benzene ring. Preferably, each R3 and R4 is independently selected from halogen, OH, OR ’, C1-6 alkyl and C1-6 haloalkyl, where R’ is selected from C1-6 alkyl and C1-6 haloalkyl.
    [0151]
    [0152] In a particular embodiment, n and m are independently selected from 0, 1 and 2, preferably from 0 and 1. In one embodiment of the invention n and m are 0.
    [0153]
    [0154] In one embodiment, R6 is H and n and m are 0.
    [0155]
    [0156] In another embodiment, R5 is a group of formula (A) as defined above and R6 is selected from H, halogen, OH, OR ', NR'2, C1-6 alkyl and haloalkyl, where each R' is independently selects C1-6 alkyl and C1-6 haloalkyl; preferably it is H.
    [0157]
    [0158] In a preferred embodiment, R5 is a group of formula (A) and R6 is H.
    [0159]
    [0160] In another preferred embodiment, R5 is a group of formula (A), R6 is H and n and m are 0.
    [0161]
    [0162] In a particular embodiment, R8 and R9 are independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl and aryl (C6-12) alkyl (C1-6), or R1 and R2 form, together with the carbon atom to which they are attached, a group C = O. Preferably, R1 and R2 form, together with the carbon atom to which they are attached, a group C = O.
    [0163]
    [0164] In one embodiment, the compound of formula (I) is compound 1a
    [0165]
    [0166]
    [0167]
    [0168] or a salt or solvate thereof.
    [0169]
    [0170] In one embodiment of the invention, the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis E virus, yellow fever, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola virus, parainfluenza virus, rotavirus, chikungunya virus, rubella virus, and measles virus, among others.
    [0171]
    [0172] Preferably, the RNA virus is HIV-1.
    [0173]
    [0174] Compounds of formula (II)
    [0175] In one aspect the invention relates to a compound of formula (II)
    [0176]
    [0177]
    [0178]
    [0179] or a salt or solvate thereof, where
    [0180] - R1, R2 and R4 are independently selected from H, halogen, OR ', OC (O) R', SR ', SOR', SO 2 R ', NR' 2 , C (O) R ', C (O) OR ', CN, NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and optionally 5-10 membered heterocyclyl substituted, where R 'is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl;
    [0181] - X is selected from O, S, SO, and SO2;
    [0182] - R3 is selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.
    [0183] 12) (C1.6) alkyl and optionally substituted 5-10 membered heterocyclyl; and - R5 and R6 are independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) (C1-6) alkyl, 5-10 membered heterocyclyl , or R5 and R6 form, together with the nitrogen atom to which they are attached, an optionally substituted 5-10 membered heterocyclyl;
    [0184] for use in the prevention or treatment of infections caused by RNA viruses.
    [0185]
    [0186] In a particular embodiment, R1, R2 and R4 are independently selected from H, halogen, OH, C1-6 alkyl and C1-6 haloalkyl. Preferably, they are independently selected from H and halogen; more preferably halogen.
    [0187]
    [0188] In one embodiment of the invention, X is selected from S, SO, and SO2, preferably it is S.
    [0189]
    [0190] In one embodiment, R 3 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and 5- to 10-membered heterocyclyl optionally substituted by halogen, OR ', OC (O) R', NR ' 2 , C (O) R', C (O) OR ', CN, NO 2 , SR', SOR ', SO 2 R', C1-6 alkyl, cycloalkyl C3-7, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C1 haloalkyl -6, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl. Preferably, R3 is C6-12 aryl optionally substituted with halogen, OR ', OC (O) R', NR ' 2 , C (O) R', C (O) OR ', CN, NO 2 , SR', SOR ', SO 2 R', C 1-6 alkyl, C 3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6_12) alkyl (C1-6) and heterocyclyl from 5 to 10.
    [0191]
    [0192] In a particular embodiment, R 5 and R 6 form, together with the nitrogen atom to which they are attached, a 5- to 10-membered heterocyclyl optionally substituted with halogen, OR ', OC (O) R', NR ' 2 , C (O) R ', C (O) OR', CN, NO 2 , SR ', SOR', SO 2 R ', C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6 aryl -12 , C 1-12 aryl (C 1-6 ) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C 1-6 alkyl, C3 cycloalkyl-
    [0193] 7 , C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6 ) alkyl and 5-10 membered heterocyclyl.
    [0194]
    [0195] In a preferred embodiment, R5 and R6 form, together with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyclyl, preferably a 5 or 6 heterocycle members, more preferably a heterocyclyl selected from pyrrolidine, piperidine, piperazine, morpholine, pyridine, pyrimidine and pyrazine; preferably piperazine. More preferably, R5 and R6 form, together with the nitrogen atom to which they are attached, a heterocyclyl selected from pyrrolidine, piperidine, piperazine, morpholine, pyridine, pyrimidine and pyrazine, even more preferably piperazine, optionally substituted with halogen, OR ', OC (O) R ', NR' 2 , C (O) R ', C (O) OR', CN, NO 2 , SR ', SOR', SO 2 R ', C1-6 alkyl, C3-7 cycloalkyl , C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl.
