WO2020049208A1 - Aurora kinase as target for treating, preventing or curing hiv infection or aids - Google Patents

Aurora kinase as target for treating, preventing or curing hiv infection or aids Download PDF

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WO2020049208A1
WO2020049208A1 PCT/ES2019/070596 ES2019070596W WO2020049208A1 WO 2020049208 A1 WO2020049208 A1 WO 2020049208A1 ES 2019070596 W ES2019070596 W ES 2019070596W WO 2020049208 A1 WO2020049208 A1 WO 2020049208A1
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group
alkyl
substituted
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amino
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PCT/ES2019/070596
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José Andrés ESTÉ ARAQUE
Edurne GARCÍA VIDAL
Ester BALLANA GUIX
Roger BADIA CÒRCOLES
Eva RIVEIRA MUÑOZ
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Fundacio Privada Institut De Recerca De La Sida - Caixa
Institut De Recerca Germans Trias I Pujol
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • Aurora kinase as a target to treat, prevent or cure an HIV infection or AIDS
  • the present invention relates to the use of aurora kinase inhibitors (AURK) to treat or prevent an infection by human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) in a subject.
  • AURK aurora kinase inhibitors
  • the present invention further relates to compositions containing AURK inhibitors and combinations of AURK inhibitors with other active agents useful for treating or preventing HIV or AIDS infection in a subject.
  • Various AURK inhibitors and their use alone or in combination with other active agents to treat or prevent HIV infection are disclosed and exemplified.
  • HIV infection is one of the main threats to global human health. It is estimated that more than 36.7 million people worldwide are currently infected with HIV. Almost 2 million of these patients became infected in 2016 alone. See UNAIDS, http://www.unaids.org/, May 2018.
  • ART antiretroviral therapy
  • HDACi histone deacetylase inhibitors
  • PLCm protein kinase C modulator
  • the present invention relates to a method of treating or preventing an HIV or AIDS infection which comprises administering a therapeutically effective amount of an aurora kinase inhibitor (AURK) to a subject in need.
  • AURK aurora kinase inhibitor
  • the invention relates to a composition comprising at least one AURK inhibitor for use in the treatment or prevention of a HIV infection or AIDS in a subject who needs it.
  • the invention relates to a combination comprising at least one AURK inhibitor and at least one additional active agent for use in treating or preventing HIV infection or AIDS in a subject in need.
  • the invention relates to a kit comprising the AURK inhibitors, additional active agents, compositions and combinations of the invention for use in the treatment or prevention of HIV infection or AIDS in a subject who needs to.
  • FIG. 1 Aurora kinase inhibitors (AURKi) can induce reactivation of HIV-1 in J-Hig cells.
  • AURKi Aurora kinase inhibitors
  • Anticancer compounds identified as hits for reactivation of HIV-1 (relative reactivation 3 panobinostat 0.16 mM ⁇ 2DE) and their relative value
  • Anticancer compounds classified as pseudo-successes panobinostat 0.16 pM ⁇ 2DE> relative reactivation 3 1, 4) and its relative reactivation of HIV-1.
  • the control conditions used in the test were: untreated (UN), percentage of DMSO present in the condition of the compounds (0.25% DMSO) and HDACi panobinostat (PNB 0.16 pM) and vorinostat (VOR 4 p.m). Drugs are classified by their target. Values represent the mean ⁇ SD of three independent experiments.
  • the Aurora kinase family is one of the most effective targets for latency reversal agents (LRA) after analyzing the library of anticancer compounds
  • AURK is classified as the second most common target with three different drugs classified as hits. It scored only below the histone deacetylase (HDAC) family, a target well known for dormancy reactivation.
  • HDAC histone deacetylase
  • the AURK family is still in the top fourth position, with seven AURK inhibitors classified as hits or pseudo-hits, out of a total of 19 different target families that can induce reactivation.
  • AURKA and B (AURKB) inhibitors act as latency reversal agents (LRA) in various latently infected cell lines and induce cell cycle arrest prior to cell division (a) Reactivation of HIV induced by AURKA inhibitor MK-5108 (20-0.8 pM) and AURKB inhibitor barasertib (20-0.8 pM) in J-Hig cells.
  • HDAC inhibitors vorinostat (VOR; 4 - 0.16 pM) and panobinostat (PNB; 4 - 0.16 pM) and acitretin (25 - 1 pM) were used as positive and negative controls, respectively.
  • Reactivation was determined by quantifying GFP + cells (%) after culturing J-HIG with the compounds for 24 h.
  • panobinostat latency reversal agent (PNB; 0.8 pM) was used as a control. Values represent the mean ⁇ SD of at least three independent experiments performed in triplicate (a) and (b), or in individual replications (c). A, untreated. DMSO at 0.5%, same amount as in compound conditions. G0-G1, phase of the G0 and G1 cell cycle. S, phase of the cell cycle S. G2-M, phase of the G2 cell cycle and mitosis. 4N, quadriploid cells arrested.
  • AURKB inhibitors (barasertib and MK-5108) induce reactivation in latently infected undifferentiated primary CD4 + T cells. HIV reactivation was measured by both GFP expression (a) and quantification of viral mRNA in supernatant (b). (c) Percentage of cell viability of (a). Viability was measured by flow cytometry as the percentage of negative cells after incubation with a cell death staining kit. ACD3aCD28 was used as a positive control for reactivation, as well as HDACi vorinostat (VOR; 25 - 0.2 mM) and panobinostat (PNB; 4 - 0.032 pM) inhibitors.
  • VOR HDACi vorinostat
  • PPB panobinostat
  • Values in (a) and (c) represent the mean ⁇ SD of at least three experiments performed in triplicate, while in (b) only the value of one triplicate of one of the independent experiments in (a) is represented.
  • A untreated. DMSO, same amount as under compound conditions.
  • FIG. 6 AURKB silencing is sufficient to reverse HIV latency and enhance the effect of HDACi.
  • (a) Reactivation of HIV in J-Hig cells 48 h after interference with siRNA that targets AURKB. At 24 h after interference, cells were treated with HDACi panobinostat and vorinostat 24 h before flow cytometric reading. Reactivation was determined by quantifying GFP + cells (%). The starting point of the graph is set at the simulated untreated value
  • AURK inhibitors show an antiviral effect in primary cells that does not affect SAMHD1 function.
  • FIG. 9 The antiviral effect of AURK inhibitors does not antagonize the activity of other antiretroviral compounds.
  • (a, b) Antiviral activity of well known antiretroviral compounds AZT (1 - 0.0016 pg / ml) (a) or raltegravir (1 - 0.0016 pg / ml) (b) in combination with AURKi barasertib (0, 8mM) and MK-5108 (0.16mM). Cells were treated for 24 hr prior to infection with AURKi and washed thereafter. Infection was measured 48 h after the addition of the antiretroviral compounds and the virus as a percentage of GFP + cells. Values in (a) and (b) represent the mean ⁇ SD of three experiments.
  • FIG. 10 AURK inhibition leads to cell cycle arrest in G2-M phases.
  • nucleic acid and amino acid sequences represented in the attached sequence list are shown using the conventional letter abbreviations and codes applied in a conventional manner in the art. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood to be included by any reference to the represented strand.
  • SEQ ID NO: 1-4 are aurora kinase receptor silencing RNA sequences.
  • the present invention relates to the use of AURK inhibitors, and especially AURKB inhibitors, to treat or prevent an HIV or AIDS infection in a subject in need.
  • AURK inhibitors and especially AURKB inhibitors
  • the application of the AURK inhibitors of the invention to treat or prevent HIV infection is not described in the prior art.
  • the present invention discloses that the combination of AURK inhibitors with latency reversal agents such as HDAC inhibitors has an unexpected synergistic effect on viral reactivation. This synergistic effect with HDAC inhibitors is also observed when AURKB is silenced using siRNA.
  • the AURK inhibitors of the present invention do not have or have very few interactions with antiretroviral drugs regularly administered to patients undergoing antiretroviral therapy. Therefore, the AURK inhibitors of the present invention would be suitable for inclusion in ART protocols commonly applied to patients with HIV or AIDS.
  • AIDS refers to the phase symptomatic of HIV infection, and includes both acquired immunodeficiency syndrome (commonly known as AIDS) and "CRS,” or AIDS-related complex. See Adler M, et al., Brit. Med. J. 1987; 294: 1145-1147.
  • the immunological and clinical manifestations of AIDS are well known in the art and include, for example, opportunistic infections and cancers resulting from immune deficiency.
  • alisertib and "S1133", as used herein, refer to 4 - [[9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5.4 -d] [2] benzazepin- 2-yl] amino] -2-methoxybenzoic, C27H2 0 CIFN4O4 CAS [1028486-01-2], a compound of chemical structure:
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function similarly to amino acids that are produced from natural way.
  • Amino acids may be referred to herein as either their commonly known three letter symbols or the one letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • nucleotides can be named by their commonly accepted individual letter codes.
  • AMG-900 and S2719 refer to N- [4- [3- (2-aminopyrimidin-4-yl) pyridin-2-yl] oxyphenyl] - 4- (4-methylthiophene-2-yl) phthalazin- 1 -amine, C28H21N7OS CAS [945595-80-2], a compound of chemical structure:
  • antiretroviral therapy refers to the administration of one or more antiretroviral drugs (ie, HIV antiretrovirals) to inhibit HIV replication.
  • TAR typically involves the administration of at least one antiretroviral agent (or, commonly, an antiretroviral cocktail) such as a nucleoside reverse transcriptase inhibitor (eg zidovudine (AZT, lamivudine (3TC) and abacavir), a non-nucleoside reverse transcriptase inhibitor) (eg nevirapine and efavirenz) and protease inhibitor (eg indinavir, ritonavir, and lopinavir.)
  • HAART highly active antiretroviral therapy
  • HAART refers to treatment regimens designed to suppress aggressive HIV replication and progression of The disease: HAART usually consists of three or more different drugs, such as, for example, two nucleoside reverse transcriptase inhibitors and one protease inhibitor.
  • aurora kinase and "AURK”, as used herein, refer to any one of a family of related serine / threonine kinases involved in mitotic progression.
  • a variety of cellular proteins that play a role in cell division are substrates for aurora kinase enzyme phosphorylation, including, without limitation, histone H3, p53, CENP-A, myosin II regulatory light chain, protein phosphatase-1, TPX. -2, INCENP, survivin, topoisomerase II alpha, vimentin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5, Ndd Op and D-TACC.
  • Aurora kinase enzymes are themselves also substrates for autophosphorylation (eg, in Thr288).
  • aurora kinase refers to any aurora kinase protein of any species, including, but not limited to, the classes of AURK aurora A (AURKA), aurora B (AURKB) and aurora C (AURKC).
  • aurora kinase inhibitor and "aurk inhibitor” as used herein refer to a compound that can interact with an aurora kinase and inhibit its enzymatic activity. Inhibiting the enzymatic activity of aurora kinase means reducing the ability of an aurora kinase to phosphorylate a peptide or protein substrate.
  • barasertib and “S1147”, as used herein, refer to 2- [3 - [[7- [3- [ethyl (2-hydroxyethyl) amino] propoxy] quinazolin-4-yl ] amino] -1 H-pyrazol-5-yl] -N- (3-fluorophenyl) acetamide, C26H30FN7O3 , CAS [722544-51-6] and PubChem CID: 16007391, a compound of chemical structure:
  • CD4 refers to differentiation pool 4, a glycoprotein expressed on the surface of helper T cells, monocytes, macrophages, and dendritic cells.
  • CD4 aids the T-cell receptor (TCR) in binding to an antigen presenting cell.
  • TCR T-cell receptor
  • CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as Lck tyrosine kinase, which is essential to activate many molecules involved in the signaling cascade of an activated T cell.
  • Lck tyrosine kinase an enzyme that is essential to activate many molecules involved in the signaling cascade of an activated T cell.
  • the complete protein sequence for human CD4 has the registration number of UniProt P01730 (June 18, 2012).
  • optimal codons refers to alteration of codons in nucleic acids to reflect the use of codons typical of the host organism to improve the expression of a reference polypeptide without altering its sequence of amino acids.
  • optimization codons There are several methods and software tools known in the art for optimizing codons. See Narum D, et al., Infec ⁇ . Immun. 2001; 69 (12): 7250-7253), Outchkourov N, et al., Protein Expr. Purif. 2002; 24 (1): 18-24, Feng L, et ai, Biochemistry 2000; 39 (50): 15399-15409 and Humphreys D, et ai, Protein Expr. Purif. 2000; 20 (2): 252-264.
  • ENMD-2076 and "S1118", as used herein, refer to 6- (4-methylpiperazin-1-yl) -N- (5-methyl-1 H-pyrazole-3- yl) -2 - [(E) -2- phenylethenyl] pyrimidin-4-amine, C21H25N7, CAS [934353-76-1] and PubChem CID: 16041424, a compound of chemical structure:
  • the term "functionally equivalent variant,” as used herein, refers to a polynucleotide that results from the modification, deletion, or insertion of one or more bases and that substantially preserves the activity of the polypeptide expressed by the nucleic acid of reference.
  • Functionally equivalent variants contemplated in the context of the present invention include polynucleotides showing at least 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% , 98%, 99% similarity or identity with the sequences SEQ ID NO: 1-4.
  • the degree of identity or similarity between two polynucleotides is determined using computer implemented algorithms and methods that are widely known in the art.
  • the identity and similarity between two polynucleotide sequences is preferably determined using the BLASTP algorithm. See Altschul S, et ai, "BLAST Manual” (NCBI NLM NIH, Bethesda, MD, USA, 2001).
  • heterosine refers to N- [2- hydroxy-3- [C-phenyl-N- [4- (piperidin-1 -ylmethyl) phenyl] carbonimidoyl] -1 H-indole-5-yl] ethanesulfonamide, C29H32N4O3S, CAS [422513-13-1] and PubChem CID: 135421442, a compound of chemical structure:
  • histone deacetylase inhibitor refers to a compound that inhibits histone deacetylase enzymes.
  • Histone deacetylases remove acetyl groups from lysine residues in histones during this process, thereby allowing histones to wrap DNA more closely.
  • HDAC inhibitors prevent deacetylation and therefore affect gene expression. Examples of HDAC inhibitors include, but are not limited to, apicidin, abexinostat (i.e. PCI-24781), belinostat (i.e. Beleodaq®), BRD 4354, dacinostat (i.e.
  • LAQ-824 depudecin, droxinostat, entinostat (i.e. SNDX-275, MS-275), givinostat (i.e. gavinostat, ITF 2357), KD 5170, LMK 235, M 344, MC 1568, MC 1742, MI 192, mocetinostat (i.e. MGCD-0103), NCH 51 (ie PTACH), NSC 3852 (ie 5-nitroso-8-quinolinol), niltubazine (ie MAZ-1391), oxamflatin (ie metacept 3), panobinostat (ie Farydak®), PCI 34051, pracinostat (i.e.
  • HIV as used herein includes HIV-1 and HIV-2, VISH and VIS.
  • HIV-1 means human immunodeficiency virus type 1. HIV-1 includes, but It is not limited to extracellular virus particles and the forms of HIV-1 associated with HIV-1 infected cells. The HIV-1 virus can represent any of the main known subtypes (classes A, B, C, DE, F, G and H) or point to the subtype (group O) including laboratory strains and primary isolates.
  • HIV-2 means the human immunodeficiency virus type -2. HIV-2 includes, but is not limited to, extracellular virus particles and the forms of HIV-2 associated with cells infected with HIV-2.
  • SIV refers to the simian immunodeficiency virus which is an HIV-like virus that infects monkeys, chimpanzees, and other non-human primates.
  • the VIS includes, but is not limited to, extracellular virus particles and forms of SIV associated with SIV infected cells.
  • HIV infection refers to indications for the presence of the HIV virus in an individual including asymptomatic seropositivity, AIDS-related complex (CRS), and acquired immunodeficiency syndrome (AIDS) .
  • CRS AIDS-related complex
  • AIDS acquired immunodeficiency syndrome
  • nucleic acids or polypeptides refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same when They compare and align (introducing gaps, if necessary) for maximum match, without considering any conservative amino acid substitutions as part of the sequence identity.
  • percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art that can be used to obtain amino acid alignments or nucleotide sequences.
  • Suitable algorithms for determining sequence similarity include, but are not limited to, the BLAST, BLAST with Gaps, and BLAST 2.0, WU-BLAST-2, ALIGN, and ALIGN-2 algorithms. See Altschul S, et al., Nuc. Acids Res. 1977; 25: 3389-3402, Altschul S, et al., J. Mol. Biol. 1990; 215: 403-410, Altschul S, et al., Met. Enzymol. nineteen ninety six; 266: 460-480, Karlin S, et ai, Proc. Nati. Acad. Sci. USA 1990; 87: 2264-2268, Karlin S, et al., Proc. Nati.
  • Sequence alignment methods for comparison are well known in the art. Optimal sequence alignment may be carried out for comparison, for example, using the Smith-Waterman local homology algorithm, using the Needleman-Wunsch homology alignment algorithm, using the Pearson-Lipman similarity search method, using Computerized implementations of these algorithms or by manual alignment and visual inspection. See Smith T, et al., Adv. Appl. Math. nineteen eighty one ; 2: 482-489, Needleman S, et ai, J. Mol. Biol. 1970; 48: 443-453, Pearson W, et al., Lipman D, Proc. Nati.
  • kit refers to a product that contains the various reagents necessary to carry out the uses and methods of the invention that are packaged to allow for transport and storage.
  • suitable materials for packaging kit components include glass, plastic (eg, polyethylene, polypropylene, polycarbonate), vials, vials, paper, or envelopes.
  • latency reversing agents includes, but is not limited to, histone deacetylase inhibitors (HDACi), protein kinase C modulators (PKCm), external bromine domain inhibitors, and bromine (BET), acetaldehyde dehydrogenase inhibitors (eg disulfiram), activated B cell nuclear factor kappa light chain enhancer activators (NF-kB), and activators of the AKT pathway.
  • HDACi histone deacetylase inhibitors
  • PLCm protein kinase C modulators
  • BET bromine
  • acetaldehyde dehydrogenase inhibitors eg disulfiram
  • activated B cell nuclear factor kappa light chain enhancer activators NF-kB
  • activators of the AKT pathway activators of the AKT pathway.
  • BET inhibitors include, but are not limited to, CPI 203, 1-BET151, 1-BET762, JQ1, MS417, MS436, OTX-015,
  • MK-5108 refers to 4- (3-chloro-2-fluorophenoxy) -1 - [[6- (1, 3-thiazol-2-ylamino) acid. pyridin-2-yl] methyl] cyclohexan-1- carboxylic, C22H21CIFN 3 O 3 S, CAS [1010085-13-8] and PubChem CID: 24748204, a compound of chemical structure:
  • nucleic acid refers to any polymeric form of nucleotide of any length, and are composed of ribonucleotides or deoxyribonucleotides. The terms include both single-stranded and double-stranded polynucleotides, as well as modified polynucleotides (eg, methylated, protected).
  • nucleic acid is a "coding sequence” that, as used herein, refers to a DNA sequence that is transcribed and translated into a polypeptide in a host cell when placed under the control of regulatory sequences adequate.
  • a coding sequence can include, but is not limited to, prokaryotic sequences, eukaryotic mRNA cDNA, eukaryotic (eg, mammalian) genomic DNA sequences, and even synthetic DNA sequences.
  • a transcription termination sequence will usually be located in the 3 'direction with respect to the coding sequence.
  • operably linked means that the nucleotide sequence of interest binds to the regulatory sequence (s) so that expression of the sequence of nucleotides (eg, in an in vitro transcription / translation system or in a host cell when the vector is introduced into the host cell). See Auer H, Nature Biotechnol. 2006; 24: 41-43.
  • parenteral administration and "parenterally administered”, as used herein, means modes of administration other than enteric and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial injection , intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal and infusion.
  • pharmaceutically acceptable carrier includes any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption retarding agent that are physiologically compatible with AURK inhibitors, Additional active agents, compositions and combinations of the invention.
  • prevention refers to inhibiting the onset or decreasing the onset of disease in a subject. Prevention can be complete (for example, the total absence of pathological cells in a subject). Prevention can also be partial, such as, for example, reducing the appearance of pathological cells in a subject. Prevention also refers to a reduced susceptibility to a clinical state. Within the context of the present invention, the terms “prevent,” “preventing” and “prevention” refer primarily to avoiding or reducing the likelihood of HIV infection in a subject who maintains exposure to HIV.
  • PKC modulator protein kinase C modulator
  • PKC modulator and “PKCm”, as used herein, refer to a compound that affects the activity of a protein kinase C enzyme ("PKC") .
  • PKCs are enzymes that regulate the function of other proteins through the phosphorylation of hydroxyl groups located in the serine and threonine residues of these proteins.
  • PKC modulators can be antagonists (i.e. inhibitors), agonists (i.e. activators), or both.
  • PKC antagonists include, but are not limited to, bisindolylmaleimide 1 (ie BIM-1, GF 109203X) and its related compounds BIM-2, BIM-3, and BIM-8, [Ala 107 J-MBP (104 -118), [Ala 113 ] -MBP (104-118), C-1, calfostina C (ie UCN 1028C, PKF 115584), CGP 53353, cheleritrin, D-erythro-sphingosine, dihydrosphingosine (ie sphinganine), enzastaurin (ie LY317615), [Glu 27 ] - PKC (19-36), Go 6976, Go 6983, gossypol, melittin, myristicrin (ie myricetrin, myricetol 3-rhamnoside), miyabenol C (ie Z-miyabenol C , E-cis-miy
  • PKC bo pseudo-substrate PKC z pseudo-substrate, Ro 32-0432 HCI, rottlerine, ruboxistaurin (ie LY 333531 HCI), staurosporinone (ie K-252c), TCS 21311, verbascoside (ie acteoside, kusaginin, orobanquin), and ZIP (ie pseudo substrate z inhibitor peptide).
  • PKC agonists include, but are not limited to, biostatin A (i. E.
  • DAG diacylglycerol mimetides
  • FR236924 i.e DCP-LA
  • ingenol mebutate i.e. Picato®, ingenol-3-angelate, PEP005
  • forbol 12, 13-di buti rata i.e. PMA
  • prostratin i.e. PMA
  • SNS-314 mesylate and "S1154", as used herein, refer to 1- (3-chlorophenyl) -3- [5- [2- (thieno [3,2-d ] pyrimidin-4-ylamino) ethyl] -1,3-thiazol-2-yl] urea; methanesulfonic acid, C1 8 H15CIN 6 OS2.CH4O 3 S CAS [1146618-41- 8], a compound of chemical structure:
  • subject refers to an individual, plant, or animal, such as a human, a non-human primate (eg, chimpanzees and other ape and monkey species); farm animals, such as birds, fish, livestock, sheep, pigs, goats, and horses; domestic mammals, such as cats and dogs; laboratory animals including rodents, such as mice, rats, and guinea pigs.
  • farm animals such as birds, fish, livestock, sheep, pigs, goats, and horses
  • domestic mammals such as cats and dogs
  • laboratory animals including rodents, such as mice, rats, and guinea pigs.
  • subject encompasses an embryo and a fetus. In a preferred embodiment, the subject is a human.
  • terapéuticaally effective amount refers to the dose or amount of an AURK inhibitor, additional active agent, combination, or composition of the invention that produces a therapeutic response or desired effect in a subject.
  • tozasertib and “S1048”, as used herein, refer to N- [4- [4- (4-methylpiperazin-1-yl) -6 - [(5-methyl-1 H -pyrazol-3-yl) amino] pyrimidin-2-yljsulfanylphenyljcyclopropanecarboxamide, C23H28N8OS, CAS [639089-54-6] and PubChem CID: 5494449, a compound of chemical structure:
  • treat refers to the administration of an AURK inhibitor, additional active agent, combination, or composition of the invention to control the progression of a disease after your clinical signs have appeared.
  • Control of disease progression is understood to mean beneficial or desired clinical outcomes that include, but are not limited to, reduction of symptoms, reduction of disease duration, stabilization of disease states (specifically to avoid further deterioration) , delay the progression of the disease, improve the disease state and remission (both partial and total).
  • Control of disease progression also implies an extension of survival compared to expected survival if no treatment was applied.
  • the terms “treat” and “treatment” refer primarily to stopping or delaying infection and destruction of healthy CD4 + T cells in a subject infected with HIV.
  • Beneficial or desired clinical outcomes include, but are not limited to, an increase in absolute undifferentiated CD4 + T cell count (range 10-3520), an increase in the percentage of CD4 + T cells relative to total circulating immune cells ( range 1-50%), or an increase in CD4 + T-cell count as a percentage of normal CD4 + T-cell count in an uninfected subject (range 1-161%).
  • Treatment can also mean prolonging the survival of the infected subject compared to expected survival if the subject does not receive any HIV-directed treatment.
  • ZM-447439 refers to N- [4- [[6-Methoxy-7- [3- (4-morpholinyl) propoxy] -4-quinazolinyl] amino] phenyl] benzamide, C29H31 N5O4 CAS [331771-20-1], a compound of chemical structure:
  • the invention also contemplates the use of salts of the compounds mentioned herein such as pharmaceutically acceptable salts of barasertib (for example barasertib dihydrogen phosphate), tozasertib, alisertib, SNS-314 (for example SNS-314 mesylate), MK- 5108, ENMD-2076, AMG-900, hesperadine, or ZM-447439.
  • barasertib for example barasertib dihydrogen phosphate
  • tozasertib alisertib
  • SNS-314 for example SNS-314 mesylate
  • MK- 5108 for example ENMD-2076, AMG-900, hesperadine, or ZM-447439.
  • the invention in a first aspect, relates to a method of treating or preventing an HIV or AIDS infection which comprises administering a therapeutically effective amount of an aurora kinase inhibitor (AURK) to a subject in need.
  • AURK aurora kinase inhibitor
  • the AURK is an AURKB.
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 2006116357 such as barasertib.
  • formula (I) is identified herein with formula (I):
  • A is a 5-membered heteroaryl containing one nitrogen atom and optionally containing one or two additional nitrogen atoms;
  • X is O, S, S (O), S (0) 2 or NR 14 ;
  • n 0, 1, 2 or 3;
  • Z is a group selected de- NR 1 R 2, fosfonooxilo, C 3-6 cycloalkyl which C 3-6 cycloalkyl is substituted by Ci -4 alkyl fosfonooxilo or substituted by fosfonooxilo, and a ring of 4 to 7 members bonded through a carbon atom containing a nitrogen atom and optionally containing an additional nitrogen atom, which may be saturated, partially saturated or unsaturated in which the ring is substituted on carbon or nitrogen by phosphonooxyl or Ci -4 alkyl substituted by phosphonoxyl, and wherein the ring is optionally further substituted on the carbon or nitrogen by 1, 2 or 3 halo or Ci -4 alkyl groups;
  • R 1 is a group selected from - COR 8 , - CONR 8 R 9 and Ci-e alkyl whose Ci-e alkyl is substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from hydrogen, - COR 10 , - CONR 10 R 11 and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci- 4 or— S (0) alkoxy.
  • p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2- e alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and C3-6 cycloalkyl-Ci -4 alkyl;
  • R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing an additional nitrogen atom the ring of which may be saturated, unsaturated or partially saturated in which the ring is carbon-substituted or nitrogen by a group selected from fosfonooxilo and alkyl Ci -4 whose alkyl Ci -4 is substituted by fosfonooxilo or - NR 8 R 9 and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo groups or Ci -4 alkyl;
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C1-6 alkoxy, C1-6 alkyl, - OR 12 , - CHR 12 R 13 , - OC (0) R 12 , - C (0) R 12 , - NR 12 C (0) R 13 , - C (0) NR 12 R 13 , - NR 12 SO 2 R 13 and - NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from Ci- 4- alkyl, heteroaryl, Ci- 4- alkyl-heteroaryl, aryl and Ci- 4- aryl-alkyl the group of which is optionally substituted by 1, 2 or 3 substituents selected from halo, methyl, ethyl , cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, Ci -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3- 6 cycloalkyl and alkyl Ci- 4 -C3-6cycloalkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, Ci- 4- alkyl, C3-6-cycloalkyl, hydroxyl and Ci- 4- alkoxy;
  • R 8 is Ci- 4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and Ci -4 alkyl
  • R 10 is selected from hydrogen and Ci- 4- alkyl (optionally substituted by halo, C- 4- alkoxy, S (0) q (where q is 0, 1 or 2) or phosphonoxyl);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, Ci- 4- alkyl and heterocyclyl;
  • the compound of formula (I) in which R 1 is 2-phosphonoxyloethyl; or a pharmaceutically acceptable salt thereof is 2-phosphonoxyloethyl; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) in which Z is— NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a ring of piperidine, pyrrolidine or piperazine which is replaced by a selected group of phosphonooxy, phosphonoxyloxymethyl, 2-phosphonoxyloethyl, N-ethyl-N- (2-phosphonoxyloethyl) aminomethyl and N- (2- phosphonoxyloethyl) aminomethyl and where the ring is optionally substituted additionally by 1 or 2 methyl.
  • the compound of formula (I) in which R 1 and R 2 together with the nitrogen to which they bind form 2- (phosphonoxymethyl) pyrrolidinyl.
  • the compound of formula (I) is selected from:
  • dihydrogenphosphate 2 - [[3 - ( ⁇ 4 - [(5- ⁇ 2 - [(3,5-difluorophenyl) amino] -2-oxoethyl ⁇ -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin- 7-yl ⁇ oxy) propyl] (ethyl) amino] ethyl;
  • A is a group of formula (a), (b), (c), (d) or (e):
  • X is NH
  • n 0, 1, 2 or 3;
  • Z is— NR 1 R 2 or a saturated 5- to 6-membered ring linked via a carbon atom containing one nitrogen atom and optionally containing one additional nitrogen atom, the ring of which is substituted on carbon or nitrogen by phosphonooxy or Ci -4 alkyl substituted by phosphonooxy;
  • R 1 is Ci-s alkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci -4 alkoxy or R 2 is selected from Ci-e-alkynyl C 2-6 -cycloalkyl C 3-6 cycloalkyl and C 3-6 -alkyl Ci -4;
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5 to 6 membered ring optionally containing an additional nitrogen atom in which the ring is substituted on carbon or nitrogen by a group selected from phosphonooxyl and Ci -4 alkyl which Ci -4 alkyl substituted by NR 8 R fosfonooxilo o- 9 and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 alkyl groups Ci -4;
  • R 3 is Ci -4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl;
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl
  • A is a group of formula (a):
  • n 1, 2 or 3;
  • Z is— NR 1 R 2 ;
  • R 1 is alkyl substituted fosfonooxilo C MS:
  • R 2 is selected from hydrogen and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci -4 alkoxy, or R 2 is selected from C2-6 alkenyl, C2-6 alkynyl C3 cycloalkyl -6 and Ci-4-cycloalkylC3-6alkyl;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • A is a group of formula (a):
  • X is NH
  • n 1, 2 or 3;
  • Z is— NR 1 R 2 ;
  • R 1 is C 1-5 alkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-e alkyl which Ci-e is optionally substituted by 1, 2 or 3 halo or Ci -4 alkoxy, or R 2 is selected from C 2-6 alkenyl, C 2-6 alkynyl , C 3-6 cycloalkyl and C 3-6 cycloalkyl Ci -4 alkyl;
  • R 3 is hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 20040049032 such as tozasertib.
  • Compounds of formula (I) as disclosed in US 20040049032 are identified herein with formula (II):
  • Q and T are each independently selected from oxygen, sulfur, or N (R);
  • each R is independently selected from hydrogen or an optionally substituted Ci-e aliphatic group, wherein:
  • R x is UR 5 ;
  • R 5 is selected from halogen, NO 2, CN, R, or Ar;
  • each U is independently selected from a valence bond or a Ci -4 alkylidene chain, wherein:
  • each Ar is independently selected from an optionally substituted ring selected from a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated, or fully unsaturated having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
  • R y is— N (R 1 ) 2 , - OR 1 , or— SR 1 ;
  • each R 1 is independently selected from R or an optionally substituted saturated, partially unsaturated or fully unsaturated 3-8 membered bicyclic, 8-10 membered bicyclic or optionally substituted 10-12 membered tricyclic ring having 0-4 heteroatoms, independently selected nitrogen, oxygen or sulfur, and in which:
  • each R 1 is optionally and independently substituted by up to four independently selected substituents on R 2 ;
  • each R 2 is independently selected from— R 3 , - OR 3 , - SR 3 , - CN, - N0 2 , oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC (0 ) R 3 , - C0 2 R 3 , - S0 2 R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , O— NR 3 C0 2 (R 3 );
  • each R 3 is independently selected from R or Ar;
  • R z1 is selected from a Ci-e aliphatic group or a 3-8 membered monocyclic, 8-10 membered bicyclic or 10-12 membered saturated, partially unsaturated or fully unsaturated tricyclic ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, in which:
  • R z1 is substituted with 0-4 independently selected R 2 groups
  • R z2 is a Ci-e aliphatic group or a 3-8 membered monocyclic ring or a saturated, partially unsaturated or fully unsaturated 8-10 membered bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, in which:
  • R z2 is substituted by 0-4 substituents independently selected from oxo or UR 5 ; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) in which T is oxygen or sulfur is oxygen or sulfur.
  • R 1 is selected from R or a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated or fully unsaturated having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, or:
  • each R 1 is R such that the two Rs on the same nitrogen atom are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms, independently selected from nitrogen, oxygen or sulfur, and in which:
  • each R 1 is optionally and independently substituted by up to four substituents selected from— R 3 , - OR 3 , - SR 3 , - CN, - NO 2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - 0C (0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ) , - C (0) N (R 3 ) 2 , - 0C (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , O—
  • each R 1 is independently selected from R, where R is hydrogen or an optionally substituted C1-4 aliphatic group.
  • each R 1 is R such that the two R groups are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms, independently selected from nitrogen, oxygen or sulfur.