    [0196]
    [0197] More preferably:
    [0198] - R3 is selected from C3-7 cycloalkyl, C6-12 aryl and 5-10 membered heterocyclyl, optionally substituted; Y
    [0199] - R5 and R6 form, together with the nitrogen atom to which they are attached, an optionally substituted 5-10 membered heterocyclyl.
    [0200]
    [0201] In one embodiment, the compound of formula (II) is compound 2a
    [0202]
    [0203]
    [0204]
    [0205] 2nd
    [0206] or a salt or solvate thereof.
    [0207]
    [0208] In one embodiment of the invention, the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis E virus, yellow fever, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola virus, parainfluenza virus, rotavirus, chikungunya virus, rubella virus, and measles virus, among others.
    [0209]
    [0210] Preferably, the RNA virus is HIV-1.
    [0211] Compounds of formula (III)
    [0212] In one aspect the invention relates to a compound of formula (III)
    [0213]
    [0214]
    [0215]
    [0216] or a salt or solvate thereof, where
    [0217] - R2, R3, R4, R5, R6 and R7 are independently selected from H, halogen, OR ', OC (O) R', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, C 1-12 aryl (C 1-6) alkyl, optionally substituted 5- to 7-membered heterocyclyl, SR ', SOR', SO2R ', NR'2, C (O) R', C (O) OR ', CN and NO2, where R 'is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5- to 7-membered heterocyclyl;
    [0218] - R1 is selected from NR ', O, S, H, halogen, OR', OC (O) R ', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6. 12) (C1-6) alkyl, optionally substituted 5-7 membered heterocyclyl, SR ', SOR', SO2R ', NR'2, C (O) R', C (O) OR ', CN and NO2, where R 'is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6_12) alkyl (C1-6) alkyl and optionally substituted 5- to 7-membered heterocyclyl;
    [0219] - R 8 may be absent or selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and optionally substituted 5- to 7-membered heterocyclyl; Y
    [0220] - ^ represents a single link or a double link, so that one of the two links indicated in this way (N ^ C or C ^ R 1) represents a single link and the other a double link;
    [0221] for use in the prevention or treatment of infections caused by RNA viruses.
    [0222]
    [0223] When the link in the C ^ R 1 position is a double bond, then R1 is selected from NR ', O and S, where R' is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl , (C6.12) aryl (C1.6) alkyl and optionally substituted 5- to 7-membered heterocyclyl. When the bond in the C ^ R 1 position is a single bond, then R1 is selected from H, halogen, OR ', OC (O) R', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, aryl C6-12, aryl (C6.12) alkyl (C1.6), optionally substituted 5- to 7-membered heterocyclyl, SR ', SOR', SO2R ', NR'2, C (O) R', C (O) OR ', CN and NO2, where R' is selected independently of H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5- to 7-membered heterocyclyl.
    [0224]
    [0225] In a particular embodiment, R1 is selected from NR ', O, S, OR', SR ', SOR', SO2R ', NR'2 and 5- to 7-membered heterocyclyl, where each R' is independently selected from H, alkyl C1-6, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and heterocyclyl of 5 to 7 or two R 'groups form together with the atom to which they are attached a 5- to 7-membered heterocyclyl.
    [0226]
    [0227] In one embodiment of the invention, R1 is selected from NR9 and NR9R10, where R9 and R10 are independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12 ) (C1-6) alkyl, 5-7 membered heterocyclyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclyl.
    [0228]
    [0229] In a preferred embodiment, the bond in the C ^ R 1 position is a double bond, and R1 represents NR9, where R9 is selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl , C 1-12 aryl (C 1-6) alkyl and 5-7 membered heterocyclyl. More preferably, R1 represents NH.
    [0230]
    [0231] In another preferred embodiment, R 1 represents NR 9 R 10, where R 9 and R 10 are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl ) and 5-7 membered heterocyclyl. More preferably, R9 and R10 are independently selected from H and C1-6 alkyl. More preferably, R9 and R10 are H.
    [0232]
    [0233] In one embodiment, R2 is selected from OR ', SR', SOR 'and SO 2 R', where R 'is independently selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) (C1-6) alkyl and optionally substituted 5- to 7-membered heterocyclyl
    [0234]
    [0235] In a preferred embodiment R2 is selected from OR ', SR', SOR 'and SO2R', where R 'is independently selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6 -12) (C 1-6) alkyl and 5- to 7-membered heterocyclyl optionally substituted by halogen, OR '', OC (O) R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , SR '', SOR '', SO 2 R '', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-7 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) (C1-6) alkyl and 5-7 membered heterocyclyl.
    [0236] More preferably, R2 is SO2R ', where R' is C6-12 aryl optionally substituted with halogen, OR '', OC (O) R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , SR '', SOR '', SO 2 R '', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-7 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-7 membered heterocyclyl.
    [0237]
    [0238] In one embodiment, R3, R4, R5, R6 and R7 are independently selected from H, halogen, OR ', C1-6 alkyl and C1-6 haloalkyl, where R' is independently selected from H, C1-6 alkyl and C1 haloalkyl -6. In a particular embodiment, R3, R4, R5, R6 and R7 are H.
    [0239]
    [0240] In one embodiment, R8 is absent.
    [0241]
    [0242] In another embodiment, R 8 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and 5- to 7-membered heterocyclyl. Preferably, R8 is selected from C1-6 alkyl and C3-7 cycloalkyl; preferably C3-7 cycloalkyl.
    [0243]
    [0244] According to one embodiment, when the bond in the N ^ C position is a single bond, then R8 is selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-7 membered heterocyclyl, more preferably, is selected from C1-6 alkyl and C3-7 cycloalkyl; even more preferably C3-7 cycloalkyl. According to an embodiment of the invention, when the link in the N ^ C position is a double bond, then R8 is absent. According to another embodiment, when the bond in the N ^ C position is a double bond, then R8 is selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and 5-7 membered heterocyclyl, more preferably, is selected from C1-6 alkyl and C3-7 cycloalkyl; even more preferably C3-7 cycloalkyl and, in this case (when R8 is not absent and N ^ C is a double bond), the nitrogen atom substituted with one of these groups is positively charged.
    [0245]
    [0246] In one embodiment:
    [0247] - R1 is selected from NR ', O, S, OR', SR ', SOR', SO2R ', NR'2 and 5- to 7-membered heterocyclyl, where each R' is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and heterocyclyl of 5 to 7 or two R 'groups form together with the atom to which a heterocyclyl is attached 5 to 7 members;
    [0248] - R2 is selected from OR ', SR', SOR 'and SO2R', where R 'is independently selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) C1-6 alkyl and 5-7 membered heterocyclyl optionally substituted by halogen, OR '', OC (O) R '', NR '' 2 , C (O) R '', C (O) OR '' , CN, NO 2 , SR '', SOR '', SO2R '', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1.
    [0249] 6) and 5-7 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) alkyl (C1-6) and heterocyclyl of 5 to 7 members.
    [0250]
    [0251] In a particular embodiment:
    [0252] - R1 represents NR9 or NR9R10, where R9 and R10 are independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) alkyl (C1-6), 5 to 7 membered heterocyclyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a 5 to 7 membered heterocyclyl;
    [0253] - R2 is SO2R ', where R' is C6-12 aryl optionally substituted with halogen, OR '', OC (O) R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , SR'',SOR'', SO 2 R'', Ci-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) alkyl (C1 .6) and 5-7 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) alkyl (C1 .6) and 5-7 membered heterocyclyl.
    [0254]
    [0255] In one embodiment, the compound of formula (III) is compound 2b
    [0256]
    [0257]
    [0258]
    [0259] or a salt or solvate thereof.
    [0260]
    [0261] In one embodiment of the invention, the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis E virus, yellow fever, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola virus, parainfluenza virus, rotavirus, Chikungunya virus, rubella virus, and measles virus, among others.
    [0262]
    [0263] Preferably, the RNA virus is HIV-1.
    [0264]
    [0265] The following non-limiting examples are intended to illustrate the present invention and should not be construed as limitations on its scope.
    [0266]
    [0267] EXAMPLES
    [0268] Materials and methods
    [0269] Compounds Compound 1a was obtained through Sigma-Aldrich, St. Louis USA (MyriaScreen compound library). Compound 2a was obtained through Sigma-Aldrich (St. Louis, USA). Compound 2b was obtained through AKos GmbH (Steinen, Germany). Neomycin B used as a control in FA experiments was acquired through Sigma-Aldrich (St. Louis, USA) (Figure 1).
    [0270]
    [0271] Samples of RNA, DNA, peptide and protein. The composition and preparation of the following species have been previously described in detail in the prior art (S. Prado et al., Biochem Pharmacol 107 (2016) 14-28; Gonzalez-Bulnes et al., Angewandte Chemie-International Edition 52 (50) (2013) 13405-13409): RNA sequence of 234 RRE nucleotides, RNA oligonucleotides corresponding to subdomain IIB IIBh, IIBh-19ap and IIBh-23fl, Escherichia coli tRNA, self-complementary DNA nucleotide oligonucleotide of 26 LTRd , complete Rev protein, and Rev34-50 peptide labeled with FITC frevp. RRE and Rev were used in EMSA assays, and unlabelled IIBh was used in NMR and FA spectroscopy experiments. Frevp was used in FA trials. IIBh-19ap and IIBh-23fl contained 2-amino purine instead of A in the missing nucleotide A19 of the loop and FITC covalently linked to the extra-helical nucleotide U23 of the loop, respectively, and were used in fluorescence intensity assays. TRNAs and LTRd were used as controls for RNA and DNA specificity in these fluorescence intensity experiments.