  • the compound of formula (II) wherein R y is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, in which each ring is optionally substituted with one or two independently selected groups of methyl, ethyl, methylsulfonyl, (CH 2 ) 2 SC> 2 CH 3 , cyclopropyl, Chhciclopropil, (Chh ⁇ OH, CC> 2t -butyl, CH 2 phenyl, phenyl, NH 2 , NH (CH 3 ), N (CH 3 ) 2 , (OH 2 ) 2 NH 2 , (CH 2 ) 2morfolin-4-ylo,
  • the compound of formula (II) wherein R z1 is a saturated, partially unsaturated or fully unsaturated 3-7 membered bicyclic or 8-10 membered bicyclic ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, in which said ring is optionally and independently substituted by up to three substituents selected from - R 3 , - OR 3 , - SR 3 , - CN, - NO2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC (0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C ( 0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ), - 0
  • the compound of formula (II) wherein R z1 is a 5-6 membered fully unsaturated ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen or sulfur, wherein said ring is optional and independently substituted by up to three substituents selected from - R 3 , - OR 3 , - SR 3 , - CN, - NO2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC ( 0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) R
  • the compound of formula (II) wherein R z1 is an optionally substituted ring selected from pyrazole or any one of the following 5-6 membered rings in which R z 1
  • the compound of formula (II) wherein R z2 is an optionally substituted ring selected from a saturated, partially unsaturated or fully unsaturated 5-6 membered monocyclic or 8-10 membered bicyclic ring having 0- 4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, in which said ring is optionally substituted by up to three independently selected substituents from halogen, - CN, - NO 2, - C (0) R 3 , - CO2R 3 , - C (0) NR (R 3 ), - NR 3 C (0) R 3 , - N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - NR 3 C (0) N (R 3 ) 2 , O— NR 3 CO 2 R 3 .
  • R z2 is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxynyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl,
  • R z2 is optionally substituted with up to three independently selected substituents from— Cl, - Br, -F, - CN, - CF 3 , - COOH, - CONHMe, - CONHEt, - NH 2 , - NHAC, - NHS0 2 Me, - NHS0 2 Et, - NHS0 2 (n-propyl), - NHS0 2 (isopropyl), - NHCOEt, - NHCOCH2NHCH3, - NHC0CH 2 N (C0 2 t-Bu) CH 3 , - NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , - NHCOCH2CH 2 CH 2 N (CH 3 ) 2, - NHCO (cyclopropyl), - NHCO (isopropyl), -NHCO (isobutyl), -
  • each R 3 is independently selected from R or Ar, and wherein:
  • R is hydrogen or an optionally substituted Ci -4 aliphatic group.
  • the compound of formula (II) is selected from:
  • the compound of formula (II) has the following formula:
  • R 5 is selected from hydrogen or aliphatic Ci -4 such as hydrogen, methyl, ethyl, t-butyl or isopropyl.
  • R 6 is selected from C1 -3 aliphatic such as methyl, ethyl or cyclopropyl; Y
  • R 7 is selected from aliphatic Cab such as methyl, ethyl, t-butyl or cyclopropyl.
  • the compound of formula (II) is selected from:
  • the compound of formula (II) is selected from:
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 20080167292 such as alisertib.
  • Compounds of formula (I) as disclosed in US 20080167292 are identified herein with formula (III):
  • R a is selected from the group consisting of aliphatic C 1-3 fluoroaliphatic C 1-3 - R ⁇ -T- R 1 - R 2 and -TR 2;
  • T is a C 1-3 alkylene chain optionally substituted with fluoro
  • R 1 is an optionally substituted aryl, heteroaryl or heterocyclyl group
  • R 3 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group
  • each R 4 is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4's on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring which has, in addition to the nitrogen atom, 0 to 2 heteroatoms selected from N, O and S;
  • R 5 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group
  • R b is selected from the group consisting of fluoro, chloro, - CH 3 , - CF 3 , - OH, - OCH 3 , - OCF 3 , - OCH2CH3, and - OCH2CF3.
  • the compound of formula (III) wherein R a is halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, -OH, - 0 (C 1-3 aliphatic), - 0 (C fluoroaliphatic 1-3 ), or - C ° C - R 3 , - CH CH - R 3 , where R 3 is hydrogen, aliphatic C 1-3 , fluoroaliphatic C 1-3 , or - CH 2 -OCH 3 ; or R a is a phenyl, furyl, pyrrolidinyl or thienyl ring optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-3 aliphatic and fluoroaliphatic C1-3.
  • the compound of formula (III) is 4 - ([9-ethinyl-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2 acid) -yl] amino) -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
  • the compound of formula (III) is 4 - ([7- (2-fluoro-6-methoxyphenyl) -9- (1-methyl-1 H-pyrrol-2-yl) -5H-pyrimido acid. [5,4-d] [2] benzazepin-2-yl] amino) -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
  • the compound of formula (III) is 4 - ⁇ [9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2 acid -yl] amino ⁇ -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
  • the compound of formula (III) is 4 - ⁇ [9-chloro-7- (2-fluoro-6- methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2- yl] amino ⁇ -2-methoxybenzoate sodium.
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 2006035908 such as SNS-314 mesylate.
  • Compounds of formula (I) as disclosed in US 2006035908 are identified herein with formula (IV):
  • R X1 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, or heteroaromatic moiety;
  • Y is an optionally substituted phenyl or thiazolyl ring
  • Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic residue
  • Q 2 is— (CR 1A R 1 B ) m CoC— (CR 1A R 1 B ) k R 1 E , - (CR 1A R 1 B ) m CoC (CR 1A R 1 B ) k where k is a integer from 1 to 3 and m is an integer from 0 to 3;
  • - W 1 -Alkr is - OCH 2 - or - N (R) CH 2 -, where R is H or Ci-s alkyl; Y is phenyl; and Z is a 5-10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • one of X 1 and X 2 is S, the other is CR ⁇ where R ⁇ is hydrogen, Ci -4 alkyl or phenyl optionally substituted by halogen, (halo) Ci -4 alkyl or (halo) Ci alkoxy -4; - W 1 -Alki- is- ⁇ alkyl NRC -, - OC ⁇ SC ⁇ alkyl- o- alkyl- wherein R is hydrogen, Ci -4 alkyl, Ci -4 acyl; Y is phenyl; L 2 -Z is a saturated or unsaturated hydrocarbon chain of CM 2 alkyl including - NR- and optionally substituted Ci -4 haloalkoxy, C3-8 cycloalkyl, C3-8 acyl , Ci -4, phenoxy, phenyl or phenylthiol.
  • W 1 is O or NR W1 , wherein R W1 is hydrogen, lower alkyl, C3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl; and Alki is a residue of C 1-6 alkylene or C 2-6 alkenylene; and each occurrence of R Y1 is independently hydrogen, halogen, or lower alkyl.
  • the compound of formula (IV) in which Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety.
  • R Z1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, or acyl.
  • R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and R Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl.
  • X 3 is N or CR Z1 ;
  • R Z1 is hydrogen, halogen, lower alkyl or haloalkyl lower; and
  • R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2 and R Z3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
  • X is halogen,
  • R Z1A is hydrogen, halogen, -CN , lower alkyl, lower alkoxy, halo lower alkyl, or— S0 2 R Z4 ; wherein R Z4 is lower alkyl; and
  • R Z2A is hydrogen or lower alkyl.
  • R Z1 is independently Cl, F, methyl or CF 3 ;
  • R Z2 and R Z3 are each methyl or ethyl, or taken together with the nitrogen atom to which they are attached form a saturated or unsaturated pyrrolidinyl ring; and
  • R Z2A is hydrogen or methyl.
  • R Z1 is Cl, F, methyl or CF 3 .
  • R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Z2 , - SR Z2 , - NR Z2 R Z3 , -S0 2 NR Z2 R Z3 , S0 2 R Z1 , -
  • R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached they form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
  • R Z1 is halogen, lower alkyl or haloalkyl lower.
  • R X1 is hydrogen, lower alkyl, or heterocyclyl; and R Z1 is halogen, lower alkyl or haloalkyl lower.
  • R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Z2 , - SR Z2 , - NR Z3 R Z3 , -S0 2 NR Z2 R Z3 , - S0 2 R Z1 , -
  • R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached they form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
  • R Z1 is halogen, lower alkyl or haloalkyl lower.
  • the compound of formula (IV) having the structure:
  • R X1 is hydrogen, lower alkyl, or heterocyclyl; and R Z1 is halogen, lower alkyl or haloalkyl lower.
  • the compound of formula (IV) wherein— W 1 -Alkr is— NH- C1-6alkyl- or -O- C1-6alkyl-; wherein the C1-6 alkyl moiety can be substituted or unsubstituted.
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2008026768 such as MK-5108.
  • Compounds of formula (I) as disclosed in WO 2008026768 are identified herein with formula (V):
  • Ri is a hydrogen atom, F, CN, COORai, CONR a 2Ra2 ', NR a3 COR a3' , C0NR a4 0R a4 ' , NR a5 CONR a5' R a5 ", NR a6 COOR a6 ', S02NR a7 R a7' , NR to sS02R a8 ', COR a9 , S0 2 Raio, N0 2 , OR ai i , or NR ai2 Rai2 ', in which:
  • R ai , R a3 , R a4 , R a s, R a6 , and R a s are each independently a hydrogen or lower alkyl atom;
  • Ra2, Ra2 ', Ras', Ras ”, Ra7, Ra7 ', Rai2, and Rai2' are each independently a hydrogen or lower alkyl atom that may be substituted with one or more of the same or different substituents selected from ⁇ group Li substituent>, where ⁇ Li substituent group> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl, aminosulfonyl, imino, lower alkylamino, dialkylamino lower, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthiol, and carboxyl; provided, however, that R a2 and Ra2 ';Ras' and Ras ”; Ra7 and Ra7 '; Rai2 and R ai 2 'each independently, together with the nitrogen
  • Ra3 ’, Ra, Rae’, Ras ’, Ra9, Raio and Ran are each independently a hydrogen or lower alkyl atom that may be substituted with one or more of the same or different substituents selected from ⁇ substituent group Li>; or
  • R1 is a lower alkyl which may be substituted with one or more of the same or different substituents selected from ⁇ substituent group M>, where ⁇ substituent group M> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl atom , aminosulfonyl, imino, lower alkylamino, dialkylamino lower, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthiol, and carboxyl; or
  • R1 is a heterocyclic group selected from the following, where Y1 and Y 2 are the same and different, and each is a hydrogen or lower alkyl atom that may be substituted:
  • R 2 is O, S, SO, SO 2 , NH, NR b , or CR C IR C2 where R b is a lower alkyl that may be substituted, and R d and Rc2, which may be the same or different, they are a hydrogen or lower alkyl atom;
  • R3 is a phenyl that can be substituted
  • X 2 is CH, CX 2a , or N where:
  • X 2a is a lower alkyl
  • X 2a is a substituent selected from ⁇ substituent group Ai>, or lower alkyl that is substituted with one or more of the same or different selected substituents of ⁇ substituent group Ai>, in which ⁇ substituent group Ai> is halogen atom; cyano; hydroxyl; lower alkylamino; lower dialkylamino; lower alkoxy that may be substituted with one or more hydroxyl groups; lower alkylthiol; and lower alkylsulfonyl; or
  • X 2a is COORxi, CONR ⁇ Rxs, NHCORxi, NHCONR ⁇ Rxs, NHS02NRx2Rx3, NR X4 R X5 , or CH2NR X 4R X 5, where:
  • R xi is a hydrogen or lower alkyl atom that may be substituted
  • R X 2 and R X3, which may be the same or different, are each a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl which may be substituted; or alternatively R ⁇ and R x s, together with the nitrogen atom to which they are attached, form a 5- or 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; Y
  • R X 4 and R x 5, which can be the same or different, are a hydrogen atom, lower alkyl that can be substituted, or cycloalkyl that can be substituted; or
  • X 2a is a 5- to 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted, in which two hydrogen atoms are attached to the same carbon atom of the aliphatic heterocyclic group they can be substituted with oxo and two neighboring carbon atoms that make up the aliphatic heterocyclic ring can form a double bond; or a lower alkyl that is substituted with the aliphatic heterocyclic group; or
  • X 2a is a 5- to 6-membered aromatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; or a lower alkyl that is substituted with the aromatic heterocyclic group;
  • Wi is CH, N, NH, O or S;
  • W 2 is CH, CW 2a , N, NW 2b , O, or S, where W 2a and W 2b are each independently a hydrogen atom, halogen atom, cyano, lower alkyl having one to two atoms of carbon, cycloalkyl having three to five carbon atoms, or lower alkyl having one to two carbon atoms that may be substituted with one or more halogen atoms;
  • W 3 is C or N;
  • W 1 , W 2 , and W 3 are carbon atom; however, two of W 1 , W 2 , and W 3 are not simultaneously O and S,
  • the compound of formula (V) or a salt or a pharmaceutically acceptable ester of the same in which R 3 is a phenyl which positions 2 and 3 are substituted with the same or two different substituents selected from F , Cl, CF 3 , and CN.
  • the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof in which ⁇ substituent group> is a halogen, hydroxyl, amino, carbamoyl, lower alkylamino, dialkylamino, and alkoxy atom lower; and ⁇ substituent group M> is a hydroxyl, carbamoyl, aminosulfonyl, lower alkylsulfonylamino, and carboxyl.
  • the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof wherein R 1 is OH, COOH, or CONR a2 R a2 'where R a2 and R a2 ' are the same or different, and each a hydrogen or lower alkyl atom having one to three carbon atoms; or R 1 is selected from the following:
  • R 2 is O, S, SO or SO 2 .
  • W is selected from:
  • W 2a is a hydrogen, halogen, cyano, or methyl atom which may be substituted with one to three fluorine atoms.
  • the compound of formula (V) is selected from:
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2007041358 such as ENMD-2076.
  • Compounds of formula (I) as disclosed in WO 2007041358 are identified herein with formula (VI):
  • R x and R y are independently selected from the group consisting of -TR 3 and -LZR 3 ;
  • CR 6 CR 6 - can be a cis or trans double bond or a mixture thereof; R 1 is -T- (ring D);
  • Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl and carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable ring D ring carbon is independently substituted by oxo, -TR 5 , or -VZR 5 , and each substitutable D ring ring nitrogen is independently substituted by -R 4 ;
  • T is a valence bond or - (C (R 6 ' ) 2 ) -A-;
  • A is a valence bond or an alkylidene chain C1-C 3 in which a methylene unit of said C 1-3 alkylidene chain is optionally replaced by -O-, -S-, -N (R 4) - , -CO-, -CONH-, -NHCO-, -S0 2 -, -SO2NH-, -NHSO2 -, -C0 2 -, -OC (O) -, - OC (0) NH-, or -NHCO 2 -;
  • Z is a Ci -4 alkylidene chain
  • L is selected from the group consisting of -O-, -S-, -SO-, -SO2-, -N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -CO2-, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, -
  • R 2 and R 2 are independently selected from the group consisting of -R and -TWR 6 , or R 2 and R 2 ' taken together with their intervening atoms form a fused 5-8 membered unsaturated or partially unsaturated ring having 0- 3 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable carbon of the ring of said condensed ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO2, R 7 , or -VR 6 , and each substitutable nitrogen in the ring of said ring formed by R 2 and R 2 ' is independently substituted by -R 4 ;
  • each R is independently hydrogen or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, Ce-io aryl, a heteroaryl ring having 5-10 ring atoms, and a heterocyclyl ring having 5-10 ring atoms;
  • each R 4 is independently selected from the group consisting of -R 7 , -COR 7 , - C0 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2, and -SO2R 7 ;
  • V is selected from the group consisting of -O-, -S-, -SO-, -S0 2 -, - N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -C0 2 -, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, -
  • each R 6 ' is independently selected from the group consisting of hydrogen and one Ci -4 aliphatic group, or two R 6s on the same carbon atom are taken together to form a 3-8 membered carbocyclic ring;
  • each R 6 is independently selected from the group consisting of hydrogen, an aliphatic group Ci- 4, halogen, optionally substituted aryl, and optionally substituted heteroaryl, or two R 6 'on adjacent carbon atoms are taken together to form a carbocyclic ring 5-7 members; Y
  • each R 7 is independently selected from the group consisting of hydrogen and an optionally substituted C 4 -aliphatic group, or two R 7's in the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
  • the compound of formula (VI) is selected from the group:
  • the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2007087276 such as AMG-900.
  • 2007087276 are identified in the present document with formula (Vil):
  • C 1 is N or CR 10 ;
  • C 2 is N or CH
  • D 1 is N or CR 1 1 ;
  • D 2 is N or CR 12 ;
  • D 3 is N or CR 2 ;
  • D 4 is NR 1 a , O, S or CR 12 ;
  • D 5 is N or CR 2 ;
  • R 1 is H, OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R, NR 15 R, (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 , in where n is 0, 1, 2, 3 or 4;
  • R a is H, CN or alkyl CMO
  • R 1 taken together with either R 11 and R 1a and the carbon or nitrogen atoms to which they are attached form a 5- or 6-membered ring of partially or completely unsaturated carbon atoms optionally including 1-3 heteroatoms selected from O , N and S, and the ring optionally independently substituted with 1-3 oxo substituents, R 15 , SR 14 , OR 14 , SR 15 , OR 15 , OC (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or NR 15 R 15 ; Y
  • R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 ,
  • U is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
  • L 2 is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
  • Z is a 5-6 membered fully unsaturated monocyclic first ring, said first ring (1) formed of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, (2) optionally fused with a second monocyclic ring partially or fully saturated or fully unsaturated 5-6 membered carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and (3) wherein 0, 1, 2 or 3 atoms each of said first and second rings are optionally independently substituted with 1-5 substituents of R 5 ;
  • each of R 3 and R 4 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C ( 0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 ,
  • any of R 3 or R 4 independently, taken together with R 10 and the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-3 substituents of R 13 , R 14 or R 15 ;
  • each R 5 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 13 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0)
  • each of R 6 , R 7 and R 8 is R 13 , R 14 or R 15 ;
  • any of R 6 or R 8 independently, taken together with R 7 and the carbon atoms to which they are attached form a fully or partially saturated or fully saturated 5 or 6 membered ring of carbon atoms optionally including 1 -3 hetero atoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ; each of R 9 , R 10 , R 11 and R 12 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0 ) R 15 , COOR 15 , 0C (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C
  • R 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , 0C (0) R 14 , 0C (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , C (0) C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ),
  • NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R 1 S , NR 15 C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 O NR 15 S (0) 2 NR 15 R 15 ;
  • R 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered tricyclic system partially or completely unsaturated, the ring system being formed by carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-5 R 15 substituents; and R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2 , NH 2 , acetyl, alkyl
  • D 1 is N
  • D 2 is CR 12
  • D 3 is CH
  • D 1 is CR 11
  • D 2 is N
  • D 3 is CH
  • C 1 is CR 10 and R 10 is H , halo, haloalkyl, haloalkoxy, CN, OH, SH, NO2, NH2, acetyl, CMO alkyl, or CMO alkoxy;
  • R 2 is H, halo, NO2, CN, CMO alkyl, or CMO alkoxy.
  • U is NR 15 , O, CHR 15 , S, C (O), S (O) or S0 2 ; Y
  • R 2 is H, halo, NO2, CN, CMO alkyl or CMO alkoxy.
  • L 2 is NR 15 , O or S;
  • each of R 3 , R 4 and R 9 is H;
  • C 1 is CR 10 ; Y
  • Z is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, or isothiazolyl or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazole, isothiazole, or isothiazole, isolyl, or isothiazole, iso
  • each of A 1 and A 2 is N; Y
  • R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, piazinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, furyl, tetrayl , tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, pyridinyl, imidazoly
  • each of A 1 and A 2 independently, is N or CR 9 , provided that at least one of A 1 and A 2 is N;
  • each of B 1 , B 2 , B 3 and B 4 is N or CR 5 , provided that no more than two of B 1 , B 2 , B 3 and B 4 are N;
  • C 1 is N or CR 10 ;
  • D 1 is N or CR 11 ;
  • D 2 is N or CR 12 ;
  • U is NR 3 , O, S, or CR 3 R 3 ;
  • L 2 is NR 3 , O, S or CR 3 R 3 ;
  • R 1 is OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 1 'taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O , N and S , and the ring optionally independently substituted with 1-3 oxo substituents, R 15 , SR 14 , OR 14 , SR 15 , OR 15 , 0C (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or
  • R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C ( 0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ),
  • each of R 3 and R 4 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 or R 15 ; alternatively, any of R 3 or R 4 , independently, taken together with R 10 and the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-3 substituents of R 13 , R 14 or R 15 ;
  • each R 5 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , 0C (0 ) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S
  • R 6 is R 13 or R 14 ;
  • each of R 7 and R 8 is R 13 , R 14 or R 15 ;
  • any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully saturated or partially or fully unsaturated 5 or 6 membered carbon atom ring optionally including 1-3 heteroatoms selected from O , N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ;
  • each of R 9 , R 10 , R 11 and R 12 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0 ) R 15 or R 15 ;
  • R 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , OC (0) R 14 , OC (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , C (0) C (0) R 15 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ), NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 ,
  • R 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic system partially or completely saturated or completely unsaturated, the ring system formed by carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or
  • R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2 , NH 2 , acetyl, CMO alkyl, C 2 -i alkenyl or, C 2 -i alkynyl or C3-10 cycloalkenyl, cycloalkenyl C4-10, CMO- alkylamino-, Ci-10-dialkylamino-, alkoxy CMO, thioalkoxy CMO OR 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered tricyclic saturation system or partially or completely unsaturated, said ring system consisting of carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O , N, or S, in each of CMO alkyl, C 2 -i
  • n 0, 1, 2, 3, or 4;
  • each of A 1 and A 2 is N;
  • each of B 1 , B 2 , B 3 and B 4 is N or CR 5 , provided that not more than one of B 1 , B 2 , B 3 and B 4 is N;
  • C 1 is CR 10 ;
  • D 1 is N or CR 11 ;
  • D 2 is N or CR 12 ;
  • U is NH, O or S
  • L 2 is NH, O or S; provided that both of U and L 2 are neither O nor S;
  • R 1 is H, halo, haloalkyl, NO 2, NH 2, acetyl, alkyl CM O alkenyl, C 2-10 alkynyl C 2-10, C 3-10 cycloalkyl, cycloalkenyl C 4-10, Ci-io-alkylamino -, Ci- 10 -dyalkylamino-, alkoxy CM O , thioalkoxy CM O , NHR 14 , NHR 15 , OR 15 , SR 15 O CH 2 R 15 ;
  • R 2 is H, halo, NO 2 , CN, CMO alkyl, or CMO alkoxy;
  • each of R 3 and R 4 is SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 1S or R 15 ;
  • each R 5 is independently SR 15 , OR 15 , NR 15 R 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 15 , NR 15 C (0) NR 15 R 15 , NR 15 (COOR 15 ), S (0) 2 R 15 , S (0) 2 NR 15 R 15 ,
  • R 6 is R 14 ;
  • each of R 7 and R 8 is R 15 ;
  • any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents on R 13 or R 15 ; and each of R 9 , R 10 , R 11 and R 12 , independently, is R 15 .
  • R 1 is NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 11 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally independently substituted with 1-3 R 15 substituents;
  • R 2 is H, halo, haloalkyl, CN, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine , isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;
  • each of R 3 and R 4 is H, halo, haloalkyl, CN 3 NO 2 , NH 2 , OH, methyl, ethoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, ethyla ina, di ethyla ina, ethyla ina, diethyla ina, propyla ina, isopropyl ina, dipropyl ina, diisopropyl ina, benzyl or phenyl;
  • each R 5 is independently H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, terebutyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, or diisopropylamine;
  • R 6 is R 13 or R 14 ;
  • each of R 7 and R 8 is R 15 ;
  • any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ; Y
  • each of R 9 , R 10 , R 1 1 and R 12 is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl , butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine or diisopropylamine.
  • each of A 1 and A 2 is N; Y
  • R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 .
  • D 2 is CR 12 wherein R 12 is H, halo, NO 2, CN, C MO alkyl or alkoxyl CMO;
  • U is NH 3 , O or S
  • L 2 is NH;
  • R 1 is H, halo, haloalkyl, acetyl, alkyl CM O O NHR 15 ;
  • each of R 2 , R 3 and R 4 independently, is H, halo, CMO-alkyl or CMO-alkoxy;
  • R 6 is R 14 ;
  • R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents on R 13 or R 15 .
  • each of A 1 and A 2 independently, is N or CR 9 , provided that at least one of A 1 and A 2 is N;
  • each of B 1 , B 2 , B 3 and B 4 is N or CR 5 , provided that no more than two of B 1 , B 2 , B 3 and B 4 are N;
  • C 1 is N or CR 10 ;
  • U is O, S , C (O), S (O), S0 2 or CR 3 R 3 ;
  • L 2 is NR 3 , O, S or CR 3 R 3 ;
  • R 1 is OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 11 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally independently substituted with 1-3 substituents of R 15 , SR 14 , OR 14 , SR 15 , OR 15 , OC (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or
  • R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C ( 0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0 ) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 14 R 15 , 0C (0) NR 15 R 15 , S (0 ) 2 R 14 , S (0) 2 R 15
  • each of R 3 and R 4 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 or R 15 ;
  • R 3 or R 4 independently, taken together with R 10 and the carbon atoms to which they are attached form a ring of carbon atoms partially or completely unsaturated 5 or 6 membered optionally including 1-3 heteroatoms selected from O, N or Ss and the ring optionally independently substituted with 1-3 substituents from R 13 , R 14 or R 15 ;
  • each R 5 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 1 S , COOR 15 , 0C ( 0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 ,
  • NR 15 C (0) R 14 NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 ,
  • R 6 is R 13 or R 14 ;
  • each of R 7 and R 8 is R 13 , R 14 or R 15 ;
  • any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully saturated or partially or fully unsaturated 5 or 6 membered carbon atom ring optionally including 1-3 heteroatoms selected from O , N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ;
  • each of R 9 , R 10 , R 11 and R 12 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 ,
  • R 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , OC (0) R 14 ,
  • R 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic system partially or completely saturated or completely unsaturated, the ring system formed by carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic. or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-3 substituents of R 15 ;
  • R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2, NH 2, acetyl, alkyl Ci- 10 alkenyl or C 2 i, C 2 i alkynyl or C3-10 , C4-10 cycloalkenyl, CMO-alkylamino-, Ci-10-dialkylamino-, alkoxy CMO, thioalkoxy CMO OR 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered saturated or partial tricyclic ring system or completely unsaturated, said ring system consisting of carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O , N, or S , wherein each of the CMO alkyl, C 2 -i alkenyl or, C
  • the compound of formula (Vil) is selected from:
  • the AURK inhibitor is a compound encompassed by formula (I) as disclosed in US2003069299 such as hesperadine.
  • Compounds of formula (I) as disclosed in US2003069299 are identified herein by formula (VIII):
  • X is an oxygen or sulfur atom
  • Ri is a hydrogen atom, a C 1-4 alkoxycarbonyl group or C 2-4 alkanoyl
  • R 2 is a Ci-e alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C 2-6 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety can be substituted in each case by a fluorine, chlorine, bromine or iodine, an alkyl group or C 1-3 alkoxy C1-3, a phenyl group which may be mono- or disubstituted by fluorine, chlorine, bromine or iodine, a group C 1-3 alkyl or alkoxy C 1-3, in which the substituents may be identical or different,
  • an imino group optionally substituted by a C 1-3 alkyl group, an oxygen or sulfur atom,
  • an imino group optionally substituted by a C 1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
  • o is a 6-membered heteroaromatic group optionally substituted by a C 1-3 alkyl group, which contains one or two heteroatoms in the heteroaromatic moiety and to which a phenyl ring can be fused through two adjacent carbon atoms,
  • R 3 is a hydrogen atom or a C 1-6 alkyl group
  • a phenyl group optionally substituted by a fluorine, chlorine or bromine, an alkyl group C 1-3, hydroxy, alkoxy C 1-3, C 1-3 alkylsulfenyl, alkylsulfinyl C 1-3 alkylsulfonyl C 1-3, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, alkylamino C 1-3 -alkylamino, di (Ci- 3) alkylamino, alkanoylamino or C 2-5 N- (Ci- 3 alkylamino) C 2-5 alkylamino,
  • R 4 is a phenyl or naphthyl group optionally substituted by R 7 , which may be further substituted by a chlorine or bromine atom or a nitro group, a 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, while the aforementioned 5- and 6-membered heteroaromatic groups may be additionally substituted by a chlorine or bromine atom or by a methyl group or in which a phenyl ring can be condensed with the above mentioned 5- and 6-membered heteroaromatic groups through 2 adjacent carbon atoms, or
  • R 5 and R 6 in each case independently of each other are hydrogen atoms or C 1-3 alkyl groups, and R 7 is a fluorine, chlorine, bromine or iodine atom or a cyano group,
  • a methoxy group or a C 2-3 alkoxy group which may be substituted in position 2 or 3 by an amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino or 5-7 membered cycloalkyleneimino group, while in each case an alkyl residue in the aforementioned alkylamino and dialkylamino groups may be additionally substituted by a phenyl group, a trifluoromethyl group, nitro, amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino, C 2-5 alkanoylamino, N- (Ci- 3- alkyl) -C 2-5- alkanoylamino, C 1-5 -alkylsulfonylamino, N- (Ci- 3- alkyl) -C 1-5 alkylsulfonylamino, N- (Ci-alkyl) 3 ) -phenylsulfonyla
  • a C1-3 alkyl group which may be substituted by an amino, C1-5 alkylamino, C5-7 cycloalkylamino or phenyl-C1-3 alkylamino group which may be additionally substituted in the nitrogen atom of the amino in each case by an alkyl group C1-4, C5-7 cycloalkyl or C2-4 alkenyl or C1-4 alkyl, while the aforementioned C1-4 alkyl substituent in each case may additionally be mono, di or trisubstituted by a cyano, carboxyl, C1 alkoxycarbonyl group -3, C2-4 alkanoyl, pyridyl, imidazolyl, benzo [1, 3] dioxol or phenyl, while the phenyl group can be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents can be identical or different, or in the 2, 3 or 4 position by a
  • a C1-3 alkyl group which is substituted by a hydroxyl, carboxyl, morpholino, thiomorpholine, 1-oxo-thiomorpholine, 1,1-dioxo-thiomorpholine, piperazine, N- (C-1-3 alkyl) -piperazine or N group -benzyl-piperazino, by a 5-7 membered cycloalkenyleneimino group or by a 4-7 membered cycloalkyleneimino group, whereas the aforementioned 5-7 membered cycloalkyleneimino groups may be substituted by one or two C1-3 alkyl groups, instead they may be terminally substituted by a C2-4 hydroxyl, amino or alkanoylamino group, or by a C5-7 cycloalkyl or phenyl group and by a hydroxyl group, and in the aforementioned cycloalkyleneimino groups a methylene group adjacent to the atom nitrogen can be
  • R 3 is a phenyl group optionally substituted by a fluorine, chlorine or bromine, an alkyl group C 1-3, hydroxy, C 1-3 alkoxy, C 1-3 alkylsulfenyl, alkylsulfinyl C 1-3 alkylsulphinyl, C 1 -3, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, alkylamino C 1-3 -alkylamino, di (Ci- 3) alkylamino, alkanoylamino or C 2-5 N- (Ci- 3 alkylamino) C 2-5 alkanoylamino.
  • R 2 is a C 1-3 alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C 2-4 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety in each case can be substituted by a fluorine, chlorine, bromine or iodine atom or by a C 1-3 alkyl or C 1-3 alkoxy group.
  • X is an oxygen atom
  • R 1 is a hydrogen atom
  • R 2 is a C 1-3 alkyl group optionally substituted by one or more fluorine atoms or a phenyl group or a C 2-4 alkenyl group optionally substituted by a phenyl group; a phenyl group which may be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-3 alkyl or C 1-3 alkoxy groups, in which the substituents may be identical or different,
  • R 3 is a hydrogen atom or an alkyl group C 1-4, or a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine, an alkyl group C 1-3, alkoxy C 1-3, nitro or amino,
  • R 4 is a phenyl group optionally substituted by R 7 ,
  • R 5 and R 6 in each case indicate a hydrogen atom
  • R 7 is a fluorine, chlorine, bromine or iodine atom
  • C 1-3 alkyl group which is substituted by a carboxyl group, alkoxycarbonyl C 1-3 aminocarbonyl, C 1-3 -alkylamino, di (Ci- 3) alkylaminocarbonyl, phenyl- C 1-3 alkylaminocarbonyl, N- ( phenyl-Ci- 3 -alkyl) C 1-3 alkylaminocarbonyl, 5-7 membered cycloalkyleneiminocarbonyl, amino, C 1-3 alkylamino, di (C 1-3 alkyl) -amino, phenyl-C 1-3 alkylamino, N- ( phenyl-Ci-alkyl 3 ) C 1-3 alkylamino or 5-7 membered cycloalkyleneimino,
  • a methylene group in position 2 can be replaced by a carbonyl group or in the aforementioned 6 and 7-membered cycloalkyleneimino residues, a methylene group in position 4 can be replaced by an oxygen atom, for an imino group, N- (Ci- 3- alkyl) -imino, N- (phenyl-Ci- 3 -alkyl) -imino or N- (Ci- 5- alkoxycarbonyl) -imino,
  • phenyl-C 1-3 alkylsulfonylamino or phenylsulfonylamino in which the hydrogen atom of the amino group can be replaced by a C 1-3 alkyl group, while the C 1-3 alkyl moiety can be substituted by a carboxyl group , C 1-3 alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, di (C 1-3 alkyl) -aminocarbonyl, phenyl-C 1-3 alkylaminocarbonyl, N- (phenyl-C 1-3 alkyl) -C 1- alkylaminocarbonyl 3 , 2-dimethylaminoethylaminocarbonyl, N-methyl- (2- dimethylaminoethyl) -aminocarbonyl or cycloalkyleneiminocarbonyl C 4-6 or in the 2-position by an amino group, C 1-3 alkylamino, di (Ci-
  • R 2 is a C 1-3 alkyl group optionally substituted by a phenyl group, a C 1-3 perfluoroalkyl group or a phenylvinyl group,
  • a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine, an alkyl group C 1-3, alkoxy C 1-3, nitro, amino, cyano, cyanomethyl or aminomethyl, an alkyl group C 4- 6 , C 3-7 cycloalkyl, trimethylphenyl or naphthyl, a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1 - (Ci- 3- alkyl) -imidazolyl group optionally substituted by a C 1-3 alkyl group,
  • R 3 is a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine, an alkyl amino group C 1-3, alkoxy C 1-3, or nitro,
  • R 4 is a phenyl group which may be substituted by R 7 and additionally by a chlorine atom or a nitro group, while
  • R 7 is a fluorine, chlorine, bromine or iodine atom
  • R2 is selected from the group consisting of:
  • the compound of formula (VIII) is selected from the group consisting of:
  • the AURK inhibitor is a compound encompassed by formula (I) as disclosed in WO 2001021596 such as ZM-447439.