    [0272]
    [0273] Fluorescence anisotropy (FA). These experiments were performed and analyzed as described in the prior art (Prado et al., Biochem Pharmacol 107 (2016) 14 28; Gonzalez-Bulnes et al., Angewandte Chemie-International Edition 52 (50) (2013) 13405-13409; Luedtke et al., Biopolymers 70 (1) (2003) 103-19), using 96-well plates and Victor X3 or Victor X5 plate readers (PerkinElmer, Waltham USA). The trials used 10 nM of frevp and 60 nM of IIBh, and included a positive control (one mixture of IIBh and frevp) and two negative controls (frevp and a mixture of IIBh, frevp and neomycin B). It was only considered that there was inhibition of IIBh-frevp when the anisotropy reached the minimum expected value at the highest inhibitor concentrations. In order to ensure that there was no spectral overlap with FITC, anisotropy data was also collected for each of the compounds. None of them emitted fluorescence under the test conditions. These experiments were repeated three times for each compound.
    [0274]
    [0275] Testing of electrophoretic mobility change (EMSA). These experiments used 78 nM of complete RRE, 1.32 ^ M of complete Rev and increasing concentrations of each compound, and were carried out and analyzed as previously described in the prior art (Prado et al., Biochem Pharmacol 107 (2016) 14-28; Fang, et al., Cell 155 (3) (2013) 594-605). The IC50 values were determined by measuring the area and intensity of the band corresponding to free RRE. These experiments were performed at least three times for each compound.
    [0276]
    [0277] Fluorescence Intensity Depending on the absorption spectra of the compounds, these experiments measured association to the IIBh-19ap or IIBh-23fl RNA sequences labeled with 2-aminopurine and fluorescein in residues A19 and U23 of loop IIB, respectively (Prado et al., Biochem Pharmacol 107 (2016) 14-28), and were carried out on SPECTRA GEMINI XPS (Molecular Devices, Sunnyvale, USA) or Victor X5 (Perkin Elmer) plate readers. The concentration of RNA IIB in these assays was 100 nM, and the specificity with respect to RNA and DNA of the interactions was evaluated by doubling the experiments in the presence of a 100-fold (10 ^ M) molar excess of tRNA or duplex of LTRd DNA. All fluorescence intensity experiments were performed at least three times for each compound.
    [0278]
    [0279] NMR spectroscopy. NMR spectra were acquired on a Bruker Avance 500 MHz spectrometer and analyzed with Topspin 3.5 (Bruker Biospin, Billerica, USA). The interaction between the tested compounds and IIBh RNA samples dissolved at a concentration of 40-60. ^ M were monitored as previously described in the prior art (Prado et al., Biochem Pharmacol 107 (2016) 14 28; Gonzalez-Bulnes et al., Angewandte Chemie-International Edition 52 (50) (2013) 13405-13409), using single-dimensional and two-dimensional experiments (TOCSY) at molar ligand ratios: increasing RNA.
    [0280] Plasmids, viruses and cells for ex vivo assays. Vectors pNL4.3-Luc and pNL4.3-Ren were generated by cloning luciferase and renilla genes, respectively, at the nef site of HIV-1 proviral plasmid pNL4.3 (Adachi et al., J Virol 59 (2) (1986) 284-91), as previously described in the prior art (Garcia-Perez et al., J Med Virol 79 (2) (2007) 127-37). MT-2 cells (Harada et al., Science 229 (4713) (1985) 563-6) and 293T (American Type Culture Collection, Rockville USA) were cultured as previously described (Prado et al., Biochem Pharmacol 107 (2016) 14-28).
    [0281]
    [0282] Anti-HIV-1 activity and cellular toxicity. The methodology used to perform and analyze these experiments has been previously described (Prado et al., Biochem Pharmacol 107 (2016) 14-28; Gonzalez-Bulnes et al., Angewandte Chemie-International Edition 52 (50) (2013) 13405- 13409). Briefly, infectious supernatants were obtained from the transfection of 293T cells with plasmid pNL4.3-Ren. MT-2 cells were infected with these supernatants in the presence of the compounds, and quantification of anti-HIV activity was performed 48 h after infection determining luciferase activity in cell lysates. Cell viability was evaluated in cells treated with the same concentrations of compounds using the CellTiterGlo assay (Promega). The results of antiviral activity and cellular toxicity represent the average of at least three independent experiments.
    [0283]
    [0284] Cellular transfection assays. MT-2 cells were transfected with plasmids containing a luciferase reporter gene whose expression was under the control of complete HIV-1 (NL4.3-luc) or of the HIV-1 LTR promoter (LTR-Luc). After transfection, cells were treated with different concentrations of compound, and 48 h later luciferase activity was quantified in cell lysates (Prado et al., Biochem Pharmacol 107 (2016) 14-28; Gonzalez-Bulnes et al ., Angewandte Chemie-International Edition 52 (50) (2013) 13405-13409).
    [0285]
    [0286] Analysis of HIV-1 RNA processing. MT-2 cells, previously treated for 72 or 96 hours were transfected with two different concentrations (5 and 10 ^ M) of compound 1a or 2a, with a plasmid pNL4.3. The total cellular RNA was then isolated, treated with DNase I and re-transcribed as described in the prior art (Prado et al., Biochem Pharmacol 107 (2016) 14-28). Transcripts of unprocessed, semi-processed and fully processed HIV-1 RNA were quantified by qPCR in relation to a control obtained without treatment, using the primers described by Mohammadi et al. (PLoS Pathog 9 (1) (2013) e1003161), and GAPDH as an endogenous control.
    [0287]
    [0288] Results
    [0289] Inhibition of the interaction between subdomain IIB of RRE and Rev34-50, and inhibition of the complete RRE-Rev complex
    [0290] The ability of the compounds to inhibit the NB-Rev34_50 interaction was assessed by an assay based on the detection by fluorescence anisotropy (FA) of the displacement of a F34-labeled Rev34-50 peptide from its binding site in the IIB RRE subdomain. The ability of the compounds to inhibit the formation of the RRE-Rev complex was evaluated by an electrophoretic mobility change assay (EMSA)
    [0291] Compounds 1a , 2a and 2b were found to interfere with both the NB-Rev34 interaction.
    [0292] 50 as with the formation of the complete RRE-Rev complex (Table 1, Figure 2). The most potent compound was 2a (with IC50 between 4.7 and 4.8 ^ M in both FA and EMSA experiments), followed by 2b (10.3-13.7 ^ .M). The increase in the concentrations of these two compounds increased the intensity of the band corresponding to free RRE in the EMSA assays. This indicates the inhibition of the full-length RRE-Rev complex, which typically has several electrophoretic bands corresponding to complexes with different numbers of associated Rev monomers (Figure 2b). Compound 1a blocked the interaction between subdomain IIB and Rev34-50 with an IC506.7 ^ .M), and promoted the formation of RRE-Rev complexes with an unusual molecular weight at concentrations greater than 10. ^ M (Figure 2b) .
    [0293]
    [0294] Table 1
    [0295]
    [0296]
    [0297]
    [0298] a The IC50 IIBh-R ev34-50 values were obtained by FA experiments using 60 nM IIBh and 10 nM frevp, and the IC50 RRE-Rev values were measured by EMSA with 78 nM RRE and 1.32 ^ M Rev. The table shows IC50 values obtained by two (EMSA) or three (FA) independent experiments; in brackets the 95% confidence intervals and the R2 coefficients are shown.
    [0299] b At concentrations> 10 ^ M, 1a induced an unusual accumulation of RRE-Rev complexes of intermediate molecular weight instead of free RRE. This prevented the determination of the IC50 RRE-Rev value.
    [0300]
    [0301] RNA binding properties
    [0302] To verify whether the compounds inhibit the interaction between RRE and Rev by binding to the RRE RNA, association to the RB subdomain IIB was measured with fluorescence intensity experiments, using the IIBh-19ap or IIBh-23fl RNA sequences containing 2- probes. amino purine and fluorescein in the missing residues A19 and U23 of loop IIB, respectively (Prado et al., Biochem Pharmacol 107 (2016) 14-28) (Figure 3). The specificity of the interaction was evaluated by duplicating the experiments in the presence of a 100-fold molar excess of tRNAs. Likewise, we evaluate the specificity related to double-stranded DNA by additionally performing the experiments with a 100-fold molar excess of a 26-base-pair DNA duplex (identified as LTRd) that contains binding sites of NF- k B and Sp transcription factors -1 (Prado et al., Biochem Pharmacol 107 (2016) 14-28). These two factors bind to the LTR promoter of HIV-1 DNA and are essential for virus replication (Jones et al., Annu Rev Biochem 63 (1994) 717-43).
    [0303] All compounds 1a , 2a and 2b were associated with the RB subdomain IIB of the RNA. The most potently bound compound was 1a with a Kd of 1.4 ^ M, followed by 2a and 2b (10.8-12.1 ^ .M) (Table 2, Figure 3). The interaction was specific for 2a and 2b , as indicated by the binding curves obtained in the presence of a 100-fold molar excess of tRNA or LTRd. Compound 1a exhibited moderate specificity.