  • Compounds of formula (I) as disclosed in WO 2001021596 are identified herein with formula (IX): Formula (IX) or a salt, an ester, an amide or a prodrug thereof;
  • X is O, or S, S (O) or S (0) 2, NH or NR 12 where R 12 is hydrogen or Ci alkyl.
  • R 5 is selected from a group NHC (0) 0R 9 , NHC (0) R 9 , NHS (0) 2 R 9 C (0) R 9 , C (0) 0R 9 , S (0) R 9 , S (0) 0R 9 , S (0) 2 0R 9 , C (O) NR 10 R 11 , S (O) NR 10 R 11 , S (O) ONR 10 R 11
  • R 9 , R 10 or R 11 are independently selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 together with the nitrogen atom to which they are attached may additionally form an optionally substituted heterocyclic ring which optionally contains additional heteroatoms;
  • R 6 is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl
  • R 7 and R 8 are independently selected from hydrogen, halo, Ci- 4- alkyl, Ci- 4- alkoxy, Ci- 4- alkoxymethyl, di (Ci- 4- alkoxy) -methyl, Ci- 4- alkanoyl, trifluoromethyl, cyano, amino, alkenyl C 2 -5, C 2 -s alkynyl, a phenyl group, a benzyl group, or a 5-6 membered heterocyclic group with 1-3 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which may or may not be aromatic aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl, benzyl or heterocyclic group can harbor one or more atoms of ring carbon to 5 substituents selected from hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl,
  • R 1 , R 2 , R 3 , R 4 are independently selected from halogen, cyano, nitro, C1-3 alkylsulfanyl, -N (OH) R 13 - (where R 13 is hydrogen or C1-3 alkyl), or R 15 X 1 - (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -S0 2 -, - NR 16 CO-, -CONR 16 -, -S0 2 NR 16 -, -NR 17 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C1-3 alkyl or Ci-3 alkoxy -C 2 -3 alkyl), and R 1 5 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy
  • the compound according to formula (IX) in which the hydrocarbyl, heterocyclyl or alkoxy groups R 77 , R 78 and R 79 as well as the rings formed by R 78 and R 79 are optionally substituted by halo, perhaloalkyl, mercapto, alkylthio, hydroxyl, carboxyl, alkoxy, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may be substituted by halo, nitro or hydroxy), cyano, nitro, , mono or dialkylamino, oximino or S (0) and R 9 ° where y is as defined above and R 90 is an alkyl.
  • the compound according to formula (IX) in which at least one group R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 and R 15 is selected from one of the following twenty-two groups :
  • Cis alkyl which may be unsubstituted or which may be substituted with one or more functional groups
  • R 19 represents -R to X 2 C (0) R 19 (where X 2 represents -O- or -NR 20 - (where R 20 represents hydrogen or alkyl optionally substituted with a functional group) and R 19 represents alkyl C1 -3, -NR 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen or alkyl optionally substituted with a functional group);
  • R 29 each independently represents hydrogen or alkyl optionally substituted with a functional group and s is 1 or 2) and R 24 represents hydrogen, hydrocarbyl (as defined herein) or a saturated heterocyclic group, in which the hydrocarbyl groups or heterocyclic can be optionally substituted by one or more functional groups and the heterocyclic groups can be additionally substituted by a hydrocarbyl group;
  • -R C X 4 R C X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -C (O) -, -S-, -SO- , -SO2-, -OC (O) -, -NR 31 C (0) s -, -C (0) x NR 32 -, -SO2NR 33 -, -NR 34 S0 2 - or -NR 35 - (in where R 31 , R 32 , R 33 , R 34 and R 35 each independently represents hydrogen or alkyl optionally substituted by a functional group and s is 1 or 2) and R 30 represents hydrogen or alkyl optionally substituted by a functional group;
  • R 37 represents a pyridone group, an aryl group, or an aromatic heterocyclic group (bonded via carbon or nitrogen) with 1-3 heteroatoms selected from O, N, and S, of which the pyridone group, aryl or aromatic heterocyclic may be substituted by one or more functional groups or by a hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or by a heterocyclyl group optionally substituted by one or more functional groups or hydrocarbyl groups;
  • R 37 (where X 6 represents -O-, -S-, -SO-, -S0 2 -, -OC (O) -, -NR 42 C (0) -, - C (0) NR 43 -, -S0 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45 and R 46 each independently represents hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
  • R 37 (where X 7 represents -O-, -C (O) -, -S-, -SO-, -SO -, -OC (O) -, - NR 47 C (0) -, -C (0) NR 48 -, -S0 2 NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represents hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
  • R 52 C (0) -, -C (0) NR 53 -, -S0 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (where R 52 , R 53 , R 54 , R 55 and R 56 each independently represents hydrogen, hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
  • R 62 is a C1 -3 alkylene group or a cyclic group selected from a divalent cycloalkyl or heterocyclic group, whose C1-3 alkylene group may be substituted by one or more functional groups and whose cyclic group may be substituted by one or more functional groups or by a hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or by a heterocyclyl group optionally substituted by one or more functional groups or hydrocarbyl groups; and R 63 is hydrogen, C1-3 alkyl, or a cyclic group selected from cycloalkyl or heterocyclic group, whose C1 -3 alkyl group may be substituted by one or more functional groups and whose cyclic group may be substituted by one or more functional groups or
  • R a , R b , R c , R c ' , R d , R 9 , R j , R n , R n' , R p , R p ' , R 1' , R u ' , R v and R v ' are independently selected from C1 -8 alkylene groups optionally substituted by one or more substituent functional groups,
  • R e , R h , R k and R ' are independently selected from C2-8 alkenylene groups optionally substituted by one or more functional groups
  • R f , R 1 , R m and R u are independently selected from C2-8 alkynylene groups optionally substituted by one or more functional groups.
  • the compound according to formula (IX) in which at least one group R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 and R 15 is selected from one of the following twenty-two groups :
  • Cis alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, oxiranyl, fluoro, chloro, bromo and amino (including Ci-3alkyl and trifluoromethyl);
  • R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, alkyl ⁇ 1 -5 , hydroxy-C 1-5 -alkyl or C- 3- alkoxy-C 2-3- alkyl));
  • R 25 , R 26 , R 27 , R 28 and R 29 each independently represent hydrogen, Ci-3alkyl, hydroxyl-C1 -3alkyl or Ci-3-C2-3alkyl and s is 1 or 2) and R 24 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, or a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S, and N, whose Ci-e alkyl group can harbor 1, 2 or 3 substituents selected from oxo, hydroxyl, halogen, cyclopropyl, amino, C1-4 alkylamino, C1-4 dialkylamino, alkylthio C 1-4, alkoxy C 1-4 cyclic group and which can accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, cyano
  • R 36 (wherein R 36 is a 4-6 membered cycloalkyl or saturated heterocyclic ring (bonded via carbon or nitrogen) with 1 -2 heteroatoms, independently selected from O, S, and N, whose cycloalkyl group or Heterocyclic can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, cyano, C 1-4 alkyl, hydroxy-C 1-4 -alkyl, cyano-C 1-4 -alkyl, cyclopropyl, alkylsulfonyl C- 4- C 1- alkyl.
  • R 38, R 39, R 40 and R 41 which may be the same or different, each represents hydrogen, C 1-4 -alkyl, hydroxy-C 1-4 alkyl or alkoxyl C 2-3 Ci- 3 alkyl) and a group - (- O-) f (C 4 -alkyl) g- ring D (where f is 0 or 1, g is 0 or 1 and ring D is a cyclic group selected from C 3-6 cycloalkyl, aryl or 5-6 membered heterocyclic group saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, the cyclic group of which may harbor one or more substituents selected from halo and C 1-4 alkyl);
  • R 37 (where R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (bonded via carbon or nitrogen) with
  • heteroatoms selected from O, N and S which pyridone, phenyl or aromatic heterocyclic may carry selected from hydroxyl, nitro, halogen, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-5 hydroxyalkyl substituents -4, aminoC 1-4 alkylamino C 1-4 hydroxyalkoxy C 1-4 oxo, cyano - C 1-4 cyclopropyl, Ci- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, di ( alkyl examined, Ci- 4 alkylamino C 1-4 alkyl, C 1-4 alkanoyl, di (Ci- 4) amino-C 1-4 alkyl, Ci- 4 alkylamino C 1-4 -alkoxy, di (C 1 - 4) amino-C 1-4 -alkoxy, carboxyl, carboxamido, trifluoromethyl, cyano, -C (0) NR 38 R
  • R 37 (where X 6 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -OC (O) -, - NR 42 C (0) -, -C (0) NR 43 -, -SO2NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45 and R 46 each each independently represents hydrogen, C1-3 alkyl, hydroxy-C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 37 is as hereinbefore defined herein);
  • C ⁇ alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro, amino, C1-4 alkylamino, carboxyl (and particularly alkyl esters thereof), N, N-di (Ci- 4- alkyl) amino, aminosulfonyl, C- 4 -N-alkylaminosulfonyl and N, N-di (Ci- 4- alkyl) aminosulfonyl;
  • C2-5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro, amino, Ci- 4- alkylamino, N, N-di (Ci- 4- alkyl) amino, aminosulfonyl, N -Ci- 4- alkylaminosulfonyl and N, N-di (C 1-4 -alkyl) aminosulfonyl;
  • R v R 62 (R v ' ) q (X 9 ) r R 63 (where X 9 is as defined herein above, q is 0 or 1, r is 0 or 1, and R 62 is a C1-3 alkylene group or a group cyclic selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, in which the C 1-3 alkylene group can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen and Ci- 4 alkoxy and which cyclic group may accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, cyano, C1-4 cyanoalkyl, C 1-4 alkyl, hydroxy C 1-4, alkoxy C 1-4, alkoxyl C 1-4 Ci- 4 alkyl, Ci- 4 alkyls
  • R a , R b , R b ' , R c , R c' , R d , R 9 , R j , R n , R n ' R p , R p' , R 1 ' , R u' , R v and R '' ' are independently selected from Ci-e alkylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino,
  • R e , R h , R k and R * are independently selected from C 2-8 alkenylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino, and R * may additionally be a bond;
  • R f , R ', R m and R u are independently selected from C 2-5 alkynylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino.
  • alkyl CI- S -X 2 COR 19 (where X 2 represents -O- or -NR 20 - where R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 1 9 represents C 1-3 alkyl, - NR1 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, C 1-3 alkyl or C 3 -alkoxy-C 2-3 alkyl)) ;
  • Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO-, -NR 25 CO-, - CONR 26 -, - SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represents hydrogen, C 1-3 -alkyl or C-alkoxy 3- C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, whose group C 1-3 alkyl can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and C 1-4 alkoxy and whose cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl,
  • R 36 (where R 36 is a saturated 5-6 membered heterocyclic group (bonded via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, where the group heterocyclic can accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, C 1-4 alkyl, hydroxy C 1-4, alkoxy C 1-4, alkoxyl Ci- 4 alkyl and Ci- 4 alkylsulfonyl Ci- 4 -C 1-4 );
  • R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S wherein the pyridone, phenyl or aromatic heterocyclic I may carry up to 5 substituents on available carbon atom selected from hydroxy, halogen, amino, C 1-4 alkyl, C 1-4 alkoxy, hydroxy C 1-4 aminoalkyl C 1-4 alkylamino C 1-4 hydroxyalkoxy C 04.01, carboxyl, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (wherein R 38, R 39, R 40 and R 41, which may be the same or different, each representing hydrogen, C 1-4 -alkyl or C- 3- alkoxy-C 2-3 alkyl));
  • Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, - CONR 43 -, -SO 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45, and R 46 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy-C-alkyl 2-3 ) and R 37 is as defined herein above);
  • Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
  • the compound according to formula (IX) in which at least one of R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 including alkylene, alkenylene or alkynylene groups in bridging R to , R b , R b ' , R c , R c' , R d , R 9 , R j , R n , R n ' , R p , R 1' , R u ' , R v , R v' , R e , R h , R k , R ', R f , R', R m and R u and at least one such group includes a hydroxyl substituent.
  • the compound according to formula (IX) in which R 5 is an NHC (0) R 9 or NHS (0) 2 R 9 group in which R 9 is as defined herein above. .
  • aralkyl optionally substituted with one or more functional groups and in which the aryl part may further comprise one or more alkyl substituents;
  • heterocyclyl optionally substituted with one or more alkyl, alkenyl or alkynyl functional groups
  • alkyl optionally substituted by a functional group or a cycloalkyl or heterocyclyl group in which the cycloalkyl or heterocyclyl group may themselves be optionally substituted with one or more functional or alkyl groups;
  • alkenyl optionally substituted by a functional group or an aryl group or heterocyclyl in which the aryl or heterocyclyl group may be optionally substituted with one or more functional or alkyl groups;
  • alkynyl optionally substituted by a functional group or an aryl or heterocyclyl group in which the aryl or heterocyclyl group may be optionally substituted with one or more functional groups or alkyl groups.
  • the compound according to formula (IX) has formula (IXa)
  • Z is C (O) or S (0) 2
  • R 64 is an optionally substituted hydrocarbyl or optionally substituted heterocyclyl.
  • the compound according to the formula (IXa) has the formula (IXb)
  • X is O, or S, S (O) or S (0) 2 or NR 8 where R 8 is hydrogen or C 1-6 alkyl;
  • Z is C (O) or S (0) 2
  • R 65 is an optionally substituted hydrocarbyl or optionally substituted heterocyclyl
  • R 7 and R 8 are independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (alkoxyl Ci- 4) methyl, alkanoyl Ci- 4, trifluoromethyl, cyano, amino alkenyl, C 2-5 alkynyl , C 2-5, a phenyl group, a benzyl group or a heterocyclic group 5-6 membered with 1-3 heteroatoms, independently selected from O, S, and
  • heterocyclic group can be aromatic or non-aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl group, benzyl or heterocyclic can hold one or more ring carbon atoms of up to 5 substituents selected from hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C 2-4 alkanoylamino C 1-4 alkoxycarbonyl C 1-4 alkylsulfanyl C 1-4 alkylsulfinyl C 1-4 alkylsulfonyl C 1-4, carbamoyl, N-alkylcarbamoyl C 1-4 N, N-di ( alkyl Ci- 4) carbamoyl, aminosulfonyl, alkylaminosulfonyl C 1-4, carb
  • R 1 , R 2 , R 3 and R 4 are independently selected from, halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (where R 13 and R 14 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or -X 1 R 15 (where X 1 'represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl , -S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 15 is selected from one of the following groups:
  • alkyl CI- S -X 2 COR 19 (where X 2 represents -O- or -NR 20 - where R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 19 represents C 1-3 alkyl, - NR1 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, C 1-3 alkyl O Ci- 3 alkoxyl C 2-3 alkyl));
  • Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO-, NR 25 CO-, - CONR 26 -, -SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy -C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from
  • the C1-3 alkyl group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and C1-4 alkoxy and in which the cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C1-4 alkyl, Ci- 4 hydroxyalkyl and C1-4 alkoxy);
  • R 36 is a saturated 5-6 membered heterocyclic group (bonded via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxyl, alkoxyl Ci-4-alkyl and Ci - 4 alkylsulfonyl-Ci-4 alkyl C1-4);
  • R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S , whose pyridone, phenyl or aromatic heterocyclic group can carry up to 5 substituents on an available carbon atom selected from hydroxyl, halogen, amino, C1-4alkyl, C1-4alkoxy, hydroxyalkylC1-4, aminoalkylC1-4, alkylaminoC1 -4, C1-4 hydroxyalkoxy, carboxyl, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (where R 38 , R 39 , R 40 and R 41 , which may be the same or different, each one represents hydrogen, C1-4alkyl or Ci-3-alkoxyC2-3alkyl));
  • Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -
  • Ci-3-X 9 -alkyl-C1-3-alkyl- 37 (in which X 9 represents -O-, -S-, -SO-, -SO2-, - NR 57 CO-, -CONR 58 -, -SO2NR 59 -, -NR 60 SO 2 - O -NR 61 - (where R 57 , R 58 , R 59 , R 60 and R 61 each independently represents hydrogen, C1-3-alkyl or C-alkoxy 3-C2-3alkyl) and R 37 is as defined herein above); Y
  • Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
  • the compound according to formula (IX) has formula (IXc)
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined herein above;
  • Y is C, S or S (O),
  • R 65 is a group R 9 , OR 9 or NR 10 R 11 in which R 9 , R 10 and R 11 are as defined herein above.
  • X is O, or S, S (O) or S (0) 2, or NR 8 wherein R 8 is hydrogen or C1- 6 alkyl;
  • Y is C, S or S (O),
  • R 65 is a group R 9 , OR 9 or NR 10 R 11 in which R 9 , R 10 and R 11 are independently selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 can, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring optionally containing additional heteroatoms,
  • R 6 and R 7 are independently selected from hydrogen, halo, Ci- 4, C1-4alkoxy, Ci- 4 alkoxymethyl, di (alkoxyl Ci- 4) methyl, alkanoyl Ci- 4, trifluoromethyl, cyano, amino, C2 -5, C2-5 alkynyl, a phenyl group, a benzyl group or a 5-6 membered heterocyclic group with 1-3 heteroatoms, independently selected from O, S and N, wherein the heterocyclic group may or may not be aromatic aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl, benzyl or heterocyclic group can harbor one or more atoms of ring carbon to 5 substituents selected from hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C2-
  • R 15 (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S- , -SO-, -S0 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR I7 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 15 is selected from one of the following groups:
  • alkyl CI- S -X 2 COR 19 (in which X 2 represents -O- or -NR 20 - in which R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 19 represents C 1-3 alkyl, -NR1 2I R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, alkyl 1-3 alkoxyl or C 2-3 -alkyl Ci- 3));
  • Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO -, - NR 25 CO-, - CONR 26 -, - SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represents hydrogen, C 1-3 -alkyl or C-alkoxy 3- C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, whose group C 1-3 alkyl can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and Ci- 4 alkoxy and in which the cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxy
  • R 36 (where R 36 is a 5-6 membered heterocyclic group saturated (linked via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen, Ci -4 alkyl, Ci -4 hydroxyalkyl, C1-4 alkoxyl, alkoxyl alkyl Ci-4-Ci- 4 alkylsulfonyl and Ci-4-alkyl Ci -4);
  • R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S wherein the pyridone, phenyl or aromatic heterocyclic I may carry up to 5 substituents on available carbon atom selected from hydroxy, halogen, amino, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 hydroxyalkyl, aminoalkyl Ci -4 , Ci -4 alkylamino, Ci -4 hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (wherein R 38, R 39, R 40 and R 41, which may be the same or different, each represents hydrogen, Ci -4 alkyl or alkoxyl Ci-3-alkyl C 2-3));
  • Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, - CONR 43 -, -SO 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45, and R 46 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy-C-alkyl 2-3 ) and R 37 is as defined herein above);
  • Ci-3-X 9 -alkyl C1-3-R-alkyl 37 (where X 9 represents -O-, -S-, -SO-, -SO2-, -
  • Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
  • R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are both hydrogen or both methoxy, R 64 is other than phenyl;
  • R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are methoxy, and Z is C (O), R 64 is other than methyl;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are all hydrogen, X is oxygen, R 6 is 4-methyl-1-piperazinyl and Z is C (O ), R 64 is other than methyl.
  • R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are methoxy, and Z is C (O), R 64 is other than methyl.
  • R 1 , R 4 , R 6 , R 7 , R 8 , R 64 , Z and X are as defined for formula (IXa) and R 2 ' and R 3' are the groups R 2 and R 3 respectively, provided that at least one of said groups and preferably R 3 is a group of sub-formula X 1 -R 15 in which X 1 is as defined above, and R 15 is a group R 15 as defined above in formula (IX), provided it is other than methyl.
  • R 1 , R 4 , R 6 , R 7 , R 8 , X, Z and R 64 are as defined for formula (IXb) and R 2 ' and R 3' are the groups R 2 and R 3 as defined for formula (IXb) respectively, provided that at least one of said groups and preferably R 3 is a group of sub-formula X 1 -R 15 where X 1 is as defined for formula (IXb ), and R 15 is a group R 15 as defined for formula (IXb), provided it is other than methyl.
  • R 65 is as defined for formula (IXc)
  • R 68 and R 69 are equivalent to R 2 and R 3 as defined above for formula (IX) except that at least one of R 68 or R 69 is a group of sub-formula X 1 R 15 in which R 15 is as is defined above for formula (IX), provided that said one of R 68 or R 69 is morpholinopropoxy, the other is not a sub-formula group (18) as defined for formula (IX); and further provided that when said one of R 68 or R 69 is methoxyethoxy, the other is not methoxy.
  • R 65 is as defined for formula (IXd)
  • R 68 and R 69 are equivalent to R 2 and R 3 as defined for formula (IXd) except that at least one of R 68 or R 69 is a group of sub-formula X 1 R 15 where R 15 is as defines for formula (IXd), provided that when said one of R 68 or R 69 is morpholino propoxy, the other is not a group of sub-formula (18) as defined for formula (IXd); and further provided that when said one of R 68 or R 69 is methoxyethoxy, the other is not methoxy.
  • X is preferably NH and X 1 is oxygen.
  • the AURK inhibitor is selected from a compound of formula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) or (IX ) as defined above.
  • the AURK inhibitor comprises anti-AURK siRNA (eg, siRNA that targets AURKB), barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG-900, hesperadine, ZM-447439 or a combination thereof.
  • the AURK siRNA comprises any of SEQ ID NO: 1-4, a functionally equivalent variant thereof, or a combination of at least any of two sequences selected from the group consisting of SEQ ID NO: 1-4 or their equivalent functional variants.
  • the AURK inhibitor comprises barasertib, tozasertib, or a combination thereof. Most preferably, the AURK inhibitor is barasertib.
  • the beneficial treatment or preventive effects of AURK inhibitors, active agents, compositions and additional combinations of the invention in relation to HIV infection or AIDS symptoms include, for example, the prevention or delay of initial infection of a subject exposed to HIV, the reduction of viral load in an HIV-infected subject, prolongation of the asymptomatic phase of HIV infection, maintenance of low viral loads in HIV-infected subjects whose viral levels have been reduced through antiretroviral therapy (ART), by increasing levels of CD4 T cells or reducing the decrease in CD4 T cells, both HIV-1 specific and nonspecific, in subjects not treated with drugs and in subjects treated with AT, increasing overall health and quality of life in a subject with AIDS and prolonging the life expectancy of a subject with AIDS.
  • ART antiretroviral therapy
  • a physician or veterinarian may compare the effect of the treatment with the condition of the subject prior to treatment, or with the expected state of an untreated subject, to determine if the treatment is effective in inhibiting AIDS.
  • the AURK inhibitors, active agents, compositions, and additional combinations of the invention are used for the prevention of HIV infection or AIDS.
  • the AURK inhibitors, active agents, compositions, and additional combinations of the invention are used for the treatment of HIV infection or AIDS. Therefore, the AURK inhibitors of the present invention will be suitable for inclusion in ART protocols commonly applied to patients with HIV or AIDS.
  • Additional AURK inhibitors, active agents, compositions, and combinations of the invention may be useful in the treatment of HIV infection or AIDS. While all subjects who may be affected with HIV or their equivalents can be treated in this manner (eg, chimpanzees, macaques, baboons, or humans), the AURK inhibitors, active agents, compositions, and additional combinations of the invention are particularly concerned with its therapeutic uses in humans. Often, more than one administration may be required to achieve the desired therapeutic effect; the exact protocol (dosage and frequency) can be established using conventional clinical procedures.
  • the present invention further relates to the reduction or elimination of symptoms associated with HIV infection or AIDS.
  • symptoms associated with the mild symptomatic phase of HIV infection including, for example, zoster, rash and nail infections, oral sores, recurrent nose and throat infection, and weight loss.
  • additional symptoms associated with the main symptomatic phase of HIV infection include, for example, oral and vaginal thrush (Candida), persistent diarrhea, weight loss, persistent cough, and reactivated tuberculosis or recurrent herpes infections, such as herpes labial (herpes simplex).
  • AIDS advanced AIDS
  • Other symptoms of advanced AIDS include, for example, diarrhea, nausea and vomiting, candidiasis and oral sores, persistent, recurrent vaginal infections and cervical cancer, persistent generalized lymphadenopathy (PGL), severe skin infections, condylomas and ringworm, respiratory infections, pneumonia, especially Pneumocystis carinii pneumonia (PCP), herpes zoster (or zoster), nervous system problems such as pain, numbness or "tingling" in the hands and feet, neurological abnormalities, sarcoma of Kaposi, lymphoma, tuberculosis, or other similar opportunistic infections.
  • PGP generalized lymphadenopathy
  • severe skin infections condylomas and ringworm
  • respiratory infections pneumonia, especially Pneumocystis carinii pneumonia (PCP), herpes zoster (or zoster)
  • nervous system problems such as pain, numbness or "tingling" in the hands and
  • the AURK inhibitors, compositions and combinations of the invention are administered to a subject infected with HIV or a subject exposed to HIV together with at least one additional active agent (therapeutic agent).
  • the therapeutic agent is commonly indicated for the prevention or treatment of HIV or AIDS.
  • Suitable therapeutic agents include, but are not limited to, drugs that are part of the protocols for current antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) such as non-nucleoside reverse transcriptase inhibitor (eg.
  • HIV antiretroviral (s) or simply “antiretroviral (s)”.
  • the AURK inhibitors, compositions and combinations of the invention are administered before any HIV antiretroviral is applied to the subject.
  • the AURK inhibitors, compositions and combinations of the invention are administered after the HIV antiretroviral has been applied to the subject, such as, for example, after discontinuation of a TAR or HAART protocol and before resuming their regimes.
  • the additional active agent is a latency reversing agent.
  • the latency reversing agent comprises a histone deacetylase (HDAC inhibitor). More preferably, the HDAC inhibitor comprises panobinostat, vorinostat, or a combination thereof.
  • compositions containing AURK inhibitors and combinations of AURK inhibitors with other active agents are described.
  • the present invention relates to a composition
  • a composition comprising at least one AURK inhibitor of the invention formulated with a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions are used to treat HIV or AIDS in a subject or to prevent HIV infection in an uninfected subject.
  • the composition comprises a compound of formula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) or (IX) as defined above or a combination thereof.
  • the composition comprises an anti-AURK siRNA (eg, siRNA targeting AURKB), barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG-900, hesperadine, ZM-447439 or a combination thereof.
  • the AURK siRNA comprises any of SEQ ID NO: 1-4, a functionally equivalent variant thereof, or a combination of at least any of two sequences selected from the group consisting of SEQ ID NO: 1-4 or their equivalent functional variants.
  • the AURK inhibitor comprises barasertib, tozasertib, or a combination thereof. Most preferably, the AURK inhibitor is barasertib.
  • a combination of at least one AURK inhibitor and at least one additional active agent is administered to a subject who needs it to treat or prevent HIV infection or AIDS.
  • the combination is administered together in the same composition.
  • the combination is administered separately and sequentially.
  • at least 24 hours are allowed between the administration of the AURK inhibitor and the additional active agent.
  • the combination comprises an AURK inhibitor, an anti-AURK siRNA, and an additional active agent.
  • the additional active agent is an HIV antiretroviral drug or a dormancy reversal agent.
  • the latency reversing agent comprises a histone deacetylase (HDAC inhibitor).
  • the HDAC inhibitor comprises panobinostat, vorinostat, or a combination thereof.
  • the preparation of the compositions and combinations of the invention is known in the art. See Remington: The Science and Practice of Pharmacy, 21 ed. (Pharmaceutical Press, Philadelphia, PA, USA, 2011).
  • the carrier is suitable for parenteral (eg, intravenous, intramuscular, subcutaneous, spinal, or epidermal) administration (eg, by injection or infusion).
  • the active agent of the invention can be coated with a material to protect the agent from the action of conditions that can inactivate the agent.
  • compositions and combinations of the present invention can be administered by a variety of methods known in the art. As will be appreciated by one skilled in the art, the route or mode of administration will vary depending on the desired results.
  • the active agents of the invention can be prepared with carriers that protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene and vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are known in the art. See Robinson J, et al., Editors, "Sustained and Controlled Release Drug Delivery Systems” (Marcel Dekker, Inc., New York, NY, USA, 1978).
  • the agent can be administered to a subject in an appropriate carrier (eg, liposome) or a diluent.
  • an appropriate carrier eg, liposome
  • Pharmaceutically acceptable diluents include, but are not limited to, saline and aqueous buffer solutions.
  • Liposomes include CGF water-in-oil-in-water emulsions as well as conventional liposomes. See Strejan G, et al., J. Neuroimmunol. 1984; 7: 27-41. Many methods of manufacturing liposomes are known in the art.
  • Liposomes can comprise one or more residues that are selectively transported to specific cells or organs and thus enhance targeted drug delivery.
  • exemplary targeting moieties include folate or biotin, mannosides, and surfactant protein A receptor.
  • the active agents of the invention are formulated into liposomes; in a more preferred embodiment, the liposomes include a targeting moiety. In a most preferred embodiment, the active agents in the liposomes are administered by bolus injection.
  • compositions and combinations of the invention include sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.
  • sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.
  • the use of such media in the preparation of the compositions and combinations of the invention is contemplated herein in that their use is not incompatible with the active agents of the invention.
  • Complementary active compounds can also be incorporated into the compositions and combinations of the invention.
  • compositions and combinations of the invention are normally sterile and stable under manufacturing and storage conditions.
  • a composition and combination according to the invention can be formulated as a solution, microemulsion, liposome or other ordered structure suitable for the concentration of active agent.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), or suitable mixtures thereof.
  • polyol eg, glycerol, propylene glycol, liquid polyethylene glycol
  • Proper fluidity can be maintained, for example, by using a coating such as lecithin, reducing deviation in particle size and using surfactants.
  • isotonic agents such as, for example, sugars, polyalcohols (for example, mannitol, sorbitol) or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be achieved by including in the composition or combination compounds that delay absorption (eg, monostearate salts, gelatin).
  • Sterile injectable solutions can be prepared by incorporating the active agent of the invention in the required amount in an appropriate solvent with one or a combination of the components listed above, as required, followed by sterilization-microfiltration.
  • dispersions are prepared by incorporating the active agent into a sterile vehicle that contains a basic dispersion medium and the required other components from those enumerated above.
  • the preferred preparation methods are vacuum drying and freeze drying (i.e. lyophilization) which produce a powder of the active ingredient plus any additional desired components from a solution. Filtered previously sterilized thereof.
  • Dosage regimens are adjusted to provide the optimal desired response (eg, a therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be reduced or increased proportionally, as indicated by the demands of the therapeutic situation.
  • the unit dosage form as used herein refers to physically suitable discrete units as unit dosages for the subjects to be treated; each unit contains a predetermined amount of active agent calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active agent and the particular therapeutic effect to be achieved.
  • compositions and combinations of the invention may comprise pharmaceutically acceptable antioxidants.
  • pharmaceutically acceptable antioxidants include, but are not limited to, water soluble antioxidants (eg, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite), oil soluble antioxidants (eg, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol) and metal chelating agents (eg citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid ).
  • water soluble antioxidants eg, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite
  • oil soluble antioxidants eg, ascorbyl palmitate, butylated hydroxyanisole (BHA), buty
  • Formulations of the pharmaceutical compositions of the invention include those suitable for oral, nasal, topical (eg, buccal and sublingual), rectal, vaginal, or parenteral administration.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by any method known in the art.
  • the amount of active agent that can be combined with a carrier material to produce a single dosage form will vary depending on the subject to be treated and the particular mode of administration.
  • the amount of active agent that can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition that produces a therapeutic effect. Generally, this amount will range from about 0.001% and about 90% active agent, preferably between about 0.005% and about 70%, and most preferably between about 0.01% and about 30%.
  • compositions and combinations of the present invention that are suitable for vaginal administration also include formulations of vaginal ovules, tampons, creams, gels, pastes, foams or sprays containing such carriers that are appropriate as is known in the art.
  • Dosage forms for topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active agent of the invention can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservative, buffer or propellant that may be required.
  • compositions and combinations of the invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • the prevention of the presence of microorganisms can be ensured by both sterilization procedures and the inclusion of various antibacterial and antifungal agents (for example, paraben, chlorobutanol, phenolic sorbic acid). It may also be desirable to include isotonic agents (eg, sugars, sodium chloride) in the compositions and combinations.
  • the current dosage levels of the active agents in the compositions and combinations of the invention can be varied to achieve the desired therapeutic response in a subject.
  • the selected dosage level will depend on a variety of pharmacokinetic factors including the activity of the particular agent of the invention employed, its amount, the route of administration, the time of administration, the rate of excretion or expression of the particular active agent employed, the duration of treatment, other drugs, compounds or materials used in combination with the particular pharmaceutical compositions used, age, sex, weight, condition, general health and previous medical history of the subject to be treated and other similar factors known in medical techniques.
  • a physician or veterinarian having ordinary skill in the art can easily determine and prescribe the required therapeutically effective amount of the active agent (s).
  • a suitable daily dose of a composition of the invention will be that amount of the active agent that is the lowest effective dose to produce a therapeutic effect.
  • Such an effective dose will generally depend on the factors described above. Administration is preferred to be parenteral, more preferably intravenous, intramuscular, intraperitoneal, or subcutaneous.
  • the effective daily dose of a pharmaceutical composition can be administered as two, three, four, five, six or more subdoses applied separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for an active agent of the invention to be administered alone, it is preferred to administer said agent as a pharmaceutical composition.
  • compositions and combinations of the invention can be administered with medical devices known in the art.
  • the pharmaceutical composition of the invention can be administered with a needleless hypodermic injection device.
  • a needleless hypodermic injection device See US 5,399,163, US 5,383,851, US 5,312,335, US 5,064,413, US 4,941,880, US 4,790,824 or US 4,596,556.
  • Examples of well known implants and modules useful in the present invention include, but are not limited to, infusion pumps for dispensing medications at different rates (eg, US 4,447,233 (non-implantable, controlled rate), US Pat.
  • US 4,447,224 (implantable, variable speed), US 4,487,603 (implantable, controlled speed)), devices for delivering medications through the skin (eg, US 4,486,194) and osmotic delivery systems of drugs (eg, US 4,439,196 and US 4,475,196).
  • devices for delivering medications through the skin eg, US 4,486,194
  • osmotic delivery systems of drugs eg, US 4,439,196 and US 4,475,196.
  • Many other such implants, systems and delivery modules are known to those skilled in the art.
  • compositions and combinations of the invention must be sterile and fluid to the extent that the composition is administrable by syringe.
  • the carrier may be isotonic buffered saline, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants.