    [0304]
    [0305] Table 2
    [0306]
    [0307]
    [0308] a For each compound, the table shows dissociation equilibrium constants of IIBh (Kd) in the absence (IIBh) and presence of tRNA (IIBh tRNA) or LTRd DNA duplex (IIBh LTRd). The specificity of the interaction was quantified by calculating the ratios Kd (NBh) / Kd (NBh + tRNA) and Kd (NBh) / Kd (NBh + LTRd). The interactions with specificity relationships close to 1 or> 1 are specific, while those with << 1 relationships are nonspecific. All compounds were analyzed using IIBh-19ap. The table shows the Kd values obtained with two independent experiments; in brackets the 95% confidence intervals and the R2 coefficients are indicated.
    [0309]
    [0310] Subsequently, we use NMR spectroscopy to identify the binding sites in the IIBh hairpin of the compounds. The NMR results were consistent with fluorescence observations: 1a , which showed greater affinity for IIBh in the fluorescence assay, widened or altered the chemical shift of IIBh resonances at low molar ratios of drug: RNA. This compound altered the signals of residues C9, A 19, C20 and U23 that comprise the Rev binding site, but also disturbed the signals of the double helix stems flanking the loop. 2a and 2b required a drug: higher RNA molar ratio to induce changes in IIBh RNA signals. The binding of 2a affected the residue signals located on the stems flanking the inner loop, while 2b , the compound that presented a greater Kd in the fluorescence test, only induced signal broadening of the residue U23 of the loop at a molar ratio drug: high RNA.
    [0311]
    [0312] Antiretroviral activity and cellular toxicity
    [0313] Compounds 1a , 2a and 2b were found to have antiretroviral activity in a cell infection assay. The most potent inhibitor was 1a , with a submicromolar value of EC50 (830 nM), followed by 2a (EC50 = 2.0 ^ M) and 2b (EC50 = 10.2 ^ M) (Table 3 and Figure 4a). Cytotoxic concentrations of the compounds were also measured and compared with the antiviral concentrations obtained in the infection experiments. The CC50 values were 34, 22 and> 10 times higher than the antiviral concentrations for 1a , 2a and 2b (Table 3 and Figure 4a).
    [0314]
    [0315] Table 3
    [0316]
    [0317]
    [0318]
    [0319] a In brackets, the confidence intervals and R2 coefficients are indicated; n / a: not determined
    [0320]
    [0321] Location of antiviral targets
    [0322] In order to identify the target, or set of targets, of the compounds tested, we performed an assay based on the transfection of a full-length HIV-1 vector. In this experiment, the phases of entry, reverse transcription and integration of DNA from the virus cycle are avoided, so that only transcriptional or post-transcriptional events that can be blocked by the inhibitor being studied occur. When the compounds were evaluated with this transfection assay, compounds 1a and 2a showed low EC50 values ranging between 2.5 and 3.3 ^ M (Table 3 and Figure 4b). This result indicated that these compounds act in transcriptional or post-transcriptional processes of the virus cycle. In contrast, 2b was found to be inactive in the transfection assay at concentrations below 100 ^ M. Since this compound had an EC50 value of 10.2 ^ M in the infection experiment, this result suggests that 2b acts primarily in the pre-transcriptional processes of the virus cycle in a cellular context.
    [0323]
    [0324] Inhibition of HIV-1 transcription and Rev function
    [0325] RRE-Rev ribonucleoprotein allows the transport of unprocessed or partially processed viral transcripts to the cytoplasm, an essential post-transcriptional process required by the virus to complete its replication cycle. Compounds 1a and 2a altered the full-length NB-Rev34.50 and RRE-Rev interactions at low concentrations (Table 1 and Figure 2), recognized subdomain IIB of RRE with high or moderate specificity in fluorescence experiments (Table 2 and Figure 3), and exhibited lower EC50 values in the HIV-1 transfection assay (Table 3 and Figure 4b). In contrast, compound 2b inhibited the NB-Rev34_50 and RRE-Rev complexes at higher concentrations, joined sub-domain IIB of RRE with lower affinity (Tables 1 and 2 and Figure 3), and had less activity in the test. HIV-1 transfection (Table 3 and Figure 4b).
    [0326]
    [0327] The antiviral mechanism of compounds 1a and 2a was explored with additional cell assays. First it was evaluated whether they had an effect on viral transcription by determining their inhibitory activity in an experiment based on the transfection of a plasmid encoding a luciferase gene whose expression depends on the LTR promoter of the virus (Hazan et al., Proc Natl Acad Sci USA 87 (20) (1990) 7861-5). 1a showed a weaker inhibition of LTR-dependent expression in relation to the activity detected in the complete HIV-1 transfection assay, while 2a inhibited LTR-dependent expression with an EC50 value similar to those measured in the experiments. of infection and transfection of HIV-1 (Table 3). These results suggest that while the antiviral activity of 1a is independent of LTR-dependent transcription, the effect of 2a could be due to inhibition of LTR-mediated transcription.
    [0328]
    [0329] Next, it was checked whether compounds 1a and 2a acted in the RRE-Rev system in a cellular context. After transfecting the cells with a full-length proviral vector, the amounts of unprocessed, semi-processed and fully processed HIV-1 RNA transcripts were quantified by RT-qPCR in the absence and presence of each compound (Prado et al., Biochem Pharmacol 107 (2016) 14-28). Since Rev indirectly disadvantages the splicing process when transporting unprocessed or semi-processed viral transcripts from the nucleus to the cytoplasm, blocking the RRE-Rev system should increase levels of fully processed species and reduce the amount of HIV-1 transcripts without process or semi-processed. This effect was clearly observed when the cells were exposed to compound 1a at concentrations of 5 and 10 ^ M (Figure 5). A significant reduction in viral transcript levels was also detected in relation to untreated cells in the presence of this inhibitor. On the contrary, the same concentration of 2a did not induce clear changes in the patterns of unprocessed viral transcripts versus processed ones, and reduced the amount of viral transcripts to a lesser extent with respect to 1a .
    权利要求:
    Claims (40)
    [1]
    1. Compound of formula (I)

    [2]
    2. A compound for use according to claim 1, wherein the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis A virus hepatitis E, yellow fever virus, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola virus, parainfluenza virus, rotavirus, chikungunya virus, rubella virus, measles virus.
    [3]
    3. Compound for use according to claim 1 or 2, wherein the RNA virus is HIV-1.
    [4]
    4 . Compound for use according to any one of claims 1 to 3, wherein the compound of formula (I) is a compound of formula (I ')

    [5]
    5. Compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) is a compound of formula (I ’’)

    [6]
    6. A compound for use according to any one of claims 1 to 5, wherein R8 and R9 form, together with the carbon atom to which they are attached, a group C = O.
    [7]
    7. Compound for use according to any one of claims 1 to 6, wherein R5 is a group of formula (A)

    [8]
    8. Compound for use according to claim 7, wherein
    - Z is selected from 5-10 membered heterocyclyl, O, S and NR ', where R' represents H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, C6-12 aryl (C1-) alkyl 6) or 5-10 membered heterocyclyl;
    - each Ra and Rb is independently selected from H, halogen, OH, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and heterocyclyl of 5 to 10 members;
    - Y is selected from NR'2, NR'3, OR ', OC (O) NR'2, C (O) NR'2 and 5-10 membered heterocyclyl, where each R' is independently selected from H, alkyl C1-6, C3.7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl;
    - p represents 0, 1,2, 3, 4, 5 or 6; Y
    - q represents 0, 1, 2 or 3.
    [9]
    9. Compound for use according to any of claims 7 to 8, wherein q is 0.
    [10]
    10. Compound for use according to any of claims 7 to 9, wherein Ra and Rb are H.
    [11]
    11. A compound for use according to any one of claims 1 to 10, wherein n and m are independently selected from 0, 1 and 2, preferably from 0 and 1.
    [12]
    12. Compound for use according to any of claims 1 to 11, wherein n and m are 0.
    [13]
    13. Compound for use according to any one of claims 1 to 12, wherein each R3 and R4 is independently selected from halogen, OH, OR ', C1-6 alkyl and C1-6 haloalkyl, wherein R' is selected from C1- alkyl 6 and C1-6 haloalkyl; or two adjacent R3 or R4 groups form a benzene ring.
    [14]
    14. Compound for use according to any one of claims 1 to 13, wherein R6 is selected from H, halogen, OH, OR ', NR'2, C1-6 alkyl and haloalkyl, wherein each R' is independently selected from C1 alkyl -6 and C1-6 haloalkyl.
    [15]
    15. Compound for use according to any of claims 1 to 14, wherein R6 is H.
    [16]
    16. Compound for use according to any one of claims 1 to 15, wherein n and m are 0 and R6 is H.
    [17]
    17. Compound for use according to any one of claims 1 to 16, wherein the compound of formula (I) is

    [18]
    18. Compound of formula (II)

    [19]
    19. Compound for use according to claim 18, wherein the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis A virus hepatitis E, yellow fever virus, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola, parainfluenza virus, rotavirus, chikungunya virus, rubella virus, measles virus.
    [20]
    20. Compound for use according to any of claims 18 or 19, wherein the RNA virus is HIV-1.
    [21]
    21. Compound for use according to any of claims 18 to 20, wherein R1, R2 and R4 are independently selected from H, halogen, OH, C1-6 alkyl and C1-6 haloalkyl.
    [22]
    22. Compound for use according to any of claims 18 to 21, wherein X is selected from S, SO, and SO2, preferably is S.
    [23]
    23. Compound for use according to any of claims 18 to 22, wherein R3 is selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-) alkyl 6) and 5-10 membered heterocyclyl optionally substituted with halogen, OR ', OC (O) R', NR'2, C (O) R ', C (O) OR', CN, NO2, SR ', SOR ', SO2R', C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl (C 1-6) alkyl and 5-10 membered heterocyclyl, where R 'is selected independently of H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6.12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl.