  • isotonic agents such as, for example, sugars, polyalcohols (for example, mannitol, sorbitol) and sodium chloride in the composition.
  • Long-term absorption of injectable compositions can be achieved by including an agent that delays absorption (eg, aluminum monostearate, gelatin) in the composition or combination.
  • kits comprising at least one of the AURK inhibitors, active agents, compositions and additional combinations of the invention or mixtures thereof.
  • the components of the kits of the invention can optionally be packaged in suitable containers and labeled for the prevention or treatment of HIV or AIDS or its related conditions.
  • Kit components can be stored in unit or multiple dose containers as an aqueous solution, preferably sterile, or as a lyophilized, preferably sterile formulation for reconstitution.
  • the packages can be made of a variety of materials such as glass or plastic and can have a sterile access hole (for example, the package can be an intravenous solution bag or a vial that has a cap that can be pierced by a hypodermic injection needle. ).
  • kits may further comprise more packages comprising a pharmaceutically acceptable carrier. They may also include other commercially desirable and useable materials, including, but not limited to, buffers, diluents, filters, needles, syringes, culture media for one or more of the appropriate host cells or other agents. assets.
  • the kits may contain instructions normally included in commercial packages of therapeutic products that contain information, for example, on the indications, use, dosage, manufacture, administration, contraindications or warnings regarding the use of such therapeutic products.
  • PBMC Peripheral blood mononuclear cells
  • buffy coats were obtained from healthy donors (Banco Catalán de Sangre y Tejidos, Barcelona, ES, http://www.bancsang.net/en/index.html) by means of density gradient centrifugation Ficoll-Paque and used for fresh purification of CD4 + T cells, monocytes, or undifferentiated CD4 + T cells by negative selection (StemCell Technologies Inc., Cambridge, UK). The purity of the populations was confirmed by flow cytometry.
  • CD4 + T cells were maintained in complete RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum (FBS; Gibco, Thermo Fisher Scientific, Waltham, MA, USA), penicillin 100 U / ml and streptomycin 100 mg / ml (Gibco, Thermo Fisher Scientific, Waltham, MA, USA).
  • FBS heat inactivated fetal bovine serum
  • penicillin 100 U / ml penicillin 100 U / ml
  • streptomycin 100 mg / ml
  • Monocytes were grown in complete culture medium (RPMI 1640 medium) supplemented with 10% heat inactivated fetal bovine serum (FBS; Gibco) and penicillin / streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and they differentiated into monocyte derived macrophages (MDM) for 4 days in the presence of monocyte colony stimulating factor (M-CSF, PeproTech EC, Ltd., London, UK) at 100 ng / ml.
  • FBS heat inactivated fetal bovine serum
  • Gibco Thermo Fisher Scientific, Waltham, MA, USA
  • MDM monocyte derived macrophages
  • CD4 + T cells were activated with phytohemagglutinin (PHA) (4 mg / ml, Sigma-Aldrich Co., Saint Louis, MO, USA) in the presence of interleukin-2 (IL-2) (16 U / ml, Roche Diagnostics GmbH, Manheim, DE) for 3 days or left untreated with IL-2.
  • PHA phytohemagglutinin
  • IL-2 interleukin-2
  • Human ACH-2 cell lines and 9.2 cells were obtained from Jurkat clone (J-Lat) from the AIDS Reagent Program, National Institutes of Health (Bethesda, MD, USA). All cell lines were grown in RPMI 1640 medium, supplemented with 10% heat inactivated fetal bovine serum (FCS, Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and 100 U / ml penicillin antibiotics, streptomycin. 100 mg / ml (Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA) and maintained at 37 ° C in a 5% CO2 incubator.
  • FCS heat inactivated fetal bovine serum
  • the envelope-deficient HIV-1 clone NL4-3 encoding the internal ribosome entry site (I RES) - green fluorescent protein (GFP) (NL4-3-GFP) was pseudotyped with the G protein of stomatitis virus Vesicular (VEV-G) by HEK293 T cell cotransfection using polyethyleneimine (Polysciences, Inc., Warrington, PA, USA). Three days after transfection, supernatants were collected, filtered, and stored at -80 ° C. Viral stocks were concentrated using Lenti-X concentrator (Clontech Laboratories, Inc., Mountain Vista, CA, USA). Viruses were assessed by TZM cell infection followed by GFP quantification by flow cytometry.
  • NL4-3 * GFP was cotransfected with a Vpx-encoding plasmid (SIVmac239) in HEK293 T cells to produce viral stores. Three days after transfection, supernatants were collected, filtered, and concentrated using Lenti-X concentrator (Clontech
  • Latently infected cells were generated following a modified protocol described by Li et al. Briefly, cells were generated after acute infection of Jurkat cells with a pseudotyped NL4-3-GFP virus such as VEV and maintained in culture for 10 days to allow for the wear of infected cells productively.
  • a pseudotyped NL4-3-GFP virus such as VEV
  • Latently infected primary CD4 + T cells were generated according to the cytokine polarized primary T cell latency model with little modification. Briefly, undifferentiated CD4 + T cells were activated with aCD3 / aCD28 antibodies (1 mg / ml each; BD Biosciences, Madrid, ES) and supplemented with TGFpi (10 mg / ml; Peprotech EC, Ltd., London, UK) , alL-12 (2 mg / ml) and alL-4 (1 mg / ml; Peprotech EC, Ltd., London, UK). Medium supplemented with rLL-2 (30 lU / ml, Roche) was replaced every 3 days.
  • CD4 + T cells were infected with a Vpx binding NL4-3 * GFP by spinoculation (1200xg, 1 hr 30 min at 37 ° C) and GFP negative / latent infected cells classified three days then using a FACSAria II flow cytometer (BD
  • J-Hig latently infected cells were incubated with the library of 424 anticancer compounds, MK-5108 drugs, and HDACi for 24 h.
  • the hits were determined as the compounds whose reactivation was equal to or greater than the mean reactivation for panobinostat at 0.16 mM plus / minus 2 standard deviations.
  • latent-infected undifferentiated CD4 + T cells were also treated for 24 h before evaluating their reactivation capacity.
  • J-Hig cells and the established J-Lat cell line, harboring an HIV provirus containing the green fluorescent protein (GFP) ORF rather than nef, and a displacement mutation were incubated. frame in env, with barasertib in combination with vorinostat or panobinostat for 24 h before analysis.
  • GFP green fluorescent protein
  • ACH-2 cells a latent model of T cells with an integrated proviral copy, were cultured for 48 h in the presence of HDACi, acitretin or barasertib and reactivation was measured by production of CAp24 antigen against HIV using Genscreen HIV-1 Ag ELISA (BioRad Laboratories, Inc., Hercules, CA, USA) according to the manufacturer's instructions.
  • the cycling conditions were as follows: 50 ° C for 2 min followed by 95 ° C for 10 min for polymerase activation, followed by 50 cycles of 95 ° C for 15 s and 60 ° C for 1 min.
  • a calibration curve of 10 6 to 10 2 copies of HIV-1 5'LTR was performed using ACH-2 DNA and run in parallel with samples to quantify the absolute RNA copy numbers present in the T cell supernatant Latently infected undifferentiated CDD4 +.
  • J-Hig cells were transfected with siRNA by nucleofection.
  • 50 pmol of the corresponding siRNA (AURKB ON-TARGETplus SMARTpool, Dharmacon, Thermo-Scientific, Waltham, MA, USA and ThermoFisher Scientific) were transfected using a nucleofection V kit (Lonza, Basel, Switzerland) following the manufacturer's instructions.
  • Cells were left untreated for 24 h before adding HDACi vorinostat and panobinostat or barasertib. 24 h after drug addition, reactivation was measured by flow cytometry (LSRII, BD Biosciences) as the percentage of GFP + cells compared to untreated, uninterrupted cells.
  • the following antibodies were used for immunoblotting: secondary antibodies anti-rabbit and anti-mouse horseradish peroxidase conjugates (1: 5000; Pierce); anti-human Hsp90 antibody (1: 1000; BD Biosciences); anti-human SAMHD1 antibody (1: 2500; Abcam); human anti-phospho-SAMHD1 antibody (T592) (1: 1000; kindly provided by O. Keppler, University of Frankfurt); anti-human pRB antibody (1: 1000; Cell Signaling); anti-phospho-human pRB antibody (S807 / 811) (1: 1000; Cell Signaling).
  • CD4 + and MDM T cells in M-CSF were incubated with antiviral drugs 24 h prior to infection.
  • M-CSF macrophages and CD4 + T cells were acutely infected with a pseudotyped NL4-3-GFP virus such as VEV.
  • infection was performed by spinoculation (1200xg, 1 hr 30 min at 37 ° C) to enhance the infection rate.
  • Viral replication and antiviral activity were measured in all cases two days later by flow cytometry (LSRII, BD Biosciences).
  • cells were suspended in 0.03% saponin (Sigma-Aldrich Co., Saint Louis, MO, USA) in PBS and then incubated in 20mM 7-aminoactinomycin D (7AAD; Sigma -Aldrich Co., Saint Louis, MO, USA) for 30 min at room temperature in the dark, followed by 5 min at 4 ° C. Then, pyronine Y (Sigma-Aldrich Co., Saint Louis, MO, USA) was added to a final concentration of 1.5 mg / ml and the cells were further incubated at 4 ° C for 15 min. Flow cytometry was performed on an LSRII flow cytometer (BD Biosciences). Data were analyzed using FlowJo software (BD Biosciences).
  • AURK inhibitors as possible latency reversing agents
  • Sorting target compounds by their target showed that a majority were HDAC targeting agents (7 compounds), while the second most common target was the aurora kinase family (AURK) (3 compounds). See figure 2A. When pseudo-hits were added to the classification, the HDAC family prevailed as the most common target (9 compounds), while the AURK family ranked fourth (7 compounds). See figure 2B.
  • aCI 5 o mean maximum inhibitory concentration, or the concentration necessary to induce 50% inhibition of the target for the indicated drug.
  • IC 50 reflects the functional strength of the inhibitor.
  • b K constant of inhibition, or the concentration necessary to reduce the activity of that enzyme in half.
  • K reflects the binding affinity of a compound towards its target.
  • apparent K is the same as K, while for competitive inhibitors, the apparent K, will depend on the concentration of the enzyme substrate.
  • AURK inhibitors induce reactivation in cell lines and primary cells
  • Dose-dependent activity of barasertib and MK-5108, the pseudo-certainty with the highest specificity and potency for aurora kinase A (AURKA) was assayed in J-Hig cells .
  • HDACi panobinostat and vorinostat were used as controls, along with DMSO at the same final concentration, and acitretin, an antipsoriasis compound ruled out as LRA in view of previous studies.
  • acitretin an antipsoriasis compound ruled out as LRA in view of previous studies.
  • GFP + cells were observed in cells treated with both HDAC and AURK inhibitors.
  • acitretin did not induce any significant reactivation.
  • the latency reversal capacity of the above active agents was analyzed by quantifying viral RNA in the supernatant of the primary latently infected undifferentiated CDD4 + T cells. See figure 4B. As seen by flow cytometry, aCD3aCD28 induced viral RNA production as well as vorinostat at 1 mM. In addition, barasertib-induced reactivation at 1 mM was also analyzed. Although the barasertib-induced reactivation was not as high as that of the controls, more viral RNA was detected than in the DMSO-treated cells. As reported in the flow cytometric assay, panobinostat at O, dmM did not induce any reactivation.
  • Cl values were obtained using CompuSyn® software (ComboSyn, Inc., New York, NY, USA, http://www.combosyn.com/index.html, May 2018 ).
  • Cl> 1 indicates an antagonistic interaction;
  • Cl ⁇ 1 indicates synergistic interaction.
  • Table 2 combination index (Cl) between barasertib and HDACi in J-Hig cells.
  • Table 3 combination index (Cl) between barasertib and HDACi in 9.2 J-Lat cells.
  • AURKB interference is sufficient to trigger reactivation of HIV-1
  • AURK mRNA levels were quantified by real-time PCR at the time the active agents were added (24 h after interference) and when a flow cytometry assay was performed (48 h after interference).
  • AURKB mRNA levels were lower than in the simulation and siRNA NT controls in both cases, showing effective down-regulation of AURKB. See figure 6B.
  • AURK inhibitors have a protective effect against HIV-1 infection
  • anti-AURK compounds were evaluated prior to acute infection.
  • Primary CD4 + T cells and monocyte derived macrophages were incubated with anti-AURK compounds 24 h prior to infection. See figure 7A and 7B.
  • the antiretroviral agent 3-azido-3-deoxythymidine (zidovudine; AZT) was used as a positive control in both cases, along with palbociclib and MK-1775.
  • LY2603618 anti-kinase control 1 (Chk1) was used in macrophages and BML-277 anti-kinase control 2 (Chk2) was used in CD4 + T cells.

Abstract

The present invention relates to the use of Aurora kinase (AURK) inhibitors for treating or preventing an HIV infection or AIDS in a subject. The present invention further relates to compositions containing AURK inhibitors and combinations of AURK inhibitors with other active agents useful for treating or preventing an HIV infection or AIDS in a subject.

Description

DESCRIPCIÓN  DESCRIPTION
Aurora cinasa como diana para tratar, prevenir o curar una infección por VIH o SIDA Aurora kinase as a target to treat, prevent or cure an HIV infection or AIDS
Campo de la invención Field of the Invention
La presente invención se refiere al uso de inhibidores de aurora cinasa (AURK) para tratar o prevenir una infección por virus de la inmunodeficiencia humana (VIH) o el síndrome de deficiencia inmunitaria adquirida (SIDA) en un sujeto. La presente invención se refiere además a composiciones que contienen inhibidores de AURK y combinaciones de inhibidores de AURK con otros agentes activos útiles para tratar o prevenir una infección por VIH o SIDA en un sujeto. Se dan a conocer y se ejemplifican varios inhibidores de AURK y su uso individual o en combinación con otros agentes activos para tratar o prevenir una infección por VIH.  The present invention relates to the use of aurora kinase inhibitors (AURK) to treat or prevent an infection by human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) in a subject. The present invention further relates to compositions containing AURK inhibitors and combinations of AURK inhibitors with other active agents useful for treating or preventing HIV or AIDS infection in a subject. Various AURK inhibitors and their use alone or in combination with other active agents to treat or prevent HIV infection are disclosed and exemplified.
Antecedentes de la invención  Background of the Invention
La infección por VIH es una de las principales amenazas para la salud humana global. Se estima que más de 36,7 millones de personas a nivel mundial están actualmente infectadas con el VIH. Casi 2 millones de estos pacientes se infectaron sólo en 2016. Véase ONUSIDA, http://www.unaids.org/, mayo de 2018.  HIV infection is one of the main threats to global human health. It is estimated that more than 36.7 million people worldwide are currently infected with HIV. Almost 2 million of these patients became infected in 2016 alone. See UNAIDS, http://www.unaids.org/, May 2018.
La introducción de terapia antirretroviral (TAR) ha conducido a un aumento drástico en la esperanza de vida de los pacientes infectados con VIH. Sin embargo, la TAR es de por vida y no recupera completamente la salud de los pacientes infectados. Esta situación conduce a comorbilidades aumentadas asociadas con mayor riesgo cardiovascular, senescencia inmunitaria y toxicidad orgánica. Véase Deeks S, et al., Nature 2012; 487:439-440.  The introduction of antiretroviral therapy (ART) has led to a drastic increase in the life expectancy of patients infected with HIV. However, ART is for life and does not completely restore the health of infected patients. This situation leads to increased comorbidities associated with increased cardiovascular risk, immune senescence and organic toxicity. See Deeks S, et al., Nature 2012; 487: 439-440.
Una principal limitación a la eficacia de la TAR es la latencia de VIH-1. Véase Chun T, et al., Proc Nati Acad Sci USA 1997; 94:13193-13197 y Finzi D, et al., Science 1997; 278:1295-1300. Las células T CD4+ en reposo albergan provirus latentes que permiten poca o ninguna expresión génica de VIH haciendo de ese modo que el virus sea imperceptible al sistema inmunitario del huésped. Véase Hermankova M, et al., J Virol 2003; 77:7383-7392. Además, estos provirus silenciosos son susceptibles a nuevas rondas de infección o proliferación homeostática, lo que conduce a la reposición continua de los depósitos virales. Véase Chomont N, et al., Nat Med 2009; 15(8):893-900. Estos depósitos estables y latentes requieren TAR de por vida y son una barrera principal para curar el VIH. Véase Finzi D, et al., Nat Med 1999; 5:512- 517, Siliciano J, et al., Nat Med 2003; 9:727-728 y Strain M, et al., Proc Nati Acad Sci USA 2003; 100:4819-4824. Por ejemplo, los inhibidores de histona desacetilasas (HDACi) solos o en combinación con el modulador de la proteína cinasa C (PKCm) se han descrito recientemente como activadores de la transcripción del provirus VIH-1. Véase Wei D, et al., PLoS Pathog 2014; 10(4):e1004071 y Archín N, et al., Nature 2012; 487:482-485. Sin embargo, existe una necesidad no satisfecha de estrategias terapéuticas más eficaces para controlar o eliminar los depósitos virales.  A major limitation to the efficacy of ART is the latency of HIV-1. See Chun T, et al., Proc Nati Acad Sci USA 1997; 94: 13193-13197 and Finzi D, et al., Science 1997; 278: 1295-1300. Resting CD4 + T cells harbor latent proviruses that allow little or no gene expression of HIV thereby making the virus imperceptible to the host immune system. See Hermankova M, et al., J Virol 2003; 77: 7383-7392. Furthermore, these silent proviruses are susceptible to new rounds of homeostatic infection or proliferation, leading to continued replenishment of viral stores. See Chomont N, et al., Nat Med 2009; 15 (8): 893-900. These stable and latent deposits require ART for life and are a major barrier to curing HIV. See Finzi D, et al., Nat Med 1999; 5: 512-517, Siliciano J, et al., Nat Med 2003; 9: 727-728 and Strain M, et al., Proc Nati Acad Sci USA 2003; 100: 4819-4824. For example, histone deacetylase inhibitors (HDACi) alone or in combination with protein kinase C modulator (PKCm) have recently been described as transcription activators of the HIV-1 provirus. See Wei D, et al., PLoS Pathog 2014; 10 (4): e1004071 and Archín N, et al., Nature 2012; 487: 482-485. However, there is an unmet need for more effective therapeutic strategies to control or eliminate viral stores.
Sumario de la invención  Summary of the invention
En un primer aspecto, la presente invención se refiere a un método de tratamiento o prevención de una infección por VIH o SIDA que comprende administrar una cantidad terapéuticamente eficaz de un inhibidor de aurora cinasa (AURK) a un sujeto que lo necesita.  In a first aspect, the present invention relates to a method of treating or preventing an HIV or AIDS infection which comprises administering a therapeutically effective amount of an aurora kinase inhibitor (AURK) to a subject in need.
En un aspecto adicional, la invención se refiere a una composición que comprende al menos un inhibidor de AURK para su uso en el tratamiento o la prevención de una infección por VIH o SIDA en un sujeto que lo necesita. In a further aspect, the invention relates to a composition comprising at least one AURK inhibitor for use in the treatment or prevention of a HIV infection or AIDS in a subject who needs it.
En un aspecto adicional, la invención se refiere a una combinación que comprende al menos un inhibidor de AURK y al menos un agente activo adicional para su uso en el tratamiento o la prevención de una infección por VIH o SIDA en un sujeto que lo necesita.  In a further aspect, the invention relates to a combination comprising at least one AURK inhibitor and at least one additional active agent for use in treating or preventing HIV infection or AIDS in a subject in need.
En un aspecto todavía adicional, la invención se refiere a un kit que comprende los inhibidores de AURK, agentes activos adicionales, composiciones y combinaciones de la invención para su uso en el tratamiento o la prevención de infección por VIH o SIDA en un sujeto que lo necesita.  In a still further aspect, the invention relates to a kit comprising the AURK inhibitors, additional active agents, compositions and combinations of the invention for use in the treatment or prevention of HIV infection or AIDS in a subject who needs to.
Breve descripción de los dibujos Brief description of the drawings
Figura 1. Los inhibidores de aurora cinasa (AURKi) pueden inducir reactivación de VIH-1 en células J-Hig. (a) Compuestos anticancerosos identificados como aciertos para la reactivación de VIH-1 (reactivación relativa ³ panobinostat 0,16 mM ± 2DE) y su valor relativo (b) Compuestos anticancerosos clasificados como pseudoaciertos (panobinostat 0,16 pM ± 2DE > reactivación relativa ³ 1 ,4) y su reactivación de VIH-1 relativa. Las condiciones de control usadas en el ensayo fueron: sin tratar (UN), porcentaje de DMSO presente en la condición de los compuestos (DMSO al 0,25%) y los HDACi panobinostat (PNB 0,16 pM) y vorinostat (VOR 4 pM). Los fármacos se clasifican por su diana. Los valores representan la media ± DE de tres experimentos independientes.  Figure 1. Aurora kinase inhibitors (AURKi) can induce reactivation of HIV-1 in J-Hig cells. (a) Anticancer compounds identified as hits for reactivation of HIV-1 (relative reactivation ³ panobinostat 0.16 mM ± 2DE) and their relative value (b) Anticancer compounds classified as pseudo-successes (panobinostat 0.16 pM ± 2DE> relative reactivation ³ 1, 4) and its relative reactivation of HIV-1. The control conditions used in the test were: untreated (UN), percentage of DMSO present in the condition of the compounds (0.25% DMSO) and HDACi panobinostat (PNB 0.16 pM) and vorinostat (VOR 4 p.m). Drugs are classified by their target. Values represent the mean ± SD of three independent experiments.
Figura 2. La familia de aurora cinasa (AURK) es una de las dianas más eficaces para agentes de reversión de latencia (LRA) después de analizar la biblioteca de compuestos anticancerosos (a) Clasificación de las dianas respecto al número de inhibidores identificados como aciertos. La AURK se clasifica como la segunda diana más común con tres fármacos diferentes clasificados como aciertos. Puntuó sólo por debajo de la familia de la histona desacetilasa (HDAC), una diana bien conocida por reactivación de latencia. (b) Clasificación de las dianas respecto al número de inhibidores identificados como aciertos o pseudoaciertos. La familia de AURK se encuentra todavía en la cuarta posición superior, con siete inhibidores de AURK clasificados como aciertos o pseudoaciertos, de un total de 19 familias diana diferentes que pueden inducir reactivación.  Figure 2. The Aurora kinase family (AURK) is one of the most effective targets for latency reversal agents (LRA) after analyzing the library of anticancer compounds (a) Classification of targets with respect to the number of inhibitors identified as hits . AURK is classified as the second most common target with three different drugs classified as hits. It scored only below the histone deacetylase (HDAC) family, a target well known for dormancy reactivation. (b) Classification of the targets with respect to the number of inhibitors identified as hits or pseudo-hits. The AURK family is still in the top fourth position, with seven AURK inhibitors classified as hits or pseudo-hits, out of a total of 19 different target families that can induce reactivation.
Figura 3. Los inhibidores de aurora cinasa A (AURKA) y B (AURKB) actúan como agentes de reversión de latencia (LRA) en varias líneas celulares infectadas de manera latente e inducen detención del ciclo celular antes de la división celular (a) Reactivación de VIH inducida por el inhibidor de AURKA MK-5108 (20 - 0,8 pM) y el inhibidor de AURKB barasertib (20 - 0,8 pM) en células J-Hig. Se usaron inhibidores de HDAC vorinostat (VOR; 4 - 0,16 pM) y panobinostat (PNB; 4 - 0,16 pM) y acitretina (25 - 1 pM) como controles positivos y negativos, respectivamente. Se determinó la reactivación mediante la cuantificación de células GFP+ (%) después de cultivar J-HIG con los compuestos durante 24 h. (b) Reactivación de VIH inducida por el AURKi en células ACH-2. Se usaron vorinostat (VOR; 0,8 - 0,16 pM) y acitretina (25 - 1 pM) como controles positivos y negativos, respectivamente. Se determinó la reactivación como la cantidad relativa de VIH-1 CAp24 en el sobrenadante después de cultivar ACH-2 con los compuestos durante 48 h. (c) Distribución del ciclo celular de células J- Hig según su contenido de ADN después de incubar con el inhibidor de AURKA MK- 5108 (5pM) y el inhibidor de AURKB barasertib (5pM) durante 24 h. Se usó el agente de reversión de la latencia panobinostat (PNB; 0,8 pM) como control. Los valores representan la media ± DE de al menos tres experimentos independientes realizados por triplicado (a) y (b), o en replicaciones individuales (c). UN, sin tratar. DMSO al 0,5%, misma cantidad que en las condiciones del compuesto. G0-G1 , fase del ciclo celular G0 y G1. S, fase del ciclo celular S. G2-M, fase del ciclo celular G2 y mitosis. 4N, células cuadriploides detenidas. Figure 3. Aurora kinase A (AURKA) and B (AURKB) inhibitors act as latency reversal agents (LRA) in various latently infected cell lines and induce cell cycle arrest prior to cell division (a) Reactivation of HIV induced by AURKA inhibitor MK-5108 (20-0.8 pM) and AURKB inhibitor barasertib (20-0.8 pM) in J-Hig cells. HDAC inhibitors vorinostat (VOR; 4 - 0.16 pM) and panobinostat (PNB; 4 - 0.16 pM) and acitretin (25 - 1 pM) were used as positive and negative controls, respectively. Reactivation was determined by quantifying GFP + cells (%) after culturing J-HIG with the compounds for 24 h. (b) AURKi-induced reactivation of HIV in ACH-2 cells. Vorinostat (VOR; 0.8-0.16 pM) and acitretin (25-1 pM) were used as positive and negative controls, respectively. Reactivation was determined as the relative amount of HIV-1 CAp24 in the supernatant after culturing ACH-2 with the compounds for 48 h. (c) Cell cycle distribution of J-Hig cells according to their DNA content after incubation with AURKA inhibitor MK-5108 (5pM) and AURKB inhibitor barasertib (5pM) for 24 h. The panobinostat latency reversal agent (PNB; 0.8 pM) was used as a control. Values represent the mean ± SD of at least three independent experiments performed in triplicate (a) and (b), or in individual replications (c). A, untreated. DMSO at 0.5%, same amount as in compound conditions. G0-G1, phase of the G0 and G1 cell cycle. S, phase of the cell cycle S. G2-M, phase of the G2 cell cycle and mitosis. 4N, quadriploid cells arrested.
Figura 4. Los inhibidores de AURKB (barasertib y MK-5108) inducen la reactivación en células T CD4+ indiferenciadas primarias infectadas de manera latente. Se midió la reactivación de VIH mediante tanto la expresión de GFP (a) como por la cuantificación de ARNm viral en el sobrenadante (b). (c) Porcentaje de viabilidad celular de (a). Se midió la viabilidad mediante citometría de flujo como el porcentaje de células negativas después de la incubación con un kit de tinción de muerte celular. Se usó aCD3aCD28 como control positivo para la reactivación, así como los inhibidores HDACi vorinostat (VOR; 25 - 0,2 mM) y panobinostat (PNB; 4 - 0,032 pM). Los valores de (a) y (c) representan la media ± DE de al menos tres experimentos realizados por triplicado, mientras que en (b) se representa sólo el valor de un triplicado de uno de los experimentos independientes de (a). UN, sin tratar. DMSO, misma cantidad que en las condiciones del compuesto.  Figure 4. AURKB inhibitors (barasertib and MK-5108) induce reactivation in latently infected undifferentiated primary CD4 + T cells. HIV reactivation was measured by both GFP expression (a) and quantification of viral mRNA in supernatant (b). (c) Percentage of cell viability of (a). Viability was measured by flow cytometry as the percentage of negative cells after incubation with a cell death staining kit. ACD3aCD28 was used as a positive control for reactivation, as well as HDACi vorinostat (VOR; 25 - 0.2 mM) and panobinostat (PNB; 4 - 0.032 pM) inhibitors. Values in (a) and (c) represent the mean ± SD of at least three experiments performed in triplicate, while in (b) only the value of one triplicate of one of the independent experiments in (a) is represented. A, untreated. DMSO, same amount as under compound conditions.
Figura 5. La adición de barasertib potencia el efecto de HDACi en varias líneas celulares (a, b) Reactivación de VIH en células J-Hig después de una incubación de 24 h de diferentes concentraciones de barasertib con vorinostat (a) o panobinostat (b). Se cuantificó la reactivación como porcentaje de células GFP+ y se relativizó a la condición sin tratar (c, d) Reactivación de VIH en células 9.2 de clon J-Lat después de una incubación de 24 h de diferentes concentraciones de barasertib con vorinostat (c) y panobinostat (d). Se determinó la reactivación de VIH mediante la cuantificación de células GFP+ (%). Los valores para (a), (b), (c) y (d) representan la media ± DE de al menos tres experimentos independientes.  Figure 5. The addition of barasertib potentiates the effect of HDACi on various cell lines (a, b) Reactivation of HIV in J-Hig cells after 24-hour incubation of different concentrations of barasertib with vorinostat (a) or panobinostat (b ). Reactivation was quantified as a percentage of GFP + cells and was relativized to the untreated condition (c, d). Reactivation of HIV in 9.2 cells of the J-Lat clone after a 24 h incubation of different concentrations of barasertib with vorinostat (c) and panobinostat (d). HIV reactivation was determined by quantifying GFP + cells (%). Values for (a), (b), (c) and (d) represent the mean ± SD of at least three independent experiments.
Figura 6. El silenciamiento de AURKB es suficiente para revertir la latencia de VIH y potenciar el efecto de HDACi. (a) Reactivación de VIH en células J-Hig 48 h tras la interferencia con ARNip que selecciona como diana AURKB. A las 24 h tras la interferencia, se trataron las células con el HDACi panobinostat y vorinostat 24 h antes de la lectura de citometría de flujo. Se determinó la reactivación mediante la cuantificación de células GFP+ (%). El punto de inicio del gráfico se establece en el valor sin tratar simulado (b) Cuantificación de niveles de ARNm de AURKB en las células J-Hig interferidas en el momento de adición de fármaco (24 h) y en el momento de lectura del citómetro de flujo (48 h). Se muestra un experimento representativo. Simulación, células tratadas sin ARNip; NTip, células tratadas con un ARNip que no selecciona como diana; AURKBip, células tratadas con ARNip que selecciona como diana AURKB. Figure 6. AURKB silencing is sufficient to reverse HIV latency and enhance the effect of HDACi. (a) Reactivation of HIV in J-Hig cells 48 h after interference with siRNA that targets AURKB. At 24 h after interference, cells were treated with HDACi panobinostat and vorinostat 24 h before flow cytometric reading. Reactivation was determined by quantifying GFP + cells (%). The starting point of the graph is set at the simulated untreated value (b) Quantification of AURKB mRNA levels in the interfered J-Hig cells at the time of drug addition (24 h) and at the time of cytometer reading flow (48 h). A representative experiment is shown. Simulation, cells treated without siRNA; NTip, cells treated with a siRNA that does not target; AURKBip, siRNA treated cells that target AURKB.
Figura 7. Los compuestos antirretrovirales no aumentan la actividad de reversión de latencia del AURKi barasertib y MK-5108. (a, b) Reactivación de VIH en células J-Hig después de una incubación de 24 h con el AURKi barasertib (25 - 0,04 mM) (a) o MK- 5108 (25 - 0,04 pM) (b) en combinación AZT (1 pg/ml) y raltegravir (1 pg/ml), agentes antivirales bien conocidos. Se determinó la reactivación mediante la cuantificación de células GFP+ (%). Los valores de (a) y (b) representan la media ± DE de tres experimentos.  Figure 7. Antiretroviral compounds do not increase the latency reversal activity of AURKi barasertib and MK-5108. (a, b) Reactivation of HIV in J-Hig cells after a 24 h incubation with the AURKi barasertib (25 - 0.04 mM) (a) or MK-5108 (25 - 0.04 pM) (b) in combination AZT (1 pg / ml) and raltegravir (1 pg / ml), well known antiviral agents. Reactivation was determined by quantifying GFP + cells (%). Values in (a) and (b) represent the mean ± SD of three experiments.
Figura 8. Los inhibidores de AURK presentan un efecto antiviral en células primarias que no afecta a la función de SAMHD1. (a, b) Se midió la actividad antiviral de los inhibidores de AURK MK-5108, barasertib, alisertib, hesperadina, mesilato de SNS- 314 y tozasertib en células T CD4+ primarias (a) y macrófagos derivados de monocitos (b) cuando se añaden 24 h antes de la infección. Se midió la infección como porcentaje de células GFP+ 48 h después de la infección. Se usó AZT como control positivo (c) Niveles de proteínas de pRB y SAMHD1 totales y sus formas fosforiladas en células T CD4+ 48 h después de la adición de fármaco. Se usaron palbociclib y MK-1775, agentes antivirales conocidos, como controles puesto que su efecto sobre la ruta de SAMHD1 se conoce bien. Se usó inmunotransferencia de Hsp90 como control de carga. Se incubaron macrófagos con M-CSF. Se incubaron células T CD4+ con IL- 2 y se activaron con PHA. Los valores en (a, b) representan la media ± DE de al menos tres experimentos independientes realizados por triplicado, mientras que la inmunotransferencia (c) es un experimento representativo. UN, sin tratar. Figure 8. AURK inhibitors show an antiviral effect in primary cells that does not affect SAMHD1 function. (a, b) Antiviral activity of inhibitors of AURK MK-5108, barasertib, alisertib, hesperadine, SNS-314 mesylate and tozasertib was measured in primary CD4 + T cells (a) and monocyte-derived macrophages (b) when added 24 h before infection. Infection was measured as a percentage of GFP + cells 48 h after infection. AZT was used as a control positive (c) Total pRB and SAMHD1 protein levels and their phosphorylated forms in CD4 + T cells 48 h after drug addition. Palbociclib and MK-1775, known antiviral agents, were used as controls since their effect on the SAMHD1 pathway is well known. Hsp90 immunoblot was used as loading control. Macrophages were incubated with M-CSF. CD4 + T cells were incubated with IL-2 and activated with PHA. Values in (a, b) represent the mean ± SD of at least three independent experiments performed in triplicate, whereas immunoblot (c) is a representative experiment. A, untreated.
Figura 9. El efecto antiviral de inhibidores de AURK no antagoniza con la actividad de otros compuestos antirretrovirales. (a, b) Actividad antiviral de compuestos antirretrovirales bien conocidos AZT (1 - 0,0016 pg/ml) (a) o raltegravir (1 - 0,0016 pg/ml) (b) en combinación con el AURKi barasertib (0,8 mM) y MK-5108 (0,16 mM). Se trataron las células durante 24 h antes de la infección con el AURKi y se lavaron después de eso. Se midió la infección 48 h después de la adición de los compuestos antirretrovirales y el virus como porcentaje de células GFP+. Los valores de (a) y (b) representan la media ± DE de tres experimentos.  Figure 9. The antiviral effect of AURK inhibitors does not antagonize the activity of other antiretroviral compounds. (a, b) Antiviral activity of well known antiretroviral compounds AZT (1 - 0.0016 pg / ml) (a) or raltegravir (1 - 0.0016 pg / ml) (b) in combination with AURKi barasertib (0, 8mM) and MK-5108 (0.16mM). Cells were treated for 24 hr prior to infection with AURKi and washed thereafter. Infection was measured 48 h after the addition of the antiretroviral compounds and the virus as a percentage of GFP + cells. Values in (a) and (b) represent the mean ± SD of three experiments.
Figura 10. La inhibición de AURK conduce a una detención del ciclo celular en las fases G2-M. (a, b) Distribución del ciclo celular de macrófagos (a) y células T CD4+ (b) según su contenido de ADN después de incubar con los fármacos durante 24 h. Se incubaron macrófagos con M-CSF. Se incubaron células T CD4+ con IL-2 en todas las condiciones y se activaron con PHA en todas las condiciones excepto“en reposo”. Los valores en (a) y (b) representan la media ± DE de al menos tres experimentos independientes. ND, sin fármaco.  Figure 10. AURK inhibition leads to cell cycle arrest in G2-M phases. (a, b) Distribution of the macrophage cell cycle (a) and CD4 + T cells (b) according to their DNA content after incubation with the drugs for 24 h. Macrophages were incubated with M-CSF. CD4 + T cells were incubated with IL-2 in all conditions and activated with PHA in all conditions except "resting". Values in (a) and (b) represent the mean ± SD of at least three independent experiments. ND, without drug.
Lista de secuencias  Sequence list
Las secuencias de ácidos nucleicos y aminoácidos representadas en la lista de secuencias adjunta se muestran usando las abreviaturas de letras convencionales y códigos aplicados de manera convencional en la técnica. Sólo se muestra una cadena de cada secuencia de ácido nucleico, pero se entiende que la cadena complementaria se incluye por cualquier referencia a la cadena representada. En la lista de secuencias adjunta SEQ ID NO: 1-4 son secuencias de ARN de silenciamiento del receptor de aurora cinasa. The nucleic acid and amino acid sequences represented in the attached sequence list are shown using the conventional letter abbreviations and codes applied in a conventional manner in the art. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood to be included by any reference to the represented strand. In the attached sequence list SEQ ID NO: 1-4 are aurora kinase receptor silencing RNA sequences.
Descripción detallada de la invención  Detailed description of the invention
La presente invención se refiere al uso de inhibidores de AURK, y especialmente inhibidores de AURKB, para tratar o prevenir una infección por VIH o SIDA en un sujeto que lo necesita. La aplicación de los inhibidores de AURK de la invención para tratar o prevenir una infección por VIH no se describe en la técnica anterior. Además, la presente invención da a conocer que la combinación de inhibidores de AURK con agentes de reversión de latencia tales como inhibidores de HDAC tiene un efecto sinérgico inesperado sobre la reactivación viral. Este efecto sinérgico con inhibidores de HDAC también se observa cuando AURKB se silencia usando ARNip.  The present invention relates to the use of AURK inhibitors, and especially AURKB inhibitors, to treat or prevent an HIV or AIDS infection in a subject in need. The application of the AURK inhibitors of the invention to treat or prevent HIV infection is not described in the prior art. Furthermore, the present invention discloses that the combination of AURK inhibitors with latency reversal agents such as HDAC inhibitors has an unexpected synergistic effect on viral reactivation. This synergistic effect with HDAC inhibitors is also observed when AURKB is silenced using siRNA.
Además, los inhibidores de AURK de la presente invención no tienen o tienen muy pocas interacciones con fármacos antirretrovirales administrados regularmente a pacientes que experimentan terapia antirretroviral. Por tanto, los inhibidores de AURK de la presente invención serían adecuados para la inclusión en los protocolos de TAR comúnmente aplicados a pacientes con VIH o SIDA.  Furthermore, the AURK inhibitors of the present invention do not have or have very few interactions with antiretroviral drugs regularly administered to patients undergoing antiretroviral therapy. Therefore, the AURK inhibitors of the present invention would be suitable for inclusion in ART protocols commonly applied to patients with HIV or AIDS.
1. Definiciones de expresiones y términos generales  1. Definitions of expressions and general terms
El término“SIDA”, tal como se usa en el presente documento, se refiere a la fase sintomática de la infección por VIH, e incluye tanto el síndrome de inmunodeficiencia adquirida (conocido comúnmente como SIDA) como el“CRS,” o complejo relacionado con el SIDA. Véase Adler M, et al., Brit. Med. J. 1987; 294: 1145-1147. Las manifestaciones inmunológicas y clínicas del SIDA se conocen bien en la técnica e incluyen, por ejemplo, infecciones oportunistas y cánceres que resultan de la deficiencia inmunitaria. The term "AIDS", as used herein, refers to the phase symptomatic of HIV infection, and includes both acquired immunodeficiency syndrome (commonly known as AIDS) and "CRS," or AIDS-related complex. See Adler M, et al., Brit. Med. J. 1987; 294: 1145-1147. The immunological and clinical manifestations of AIDS are well known in the art and include, for example, opportunistic infections and cancers resulting from immune deficiency.
Los términos“alisertib” y“S1133”, tal como se usan en el presente documento, se refieren a ácido 4-[[9-cloro-7-(2-fluoro-6-metoxifenil)-5H-pirimido[5,4-d][2]benzazepin- 2-il]amino]-2-metoxibenzoico, C27H20CIFN4O4 CAS [1028486-01-2], un compuesto de estructura química: The terms "alisertib" and "S1133", as used herein, refer to 4 - [[9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5.4 -d] [2] benzazepin- 2-yl] amino] -2-methoxybenzoic, C27H2 0 CIFN4O4 CAS [1028486-01-2], a compound of chemical structure:
Figure imgf000006_0001
Figure imgf000006_0001
El término“aminoácido”, tal como se usa en el presente documento, se refiere a aminoácidos que se producen de manera natural y sintéticos, así como a análogos de aminoácido y miméticos de aminoácido que funcionan de manera similar a los aminoácidos que se producen de manera natural. Los aminoácidos pueden denominarse en el presente documento o bien por sus símbolos de tres letras conocidos comúnmente o por los símbolos de una letra recomendados por la Comisión de Nomenclatura Bioquímica de la IUPAC-IUB. Asimismo, los nucleótidos pueden denominarse por sus códigos de letras individuales comúnmente aceptados.  The term "amino acid", as used herein, refers to naturally occurring and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function similarly to amino acids that are produced from natural way. Amino acids may be referred to herein as either their commonly known three letter symbols or the one letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Also, nucleotides can be named by their commonly accepted individual letter codes.
Los términos“AMG-900” y“S2719”, tal como se usan en el presente documento, se refieren a N-[4-[3-(2-aminopirimidin-4-il)piridin-2-il]oxifenil]-4-(4-metiltiofen-2-il)ftalazin- 1 -amina, C28H21N7OS CAS [945595-80-2], un compuesto de estructura química: The terms "AMG-900" and "S2719", as used herein, refer to N- [4- [3- (2-aminopyrimidin-4-yl) pyridin-2-yl] oxyphenyl] - 4- (4-methylthiophene-2-yl) phthalazin- 1 -amine, C28H21N7OS CAS [945595-80-2], a compound of chemical structure:
Figure imgf000007_0001
Figure imgf000007_0001
El término“terapia antirretroviral” o“TAR”, tal como se usa en el presente documento, se refiere a la administración de uno o más fármacos antirretrovirales (es decir, antirretrovirales de VIH) para inhibir la replicación de VIH. Normalmente, TAR implica la administración de al menos un agente antirretroviral (o, comúnmente, un cóctel de antirretrovirales) tal como inhibidor de nucleósido transcriptasa inversa (por ejemplo zidovudina (AZT, lamivudina (3TC) y abacavir), inhibidor no de nucleósido transcriptasa inversa (por ejemplo nevirapina y efavirenz) e inhibidor de proteasa (por ejemplo indinavir, ritonavir y lopinavir). El término terapia antirretroviral altamente activa (“TARVAA”) se refiere a regímenes de tratamiento diseñados para suprimir la replicación agresiva de VIH y la progresión de la enfermedad. La TARVAA consiste habitualmente en tres o más fármacos diferentes, tales como, por ejemplo, dos inhibidores de nucleósido transcriptasa inversa y un inhibidor de proteasa.  The term "antiretroviral therapy" or "TAR", as used herein, refers to the administration of one or more antiretroviral drugs (ie, HIV antiretrovirals) to inhibit HIV replication. TAR typically involves the administration of at least one antiretroviral agent (or, commonly, an antiretroviral cocktail) such as a nucleoside reverse transcriptase inhibitor (eg zidovudine (AZT, lamivudine (3TC) and abacavir), a non-nucleoside reverse transcriptase inhibitor) (eg nevirapine and efavirenz) and protease inhibitor (eg indinavir, ritonavir, and lopinavir.) The term highly active antiretroviral therapy ("HAART") refers to treatment regimens designed to suppress aggressive HIV replication and progression of The disease: HAART usually consists of three or more different drugs, such as, for example, two nucleoside reverse transcriptase inhibitors and one protease inhibitor.
Los términos“aurora cinasa” y“AURK”, tal como se usan en el presente documento, se refieren a uno cualquiera de una familia de serina/treonina cinasas relacionadas implicadas en la progresión mitótica. Una variedad de proteínas celulares que desempeñan un papel en la división celular son sustratos para la fosforilación mediante enzimas aurora cinasa, incluyendo, sin limitación, histona H3, p53, CENP-A, cadena ligera reguladora de miosina II, proteína fosfatasa-1 , TPX-2, INCENP, survivina, topoisomerasa II alfa, vimentina, MBD-3, MgcRacGAP, desmina, Ajuba, XIEg5, Ndd Op y D-TACC. Las enzimas aurora cinasa también son por sí mismas sustratos para la autofosforilación (por ejemplo, en Thr288). A menos que el contexto indique lo contrario, el término“aurora cinasa” se refiere a cualquier proteína aurora cinasa de cualquier especie, incluyendo, pero sin limitarse a, las clases de AURK aurora A (AURKA), aurora B (AURKB) y aurora C (AURKC).  The terms "aurora kinase" and "AURK", as used herein, refer to any one of a family of related serine / threonine kinases involved in mitotic progression. A variety of cellular proteins that play a role in cell division are substrates for aurora kinase enzyme phosphorylation, including, without limitation, histone H3, p53, CENP-A, myosin II regulatory light chain, protein phosphatase-1, TPX. -2, INCENP, survivin, topoisomerase II alpha, vimentin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5, Ndd Op and D-TACC. Aurora kinase enzymes are themselves also substrates for autophosphorylation (eg, in Thr288). Unless the context indicates otherwise, the term "aurora kinase" refers to any aurora kinase protein of any species, including, but not limited to, the classes of AURK aurora A (AURKA), aurora B (AURKB) and aurora C (AURKC).
Los términos“inhibidor de aurora cinasa” e“inhibidor de AURK”, tal como se usan en el presente documento, se refieren a un compuesto que puede interactuar con una aurora cinasa e inhibe su actividad enzimática. Inhibir la actividad enzimática de aurora cinasa significa reducir la capacidad de una aurora cinasa de fosforilar un péptido o proteína sustrato.  The terms "aurora kinase inhibitor" and "aurk inhibitor" as used herein refer to a compound that can interact with an aurora kinase and inhibit its enzymatic activity. Inhibiting the enzymatic activity of aurora kinase means reducing the ability of an aurora kinase to phosphorylate a peptide or protein substrate.
Los términos“barasertib” y“S1147”, tal como se usan en el presente documento, se refieren a 2-[3-[[7-[3-[etil(2-hidroxietil)amino]propoxi]quinazolin-4-il]amino]-1 H-pirazol-5- il]-N-(3-fluorofenil)acetamida, C26H30FN7O3, CAS [722544-51-6] y PubChem CID: 16007391 , un compuesto de estructura química: The terms "barasertib" and "S1147", as used herein, refer to 2- [3 - [[7- [3- [ethyl (2-hydroxyethyl) amino] propoxy] quinazolin-4-yl ] amino] -1 H-pyrazol-5-yl] -N- (3-fluorophenyl) acetamide, C26H30FN7O3 , CAS [722544-51-6] and PubChem CID: 16007391, a compound of chemical structure:
Figure imgf000008_0001
Figure imgf000008_0001
El término“CD4” o“receptor de CD4”, tal como se usa en el presente documento, se refiere a la agrupación de diferenciación 4, una glicoproteína expresada sobre la superficie de células T cooperadoras, monocitos, macrófagos y células dendríticas. CD4 ayuda al receptor de células T (TCR) en su unión con una célula presentadora de antígeno. Usando su porción que reside dentro de la célula T, CD4 amplifica la señal generada por el TCR reclutando una enzima, conocida como tirosina cinasa Lck, que es esencial para activar muchas moléculas implicadas en la cascada de señalización de una célula T activada. La secuencia de proteína completa para CD4 humano tiene el número de registro de UniProt P01730 (18 de junio de 2012).  The term "CD4" or "CD4 receptor", as used herein, refers to differentiation pool 4, a glycoprotein expressed on the surface of helper T cells, monocytes, macrophages, and dendritic cells. CD4 aids the T-cell receptor (TCR) in binding to an antigen presenting cell. Using its portion that resides within the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as Lck tyrosine kinase, which is essential to activate many molecules involved in the signaling cascade of an activated T cell. The complete protein sequence for human CD4 has the registration number of UniProt P01730 (June 18, 2012).
El término“codones optimizados”, tal como se usa en el presente documento, se refiere a la alteración de codones en ácidos nucleicos para reflejar el uso de codones típico del organismo huésped para mejorar la expresión de un polipéptido de referencia sin alterar su secuencia de aminoácidos. Hay varios métodos y herramientas de software conocidos en la técnica para la optimización de codones. Véase Narum D, et al., Infecí. Immun. 2001 ; 69(12):7250-7253), Outchkourov N, et al., Protein Expr. Purif. 2002; 24(1 ): 18-24, Feng L, et ai, Biochemistry 2000; 39(50):15399- 15409 y Humphreys D, et ai, Protein Expr. Purif. 2000; 20(2):252-264.  The term "optimized codons", as used herein, refers to alteration of codons in nucleic acids to reflect the use of codons typical of the host organism to improve the expression of a reference polypeptide without altering its sequence of amino acids. There are several methods and software tools known in the art for optimizing codons. See Narum D, et al., Infecí. Immun. 2001; 69 (12): 7250-7253), Outchkourov N, et al., Protein Expr. Purif. 2002; 24 (1): 18-24, Feng L, et ai, Biochemistry 2000; 39 (50): 15399-15409 and Humphreys D, et ai, Protein Expr. Purif. 2000; 20 (2): 252-264.
El término “que comprende” o “comprende”, tal como se usa en el presente documento, da a conocer también“que consiste en” según la práctica de patentes aceptada generalmente. The term "comprising" or "comprising", as used herein, also discloses "consisting of" according to generally accepted patent practice.
Los términos“ENMD-2076” y“S1118”, tal como se usan en el presente documento, se refieren a 6-(4-metilpiperazin-1-il)-N-(5-metil-1 H-pirazol-3-il)-2-[(E)-2- feniletenil]pirimidin-4-amina, C21H25N7, CAS [934353-76-1] y PubChem CID: 16041424, un compuesto de estructura química: The terms "ENMD-2076" and "S1118", as used herein, refer to 6- (4-methylpiperazin-1-yl) -N- (5-methyl-1 H-pyrazole-3- yl) -2 - [(E) -2- phenylethenyl] pyrimidin-4-amine, C21H25N7, CAS [934353-76-1] and PubChem CID: 16041424, a compound of chemical structure:
Figure imgf000009_0001
Figure imgf000009_0001
La expresión“variante funcionalmente equivalente”, tal como se usa en el presente documento, se refiere a un polinucleótido que resulta de la modificación, deleción o inserción de una o más bases y que conserva sustancialmente la actividad del polipéptido expresado mediante el ácido nucleico de referencia. Las variantes funcionalmente equivalentes contempladas en el contexto de la presente invención, incluyen polinucleótidos que muestran al menos el 60%, el 70%, el 80%, el 85%, el 90%, el 92%, el 94%, el 96%, el 98%, el 99% de similitud o identidad con las secuencias SEQ ID NO: 1-4. El grado de identidad o similitud entre dos polinucleótidos se determina usando algoritmos implementados por ordenador y métodos que se conocen ampliamente en la técnica. La identidad y similitud entre dos secuencias de polinucleótidos se determina preferiblemente usando el algoritmo BLASTP. Véase Altschul S, et ai,“BLAST Manual” (NCBI NLM NIH, Bethesda, MD, USA, 2001).  The term "functionally equivalent variant," as used herein, refers to a polynucleotide that results from the modification, deletion, or insertion of one or more bases and that substantially preserves the activity of the polypeptide expressed by the nucleic acid of reference. Functionally equivalent variants contemplated in the context of the present invention include polynucleotides showing at least 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% , 98%, 99% similarity or identity with the sequences SEQ ID NO: 1-4. The degree of identity or similarity between two polynucleotides is determined using computer implemented algorithms and methods that are widely known in the art. The identity and similarity between two polynucleotide sequences is preferably determined using the BLASTP algorithm. See Altschul S, et ai, "BLAST Manual" (NCBI NLM NIH, Bethesda, MD, USA, 2001).
El término“hesperadina”, tal como se usa en el presente documento, se refiere a N-[2- hidroxi-3-[C-fenil-N-[4-(piperidin-1 -ilmetil)fenil]carbonimidoil]-1 H-indol-5- il]etanosulfonamida, C29H32N4O3S, CAS [422513-13-1] y PubChem CID: 135421442, un compuesto de estructura química: The term "hesperadine", as used herein, refers to N- [2- hydroxy-3- [C-phenyl-N- [4- (piperidin-1 -ylmethyl) phenyl] carbonimidoyl] -1 H-indole-5-yl] ethanesulfonamide, C29H32N4O3S, CAS [422513-13-1] and PubChem CID: 135421442, a compound of chemical structure:
Figure imgf000010_0001
Figure imgf000010_0001
Los términos“inhibidor de histona desacetilasa”,“inhibidor de HDAC” y“HDACi”, tal como se usan en el presente documento, se refieren a un compuesto que inhibe las enzimas histona desacetilasa. Durante la expresión génica el ADN se enrolla o desenrolla alrededor de histonas. Las histona desacetilasas eliminan grupos acetilo de residuos de lisina en histonas durante este proceso, permitiendo por tanto que las histonas envuelvan ADN más estrechamente. Los inhibidores de HDAC evitan la desacetilación y, por tanto, afectan a la expresión génica. Los ejemplos de inhibidores de HDAC incluyen, pero no se limitan a, apicidina, abexinostat (es decir PCI-24781), belinostat (es decir Beleodaq®), BRD 4354, dacinostat (es decir LAQ-824), depudecina, droxinostat, entinostat (es decir SNDX-275, MS-275), givinostat (es decir gavinostat, ITF 2357), KD 5170, LMK 235, M 344, MC 1568, MC 1742, MI 192, mocetinostat (es decir MGCD-0103), NCH 51 (es decir PTACH), NSC 3852 (es decir 5-nitroso-8-quinolinol), niltubacina (es decir MAZ-1391), oxamflatina (es decir metacept 3), panobinostat (es decir Farydak®), PCI 34051 , pracinostat (es decir SB 939), pyroxamida, quisinostat (es decir JNJ-26481585), resminostat (es decir 4SC-201 , RAS2410), RG2833 (es decir RGFP109), RGFP966, toxina de Ricinus communis (es decir RC-toxina), rocilinostat (es decir ACY-1215), romidepsina (es decir Istodax®, FK 228), scriptaid, butirato de sodio, 4-fenilbutirato de sodio, ácido suberohidroxámico (es decir SBHA, N,N’-dihidroxioctandiamida), C-H 106, tacedinalina (es decir N- acetildinalina, Cl 994), TCS HDAC6 20b, TMP269, tricostatina A, tubacina, UF 010 (es decir 4-bromo-N’-butilbenzohidrazida), ácido valproico y vorinostat (es decir Zolinza®, SAHA). The terms "histone deacetylase inhibitor", "HDAC inhibitor" and "HDACi", as used herein, refer to a compound that inhibits histone deacetylase enzymes. During gene expression, DNA coils or unwinds around histones. Histone deacetylases remove acetyl groups from lysine residues in histones during this process, thereby allowing histones to wrap DNA more closely. HDAC inhibitors prevent deacetylation and therefore affect gene expression. Examples of HDAC inhibitors include, but are not limited to, apicidin, abexinostat (i.e. PCI-24781), belinostat (i.e. Beleodaq®), BRD 4354, dacinostat (i.e. LAQ-824), depudecin, droxinostat, entinostat (i.e. SNDX-275, MS-275), givinostat (i.e. gavinostat, ITF 2357), KD 5170, LMK 235, M 344, MC 1568, MC 1742, MI 192, mocetinostat (i.e. MGCD-0103), NCH 51 (ie PTACH), NSC 3852 (ie 5-nitroso-8-quinolinol), niltubazine (ie MAZ-1391), oxamflatin (ie metacept 3), panobinostat (ie Farydak®), PCI 34051, pracinostat (i.e. SB 939), pyroxamide, quisinostat (i.e.JNJ-26481585), resminostat (i.e.4SC-201, RAS2410), RG2833 (i.e.RGFP109), RGFP966, Ricinus communis toxin (i.e. RC-toxin), rocilinostat (i.e. ACY-1215), romidepsin (i.e. Istodax®, FK 228), scriptaid, sodium butyrate, sodium 4-phenylbutyrate, suberohydroxamic acid (i.e. SBHA, N, N'-dihydroxyoctandiamide), CH 106, tacedinaline (i.e. N-acetyldinaline, Cl 994), TCS HDAC6 20b, TMP269, Trichostatin A, Tubazine, UF 010 (i.e. 4-bromo-N’-butylbenzohydrazide), Valproic Acid and vorinostat (i.e. Zolinza®, SAHA).
El término“VIH”, tal como se usa en el presente documento, incluye VIH-1 y VIH-2, VISH y VIS.“VIH-1” significa el virus de la inmunodeficiencia humana tipo 1. El VIH-1 incluye, pero no se limita a, partículas de virus extracelulares y las formas de VIH-1 asociadas con células infectadas de VIH-1. El virus VIH-1 puede representar cualquiera de los principales subtipos conocidos (clases A, B, C, D E, F, G y H) o señalar el subtipo (grupo O) incluyendo cepas de laboratorio y aislados primarios. “VIH-2” significa el virus de la inmunodeficiencia humana tipo -2. El VIH-2 incluye, pero no se limita a, partículas de virus extracelulares y las formas de VIH-2 asociadas con células infectadas por VIH-2. El término “VIS” se refiere al virus de la inmunodeficiencia en simios que es un virus similar al VIH que infecta a monos, chimpancés y otros primates no humanos. El VIS incluye, pero no se limita a, partículas de virus extracelulares y las formas de VIS asociadas con células infectadas por VIS. The term "HIV" as used herein includes HIV-1 and HIV-2, VISH and VIS. "HIV-1" means human immunodeficiency virus type 1. HIV-1 includes, but It is not limited to extracellular virus particles and the forms of HIV-1 associated with HIV-1 infected cells. The HIV-1 virus can represent any of the main known subtypes (classes A, B, C, DE, F, G and H) or point to the subtype (group O) including laboratory strains and primary isolates. "HIV-2" means the human immunodeficiency virus type -2. HIV-2 includes, but is not limited to, extracellular virus particles and the forms of HIV-2 associated with cells infected with HIV-2. The term "SIV" refers to the simian immunodeficiency virus which is an HIV-like virus that infects monkeys, chimpanzees, and other non-human primates. The VIS includes, but is not limited to, extracellular virus particles and forms of SIV associated with SIV infected cells.
El término“infección por VIH”, tal como se usa en el presente documento, se refiere a indicaciones de la presencia del virus VIH en un individuo incluyendo seropositividad asintomática, complejo relacionado con el SIDA (CRS) y síndrome de inmunodeficiencia adquirida (SIDA).  The term "HIV infection" as used herein refers to indications for the presence of the HIV virus in an individual including asymptomatic seropositivity, AIDS-related complex (CRS), and acquired immunodeficiency syndrome (AIDS) .
Los términos“idéntico” o porcentaje de“identidad” en el contexto de dos o más ácidos nucleicos o polipéptidos se refieren a dos o más secuencias o subsecuencias que son iguales o tienen un porcentaje especificado de nucleótidos o residuos de aminoácido que son iguales cuando se comparan y alinean (introduciendo huecos, si es necesario) para una correspondencia máxima, sin considerar ninguna sustitución de aminoácido conservativa como parte de la identidad de secuencia. El porcentaje de identidad puede medirse usando software de comparación de secuencias o algoritmos o mediante inspección visual. Diversos algoritmos y software se conocen en la técnica que pueden usarse para obtener alineaciones de aminoácido o secuencias de nucleótidos. Los ejemplos de algoritmos adecuados para determinar la similitud de secuencia incluyen, pero no se limitan a, los algoritmos BLAST, BLAST con huecos y BLAST 2.0, WU-BLAST-2, ALIGN y ALIGN-2. Véase Altschul S, et al., Nuc. Acids Res. 1977; 25:3389-3402, Altschul S, et al., J. Mol. Biol. 1990; 215:403-410, Altschul S, et al., Met. Enzymol. 1996; 266:460-480, Karlin S, et ai, Proc. Nati. Acad. Sci. USA 1990; 87:2264-2268, Karlin S, et al., Proc. Nati. Acad. Sci. USA 1993; 90:5873-5877, Genentech Corp, Sur de San Francisco, CA, EE.UU., abril de 2017. Métodos de alineación de secuencias para comparación se conocen bien en la técnica. Puede llevarse a cabo alineación óptima de secuencias para comparación, por ejemplo, mediante el algoritmo de homología local de Smith-Waterman, mediante el algoritmo de alineación de homología de Needleman-Wunsch, mediante el método de búsqueda de similitud de Pearson-Lipman, mediante implementaciones computarizadas de estos algoritmos o mediante alineación manual e inspección visual. Véase Smith T, et al., Adv. Appl. Math. 1981 ; 2:482-489, Needleman S, et ai, J. Mol. Biol. 1970; 48:443-453, Pearson W, et al., Lipman D, Proc. Nati. Acad. Sci. USA 1988; 85:2444-2448, los programas GAP, BESTFIT, FASTA y TFASTA, Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wl, EE.UU.; Ausubel F, et al., Eds., “Short Protocols in Molecular Biology”, 5a ed. (John Wiley and Sons, Inc., Nueva York, NY, EE.UU., 2002). The terms "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same when They compare and align (introducing gaps, if necessary) for maximum match, without considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art that can be used to obtain amino acid alignments or nucleotide sequences. Examples of suitable algorithms for determining sequence similarity include, but are not limited to, the BLAST, BLAST with Gaps, and BLAST 2.0, WU-BLAST-2, ALIGN, and ALIGN-2 algorithms. See Altschul S, et al., Nuc. Acids Res. 1977; 25: 3389-3402, Altschul S, et al., J. Mol. Biol. 1990; 215: 403-410, Altschul S, et al., Met. Enzymol. nineteen ninety six; 266: 460-480, Karlin S, et ai, Proc. Nati. Acad. Sci. USA 1990; 87: 2264-2268, Karlin S, et al., Proc. Nati. Acad. Sci. USA 1993; 90: 5873-5877, Genentech Corp, South San Francisco, CA, USA, April 2017. Sequence alignment methods for comparison are well known in the art. Optimal sequence alignment may be carried out for comparison, for example, using the Smith-Waterman local homology algorithm, using the Needleman-Wunsch homology alignment algorithm, using the Pearson-Lipman similarity search method, using Computerized implementations of these algorithms or by manual alignment and visual inspection. See Smith T, et al., Adv. Appl. Math. nineteen eighty one ; 2: 482-489, Needleman S, et ai, J. Mol. Biol. 1970; 48: 443-453, Pearson W, et al., Lipman D, Proc. Nati. Acad. Sci. USA 1988; 85: 2444-2448, GAP, BESTFIT, FASTA, and TFASTA programs, Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wl, USA; Ausubel F, et to the., Eds., "Short Protocols in Molecular Biology", 5 ed. (John Wiley and Sons, Inc., New York, NY, USA, 2002).
El término“kit”, tal como se usa en el presente documento, se refiere a un producto que contiene los diferentes reactivos necesarios para llevar a cabo los usos y métodos de la invención que se envasan para permitir su transporte y almacenamiento. Los materiales adecuados para envasar los componentes del kit incluyen vidrio, plástico (por ejemplo polietileno, polipropileno, policarbonato), frascos, viales, papel o sobres. El término “agentes reversores de latencia”, tal como se usa en el presente documento, incluye, pero no se limitan a, inhibidores de histona desacetilasa (HDACi), moduladores de proteína cinasa C (PKCm), inhibidores de dominio de bromo externo y bromo (BET), inhibidores de acetaldehído deshidrogenasa (por ejemplo disulfiram), activadores de potenciador de cadena ligera kappa de factor nuclear de células B activadas (NF-kB), y activadores de la ruta de AKT. Los ejemplos de inhibidores de BET incluyen, pero no se limitan a, CPI 203, 1-BET151 , 1-BET762, JQ1 , MS417, MS436, OTX-015, PFi-1 y RVX-208. The term "kit" as used herein refers to a product that contains the various reagents necessary to carry out the uses and methods of the invention that are packaged to allow for transport and storage. Suitable materials for packaging kit components include glass, plastic (eg, polyethylene, polypropylene, polycarbonate), vials, vials, paper, or envelopes. The term "latency reversing agents", as used herein, includes, but is not limited to, histone deacetylase inhibitors (HDACi), protein kinase C modulators (PKCm), external bromine domain inhibitors, and bromine (BET), acetaldehyde dehydrogenase inhibitors (eg disulfiram), activated B cell nuclear factor kappa light chain enhancer activators (NF-kB), and activators of the AKT pathway. Examples of BET inhibitors include, but are not limited to, CPI 203, 1-BET151, 1-BET762, JQ1, MS417, MS436, OTX-015, PFi-1, and RVX-208.
El término“MK-5108”, tal como se usa en el presente documento, se refiere a ácido 4- (3-cloro-2-fluorofenoxi)-1-[[6-(1 ,3-tiazol-2-ilamino)piridin-2-il]metil]ciclohexan-1- carboxílico, C22H21CIFN3O3S, CAS [1010085-13-8] y PubChem CID: 24748204, un compuesto de estructura química: The term "MK-5108", as used herein, refers to 4- (3-chloro-2-fluorophenoxy) -1 - [[6- (1, 3-thiazol-2-ylamino) acid. pyridin-2-yl] methyl] cyclohexan-1- carboxylic, C22H21CIFN 3 O 3 S, CAS [1010085-13-8] and PubChem CID: 24748204, a compound of chemical structure:
Figure imgf000012_0001
Figure imgf000012_0001
Los términos“ácido nucleico”,“polinucleótido” y“secuencia de nucleótidos”, se usan indistintamente en el presente documento, se refieren a cualquier forma polimérica de nucleótidos de cualquier longitud y se componen de ribonucleótidos o desoxirribonucleótidos. Los términos incluyen tanto polinucleótidos monocatenarios como bicatenarios, así como polinucleótidos modificados (por ejemplo, metilados, protegidos). Normalmente, el ácido nucleico es una“secuencia codificante” que, tal como se usa en el presente documento, se refiere a una secuencia de ADN que se transcribe y traduce en un polipéptido en una célula huésped cuando se coloca bajo el control de secuencias reguladoras adecuadas. Las limitaciones de la secuencia codificante se determinan mediante un codón de inicio en el extremo terminal 5’ (amino) y un codón de detención de la traducción en el extremo terminal 3’ (carboxilo). Una secuencia codificante puede incluir, pero no se limita a, secuencias procariotas, ADNc de ARNm eucariota, secuencias de ADN genómico de ADN eucariota (por ejemplo, de mamífero), e incluso secuencias de ADN sintético. Una secuencia de terminación de la transcripción se ubicará habitualmente en el sentido de 3’ con respecto a la secuencia codificante.  The terms "nucleic acid", "polynucleotide" and "nucleotide sequence" are used interchangeably herein, refer to any polymeric form of nucleotide of any length, and are composed of ribonucleotides or deoxyribonucleotides. The terms include both single-stranded and double-stranded polynucleotides, as well as modified polynucleotides (eg, methylated, protected). Typically, nucleic acid is a "coding sequence" that, as used herein, refers to a DNA sequence that is transcribed and translated into a polypeptide in a host cell when placed under the control of regulatory sequences adequate. The limitations of the coding sequence are determined by a start codon at the 5 'end (amino) and a translation stop codon at the 3' end (carboxyl). A coding sequence can include, but is not limited to, prokaryotic sequences, eukaryotic mRNA cDNA, eukaryotic (eg, mammalian) genomic DNA sequences, and even synthetic DNA sequences. A transcription termination sequence will usually be located in the 3 'direction with respect to the coding sequence.
El término“unido operativamente”, tal como se usa en el presente documento, significa que la secuencia de nucleótidos de interés se une a la(s) secuencia(s) reguladora(s) de manera que se permite la expresión de la secuencia de nucleótidos (por ejemplo, en un sistema de transcripción/traducción in vitro o en una célula huésped cuando el vector se introduce en la célula huésped). Véase Auer H, Nature Biotechnol. 2006; 24: 41-43.  The term "operably linked", as used herein, means that the nucleotide sequence of interest binds to the regulatory sequence (s) so that expression of the sequence of nucleotides (eg, in an in vitro transcription / translation system or in a host cell when the vector is introduced into the host cell). See Auer H, Nature Biotechnol. 2006; 24: 41-43.