    [24]
    24. Compound for use according to any of claims 18 to 23, wherein R3 is C6-12 aryl optionally substituted with halogen, OR ', OC (O) R', NR'2, C (O) R ', C ( O) OR ', CN, NO2, SR', SOR ', SO2R', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, C6-12 aryl (C1-6) alkyl and 5-10 heterocyclyl .
    [25]
    25. Compound for use according to any of claims 18 to 24, wherein R5 and R6 form, together with the nitrogen atom to which they are attached, a 5- to 10-membered heterocyclyl optionally substituted by halogen, OR ', OC (O ) R ', NR'2, C (O) R', C (O) OR ', CN, NO2, SR', SOR ', SO2R', C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, C6-12 aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, aryl C6-12, aryl (C6-12) alkyl (C1-6) and 5-10 membered heterocyclyl.
    [26]
    26. Compound for use according to any of claims 18 to 25, wherein the compound of formula (II) is

    [27]
    27. Compound of formula (III)

    [28]
    28. A compound for use according to claim 27, wherein the RNA virus is selected from HIV-1 virus, HIV-2 virus, acute severe respiratory syndrome virus, hepatitis C virus, hepatitis A virus, hepatitis A virus hepatitis E, yellow fever virus, dengue virus, West Nile virus, poliovirus, influenza virus, Ebola virus, parainfluenza virus, rotavirus, chikungunya virus, rubella virus, measles virus.
    [29]
    29. Compound for use according to any of claims 27 or 28, wherein the RNA virus is HIV-1.
    [30]
    30. Compound for use according to any of claims 27 to 29, wherein R1 is selected from NR ', O, S, OR', SR ', SOR', SO2R ', NR'2 and 5-10 membered heterocyclyl, where each R 'is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6.12) alkyl (C1-6) and heterocyclyl from 5 to 10 or two R 'groups form together with the atom to which a 5-10 membered heterocyclyl is attached.
    [31]
    31. Compound for use according to any of claims 27 to 30, wherein R1 is selected from NR9 and NR9R10, wherein R9 and R10 are independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, aryl C6-12, aryl (C6.12) alkyl (C1-6), 5-10 membered heterocyclyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-10 membered heterocyclyl.
    [32]
    32. Compound for use according to any of claims 27 to 31, wherein R2 is selected from OR ', SR', SOR ', SO2R', C (O) R ', and C (O) OR, where R' is independently selects C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and optionally substituted 5-10 membered heterocyclyl.
    [33]
    33. Compound for use according to any of claims 27 to 32, wherein R2 is selected from OR ', SR', SOR ', SO2R', C (O) R ', and C (O) OR, where R' is independently selects C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl, C 1-12 aryl, and 5-10 membered heterocyclyl optionally substituted by halogen, OR '' , OC (O) R '', NR '' 2 , C (O) R '', C (O) OR '', CN, NO 2 , SR '', SOR '', SO2R '', C1- alkyl 6, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, aryl (C6-12) (C1-6) alkyl and 5 to 10 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-6) alkyl, and 5 to heterocyclyl 10 members
    [34]
    34. Compound for use according to any of claims 27 to 33, wherein R2 is SO2R ', where R' is C6-12 aryl optionally substituted with halogen, OR '', OC (O) R '', NR '' 2 , C (O) R ', C (O) OR'', CN, NO 2, SR', SOR ', SO 2 R'', alkyl C 1-6, C3-7, haloalkyl C1- 6, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl, where R '' is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1- haloalkyl 6, C6-12 aryl, (C6-12) aryl (C1-6) alkyl and 5-10 membered heterocyclyl.
    [35]
    35. Compound for use according to any one of claims 27 to 34, wherein R3, R4, R5, R6 and R7 are independently selected from H, halogen, OR ', C1-6 alkyl and C1-6 haloalkyl, wherein R' is independently selects H, C1-6 alkyl and C1-6 haloalkyl.
    [36]
    36. Compound for use according to any one of claims 27 to 35, wherein R3, R4, R5, R6 and R7 are H.
    [37]
    37. Compound for use according to any of claims 27 to 36, wherein R8 is absent.
    [38]
    38. Compound for use according to any of claims 27 to 37, wherein R8 is selected from C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12) aryl (C1-) alkyl 6) and 5-10 membered heterocyclyl.
    [39]
    39. Compound for use according to any one of claims 27 to 38, wherein R8 is selected from C1-6 alkyl and C3-7 cycloalkyl; preferably C3-7 cycloalkyl.
    [40]
    40. Compound for use according to any of claims 27 to 41, wherein the compound of formula (III) is

    or a salt or solvate thereof.
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