La expresión“administración parenteral” y“administrado por vía parenteral”, tal como se usa en el presente documento, significa modos de administración distintos de administración entérica y tópica, habitualmente mediante inyección, e incluye, sin limitación, inyección intravenosa, intramuscular, intraarterial, intratecal, intracapsular, intraorbital, intracardíaca, intradérmica, intraperitoneal, transtraqueal, subcutánea, subcuticular, intraarticular, subcapsular, subaracnoide, intraespinal, epidural e intrasternal e infusión. La expresión“portador farmacéuticamente aceptable”, tal como se usa en el presente documento, incluye cualquier disolvente, medio de dispersión, recubrimiento, agentes antibacterianos y antifúngicos, agente isotónico y de retardo de la absorción que son fisiológicamente compatibles con los inhibidores de AURK, agentes activos adicionales, composiciones y combinaciones de la invención. The term "parenteral administration" and "parenterally administered", as used herein, means modes of administration other than enteric and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial injection , intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal and infusion. The term "pharmaceutically acceptable carrier" as used herein includes any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption retarding agent that are physiologically compatible with AURK inhibitors, Additional active agents, compositions and combinations of the invention.
Los términos“prevenir,”“que previene” y“prevención”, tal como se usan en el presente documento, se refieren a inhibir el inicio o disminuir la aparición de una enfermedad en un sujeto. La prevención puede ser completa (por ejemplo, la ausencia total de células patológicas en un sujeto). La prevención también puede ser parcial, tal como, por ejemplo, reducir la aparición de células patológicas en un sujeto. Prevención también se refiere a una susceptibilidad reducida a un estado clínico. Dentro del contexto de la presente invención, los términos“prevenir,”“que previene” y“prevención”, se refieren principalmente a evitar o reducir la probabilidad de infección por VIH en un sujeto que mantiene exposición a VIH.  The terms "prevent," "preventing" and "prevention," as used herein, refer to inhibiting the onset or decreasing the onset of disease in a subject. Prevention can be complete (for example, the total absence of pathological cells in a subject). Prevention can also be partial, such as, for example, reducing the appearance of pathological cells in a subject. Prevention also refers to a reduced susceptibility to a clinical state. Within the context of the present invention, the terms "prevent," "preventing" and "prevention" refer primarily to avoiding or reducing the likelihood of HIV infection in a subject who maintains exposure to HIV.
Los términos“modulador de proteína cinasa C”,“modulador de PKC” y“PKCm”, tal como se usan en el presente documento, se refieren a un compuesto que afecta a la actividad de una enzima proteína cinasa C (“PKC”). Las PKC son enzimas que regulan la función de otras proteínas a través de la fosforilación de grupos hidroxilo ubicados en los residuos de serina y treonina de dichas proteínas. Los moduladores de PKC pueden ser antagonistas (es decir inhibidores), agonistas (es decir activadores) o ambos. Los ejemplos de antagonistas de PKC incluyen, pero no se limitan a, bisindolilmaleimida 1 (es decir BIM-1 , GF 109203X) y sus compuestos relacionados BIM-2, BIM-3 y BIM-8, [Ala107J- MBP (104-118), [Ala113]-MBP (104-118), C-1 , calfostina C (es decir UCN 1028C, PKF 115584), CGP 53353, queleritrina, D-eritro-esfingosina, dihidroesfingosina (es decir esfinganina), enzastaurina (es decir LY317615), [Glu27]- PKC (19-36), Go 6976, Go 6983, gosipol, melitina, miricitrina (es decir myricetrin, miricetol 3-ramnósido), miyabenol C (es decir Z-miyabenol C, E-cis-miyabenol C), cloruro de (±)-palmitoilcamitina, PKC (19-36), PKC 412 (es decir CGP 41251), pseudosustrato PKC b o, pseudosustrato de PKC z, Ro 32-0432 HCI, rottlerina, ruboxistaurina (es decir LY 333531 HCI), estaurosporinona (es decir K-252c), TCS 21311 , verbascósido (es decir acteósido, kusaginina, orobanquina), y ZIP (es decir péptido inhibidor de pseudosustrato z). Los ejemplos de agonistas de PKC incluyen, pero no se limitan a, briostatina A (es decir briostatina 1 , NSC 339555) y sus análogos briostatina 2 y briostatina 3, mimétidos de diacilglicerol (DAG), FR236924 (es decir DCP- LA), mebutato de ingenol (es decir Picato®, ingenol-3-angelato, PEP005) y sus análogos, forbol 12 , 13-d i buti rato (es decir PDbu), forbol 12-miristato 13-acetato (es decir PMA), prostratina, pseudo RACK1 , SC-10 y SC-9. The terms "protein kinase C modulator", "PKC modulator" and "PKCm", as used herein, refer to a compound that affects the activity of a protein kinase C enzyme ("PKC") . PKCs are enzymes that regulate the function of other proteins through the phosphorylation of hydroxyl groups located in the serine and threonine residues of these proteins. PKC modulators can be antagonists (i.e. inhibitors), agonists (i.e. activators), or both. Examples of PKC antagonists include, but are not limited to, bisindolylmaleimide 1 (ie BIM-1, GF 109203X) and its related compounds BIM-2, BIM-3, and BIM-8, [Ala 107 J-MBP (104 -118), [Ala 113 ] -MBP (104-118), C-1, calfostina C (ie UCN 1028C, PKF 115584), CGP 53353, cheleritrin, D-erythro-sphingosine, dihydrosphingosine (ie sphinganine), enzastaurin (ie LY317615), [Glu 27 ] - PKC (19-36), Go 6976, Go 6983, gossypol, melittin, myristicrin (ie myricetrin, myricetol 3-rhamnoside), miyabenol C (ie Z-miyabenol C , E-cis-miyabenol C), (±) -palmitoylcamitin chloride, PKC (19-36), PKC 412 (i.e. CGP 41251), PKC bo pseudo-substrate, PKC z pseudo-substrate, Ro 32-0432 HCI, rottlerine, ruboxistaurin (ie LY 333531 HCI), staurosporinone (ie K-252c), TCS 21311, verbascoside (ie acteoside, kusaginin, orobanquin), and ZIP (ie pseudo substrate z inhibitor peptide). Examples of PKC agonists include, but are not limited to, biostatin A (i. E. Biostatin 1, NSC 339555) and its analogs biostatin 2 and biostatin 3, diacylglycerol mimetides (DAG), FR236924 (i.e DCP-LA), ingenol mebutate (i.e. Picato®, ingenol-3-angelate, PEP005) and its analogs, forbol 12, 13-di buti rata (ie PDbu), forbol 12-myristate 13-acetate (i.e. PMA), prostratin, pseudo RACK1, SC-10 and SC-9.
Los términos“mesilato de SNS-314” y“S1154”, tal como se usan en el presente documento, se refieren a 1-(3-clorofenil)-3-[5-[2-(tieno[3,2-d]pirimidin-4-ilamino)etil]- 1 ,3-tiazol-2-il]urea; ácido metanosulfónico, C18H15CIN6OS2.CH4O3S CAS [1146618-41- 8], un compuesto de estructura química: The terms "SNS-314 mesylate" and "S1154", as used herein, refer to 1- (3-chlorophenyl) -3- [5- [2- (thieno [3,2-d ] pyrimidin-4-ylamino) ethyl] -1,3-thiazol-2-yl] urea; methanesulfonic acid, C1 8 H15CIN 6 OS2.CH4O 3 S CAS [1146618-41- 8], a compound of chemical structure:
Figure imgf000014_0001
Figure imgf000014_0001
El término “sujeto”, tal como se usa en el presente documento, se refiere a un individuo, planta o animal, tal como un ser humano, un primate no humano (por ejemplo, chimpancés y otras especies de simios y monos); animales de granja, tales como aves, peces, ganado, ovejas, cerdos, cabras y caballos; mamíferos domésticos, tales como perros y gatos; animales de laboratorio incluyendo roedores, tales como ratones, ratas y cobayas. El término no denota una edad o sexo particular. El término “sujeto” abarca un embrión y un feto. En una realización preferida, el sujeto es un ser humano.  The term "subject", as used herein, refers to an individual, plant, or animal, such as a human, a non-human primate (eg, chimpanzees and other ape and monkey species); farm animals, such as birds, fish, livestock, sheep, pigs, goats, and horses; domestic mammals, such as cats and dogs; laboratory animals including rodents, such as mice, rats, and guinea pigs. The term does not denote a particular age or sex. The term "subject" encompasses an embryo and a fetus. In a preferred embodiment, the subject is a human.
El término “cantidad terapéuticamente eficaz”, tal como se usa en el presente documento, se refiere a la dosis o cantidad de un inhibidor de AURK, agente activo adicional, combinación, o composición de la invención que produce una respuesta terapéutica o efecto deseado en un sujeto. The term "therapeutically effective amount", as used herein, refers to the dose or amount of an AURK inhibitor, additional active agent, combination, or composition of the invention that produces a therapeutic response or desired effect in a subject.
Los términos“tozasertib” y“S1048”, tal como se usan en el presente documento, se refieren a N-[4-[4-(4-metilpiperazin-1-il)-6-[(5-metil-1 H-pirazol-3-il)amino]pirimidin-2- iljsulfanilfeniljciclopropanocarboxamida, C23H28N8OS, CAS [639089-54-6] y PubChem CID: 5494449, un compuesto de estructura química: The terms "tozasertib" and "S1048", as used herein, refer to N- [4- [4- (4-methylpiperazin-1-yl) -6 - [(5-methyl-1 H -pyrazol-3-yl) amino] pyrimidin-2-yljsulfanylphenyljcyclopropanecarboxamide, C23H28N8OS, CAS [639089-54-6] and PubChem CID: 5494449, a compound of chemical structure:
Figure imgf000015_0001
Figure imgf000015_0001
El término“tratar” o“tratamiento”, tal como se usa en el presente documento, se refiere a la administración de un inhibidor de AURK, agente activo adicional, combinación, o composición de la invención para controlar la progresión de una enfermedad después de que hayan aparecido sus signos clínicos. Se entiende que control de la progresión de la enfermedad significa los resultados clínicos beneficiosos o deseados que incluyen, pero no se limitan a, reducción de los síntomas, reducción de la duración de la enfermedad, estabilización de estados patológicos (específicamente para evitar deterioro adicional), retrasar la progresión de la enfermedad, mejorar el estado patológico y la remisión (tanto parcial como total). El control de la progresión de la enfermedad también implica una extensión de la supervivencia en comparación con la supervivencia esperada si no se aplicó tratamiento. Dentro del contexto de la presente invención, los términos “tratar” y “tratamiento” se refieren principalmente a detener o retrasar la infección y destrucción de células T CD4+ sanas en un sujeto infectado por VIH. También se refiere a la detención y retraso de la aparición de síntomas de la enfermedad de inmunodeficiencia adquirida tales como recuento de células T CD4+ extremadamente bajo e infecciones repetidas por patógenos oportunistas. Los resultados clínicos beneficiosos o deseados incluyen, pero no se limitan a, un aumento en el recuento de células T CD4+ indiferenciadas absoluto (intervalo 10-3520), un aumento en el porcentaje de células T CD4+ respecto al total de células inmunitarias en circulación (intervalo del 1-50%), o un aumento en el recuento de células T CD4+ como porcentaje de recuento de células T CD4+ normal en un sujeto no infectado (intervalo del 1-161 %). “Tratamiento” también puede significar prolongar la supervivencia del sujeto infectado en comparación con la supervivencia esperada si el sujeto no recibe ningún tratamiento dirigido a VIH.  The term "treat" or "treatment", as used herein, refers to the administration of an AURK inhibitor, additional active agent, combination, or composition of the invention to control the progression of a disease after your clinical signs have appeared. Control of disease progression is understood to mean beneficial or desired clinical outcomes that include, but are not limited to, reduction of symptoms, reduction of disease duration, stabilization of disease states (specifically to avoid further deterioration) , delay the progression of the disease, improve the disease state and remission (both partial and total). Control of disease progression also implies an extension of survival compared to expected survival if no treatment was applied. Within the context of the present invention, the terms "treat" and "treatment" refer primarily to stopping or delaying infection and destruction of healthy CD4 + T cells in a subject infected with HIV. It also refers to stopping and delaying the onset of symptoms of acquired immunodeficiency disease such as extremely low CD4 + T cell count and repeated opportunistic pathogen infections. Beneficial or desired clinical outcomes include, but are not limited to, an increase in absolute undifferentiated CD4 + T cell count (range 10-3520), an increase in the percentage of CD4 + T cells relative to total circulating immune cells ( range 1-50%), or an increase in CD4 + T-cell count as a percentage of normal CD4 + T-cell count in an uninfected subject (range 1-161%). "Treatment" can also mean prolonging the survival of the infected subject compared to expected survival if the subject does not receive any HIV-directed treatment.
El término“ZM-447439”, tal como se usa en el presente documento, se refiere a N-[4- [[6-Metoxi-7-[3-(4-morfolinil)propoxi]-4-quinazolinil]amino]fenil]benzamida, C29H31 N5O4 CAS [331771-20-1], un compuesto de estructura química: The term "ZM-447439", as used herein, refers to N- [4- [[6-Methoxy-7- [3- (4-morpholinyl) propoxy] -4-quinazolinyl] amino] phenyl] benzamide, C29H31 N5O4 CAS [331771-20-1], a compound of chemical structure:
Figure imgf000016_0001
Figure imgf000016_0001
La invención también contempla el uso de sales de los compuestos mencionados en el presente documento tales como sales farmacéuticamente aceptables de barasertib (por ejemplo dihidrogenofosfato de barasertib), tozasertib, alisertib, SNS-314 (por ejemplo mesilato de SNS-314), MK-5108, ENMD-2076, AMG-900, hesperadina o ZM- 447439.  The invention also contemplates the use of salts of the compounds mentioned herein such as pharmaceutically acceptable salts of barasertib (for example barasertib dihydrogen phosphate), tozasertib, alisertib, SNS-314 (for example SNS-314 mesylate), MK- 5108, ENMD-2076, AMG-900, hesperadine, or ZM-447439.
2. Métodos de tratamiento y prevención  2. Methods of treatment and prevention
En un primer aspecto, la invención se refiere a un método de tratamiento o prevención de una infección por VIH o SIDA que comprende administrar una cantidad terapéuticamente eficaz de un inhibidor de aurora cinasa (AURK) a un sujeto que lo necesita. En una realización, la AURK es una AURKB.  In a first aspect, the invention relates to a method of treating or preventing an HIV or AIDS infection which comprises administering a therapeutically effective amount of an aurora kinase inhibitor (AURK) to a subject in need. In one embodiment, the AURK is an AURKB.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento US 2006116357 tal como barasertib. Los compuestos de fórmula (I) tal como se da a conocer en el documento US 2006116357 se identifican en el presente documento con la fórmula (I):  In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 2006116357 such as barasertib. Compounds of formula (I) as disclosed in US 2006116357 are identified herein with formula (I):
Figure imgf000016_0002
Fórmula (I) en la que A es heteroarilo de 5 miembros que contiene un átomo de nitrógeno y que contiene opcionalmente uno o dos átomos de nitrógeno adicionales;
Figure imgf000016_0002
Formula (I) wherein A is a 5-membered heteroaryl containing one nitrogen atom and optionally containing one or two additional nitrogen atoms;
X es O, S, S(O), S(0)2 o NR14; X is O, S, S (O), S (0) 2 or NR 14 ;
m es 0, 1 , 2 ó 3; m is 0, 1, 2 or 3;
Z es un grupo seleccionado de— NR1 R2, fosfonooxilo, cicloalquilo C3-6 cuyo cicloalquilo C3-6 está sustituido por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo, y un anillo de 4 a 7 miembros unido a través de un átomo de carbono que contiene un átomo de nitrógeno y que contiene opcionalmente un átomo de nitrógeno adicional, cuyo puede estar saturado, parcialmente saturado o insaturado en el que el anillo está sustituido en el carbono o nitrógeno por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo, y en el que el anillo está opcionalmente sustituido adicionalmente en el carbono o nitrógeno por 1 , 2 ó 3 grupos halo o alquilo Ci-4; Z is a group selected de- NR 1 R 2, fosfonooxilo, C 3-6 cycloalkyl which C 3-6 cycloalkyl is substituted by Ci -4 alkyl fosfonooxilo or substituted by fosfonooxilo, and a ring of 4 to 7 members bonded through a carbon atom containing a nitrogen atom and optionally containing an additional nitrogen atom, which may be saturated, partially saturated or unsaturated in which the ring is substituted on carbon or nitrogen by phosphonooxyl or Ci -4 alkyl substituted by phosphonoxyl, and wherein the ring is optionally further substituted on the carbon or nitrogen by 1, 2 or 3 halo or Ci -4 alkyl groups;
R1 es un grupo seleccionado de— COR8,— CONR8R9 y alquilo Ci-e cuyo alquilo Ci-e está sustituido por fosfonooxilo y opcionalmente sustituido adicionalmente por 1 ó 2 grupos halo o metoxilo; R 1 is a group selected from - COR 8 , - CONR 8 R 9 and Ci-e alkyl whose Ci-e alkyl is substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 es un grupo seleccionado de hidrógeno,— COR10,— CONR10R11 y alquilo Ci-e cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4 o— S(0)pR11 (donde p es 0, 1 ó 2) o fosfonooxilo, o R2 es un grupo seleccionado de alquenilo C2-e, alquinilo C2-6, cicloalquilo C3-6 y cicloalquil C3-6-alquilo Ci-4; R 2 is a group selected from hydrogen, - COR 10 , - CONR 10 R 11 and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci- 4 or— S (0) alkoxy. p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2- e alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and C3-6 cycloalkyl-Ci -4 alkyl;
o R1 y R2 junto con el nitrógeno al que se unen forman un anillo de 4 a 7 miembros que contiene opcionalmente un átomo de nitrógeno adicional cuyo anillo puede estar saturado, insaturado o parcialmente saturado en el que el anillo está sustituido en el carbono o nitrógeno por un grupo seleccionado de fosfonooxilo y alquilo Ci-4 cuyo alquilo Ci-4 está sustituido por fosfonooxilo o — NR8R9, y donde el anillo está opcionalmente sustituido adicionalmente en el carbono o nitrógeno por 1 , 2 ó 3 grupos halo o alquilo Ci-4; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing an additional nitrogen atom the ring of which may be saturated, unsaturated or partially saturated in which the ring is carbon-substituted or nitrogen by a group selected from fosfonooxilo and alkyl Ci -4 whose alkyl Ci -4 is substituted by fosfonooxilo or - NR 8 R 9 and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo groups or Ci -4 alkyl;
R3 es un grupo seleccionado de hidrógeno, halo, ciano, nitro, alcoxilo C1-6, alquilo C1-6, — OR12, — CHR12R13, — OC(0)R12, — C(0)R12, — NR12C(0)R13, — C(0)NR12R13, — NR12SO 2R13 y— NR12R13; R 3 is a group selected from hydrogen, halo, cyano, nitro, C1-6 alkoxy, C1-6 alkyl, - OR 12 , - CHR 12 R 13 , - OC (0) R 12 , - C (0) R 12 , - NR 12 C (0) R 13 , - C (0) NR 12 R 13 , - NR 12 SO 2 R 13 and - NR 12 R 13 ;
R4 es hidrógeno o un grupo seleccionado de alquilo Ci-4, heteroarilo, alquil Ci-4- heteroarilo, arilo y alquil Ci-4-arilo cuyo grupo está opcionalmente sustituido por 1 , 2 ó 3 sustituyentes seleccionados de halo, metilo, etilo, ciclopropilo y etinilo; R 4 is hydrogen or a group selected from Ci- 4- alkyl, heteroaryl, Ci- 4- alkyl-heteroaryl, aryl and Ci- 4- aryl-alkyl the group of which is optionally substituted by 1, 2 or 3 substituents selected from halo, methyl, ethyl , cyclopropyl and ethynyl;
R5 se selecciona de hidrógeno, alquilo Ci-4, alquenilo C2-4, alquinilo C2-4, cicloalquilo C3- 6 y alquil Ci-4-cicloalquilo C3-6; R 5 is selected from hydrogen, Ci -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3- 6 cycloalkyl and alkyl Ci- 4 -C3-6cycloalkyl;
R6 y R7 se seleccionan independientemente de hidrógeno, halo, alquilo Ci-4, cicloalquilo C3-6, hidroxilo y alcoxilo Ci-4; R 6 and R 7 are independently selected from hydrogen, halo, Ci- 4- alkyl, C3-6-cycloalkyl, hydroxyl and Ci- 4- alkoxy;
R8 es alquilo Ci-4 sustituido por fosfonooxilo y opcionalmente sustituido adicionalmente por 1 ó 2 grupos halo o metoxilo; R 8 is Ci- 4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 se selecciona de hidrógeno y alquilo Ci-4; R 9 is selected from hydrogen and Ci -4 alkyl;
R10 se selecciona de hidrógeno y alquilo Ci-4 (opcionalmente sustituido por halo, alcoxilo Ci-4, S(0)q (donde q es 0, 1 ó 2) o fosfonooxilo); R 10 is selected from hydrogen and Ci- 4- alkyl (optionally substituted by halo, C- 4- alkoxy, S (0) q (where q is 0, 1 or 2) or phosphonoxyl);
R11, R12, R13 y R14 se seleccionan independientemente de hidrógeno, alquilo Ci-4 y heterociclilo; R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, Ci- 4- alkyl and heterocyclyl;
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto según la fórmula (I) en la que A es un grupo de fórmula (a), (b), (c), (d) o (e), más particularmente un grupo de fórmula (a):
Figure imgf000018_0001
In a particular embodiment, the compound according to formula (I) in which A is a group of formula (a), (b), (c), (d) or (e), more particularly a group of formula (a ):
Figure imgf000018_0001
donde * es el punto de unión al grupo X de fórmula (I) y ** es el punto de unión al grupo (CR6R7) de fórmula (I); o una sal farmacéuticamente aceptable del mismo. where * is the point of attachment to group X of formula (I) and ** is the point of attachment to group (CR 6 R 7 ) of formula (I); or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que X es NH; o una sal farmacéuticamente aceptable del mismo.  In a particular embodiment, the compound of formula (I) in which X is NH; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que Z es— NR1R2 o un anillo saturado de 5 a 6 miembros unido a través de un átomo de carbono que contiene un átomo de nitrógeno y que contiene opcionalmente un átomo de nitrógeno adicional, en el que el anillo está sustituido en el carbono o nitrógeno por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo; o una sal farmacéuticamente aceptable del mismo. In a particular embodiment, the compound of formula (I) wherein Z is —NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a additional nitrogen atom, in which the ring is substituted on the carbon or nitrogen by phosphonooxy or Ci -4 alkyl substituted by phosphonoxy; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que R1 es alquilo Ci-s sustituido por fosfonooxilo y R2 es un grupo seleccionado de hidrógeno y alquilo Ci-e cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4, o R2 es un grupo seleccionado de alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6 y alquil Ci-4-cicloalquilo C3-6; o una sal farmacéuticamente aceptable del mismo. In a particular embodiment, the compound of formula (I) in which R 1 is Ci-s alkyl substituted by phosphonooxyl and R 2 is a group selected from hydrogen and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci -4 alkoxy, or R 2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and Ci- 4 alkyl C3-6 -cycloalkyl; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que R1 es 2- fosfonooxiloetilo; o una sal farmacéuticamente aceptable del mismo. In a particular embodiment, the compound of formula (I) in which R 1 is 2-phosphonoxyloethyl; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que Z es— NR1R2 y R1 y R2 junto con el nitrógeno al que se unen forman un anillo de piperidina, pirrolidina o piperazina que está sustituido por un grupo seleccionado de fosfonooxilo, fosfonooxilometilo, 2-fosfonooxiloetilo, N-etil-N-(2-fosfonooxiloetil)aminometilo y N-(2- fosfonooxiloetil)aminometilo y donde el anillo está opcionalmente sustituido adicionalmente por 1 ó 2 metilo. In a particular embodiment, the compound of formula (I) in which Z is— NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a ring of piperidine, pyrrolidine or piperazine which is replaced by a selected group of phosphonooxy, phosphonoxyloxymethyl, 2-phosphonoxyloethyl, N-ethyl-N- (2-phosphonoxyloethyl) aminomethyl and N- (2- phosphonoxyloethyl) aminomethyl and where the ring is optionally substituted additionally by 1 or 2 methyl.
En una realización particular, el compuesto de fórmula (I) en la que R1 y R2 junto con el nitrógeno al que se unen forman 2-(fosfonooxilometil)pirrolidinilo. In a particular embodiment, the compound of formula (I) in which R 1 and R 2 together with the nitrogen to which they bind form 2- (phosphonoxymethyl) pyrrolidinyl.
En una realización particular, el compuesto de fórmula (I) en la que R4 es 3- fluorofenilo, 3,5-difluorofenilo o 2,3-difluorofenilo; o una sal farmacéuticamente aceptable del mismo. In a particular embodiment, the compound of formula (I) in which R 4 is 3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que R3 es alcoxilo C1 -4, halo o hidrógeno; o una sal farmacéuticamente aceptable del mismo. In a particular embodiment, the compound of formula (I) in which R 3 is C 1-4 alkoxy, halo or hydrogen; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) se selecciona de:  In a particular embodiment, the compound of formula (I) is selected from:
dihidrogenofosfato de {1-[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil]piperidin-4-il}metilo; {1- [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin-7 dihydrogen phosphate -yl} oxy) propyl] piperidin-4-yl} methyl;
dihidrogenofosfato 2-[[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](etil)amino]etilo; dihydrogenphosphate 2 - [[3 - ({4 - [(5- {2 - [(3,5-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin- 7-yl} oxy) propyl] (ethyl) amino] ethyl;
dihidrogenofosfato de {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2S) -1- [3 - ({4 - [(5- {2 - [(3,5-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -6-methoxyquinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2R) -1- [3 - ({4 - [(5- {2 - [(3,5-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -6-methoxyquinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de {(2S)-1-[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2S) -1- [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-dihydrogenphosphate) -methoxyquinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](propil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (propyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](isobutil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (isobutyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](isobutil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3,5-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (isobutyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](propil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3,5-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (propyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](isobutil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin-7 dihydrogen phosphate -yl} oxy) propyl] (isobutyl) amino] ethyl;
dihidrogenofosfato de 2-{(2,2-dimetilpropil)[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil)- 1 H-pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2 - {(2,2-dimethylpropyl) [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl) -1-H-pyrazol-3-yl) amino dihydrogen phosphate ] -6-methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 1-[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil]piperidin-3-ilo; 1- [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} 1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin-7-yl dihydrogen phosphate } oxy) propyl] piperidin-3-yl;
dihidrogenofosfato de {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2R) -1- [3 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -6-methoxyquinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3,5-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](prop-2-in-1-il)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3,5-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (prop-2-in-1-yl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](isopropil)amino]etilo; dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](prop-2-in-1-il)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (isopropyl) amino] ethyl; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (prop-2-in-1-yl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](2-metoxietil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -6-methoxyquinazolin dihydrogen phosphate -7-yl} oxy) propyl] (2-methoxyethyl) amino] ethyl;
dihidrogenofosfato de 2-{[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2 - {[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin-7 dihydrogen phosphate -yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{(ciclobutilmetil)[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2- oxoetil}-1 H-pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2 - {(Cyclobutylmethyl) [3 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] - 6-methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-6-metoxiquinazolin-7-il}oxi)propil](3,3,3-trifluoropropilo)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin-7 dihydrogen phosphate -yl} oxy) propyl] (3,3,3-trifluoropropyl) amino] ethyl;
dihidrogenofosfato de 2-{alil[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil})1 H-pirazol- 3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2- {allyl [3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl}) 1H-pyrazol-3-yl) amino] -6- dihydrogen phosphate methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{ciclobutil[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2- {cyclobutyl [3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6- dihydrogen phosphate methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{ciclopentil[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2- {cyclopentyl [3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6- dihydrogen phosphate) methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{ciclopropil[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2- {Cyclopropyl [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin- dihydrogen phosphate 7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{(ciclopropilmetil)[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2- oxoetil}-1 H-pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2 - {(Cyclopropylmethyl) [3 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] - 6-methoxyquinazolin-7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{ciclobutil[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-6-metoxiquinazolin-7-il}oxi)propil]amino}etilo; 2- {Cyclobutyl [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -6-methoxyquinazolin- dihydrogen phosphate 7-yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-{4-[({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil})1 H-pirazol-3- il)amino]quinazolin-7-il}oxi)metil]piperidin-1-il}etilo; 2- {4 - [({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl}) 1H-pyrazol-3- yl) amino] quinazolin-7- dihydrogen phosphate yl} oxy) methyl] piperidin-1-yl} ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](etil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) propyl] (ethyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](isopropil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) propyl] (isopropyl) amino] ethyl;
dihidrogenofosfato de 3-{[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]quinazolin-7-il}oxi)propil]amino}-3-metilbutilo; 3 - {[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] quinazolin-7- dihydrogen phosphate) yl} oxy) propyl] amino} -3-methylbutyl;
dihidrogenofosfato de 2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)propil]pirrolidin-2-il}etilo; 2 - {(2S) -1- [3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} 1 H-pyrazol-3-yl) amino dihydrogen phosphate) ] -quinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} ethyl;
dihidrogenofosfato de {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2R) -1- [3 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -quinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](propilo)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) propyl] (propyl) amino] ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](butil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3- yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) propyl] (butyl) amino] ethyl;
dihidrogenofosfato de 2-{ciclopentil[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)propil]amino}etilo; dihidrogenofosfato de {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil})1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; 2- {cyclopentyl [3 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H- pyrazol-3-yl) amino] -quinazolin- dihydrogen phosphate 7-yl} oxy) propyl] amino} ethyl; {(2S) -1- [3 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl}) 1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -quinazolin-7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de {(2S)-1-[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2S) -1- [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin dihydrogen phosphate -7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 2-{ciclopentil[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)propil]amino}etilo; 2- {cyclopentyl [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7- dihydrogen phosphate yl} oxy) propyl] amino} ethyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](etil)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7-yl dihydrogen phosphate } oxy) propyl] (ethyl) amino] ethyl;
dihidrogenofosfato de 2-{[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]quinazolin-7-il}oxi)propil]amino}-2-metilpropilo; 2 - {[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] quinazolin-7-yl} dihydrogen phosphate) oxy) propyl] amino} -2-methylpropyl;
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](propilo)amino]etilo; 2 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7-yl dihydrogen phosphate } oxy) propyl] (propyl) amino] ethyl;
dihidrogenofosfato de {(2R)-1-[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil]pirrolidin-2-il}metilo; {(2R) -1- [3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin dihydrogen phosphate -7-yl} oxy) propyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 3-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)propil](etil)amino]propilo 3 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7-yl dihydrogen phosphate } oxy) propyl] (ethyl) amino] propyl
dihidrogenofosfato de 2-[[3-({4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]quinazolin-7-il}oxi)propil](2-metoxietil)amino]etilo 2 - [[3 - ({4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] quinazolin-7-yl} dihydrogen phosphate) oxy) propyl] (2-methoxyethyl) amino] ethyl
dihidrogenofosfato de 2-[[4-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)butil](propilo)amino]etilo; 2 - [[4 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) butyl] (propyl) amino] ethyl;
dihidrogenofosfato de 2-[[4-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]-quinazolin-7-il}oxi)butil](etil)amino]etilo; 2 - [[4 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] -quinazolin-7 dihydrogen phosphate) -yl} oxy) butyl] (ethyl) amino] ethyl;
dihidrogenofosfato de {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)butil]pirrolidin-2-il}metilo; {(2R) -1- [4 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -quinazolin-7-yl} oxy) butyl] pyrrolidin-2-yl} methyl;
dihidrogenofosfato de 2-[[4-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H-pirazol-3- il)amino]quinazolin-7-il}oxi)butil](metil)amino]etilo; 2 - [[4 - ({4 - [(5- {2 - [(2,3-difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] quinazolin-7- dihydrogen phosphate) yl} oxy) butyl] (methyl) amino] ethyl;
dihidrogenofosfato de {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorofenil)amino]-2-oxoetil}-1 H- pirazol-3-il)amino]-quinazolin-7-il}oxi)butil]pirrolidin-2-il}metilo; y {(2S) -1- [4 - ({4 - [(5- {2 - [(2,3-Difluorophenyl) amino] -2-oxoethyl} -1 H-pyrazol-3-yl) amino] dihydrogen phosphate] -quinazolin-7-yl} oxy) butyl] pyrrolidin-2-yl} methyl; Y
dihidrogenofosfato de 2-{etil[3-((6-fluoro-4-[(5-{2-[(3-fluorofenil)amino]-2-oxoetil]-1 H- pirazol-3-il)amino]quinazolin-7-il}oxi)propil]amino}etilo; 2- {ethyl [3 - ((6-fluoro-4 - [(5- {2 - [(3-fluorophenyl) amino] -2-oxoethyl] -1H-pyrazol-3-yl) amino] quinazolin dihydrogen phosphate) -7-yl} oxy) propyl] amino} ethyl;
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que:  In a particular embodiment, the compound of formula (I) in which:
A es un grupo de fórmula (a), (b), (c), (d) o (e):
Figure imgf000022_0001
A is a group of formula (a), (b), (c), (d) or (e):
Figure imgf000022_0001
donde * es el punto de unión al grupo X de fórmula (I) y ** es el punto de unión al grupo (CR6R7) de fórmula (I); where * is the point of attachment to group X of formula (I) and ** is the point of attachment to group (CR 6 R 7 ) of formula (I);
X es NH;  X is NH;
m es 0, 1 , 2 ó 3; m is 0, 1, 2 or 3;
Z es— NR1R2 o un anillo saturado de 5 a 6 miembros unido a través de un átomo de carbono que contiene un átomo de nitrógeno y que contiene opcionalmente un átomo de nitrógeno adicional, cuyo anillo está sustituido en el carbono o nitrógeno por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo; Z is— NR 1 R 2 or a saturated 5- to 6-membered ring linked via a carbon atom containing one nitrogen atom and optionally containing one additional nitrogen atom, the ring of which is substituted on carbon or nitrogen by phosphonooxy or Ci -4 alkyl substituted by phosphonooxy;
R1 es alquilo Ci-s sustituido por fosfonooxilo; R 1 is Ci-s alkyl substituted by phosphonooxy;
R2 se selecciona de hidrógeno y alquilo Ci-e cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4 o R2 se selecciona de alquinil Ci-e- alquinil C2-6-cicloalquilo C3-6 y cicloalquil C3-6-alquilo Ci-4; R 2 is selected from hydrogen and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci -4 alkoxy or R 2 is selected from Ci-e-alkynyl C 2-6 -cycloalkyl C 3-6 cycloalkyl and C 3-6 -alkyl Ci -4;
o R1 y R2 junto con el nitrógeno al que se unen forman un anillo de 5 a 6 miembros saturado que contiene opcionalmente un átomo de nitrógeno adicional en el que el anillo está sustituido en el carbono o nitrógeno por un grupo seleccionado de fosfonooxilo y alquilo Ci-4 cuyo alquilo Ci-4 está sustituido por fosfonooxilo o— NR8R9, y donde el anillo está opcionalmente sustituido adicionalmente en el carbono o nitrógeno por 1 ó 2 grupos alquilo Ci-4; or R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5 to 6 membered ring optionally containing an additional nitrogen atom in which the ring is substituted on carbon or nitrogen by a group selected from phosphonooxyl and Ci -4 alkyl which Ci -4 alkyl substituted by NR 8 R fosfonooxilo o- 9 and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 alkyl groups Ci -4;
R3 es alcoxilo Ci-4, halo o hidrógeno; R 3 is Ci -4 alkoxy, halo or hydrogen;
R4 es fenilo opcionalmente sustituido por 1 ó 2 de fluoro o cloro; R5 es hidrógeno o metilo; y R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro; R 5 is hydrogen or methyl; Y
R6 y R7 son independientemente hidrógeno, fluoro, cloro o metilo; R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl;
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que:  In a particular embodiment, the compound of formula (I) in which:
A es un grupo de fórmula (a): A is a group of formula (a):
Figure imgf000023_0001
Figure imgf000023_0001
donde * es el punto de unión al grupo X de fórmula (I) y ** es el punto de unión al grupo (CR6R7) de fórmula (I); where * is the point of attachment to group X of formula (I) and ** is the point of attachment to group (CR 6 R 7 ) of formula (I);
X es NH:  X is NH:
m es 1 , 2 ó 3; m is 1, 2 or 3;
Z es— NR1R2; Z is— NR 1 R 2 ;
R1 es alquilo CM S sustituido por fosfonooxilo: R 1 is alkyl substituted fosfonooxilo C MS:
R2 se selecciona de hidrógeno y alquilo Ci-e cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4, o R2 se selecciona de alquenilo C2-6, alquinilo C2-6 cicloalquilo C3-6 y alquil Ci-4-cicloalquilo C3-6; R 2 is selected from hydrogen and Ci-e alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci -4 alkoxy, or R 2 is selected from C2-6 alkenyl, C2-6 alkynyl C3 cycloalkyl -6 and Ci-4-cycloalkylC3-6alkyl;
R3 es alcoxilo C1-4, halo o hidrógeno; R 3 is C 1-4 alkoxy, halo or hydrogen;
R4 es fenilo opcionalmente sustituido por 1 ó 2 de fluoro o cloro; R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 es hidrógeno; y R 5 is hydrogen; Y
R6 y R7 son cada uno hidrógeno; R 6 and R 7 are each hydrogen;
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (I) en la que:  In a particular embodiment, the compound of formula (I) in which:
A es un grupo de fórmula (a):  A is a group of formula (a):
Figure imgf000023_0002
Figure imgf000023_0002
donde * es el punto de unión al grupo X de fórmula (I) y ** es el punto de unión al grupo (CR6R7) de fórmula (I); where * is the point of attachment to group X of formula (I) and ** is the point of attachment to group (CR 6 R 7 ) of formula (I);
X es NH;  X is NH;
m es 1 , 2 ó 3; m is 1, 2 or 3;
Z es— NR1R2; Z is— NR 1 R 2 ;
R1 es alquilo C1-5 sustituido por fosfonooxilo; R2 se selecciona de hidrógeno y alquilo Ci-e cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4, o R2 se selecciona de alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6 y cicloalquil C3-6-alquilo Ci-4; R 1 is C 1-5 alkyl substituted by phosphonooxy; R 2 is selected from hydrogen and Ci-e alkyl which Ci-e is optionally substituted by 1, 2 or 3 halo or Ci -4 alkoxy, or R 2 is selected from C 2-6 alkenyl, C 2-6 alkynyl , C 3-6 cycloalkyl and C 3-6 cycloalkyl Ci -4 alkyl;
R3 es hidrógeno; R 3 is hydrogen;
R4 es fenilo opcionalmente sustituido por 1 ó 2 de fluoro o cloro; R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 es hidrógeno; y R 5 is hydrogen; Y
R6 y R7 son cada uno hidrógeno; R 6 and R 7 are each hydrogen;
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento US 20040049032 tal como tozasertib. Los compuestos de fórmula (I) tal como se da a conocer en el documento US 20040049032 se identifican en el presente documento con fórmula (II):  In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 20040049032 such as tozasertib. Compounds of formula (I) as disclosed in US 20040049032 are identified herein with formula (II):
Figure imgf000024_0001
Figure imgf000024_0001
Fórmula (II)  Formula (II)
en la que: in which:
Q y T se seleccionan cada uno independientemente de oxígeno, azufre o N(R); Q and T are each independently selected from oxygen, sulfur, or N (R);
cada R se selecciona independientemente de hidrógeno o un grupo alifático Ci-e opcionalmente sustituido, en donde: each R is independently selected from hydrogen or an optionally substituted Ci-e aliphatic group, wherein:
dos R unidos al mismo átomo de nitrógeno se toman opcionalmente junto con el nitrógeno para formar un anillo monocíclico de 3-7 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado opcionalmente sustituido que tiene de 0-3 heteroátomos, además del nitrógeno unido a los mismos, independientemente seleccionados de nitrógeno, oxígeno o azufre; two Rs attached to the same nitrogen atom are optionally taken together with the nitrogen to form a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated or fully unsaturated optionally substituted having 0-3 heteroatoms, in addition of the nitrogen bound thereto, independently selected from nitrogen, oxygen or sulfur;
Rx es U-R5; R x is UR 5 ;
R5 se selecciona de halógeno, NO 2, CN, R, o Ar; R 5 is selected from halogen, NO 2, CN, R, or Ar;
cada U se selecciona independientemente de un enlace de valencia o una cadena de alquilideno Ci-4, en la que: each U is independently selected from a valence bond or a Ci -4 alkylidene chain, wherein:
hasta dos unidades de metileno de U están reemplazadas opcional e independientemente por— O— ,— S— ,— SO— ,— SO2— ,— N(R)S02— ,— S02N(R)— , — N(R)— ,— C(O)— ,— C02— ,— N(R)C(0)— ,— N(R)C(0)0— ,— N(R)CON(R)— ,— N(R)S02N(R)— ,— N(R)N(R)— ,— C(0)N(R)— ,— OC(0)N(R)— ,— C(R)=NN(R)— , oUp to two U methylene units are optionally and independently replaced by— O—, - S—, - SO—, - SO2—, - N (R) S0 2 -, - S0 2 N (R) -, - N ( R) -, - C (O) -, - C0 2 -, - N (R) C (0) -, - N (R) C (0) 0—, - N (R) CON (R) -, - N (R) S0 2 N (R) -, - N (R) N (R) -, - C (0) N (R) -, - OC (0) N (R) -, - C (R ) = NN (R) -, or
— C(R)=N— O— ; - C (R) = N— O—;
cada Ar se selecciona independientemente de un anillo opcionalmente sustituido seleccionado de un anillo monocíclico de 3-7 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre;each Ar is independently selected from an optionally substituted ring selected from a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated, or fully unsaturated having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
Ry es— N(R1)2,— OR1, o— SR1; R y is— N (R 1 ) 2 , - OR 1 , or— SR 1 ;
cada R1 se selecciona independientemente de R o un anillo monocíclico de 3-8 miembros, bicíclico de 8-10 miembros o tricíclico de 10-12 miembros saturado, parcialmente insaturado o completamente insaturado opcionalmente sustituido que tiene de 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, y en la que: each R 1 is independently selected from R or an optionally substituted saturated, partially unsaturated or fully unsaturated 3-8 membered bicyclic, 8-10 membered bicyclic or optionally substituted 10-12 membered tricyclic ring having 0-4 heteroatoms, independently selected nitrogen, oxygen or sulfur, and in which:
cada R1 está opcional e independientemente sustituido por hasta cuatro sustituyentes independientemente seleccionados de R2; each R 1 is optionally and independently substituted by up to four independently selected substituents on R 2 ;
cada R2 se selecciona independientemente de— R3,— OR3,— SR3,— CN,— N02, oxo, halógeno, — N(R3)2, — C(0)R3, — OC(0)R3, — C02R3, — S02R3, — S02N(R3)2, — N(R3)S02R3, — C(0)NR(R3), — C(0)N(R3)2, — OC(0)NR(R3), — 0C(0)N(R3)2, — NR3C(0)R3,— NR3C(0)N(R3)2, O— NR3C02(R3); each R 2 is independently selected from— R 3 , - OR 3 , - SR 3 , - CN, - N0 2 , oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC (0 ) R 3 , - C0 2 R 3 , - S0 2 R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , O— NR 3 C0 2 (R 3 );
cada R3 se selecciona independientemente de R o Ar; each R 3 is independently selected from R or Ar;
Rz1 se selecciona de un grupo alifático Ci-e o un anillo monocíclico de 3-8 miembros, bicíclico de 8-10 miembros o tricíclico de 10-12 miembros saturado, parcialmente insaturado o completamente insaturado opcionalmente sustituido que tiene de 0-4 heteroátomos independientemente seleccionados de oxígeno, nitrógeno o azufre, en la que: R z1 is selected from a Ci-e aliphatic group or a 3-8 membered monocyclic, 8-10 membered bicyclic or 10-12 membered saturated, partially unsaturated or fully unsaturated tricyclic ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, in which:
Rz1 está sustituido con de 0-4 grupos R2 independientemente seleccionados; R z1 is substituted with 0-4 independently selected R 2 groups;
Rz2 es un grupo alifático Ci-e o un anillo monocíclico de 3-8 miembros o un anillo bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, en la que: R z2 is a Ci-e aliphatic group or a 3-8 membered monocyclic ring or a saturated, partially unsaturated or fully unsaturated 8-10 membered bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, in which:
Rz2 está sustituido por 0-4 sustituyentes independientemente seleccionados de oxo o U-R5; o una sal farmacéuticamente aceptable del mismo. R z2 is substituted by 0-4 substituents independently selected from oxo or UR 5 ; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (II) en la que Q es N(R).  In a particular embodiment, the compound of formula (II) in which Q is N (R).
En una realización particular, el compuesto de fórmula (II) en la que T es oxígeno o azufre.  In a particular embodiment, the compound of formula (II) in which T is oxygen or sulfur.
En una realización particular, el compuesto de fórmula (II) en la que T es azufre.  In a particular embodiment, the compound of formula (II) in which T is sulfur.
En una realización particular, el compuesto de fórmula (II) en la que Ry es— OR1 o— N(R1)2. In a particular embodiment, the compound of formula (II) in which R y is -OR 1 or -N (R 1 ) 2 .
En una realización particular, el compuesto de fórmula (II) en la que Ry es— N(R1)2, y en la que: In a particular embodiment, the compound of formula (II) in which R y is— N (R 1 ) 2 , and in which:
R1 se selecciona de R o un anillo monocíclico de 3-7 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, o: R 1 is selected from R or a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated or fully unsaturated having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, or:
cada R1 es R tal que los dos R en el mismo átomo de nitrógeno se toman juntos para formar un anillo saturado de 4-7 miembros opcionalmente sustituido que tiene hasta dos heteroátomos adicionales, independientemente seleccionado de nitrógeno, oxígeno o azufre, y en la que: each R 1 is R such that the two Rs on the same nitrogen atom are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms, independently selected from nitrogen, oxygen or sulfur, and in which:
cada R1 está opcional e independientemente sustituido por hasta cuatro sustituyentes seleccionados de— R3, — OR3, — SR3, — CN, — NO 2, oxo, halógeno, — N(R3)2, — C(0)R3,— 0C(0)R3,— CO2R3,— SO2R3,— S02N(R3)2,— N(R3)S02R3,— C(0)NR(R3), — C(0)N(R3)2,— 0C(0)NR(R3),— 0C(0)N(R3)2,— NR3C(0)R3,— NR3C(0)N(R3)2, O—each R 1 is optionally and independently substituted by up to four substituents selected from— R 3 , - OR 3 , - SR 3 , - CN, - NO 2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - 0C (0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ) , - C (0) N (R 3 ) 2 , - 0C (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , O—
NR3C02(R3). NR 3 C0 2 (R 3 ).
En una realización particular, el compuesto de fórmula (II) en la que Ry es N(R1)2, en la que: In a particular embodiment, the compound of formula (II) in which R y is N (R 1 ) 2 , in which:
cada R1 se selecciona independientemente de R, en la que R es hidrógeno o un grupo alifático C1 -4 opcionalmente sustituido. each R 1 is independently selected from R, where R is hydrogen or an optionally substituted C1-4 aliphatic group.
En una realización particular, el compuesto de fórmula (II) en la que Ry es N(R1)2 en la que: In a particular embodiment, the compound of formula (II) in which R y is N (R 1 ) 2 in which:
cada R1 es R tal que los dos grupos R se toman juntos para formar un anillo saturado de 4-7 miembros opcionalmente sustituido que tiene hasta dos heteroátomos adicionales, independientemente seleccionado de nitrógeno, oxígeno o azufre. each R 1 is R such that the two R groups are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms, independently selected from nitrogen, oxygen or sulfur.
En una realización particular, el compuesto de fórmula (II) en la que Ry se selecciona de pirrolidin-1 -ilo, piperidin-1-ilo, morfolin-4-ilo, tiomorfolin-4-ilo, piperazin-1-ilo, diazepanilo, o tetrahidroisoquinolinilo, en la que cada anillo está opcionalmente sustituido con uno o dos grupos independientemente seleccionados de metilo, etilo, metilsulfonilo, (CH2)2SC>2CH3, ciclopropilo, Chhciclopropilo, (Chh^OH, CC>2t-butilo, CH2fenilo, fenilo, NH2, NH(CH3), N(CH3)2, (OH2)2NH2, (CH2)2morfolin-4-¡lo,In a particular embodiment, the compound of formula (II) wherein R y is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, in which each ring is optionally substituted with one or two independently selected groups of methyl, ethyl, methylsulfonyl, (CH 2 ) 2 SC> 2 CH 3 , cyclopropyl, Chhciclopropil, (Chh ^ OH, CC> 2t -butyl, CH 2 phenyl, phenyl, NH 2 , NH (CH 3 ), N (CH 3 ) 2 , (OH 2 ) 2 NH 2 , (CH 2 ) 2morfolin-4-ylo,
(CH2)2N(CH3)2, isopropilo, propilo, t-butilo, (Chh^CN, o (CH2)2C(0)morfolin-4-ilo. (CH 2 ) 2N (CH 3 ) 2 , isopropyl, propyl, t-butyl, (Chh ^ CN, or (CH 2 ) 2 C (0) morpholin-4-yl.
En una realización particular, el compuesto de fórmula (II) en la que Rz1 es un anillo monocíclico de 3-7 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos independientemente seleccionados de oxígeno, nitrógeno o azufre, en la que dicho anillo está opcional e independientemente sustituido por hasta tres sustituyentes seleccionados de — R3, — OR3, — SR3, — CN, — NO2, oxo, halógeno, — N(R3)2, — C(0)R3,— OC(0)R3,— CO2R3,— SO2R3,— S02N(R3)2,— N(R3)S02R3,— C(0)NR(R3), — C(0)N(R3)2,— OC(0)NR(R3),— 0C(0)N(R3)2,— NR3C(0)R3,— NR3C(0)N(R3)2, O—In a particular embodiment, the compound of formula (II) wherein R z1 is a saturated, partially unsaturated or fully unsaturated 3-7 membered bicyclic or 8-10 membered bicyclic ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, in which said ring is optionally and independently substituted by up to three substituents selected from - R 3 , - OR 3 , - SR 3 , - CN, - NO2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC (0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C ( 0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , O—
NR3CO2R3. NR 3 CO 2 R 3 .
En una realización particular, el compuesto de fórmula (II) en la que Rz1 es un anillo completamente insaturado de 5-6 miembros que tiene 1-3 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, en la que dicho anillo está opcional e independientemente sustituido por hasta tres sustituyentes seleccionados de — R3, — OR3, — SR3, — CN, — NO2, oxo, halógeno, — N(R3)2, — C(0)R3,— OC(0)R3,— CO2R3,— SO2R3,— S02N(R3)2,— N(R3)S02R3,— C(0)NR(R3), — C(0)N(R3)2,— OC(0)NR(R3),— 0C(0)N(R3)2,— NR3C(0)R3,— NR3C(0)N(R3)2, O—In a particular embodiment, the compound of formula (II) wherein R z1 is a 5-6 membered fully unsaturated ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen or sulfur, wherein said ring is optional and independently substituted by up to three substituents selected from - R 3 , - OR 3 , - SR 3 , - CN, - NO2, oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC ( 0) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 , OR—
NR3CO2R3. NR 3 CO 2 R 3 .
En una realización particular, el compuesto de fórmula (II) en la que Rz1 es un anillo opcionalmente sustituido seleccionado de pirazol o uno cualquiera de los siguientes anillos de 5-6 miembros: En una realización particular, el compuesto de fórmula (II) en la que Rz 1 In a particular embodiment, the compound of formula (II) wherein R z1 is an optionally substituted ring selected from pyrazole or any one of the following 5-6 membered rings: In a particular embodiment, the compound of formula (II) in which R z 1
es un anillo de pirazol que tiene hasta dos sustituyentes independientemente seleccionados de— N(R3)2,— OR3, o un grupo alifático C1-C4. it's a ring Pyrazole having up to two independently selected substituents from— N (R 3 ) 2 , - OR 3 , or a C 1 -C 4 aliphatic group.
En una realización particular, el compuesto de fórmula (II) en la que Rz1 es un pirazol opcionalmente sustituido con un sustituyente seleccionado de metilo, etilo, propilo, isopropilo, t-butilo, ciclopropilo o fenilo. In a particular embodiment, the compound of formula (II) wherein R z1 is a pyrazole optionally substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl.
En una realización particular, el compuesto de fórmula (II) en la que Rz2 es un anillo opcionalmente sustituido seleccionado de un anillo monocíclico de 5-6 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, en la que dicho anillo está opcionalmente sustituido por hasta tres sustituyentes independientemente seleccionados de halógeno,— CN,— NO 2, — C(0)R3, — CO2R3, — C(0)NR(R3), — NR3C(0)R3, — N(R3)2, — N(R3)S02R3, — NR3C(0)N(R3)2, O— NR3CO2R3. In a particular embodiment, the compound of formula (II) wherein R z2 is an optionally substituted ring selected from a saturated, partially unsaturated or fully unsaturated 5-6 membered monocyclic or 8-10 membered bicyclic ring having 0- 4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, in which said ring is optionally substituted by up to three independently selected substituents from halogen, - CN, - NO 2, - C (0) R 3 , - CO2R 3 , - C (0) NR (R 3 ), - NR 3 C (0) R 3 , - N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - NR 3 C (0) N (R 3 ) 2 , O— NR 3 CO 2 R 3 .
En una realización particular, el compuesto de fórmula (II) en la que:  In a particular embodiment, the compound of formula (II) in which:
Rz2 se selecciona de fenilo, imidazolilo, pirazolilo, piridilo, piridazinilo, pirazinilo, naftilo, tetrahidronaftilo, bencimidazolilo, benztiazolilo, quinolinilo, quinazolinilo, benzodioxinilo, isobenzofurano, indanilo, indolilo, indolinilo, indazolilo, o isoquinolinilo, en la que: R z2 is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxynyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl,
Rz2 está opcionalmente sustituido con hasta tres sustituyentes independientemente seleccionados de— Cl,— Br, -F,— CN,— CF3,— COOH,— CONHMe,— CONHEt,— NH2,— NHAC,— NHS02Me,— NHS02Et,— NHS02(n-propilo),— NHS02(isopropilo),— NHCOEt, — NHCOCH2NHCH3, — NHC0CH2N(C02t-Bu)CH3, — NHCOCH2N(CH3)2, -NHCOCH2CH2N(CH3)2, — NHCOCH2CH2CH2N(CH3)2, — NHCO(ciclopropilo), — NHCO(isopropilo), -NHCO(isobutilo), — NHCOCH2(morfolin-4-ilo), — NHCOCH2CH2(morfolin-4-ilo), — NHCOCH2CH2CH2(morfolin-4-ilo), — NHC02(t-butilo), — NH(ciclohexilo), — NHMe, — NMe2, — OH, — OMe, metilo, etilo, ciclopropilo, isopropilo, o t-butilo. R z2 is optionally substituted with up to three independently selected substituents from— Cl, - Br, -F, - CN, - CF 3 , - COOH, - CONHMe, - CONHEt, - NH 2 , - NHAC, - NHS0 2 Me, - NHS0 2 Et, - NHS0 2 (n-propyl), - NHS0 2 (isopropyl), - NHCOEt, - NHCOCH2NHCH3, - NHC0CH 2 N (C0 2 t-Bu) CH 3 , - NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , - NHCOCH2CH 2 CH 2 N (CH 3 ) 2, - NHCO (cyclopropyl), - NHCO (isopropyl), -NHCO (isobutyl), - NHCOCH 2 (morpholin-4- yl), - NHCOCH 2 CH 2 (morpholin-4-yl), - NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), - NHC0 2 (t-butyl), - NH (cyclohexyl), - NHMe, - NMe 2 , - OH, - OMe, methyl, ethyl, cyclopropyl, isopropyl, or t-butyl.
En una realización particular, el compuesto de fórmula (II) en la que Rz2 tiene un sustituyente seleccionado de -NR3C(0)R3, en la que: In a particular embodiment, the compound of formula (II) in which R z2 has a substituent selected from -NR 3 C (0) R 3 , in which:
cada R3 se selecciona independientemente de R o Ar, y en la que: each R 3 is independently selected from R or Ar, and wherein:
R es hidrógeno o un grupo alifático Ci-4 opcionalmente sustituido. R is hydrogen or an optionally substituted Ci -4 aliphatic group.
En una realización particular, el compuesto de fórmula (II) se selecciona de: In a particular embodiment, the compound of formula (II) is selected from:
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
40
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
40
Figure imgf000041_0001
Figure imgf000042_0001
42
Figure imgf000041_0001
Figure imgf000042_0001
42
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000047_0001
Figure imgf000048_0001
; o una sal farmacéuticamente aceptable de los mismos.  ; or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (II) tiene la siguiente fórmula:  In a particular embodiment, the compound of formula (II) has the following formula:
Figure imgf000048_0002
Figure imgf000048_0002
o un derivado farmacéuticamente aceptable o sal del mismo, en la que: or a pharmaceutically acceptable derivative or salt thereof, in which:
R5 se selecciona de hidrógeno o alifático Ci-4 tal como hidrógeno, metilo, etilo, t-butilo o isopropilo. R 5 is selected from hydrogen or aliphatic Ci -4 such as hydrogen, methyl, ethyl, t-butyl or isopropyl.
R6 se selecciona de alifático C1 -3 tal como metilo, etilo o ciclopropilo; y R 6 is selected from C1 -3 aliphatic such as methyl, ethyl or cyclopropyl; Y
R7 se selecciona de alifático Cab tal como metilo, etilo, t-butilo o ciclopropilo. R 7 is selected from aliphatic Cab such as methyl, ethyl, t-butyl or cyclopropyl.
En una realización particular, el compuesto de fórmula (II) se selecciona de:  In a particular embodiment, the compound of formula (II) is selected from:
Figure imgf000048_0003
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
o una sal farmacéuticamente aceptable de los mismos.
Figure imgf000048_0003
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (II) se selecciona de:  In a particular embodiment, the compound of formula (II) is selected from:
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000055_0001
Figure imgf000056_0001
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento US 20080167292 tal como alisertib. Los compuestos de fórmula (I) tal como se dan a conocer en el documento US 20080167292 se identifican en el presente documento con fórmula (III): In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 20080167292 such as alisertib. Compounds of formula (I) as disclosed in US 20080167292 are identified herein with formula (III):
Figure imgf000057_0001
Figure imgf000057_0001
Fórmula (III)  Formula (III)
o una sal farmacéuticamente aceptable del mismo, en la que: or a pharmaceutically acceptable salt thereof, in which:
Ra se selecciona del grupo que consiste en alifático C1-3, fluoroalifático C1-3,— R\ -T- R1— R2, y -T-R2; R a is selected from the group consisting of aliphatic C 1-3 fluoroaliphatic C 1-3 - R \ -T- R 1 - R 2 and -TR 2;
T es una cadena de alquileno C1-3 opcionalmente sustituida con fluoro; T is a C 1-3 alkylene chain optionally substituted with fluoro;
R1 es un grupo arilo, heteroarilo o heterociclilo opcionalmente sustituido; R 1 is an optionally substituted aryl, heteroaryl or heterocyclyl group;
R2 se selecciona del grupo que consiste en halo, — CºC— R3, — CH=CH— R3, — N(R4)2, y— OR; R 2 is selected from the group consisting of halo, - C ° C - R 3 , - CH = CH - R 3 , - N (R 4 ) 2 , and - OR;
R3 es hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; R 3 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
cada R4 es independientemente hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; o dos R4 en el mismo átomo de nitrógeno, tomados junto con el átomo de nitrógeno forman un anillo de heteroarilo de 5 a 6 miembros o heterociclilo de 4 a 8 miembros opcionalmente sustituido que tiene, además del átomo de nitrógeno, de 0 a 2 heteroátomos seleccionados de N, O y S;each R 4 is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4's on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring which has, in addition to the nitrogen atom, 0 to 2 heteroatoms selected from N, O and S;
R5 es hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; y R 5 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; Y
Rb se selecciona del grupo que consiste en fluoro, cloro,— CH3, — CF3, — OH,— OCH3,— OCF3,— OCH2CH3, y— OCH2CF3. R b is selected from the group consisting of fluoro, chloro, - CH 3 , - CF 3 , - OH, - OCH 3 , - OCF 3 , - OCH2CH3, and - OCH2CF3.
En una realización particular, el compuesto de fórmula (III) en la que R1 es un anillo de arilo, heteroarilo o heterociclilo de 5 ó 6 miembros opcionalmente sustituido con uno o dos sustituyentes independientemente seleccionados del grupo que consiste en halo, alifático C1-3, y fluoroalifático C1-3. In a particular embodiment, the compound of formula (III) wherein R 1 is a 5- or 6-membered aryl, heteroaryl or heterocyclyl ring optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1 aliphatic -3 , and fluoroaliphatic C 1-3 .
En una realización particular, el compuesto de fórmula (III) en la que Ra es halo, alifático C1-3, fluoroalifático C1-3, -OH,— 0(alifático C1-3),— 0(fluoroalifático C1-3), o— CºC— R3,— CH=CH— R3, en la que R3 es hidrógeno, alifático C1-3, fluoroalifático C1-3, o— CH2— OCH3; o Ra es un anillo de fenilo, furilo, pirrolidinilo o tienilo opcionalmente sustituido con uno o dos sustituyentes independientemente seleccionados del grupo que consiste en halo, alifático C1-3 y fluoroalifático C1-3. In a particular embodiment, the compound of formula (III) wherein R a is halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, -OH, - 0 (C 1-3 aliphatic), - 0 (C fluoroaliphatic 1-3 ), or - C ° C - R 3 , - CH = CH - R 3 , where R 3 is hydrogen, aliphatic C 1-3 , fluoroaliphatic C 1-3 , or - CH 2 -OCH 3 ; or R a is a phenyl, furyl, pyrrolidinyl or thienyl ring optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-3 aliphatic and fluoroaliphatic C1-3.
En una realización particular, el compuesto de fórmula (III) en la que Ra se selecciona del grupo que consiste en cloro, fluoro, alifático C1-3, fluoroalifático C1-3,— OCH3,— OCF 3,— CºC— H,— C=C— CH3,— C=C— CH2OCH3,— CH=CH2, — CH=CHCH3, N- metilpirrolidinilo, tienilo, metiltienilo, furilo, metilfurilo, fenilo, fluorofenilo y tolilo. In a particular embodiment, the compound of formula (III) wherein R a is selected from the group consisting of chloro, fluoro, C1-3 aliphatic, C1-3 fluoroaliphatic, - OCH 3, - OCF 3, - CºC - H, - C = C— CH 3 , - C = C— CH2OCH3, - CH = CH 2 , - CH = CHCH 3 , N-methylpyrrolidinyl, thienyl, methylthienyl, furyl, methylfuryl, phenyl, fluorophenyl and tolyl.
En una realización particular, el compuesto de fórmula (III) es ácido 4-([9-etinil-7-(2- fluoro-6-metoxifenil)-5H-pirimido[5,4-d][2]benzazepin-2-il]amino)-2-metoxibenzoico o una sal farmacéuticamente aceptable del mismo.  In a particular embodiment, the compound of formula (III) is 4 - ([9-ethinyl-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2 acid) -yl] amino) -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (III) es ácido 4-([7-(2-fluoro-6- metoxifenil)-9-(1-metil-1 H-pirrol-2-il)-5H-pirimido[5,4-d][2]benzazepin-2-il]amino)-2- metoxibenzoico o una sal farmacéuticamente aceptable del mismo.  In a particular embodiment, the compound of formula (III) is 4 - ([7- (2-fluoro-6-methoxyphenyl) -9- (1-methyl-1 H-pyrrol-2-yl) -5H-pyrimido acid. [5,4-d] [2] benzazepin-2-yl] amino) -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (III) es ácido 4-{[9-cloro-7-(2- fluoro-6-metoxifenil)-5H-pirimido[5,4-d][2]benzazepin-2-il]amino}-2-metoxibenzoico o una sal farmacéuticamente aceptable del mismo.  In a particular embodiment, the compound of formula (III) is 4 - {[9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2 acid -yl] amino} -2-methoxybenzoic or a pharmaceutically acceptable salt thereof.
En una realización particular, el compuesto de fórmula (III) es 4-{[9-cloro-7-(2-fluoro-6- metoxifenil)-5H-pirimido[5,4-d][2]benzazepin-2-il]amino}-2-metoxibenzoato de sodio.In a particular embodiment, the compound of formula (III) is 4 - {[9-chloro-7- (2-fluoro-6- methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2- yl] amino} -2-methoxybenzoate sodium.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento US 2006035908 tal como mesilato de SNS-314. Los compuestos de fórmula (I) tal como se da a conocer en el documento US 2006035908 se identifican en el presente documento con fórmula (IV): In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in US 2006035908 such as SNS-314 mesylate. Compounds of formula (I) as disclosed in US 2006035908 are identified herein with formula (IV):
Figure imgf000058_0001
Fórmula (IV): o derivado farmacéuticamente aceptable del mismo;
Figure imgf000058_0001
Formula (IV): or pharmaceutically acceptable derivative thereof;
en la que uno de— . es un doble enlace, si lo permite la valencia; in which one of—. it is a double bond, if valence allows it;
uno de X1 y X2 es S, el otro es— C(RX1)— ; en la que RX1 es hidrógeno, halógeno, ciano, nitro, o un resto alifático, heteroalifático, alicíclico, heteroalicíclico, aromático o heteroaromático; one of X 1 and X 2 is S, the other is— C (R X1 ) -; wherein R X1 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, or heteroaromatic moiety;
W1 es O, S, NRW1 o— C(=0)NRW1 donde RW1 es hidrógeno, alquilo inferior, cicloalquilo C3-6, heteroalquilo inferior, heterociclilo, arilo, heteroarilo, -(alquil)arilo, (alquil)heteroarilo o acilo; o RW1 junto con un átomo de carbono presente en Alk, forma un anillo heterocíclico de 5 a 6 miembros opcionalmente sustituido; W 1 is O, S, NR W1 or— C (= 0) NR W1 where R W1 is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, (alkyl ) heteroaryl or acyl; or R W1 together with a carbon atom present in Alk, forms an optionally substituted 5- to 6-membered heterocyclic ring;
Alki es una cadena de alquileno C1-6 o alquenileno C2-6 sustituida o no sustituida en la que hasta dos unidades de metileno no adyacentes están reemplazadas opcional e independientemente por— C(=0)— ,— CO2— , — (=0)C(=0)— , — C(=0)NRL1A— , — NRL1ANRL1 B— , — NRL1 ANRL1 BC(=0)— , — NRL1AC(=0)— , — RL1 AC02— , — NRL1AC(=0)NRL1 B— ,— S(=0)— ,— S02— ,— NRUAS02— ,— S02NRL1A— ,— NRL1ASO 2NRL1 B— ,— O— ,— S— , o— NRL1A— ; en la que cada aparición de RL1A y RL1 B es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, heterociclilo, arilo, heteroarilo o acilo;
Figure imgf000059_0001
Alki is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain in which up to two non-adjacent methylene units are optionally and independently replaced by— C (= 0) -, - CO2—, - (= 0 ) C (= 0) -, - C (= 0) NR L1A -, - NR L1A NR L1 B -, - NR L1 A NR L1 B C (= 0) -, - NR L1A C (= 0) -, - R L1 A C0 2 -, - NR L1A C (= 0) NR L1 B -, - S (= 0) -, - S0 2 -, - NR UA S0 2 -, - S0 2 NR L1A -, - NR L1A SO 2 NR L1 B -, - O—, - S—, or— NR L1A -; where each occurrence of R L1A and R L1 B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
Figure imgf000059_0001
son independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, heterociclilo, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo; they are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl;
Y es un anillo de fenilo o tiazolilo opcionalmente sustituido;  Y is an optionally substituted phenyl or thiazolyl ring;
Z es un resto alifático, heteroalifático, alicíclico, heteroalicíclico, aromático o heteroaromático;  Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic residue;
con la condición de que (a) RX1 no sea Q1 , Q2 o Q3, en la que with the proviso that (a) R X1 is not Q 1 , Q 2 or Q 3 , in which
Q1 es — (CR1AR1 B) mCºC— (CR1AR1 B) tR1c, — (CR1AR1 B) mCºC— (CR1AR1 B) tR1c, — C=NOR1 D, o— X 3R1 D en la que m es un número entero desde 0 hasta 3, t es un número entero desde 0 hasta 5, y X 3 es un grupo divalente derivado de azetidina, oxetano o un grupo carbocíclico C3-4; Q 1 is - (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) t R 1c , - (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) t R 1c , - C = NOR 1 D , or— X 3 R 1 D where m is an integer from 0 to 3, t is an integer from 0 to 5, and X 3 is a divalent group derived from azetidine, oxetane, or a carbocyclic group C3-4;
Q2 es— (CR1AR1 B) mCºC— (CR1AR1 B)kR1 E,— (CR1AR1 B) mCºC(CR1AR1 B) k en la que k es un número entero desde 1 hasta 3 y m es un número entero desde 0 hasta 3; yQ 2 is— (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) k R 1 E , - (CR 1A R 1 B ) m CºC (CR 1A R 1 B ) k where k is a integer from 1 to 3 and m is an integer from 0 to 3; Y
Q3 es— (CR1AR1 B) tR1c, en la que t es un número entero desde 0 hasta 5 y el punto de unión a R1C es a través de un átomo de carbono del grupo R1C; en la que R1A y R1 B son independientemente H o alquilo Ci-e; R1C es un anillo monocíclico no aromático opcionalmente sustituido, un anillo bicíclico condensado o en puente o un anillo espirocíclico; R1 E es — NR1AR1 D o — OR1 D; R1 D es R1 F, — C(=0)R1 F, — S02R1 F, — C(=0)N(R1 F)2,— S02N(R1 f)2, O— C02R1 f, en la que R1 F es H, alquilo Ci-6, (CR1AR1 B) t(arilo Ce-io) o— (CR1AR1 B) t(heterocíclico de 4-10 miembros); y Q 3 is— (CR 1A R 1 B ) t R 1c , where t is an integer from 0 to 5 and the point of attachment to R 1C is through a carbon atom of the group R 1C ; wherein R 1A and R 1 B are independently H or Ci-e alkyl; R 1C is an optionally substituted non-aromatic monocyclic ring, a fused or bridged bicyclic ring or a spirocyclic ring; R 1 E is - NR 1A R 1 D or - OR 1 D ; R 1 D is R 1 F , - C (= 0) R 1 F , - S0 2 R 1 F , - C (= 0) N (R 1 F ) 2 , - S0 2 N (R 1 f ) 2 , O— C0 2 R 1 f , where R 1 F is H, C 6 -alkyl, (CR 1A R 1 B ) t (Ce-io aryl) or— (CR 1A R 1 B ) t (4-heterocyclic -10 members); Y
(b) en uno cualquiera o más de los siguientes grupos, las variables mencionadas no se producen simultáneamente tal como se define:  (b) in any one or more of the following groups, the mentioned variables do not occur simultaneously as defined:
(i)— W1-Alkr es— OCH2— o— N(R)CH2— , en la que R es H o alquilo Ci-s; Y es fenilo; y Z es un cicloalquilo, heterociclilo, arilo o heteroarilo de 5-10 miembros; (i) - W 1 -Alkr is - OCH 2 - or - N (R) CH 2 -, where R is H or Ci-s alkyl; Y is phenyl; and Z is a 5-10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl;
(ii) RX1 es hidrógeno, halógeno, alquilo Ci-4 o alcoxilo Ci-4;— W 1-Alkr es— NHalquilo C1-6,— Oalquilo C1-6,— NHC1 -6 o— OC i-6heteroalquilo; L2-Z es— X— Rx donde X es— NR— o— NHC(=0)— , y Rx es cicloalquilo C3-10, morfolinilo, fenilo, fenilalquilo Ci-4 o fenilalquenilo C2-3; y (ii) R X1 is hydrogen, halogen, Ci -4 alkyl or Ci -4 alkoxy; - W 1 -Alkr is- NHC 1-6 alkyl, - OC1-6alkyl, - NHC 1 -6 i- o- OC 6 heteroalkyl; L 2 -Z is— X— R x where X is— NR— or— NHC (= 0) -, and R x is C3-10 cycloalkyl, morpholinyl, phenyl, phenylalkyl Ci -4 or phenylalkenyl C 2 -3; Y
(iii) uno de X1 y X2 es S, el otro es CR^ en la que R^ es hidrógeno, alquilo Ci-4 o fenilo opcionalmente sustituido con halógeno, (halo)alquilo Ci-4 o (halo)alcoxilo Ci-4;— W 1-Alki- es— NRC ^alquil-,— OC ^alquil- o— SC ^alquil- en la que R es hidrógeno, alquilo Ci-4, acilo Ci-4; Y es fenilo; L2-Z es una cadena hidrocarbonada saturada o insaturada de alquilo CM2 que incluye — NR— y opcionalmente sustituida con haloalcoxilo Ci-4, cicloalquilo C3-8, cicloalquenilo C3-8, acilo Ci-4, fenoxilo, fenilo o feniltiol. (iii) one of X 1 and X 2 is S, the other is CR ^ where R ^ is hydrogen, Ci -4 alkyl or phenyl optionally substituted by halogen, (halo) Ci -4 alkyl or (halo) Ci alkoxy -4; - W 1 -Alki- is- ^ alkyl NRC -, - OC ^ SC ^ alkyl- o- alkyl- wherein R is hydrogen, Ci -4 alkyl, Ci -4 acyl; Y is phenyl; L 2 -Z is a saturated or unsaturated hydrocarbon chain of CM 2 alkyl including - NR- and optionally substituted Ci -4 haloalkoxy, C3-8 cycloalkyl, C3-8 acyl , Ci -4, phenoxy, phenyl or phenylthiol.
En una realización particular, el compuesto de fórmula (IV) en la que X1 es S y X2 es CH. In a particular embodiment, the compound of formula (IV) where X 1 is S and X 2 is CH.
En una realización particular, el compuesto de fórmula (IV) en la que X1 es CH y X2 es S. In a particular embodiment, the compound of formula (IV) where X 1 is CH and X 2 is S.
En una realización particular, el compuesto de fórmula (IV) en la que L2 es NH,— NHC(=0)— , — NHC(=0)0— , — NHC(=0)NH— , — NHC(=0)NHCH2— , o — CH2C(=0)NH— . In a particular embodiment, the compound of formula (IV) in which L 2 is NH, - NHC (= 0) -, - NHC (= 0) 0—, - NHC (= 0) NH—, - NHC (= 0) NHCH 2 -, or - CH 2 C (= 0) NH—.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000060_0001
Figure imgf000060_0001
en la que q es 1-4; uno de X1 y X2 es S y el otro es— CH— ; y cada aparición de RY1 es independientemente hidrógeno, alquilo, heteroalquilo, arilo, heteroarilo, -(alquil)arilo o - (alquil)heteroarilo, — ORY3— SRY3, — NRY2RY3, -S02NRY2RY3, — C(=0)NRY2RY3, halógeno,— CN,— N02,— C(=0)0RY3,— N(RY2)C(=0)RY3, en la que cada aparición de RY2 y RY3 es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo, o RY2 y RY3 tomados junto con el átomo de nitrógeno al que se unen forman un anillo heterocíclico de 5-6 miembros.where q is 1-4; one of X 1 and X 2 is S and the other is— CH—; and each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Y3 - SR Y3 , - NR Y2 R Y3 , -S0 2 NR Y2 R Y3 , - C (= 0) NR Y2 R Y3 , halogen, - CN, - N0 2 , - C (= 0) 0R Y3 , - N (R Y2 ) C (= 0) R Y3 , in which each occurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached they form a 5-6 membered heterocyclic ring.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura: In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000060_0002
Figure imgf000060_0002
en la que W1 es O o NRW1, donde RW1 es hidrógeno, alquilo inferior, cicloalquilo C3-6, heteroalquilo inferior, heterociclilo, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo; y Alki es un resto de alquileno C1-6 O alquenileno C2-6; y cada aparición de RY1 es independientemente hidrógeno, halógeno o alquilo inferior. wherein W 1 is O or NR W1 , where R W1 is hydrogen, lower alkyl, C3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl; and Alki is a residue of C 1-6 alkylene or C 2-6 alkenylene; and each occurrence of R Y1 is independently hydrogen, halogen, or lower alkyl.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:
Figure imgf000061_0002
In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000061_0002
en la que L2 es NH, — NHC(=0)— , — NHC(=0)0— , — NHC(=0)NH— , — NHC(=0)NHCH2— , o— CH2C(=0)NH— . where L 2 is NH, - NHC (= 0) -, - NHC (= 0) 0—, - NHC (= 0) NH—, - NHC (= 0) NHCH 2 -, or - CH 2 C ( = 0) NH—.
En una realización particular, el compuesto de fórmula (IV) en la que Z es un resto alquilo, alquenilo, alquinilo, hetereoalquilo o heteroalquenilo ramificado. In a particular embodiment, the compound of formula (IV) in which Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety.
En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de:  In a particular embodiment, the compound of formula (IV) in which Z is one of:
Figure imgf000061_0001
Figure imgf000061_0001
en la que cada aparición de RZ1 es independientemente hidrógeno, alquilo inferior, alquenilo inferior, arilo, heteroarilo o acilo. wherein each occurrence of R Z1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, or acyl.
En una realización particular, el compuesto de fórmula (IV) en la que Z es cicloalquilo, cicloalquenilo, o un resto de heterociclilo, arilo o heteroarilo que tiene una de las estructuras:
Figure imgf000062_0001
In a particular embodiment, the compound of formula (IV) wherein Z is cycloalkyl, cycloalkenyl, or a heterocyclyl, aryl, or heteroaryl moiety having one of the structures:
Figure imgf000062_0001
en la que el resto cíclico“A” es un anillo aromático monocíclico de 6 a 10 miembros o bicíclico condensado que comprende desde 0-4 átomos de nitrógeno; el resto“Het” representa un anillo completa o parcialmente saturado o insaturado de 5 a 8 miembros mono o bicíclico condensado que comprende 1-4 heteroátomos seleccionados de N, O y S; m es un número entero desde 0-6; y cada aparición de RZ1 es independientemente hidrógeno, alquilo, cicloalquilo, heteroalquilo, heterociclilo, arilo, heteroarilo, -(alquil)heterociclilo, -(alquil)arilo, -(alquil)heteroarilo, -ORZ2, — SRZ2, — N(RZ2)2, — S02N(RZ2)2, — S02RZ4, — C(=0)N(RZ2)2, halógeno, — CN, — N02, — C(=0)ORZ2, -N(RZ2)C(=0)RZ3 o— N(RZ2)S02RZ4; en la que cada aparición de RZ2 y RZ3 es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo, acilo; o dos apariciones cualesquiera de RZ2, tomadas junto con el átomo de nitrógeno al que se unen (por ejemplo, N(RZ2)2), forman un resto heterocíclico sustituido o no sustituido; y RZ4 es alquilo, heteroalquilo, arilo, heteroarilo, -(alquil)arilo, o -(alquil)heteroarilo; y en la que dos apariciones adyacentes cualesquiera de RZ1 pueden formar un anillo heterocíclico, de heteroarilo o de arilo de 5 a 6 miembros condensados. wherein the cyclic moiety "A" is a 6-10 membered monocyclic or fused bicyclic aromatic ring comprising from 0-4 nitrogen atoms; the "Het" moiety represents a fully or partially saturated or unsaturated 5- to 8-membered mono or bicyclic ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of R Z1 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) heterocyclyl, - (alkyl) aryl, - (alkyl) heteroaryl, -OR Z2 , - SR Z2 , - N (R Z2 ) 2 , - S0 2 N (R Z2 ) 2 , - S0 2 R Z4 , - C (= 0) N (R Z2 ) 2 , halogen, - CN, - N0 2 , - C (= 0) OR Z2 , -N (R Z2 ) C (= 0) R Z3 or— N (R Z2 ) S0 2 R Z4 ; wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl, acyl; or any two occurrences of R Z2 , taken together with the nitrogen atom to which they are attached (eg, N (R Z2 ) 2 ), form a substituted or unsubstituted heterocyclic moiety; and R Z4 is alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, or - (alkyl) heteroaryl; and wherein any two adjacent occurrences of R Z1 may form a fused 5 to 6 membered heterocyclic, heteroaryl, or aryl ring.
En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de: In a particular embodiment, the compound of formula (IV) in which Z is one of:
Figure imgf000063_0001
Figure imgf000063_0001
en la que m es un número entero desde 0 hasta 3; r es un número entero desde 1 hasta 4; X3 es N o CRZ1; cada aparición de RZ1 es independientemente hidrógeno, alquilo, heteroalquilo, arilo, heteroarilo, -(alquil)arilo o -(alquil)heteroarilo,— ORZ2,— SRZ2,— NRZ2RZ3,— S02NRZ2RZ3,— S02Rz1,— C(=0)NRZ2RZ3, halógeno,— CN,— N02,where m is an integer from 0 to 3; r is an integer from 1 to 4; X 3 is N or CR Z1 ; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Z2 , - SR Z2 , - NR Z2 R Z3 , - S0 2 NR Z2 R Z3 , - S0 2 R z1 , - C (= 0) NR Z2 R Z3 , halogen, - CN, - N0 2 ,
C(=Ó)ORZ3, N(RZ2)C(=0)RZ3, en la que cada aparición de RZ2 y RZ3 es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo, o RZ2 y RZ3 tomados junto con el nitrógeno o átomo de carbono al que se unen forman un anillo heterocíclico, de arilo o de heteroarilo de 5-6 miembros; y RZ4 es hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo. C (= Ó) OR Z3 , N (R Z2 ) C (= 0) R Z3 , where each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and R Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl.
En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de: en la que X 3 es N o CRZ1; RZ1 es hidrógeno, halógeno, alquilo inferior, hidroxialquilo inferior o haloalquilo inferior; RZ2 y RZ3 son independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, acilo, o RZ2 y RZ3 tomados junto con el átomo de nitrógeno al que se unen forman un anillo heterocíclico de 5-6 miembros; y RZ4 es hidrógeno o alquilo inferior. In a particular embodiment, the compound of formula (IV) in which Z is one of: where X 3 is N or CR Z1 ; R Z1 is hydrogen, halogen, lower alkyl, hidroxialqu i what lower or lower haloalkyl; R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2 and R Z3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; and R Z4 is hydrogen or lower alkyl.
En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de: In a particular embodiment, the compound of formula (IV) in which Z is one of:
Figure imgf000066_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000067_0001
en la que X3 es N o CRZ1; RZ1 es hidrógeno, halógeno, alquilo inferior o haloalquilo inferior; y RZ2 y RZ3 son independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, acilo, o RZ2 y RZ3 tomados junto con el átomo de nitrógeno al que se unen forman un anillo heterocíclico de 5-6 miembros; X es halógeno, RZ1A es hidrógeno, halógeno,— CN, alquilo inferior, alcoxilo inferior, haloalquilo inferior o— S02RZ4; en la que RZ4 es alquilo inferior; y RZ2A es hidrógeno o alquilo inferior. where X 3 is N or CR Z1 ; R Z1 is hydrogen, halogen, lower alkyl or haloalkyl lower; and R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2 and R Z3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; X is halogen, R Z1A is hydrogen, halogen, -CN , lower alkyl, lower alkoxy, halo lower alkyl, or— S0 2 R Z4 ; wherein R Z4 is lower alkyl; and R Z2A is hydrogen or lower alkyl.
En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de:  In a particular embodiment, the compound of formula (IV) in which Z is one of: 
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
en la que cada aparición de RZ1 es independientemente Cl, F, metilo o CF3; RZ2 y RZ3 son cada uno metilo o etilo, o tomados junto con el átomo de nitrógeno al que se unen forman un anillo de pirrolidinilo saturado o insaturado; y RZ2A es hidrógeno o metilo. En una realización particular, el compuesto de fórmula (IV) en la que Z es uno de:
Figure imgf000069_0001
Figure imgf000070_0001
wherein each occurrence of R Z1 is independently Cl, F, methyl or CF 3 ; R Z2 and R Z3 are each methyl or ethyl, or taken together with the nitrogen atom to which they are attached form a saturated or unsaturated pyrrolidinyl ring; and R Z2A is hydrogen or methyl. In a particular embodiment, the compound of formula (IV) in which Z is one of:
Figure imgf000070_0002
Figure imgf000070_0002
en la que RZ1 es Cl, F, metilo o CF3. where R Z1 is Cl, F, methyl or CF 3 .
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000070_0003
Figure imgf000070_0003
o
Figure imgf000071_0001
or
Figure imgf000071_0001
en la que X1 y X2 son tal como se definieron anteriormente; Z es un resto arilo, heteroarilo o heterocíclico; W1 es O o NRW1, donde RW1 es hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo; Alki es una cadena de alquileno Ci-e o alquenileno C2-6 sustituida o no sustituida en la que hasta dos unidades de metileno no adyacentes están reemplazadas opcional e independientemente por— C(=0)— ,— CO2— ,— C(=0)C(=0)— ,— C(=0)NRL1A— ,— 0C(=0)— , — 0C(=0)NRL1A— , — NRL1ANRL1 B— , -NRL1ANRL1 BC(=0)— , —where X 1 and X 2 are as defined above; Z is an aryl, heteroaryl, or heterocyclic moiety; W 1 is O or NR W1 , where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl; Alki is a substituted or unsubstituted Ci-e alkylene or C2-6 alkenylene chain in which up to two non-adjacent methylene units are optionally and independently replaced by— C (= 0) -, - CO2—, - C (= 0) C (= 0) -, - C (= 0) NR L1A -, - 0C (= 0) -, - 0C (= 0) NR L1A -, - NR L1A NR L1 B -, -NR L1A NR L1 B C (= 0) -, -
NRL1AC(=0)— , — NRUAC02— , — NRL1AC(=0)NRL1 B— , — S(=0)— , — S02— , -NRUAS02— ,— S02NRL1A— ,— NRL1AS02NRL1 B,—O—,— S— , o— NRL1A; en la que cada aparición de RL1A y RL1 B es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, heterociclilo, arilo, heteroarilo o acilo. NR L1A C (= 0) -, - NR UA C0 2 -, - NR L1A C (= 0) NR L1 B -, - S (= 0) -, - S0 2 -, -NR UA S0 2 -, - S0 2 NR L1A -, - NR L1A S0 2 NR L1 B , —O -, - S—, or— NR L1A ; wherein each occurrence of R L1A and R L1 B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, or acyl.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000071_0002
Figure imgf000071_0002
en la que m es un número entero desde 0 hasta 3; y cada aparición de RZ1 es independientemente hidrógeno, alquilo, heteroalquilo, arilo, heteroarilo, -(alquil)arilo o - (alquil)heteroarilo, — ORZ2, — SRZ2, — NRZ2RZ3, -S02NRZ2RZ3, S02RZ1, —where m is an integer from 0 to 3; and each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Z2 , - SR Z2 , - NR Z2 R Z3 , -S0 2 NR Z2 R Z3 , S0 2 R Z1 , -
C(=0)NRZ2RZ3, halógeno,— CN,— N02,— C(=0)ORZ3,— N(RZ2)C(=0)RZ3, en la que cada aparición de RZ2 y RZ3 es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo, o RZ2 y RZ3 tomados junto con el nitrógeno o átomo de carbono al que se unen forman un anillo heterocíclico, de arilo o de heteroarilo de 5-6 miembros . C (= 0) NR Z2 R Z3 , halogen, - CN, - N0 2 , - C (= 0) OR Z3 , - N (R Z2 ) C (= 0) R Z3 , in which each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached they form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:
Figure imgf000072_0001
In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000072_0001
en la que RZ1 es halógeno, alquilo inferior o haloalquilo inferior. wherein R Z1 is halogen, lower alkyl or haloalkyl lower.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000072_0002
Figure imgf000072_0002
O
Figure imgf000073_0001
OR
Figure imgf000073_0001
en la que RX1 es hidrógeno, alquilo inferior o heterociclilo; y RZ1 es halógeno, alquilo inferior o haloalquilo inferior. wherein R X1 is hydrogen, lower alkyl, or heterocyclyl; and R Z1 is halogen, lower alkyl or haloalkyl lower.
En una realización particular, el compuesto de fórmula (IV) en la que RZ1 es Cl, F, metilo o— CF3. In a particular embodiment, the compound of formula (IV) in which R Z1 is Cl, F, methyl or - CF3.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000073_0002
Figure imgf000073_0002
en la que m es un número entero desde 0 hasta 3; y cada aparición de RZ1 es independientemente hidrógeno, alquilo, heteroalquilo, arilo, heteroarilo, -(alquil)arilo o - (alquil)heteroarilo, — ORZ2, — SRZ2, — NRZ3RZ3, -S02NRZ2RZ3, — S02RZ1 , —where m is an integer from 0 to 3; and each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, - (alkyl) aryl or - (alkyl) heteroaryl, - OR Z2 , - SR Z2 , - NR Z3 R Z3 , -S0 2 NR Z2 R Z3 , - S0 2 R Z1 , -
C(=0)NRZ2RZ3, halógeno,— CN,— N02,— C(=0)0RZ3,— N(RZ2)C(=0)RZ3, en la que cada aparición de RZ2 y RZ3 es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo, o RZ2 y RZ3 tomados junto con el nitrógeno o átomo de carbono al que se unen forman un anillo heterocíclico, de arilo o de heteroarilo de 5-6 miembros . C (= 0) NR Z2 R Z3 , halogen, - CN, - N0 2 , - C (= 0) 0R Z3 , - N (R Z2 ) C (= 0) R Z3 , in which each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached they form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
En una realización particular, el compuesto de fórmula (IV) que tiene la estructura:  In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000073_0003
Figure imgf000073_0003
en la que RZ1 es halógeno, alquilo inferior o haloalquilo inferior. En una realización particular, el compuesto de fórmula (IV) que tiene la estructura: wherein R Z1 is halogen, lower alkyl or haloalkyl lower. In a particular embodiment, the compound of formula (IV) having the structure:
Figure imgf000074_0001
Figure imgf000074_0001
en la que RX1 es hidrógeno, alquilo inferior o heterociclilo; y RZ1 es halógeno, alquilo inferior o haloalquilo inferior. wherein R X1 is hydrogen, lower alkyl, or heterocyclyl; and R Z1 is halogen, lower alkyl or haloalkyl lower.
En una realización particular, el compuesto de fórmula (IV) en la que RZ1 es Cl, F, metilo o— CF3. In a particular embodiment, the compound of formula (IV) in which R Z1 is Cl, F, methyl or - CF3.
En una realización particular, el compuesto de fórmula (IV) en la que— W1-Alkr es— NH— alquil C1-6- o — O— alquil C1-6-; en la que el resto alquilo C1-6 puede estar sustituido o no sustituido. In a particular embodiment, the compound of formula (IV) wherein— W 1 -Alkr is— NH- C1-6alkyl- or -O- C1-6alkyl-; wherein the C1-6 alkyl moiety can be substituted or unsubstituted.
En una realización particular, el compuesto de fórmula (IV) en la que— W1-Alkr es— NHCH2CH2— , — OCH2CH2— o— NH— CH2CH(CH2OH)— , o representa una de las estructuras: In a particular embodiment, the compound of formula (IV) in which— W 1 -Alkr is— NHCH2CH2—, - OCH2CH2— or— NH— CH 2 CH (CH 2 OH) -, or represents one of the structures:
Figure imgf000074_0002
Figure imgf000074_0002
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento WO 2008026768 tal como MK- 5108. Compuestos de fórmula (I) tal como se dan a conocer en el documento WO 2008026768 se identifican en el presente documento con fórmula (V): In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2008026768 such as MK-5108. Compounds of formula (I) as disclosed in WO 2008026768 are identified herein with formula (V):
Figure imgf000074_0003
Figure imgf000074_0003
Fórmula (V)  Formula (V)
en la que: in which:
Ri es un átomo de hidrógeno, F, CN, COORai , CONRa2Ra2’, NRa3CORa3’, C0NRa40Ra4’, NRa5CONRa5’Ra5”, NRa6COORa6’, S02NRa7Ra7’, NRasS02Ra8’, CORa9, S02Raio, N02, ORai i , o NRai2Rai2’, en la que: Ri is a hydrogen atom, F, CN, COORai, CONR a 2Ra2 ', NR a3 COR a3' , C0NR a4 0R a4 ' , NR a5 CONR a5' R a5 ", NR a6 COOR a6 ', S02NR a7 R a7' , NR to sS02R a8 ', COR a9 , S0 2 Raio, N0 2 , OR ai i , or NR ai2 Rai2 ', in which:
Raí , Ra3, Ra4, Ras, Ra6, y Ras son cada uno independientemente un átomo de hidrógeno o alquilo inferior; R ai , R a3 , R a4 , R a s, R a6 , and R a s are each independently a hydrogen or lower alkyl atom;
Ra2, Ra2’, Ras’, Ras”, Ra7, Ra7’, Rai2, y Rai2’ son cada uno independientemente un átomo de hidrógeno o alquilo inferior que puede estar sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente Li>, en el que <grupo sustituyente Li> es un átomo de halógeno, hidroxilo, nitro, ciano, amino, carbamoílo, aminosulfonilo, imino, alquilamino inferior, dialquilamino inferior, alquilsulfonilo inferior, alquilsulfonilamino inferior, alcoxilo inferior, alcoxicarbonilo inferior, alcoxicarbonilamino inferior, alcanoílo inferior, alcanoiloxilo inferior, alquiltiol inferior, y carboxilo; siempre que, sin embargo, Ra2 y Ra2’; Ras’ y Ras”; Ra7 y Ra7’; Rai2 y Rai2’ cada uno independientemente, junto con el átomo de nitrógeno al que se unen, puedan formar un grupo heterocíclico alifático o aromático de 5 miembros o 6 miembros que puede estar sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente L2>, en el que <grupo sustituyente l_2> es un átomo de halógeno, hidroxilo, amino e hidroximetilo; Ra2, Ra2 ', Ras', Ras ”, Ra7, Ra7 ', Rai2, and Rai2' are each independently a hydrogen or lower alkyl atom that may be substituted with one or more of the same or different substituents selected from <group Li substituent>, where <Li substituent group> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl, aminosulfonyl, imino, lower alkylamino, dialkylamino lower, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthiol, and carboxyl; provided, however, that R a2 and Ra2 ';Ras' and Ras ”; Ra7 and Ra7 '; Rai2 and R ai 2 'each independently, together with the nitrogen atom to which they are attached, may form a 5-membered or 6-membered aliphatic or aromatic heterocyclic group that may be substituted with one or more of the same or different selected substituents of <substituent group L 2 >, in which <substituent group l_2> is a halogen, hydroxyl, amino and hydroxymethyl atom;
Ra3’, Ra , Rae’, Ras’, Ra9, Raio y Ran son cada uno independientemente un átomo de hidrógeno o alquilo inferior que puede estar sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente Li>; o  Ra3 ’, Ra, Rae’, Ras ’, Ra9, Raio and Ran are each independently a hydrogen or lower alkyl atom that may be substituted with one or more of the same or different substituents selected from <substituent group Li>; or
R1 es un alquilo inferior que puede estar sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente M>, en el que <grupo sustituyente M> es un átomo de halógeno, hidroxilo, nitro, ciano, amino, carbamoílo, aminosulfonilo, imino, alquilamino inferior, dialquilamino inferior, alquilsulfonilo inferior, alquilsulfonilamino inferior, alcoxilo inferior, alcoxicarbonilo inferior, alcoxicarbonilamino inferior, alcanoílo inferior, alcanoiloxilo inferior, alquiltiol inferior, y carboxilo; o  R1 is a lower alkyl which may be substituted with one or more of the same or different substituents selected from <substituent group M>, where <substituent group M> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl atom , aminosulfonyl, imino, lower alkylamino, dialkylamino lower, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthiol, and carboxyl; or
R1 es un grupo heterocíclico seleccionado de lo siguiente, en la que Y1 y Y2 son iguales y diferentes, y cada uno un átomo de hidrógeno o alquilo inferior que puede estar sustituido: R1 is a heterocyclic group selected from the following, where Y1 and Y 2 are the same and different, and each is a hydrogen or lower alkyl atom that may be substituted:
Figure imgf000075_0001
Figure imgf000075_0001
R2 es O, S, SO, SO2, NH, NRb, o CRCI RC2 en la que Rb es un alquilo inferior que puede estar sustituido, y Rd y Rc2, que pueden ser el mismo o diferente, son un átomo de hidrógeno o alquilo inferior; R 2 is O, S, SO, SO 2 , NH, NR b , or CR C IR C2 where R b is a lower alkyl that may be substituted, and R d and Rc2, which may be the same or different, they are a hydrogen or lower alkyl atom;
R3 es un fenilo que puede estar sustituido;  R3 is a phenyl that can be substituted;
X2 es CH, CX2a, o N en la que: X 2 is CH, CX 2a , or N where:
X2a es un alquilo inferior; o X 2a is a lower alkyl; or
X2a es un sustituyente seleccionado de <grupo sustituyente Ai>, o alquilo inferior que está sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente Ai>, en el que <grupo sustituyente Ai> es átomo de halógeno; ciano; hidroxilo; alquilamino inferior; dialquilamino inferior; alcoxilo inferior que puede estar sustituido con uno o más grupos hidroxilo; alquiltiol inferior; y alquilsulfonilo inferior; o X 2a is a substituent selected from <substituent group Ai>, or lower alkyl that is substituted with one or more of the same or different selected substituents of <substituent group Ai>, in which <substituent group Ai> is halogen atom; cyano; hydroxyl; lower alkylamino; lower dialkylamino; lower alkoxy that may be substituted with one or more hydroxyl groups; lower alkylthiol; and lower alkylsulfonyl; or
X2a es COORxi, CONR^Rxs, NHCORxi, NHCONR^Rxs, NHS02NRx2Rx3, NRX4RX5, o CH2NRX4RX5, en la que: X 2a is COORxi, CONR ^ Rxs, NHCORxi, NHCONR ^ Rxs, NHS02NRx2Rx3, NR X4 R X5 , or CH2NR X 4R X 5, where:
Rxi es un átomo de hidrógeno o alquilo inferior que puede estar sustituido; R xi is a hydrogen or lower alkyl atom that may be substituted;
RX2 y RX3, que pueden ser el mismo o diferente, son cada uno un átomo de hidrógeno, alquilo inferior que puede estar sustituido, o cicloalquilo que puede estar sustituido; o alternativamente R^ y Rxs, junto con el átomo de nitrógeno al que se unen, forman un grupo heterocíclico alifático de 5 ó 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido; y R X 2 and R X3, which may be the same or different, are each a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl which may be substituted; or alternatively R ^ and R x s, together with the nitrogen atom to which they are attached, form a 5- or 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; Y
RX4 y Rx5, que pueden ser el mismo o diferente, son un átomo de hidrógeno, alquilo inferior que puede estar sustituido, o cicloalquilo que puede estar sustituido; o R X 4 and R x 5, which can be the same or different, are a hydrogen atom, lower alkyl that can be substituted, or cycloalkyl that can be substituted; or
X2a es un grupo heterocíclico alifático de 5 a 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido, en el que dos átomos de hidrógeno que se unen al mismo átomo de carbono del grupo heterocíclico alifático pueden estar sustituidos con oxo y dos átomos de carbono vecinos que constituyen el anillo heterocíclico alifático pueden formar un doble enlace; o un alquilo inferior que está sustituido con el grupo heterocíclico alifático; o X 2a is a 5- to 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted, in which two hydrogen atoms are attached to the same carbon atom of the aliphatic heterocyclic group they can be substituted with oxo and two neighboring carbon atoms that make up the aliphatic heterocyclic ring can form a double bond; or a lower alkyl that is substituted with the aliphatic heterocyclic group; or
X2a es un grupo heterocíclico aromático de 5 a 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido; o un alquilo inferior que está sustituido con el grupo heterocíclico aromático; X 2a is a 5- to 6-membered aromatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; or a lower alkyl that is substituted with the aromatic heterocyclic group;
W es el siguiente residuo:
Figure imgf000076_0001
W is the following residue:
Figure imgf000076_0001
en el que: in which:
Wi es CH, N, NH, O o S;  Wi is CH, N, NH, O or S;
W2 es CH, CW2a, N, NW2b, O o S, en el que W2a y W2b son cada uno independientemente un átomo de hidrógeno, átomo de halógeno, ciano, alquilo inferior que tiene de uno a dos átomos de carbono, cicloalquilo que tiene de tres a cinco átomos de carbono, o alquilo inferior que tiene de uno a dos átomos de carbono que puede estar sustituido con uno o más átomos de halógeno; W 2 is CH, CW 2a , N, NW 2b , O, or S, where W 2a and W 2b are each independently a hydrogen atom, halogen atom, cyano, lower alkyl having one to two atoms of carbon, cycloalkyl having three to five carbon atoms, or lower alkyl having one to two carbon atoms that may be substituted with one or more halogen atoms;
W3 es C o N; y W 3 is C or N; Y
al menos uno de W1, W2, y W3 es átomo de carbono; sin embargo, dos de W1 , W2, y W3 no son simultáneamente O y S, at least one of W 1 , W 2 , and W 3 is carbon atom; however, two of W 1 , W 2 , and W 3 are not simultaneously O and S,
o una sal o un éster farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt or ester thereof.
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que W se selecciona de:
Figure imgf000077_0001
In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, wherein W is selected from:
Figure imgf000077_0001
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que R3 es un fenilo cuyas posiciones 2a y 3a están sustituidas con los mismos o dos sustituyentes diferentes seleccionados de F, Cl, CF3, y CN. In a particular embodiment, the compound of formula (V) or a salt or a pharmaceutically acceptable ester of the same, in which R 3 is a phenyl which positions 2 and 3 are substituted with the same or two different substituents selected from F , Cl, CF 3 , and CN.
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que <grupo sustituyente > es un átomo de halógeno, hidroxilo, amino, carbamoílo, alquilamino inferior, dialquilamino inferior, y alcoxilo inferior; y <grupo sustituyente M> es un hidroxilo, carbamoílo, aminosulfonilo, alquilsulfonilamino inferior y carboxilo.  In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, in which <substituent group> is a halogen, hydroxyl, amino, carbamoyl, lower alkylamino, dialkylamino, and alkoxy atom lower; and <substituent group M> is a hydroxyl, carbamoyl, aminosulfonyl, lower alkylsulfonylamino, and carboxyl.
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que X2 es CH o N. In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, wherein X 2 is CH or N.
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que R1 es OH, COOH, o CONRa2Ra2’ en la que Ra2 y Ra2’ son iguales o diferentes, y cada uno un átomo de hidrógeno o alquilo inferior que tiene de uno a tres átomos de carbono; o R1 se selecciona de lo siguiente:
Figure imgf000077_0002
In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, wherein R 1 is OH, COOH, or CONR a2 R a2 'where R a2 and R a2 ' are the same or different, and each a hydrogen or lower alkyl atom having one to three carbon atoms; or R 1 is selected from the following:
Figure imgf000077_0002
y R2 es O, S, SO o SO2. and R 2 is O, S, SO or SO 2 .
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que: In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, wherein:
W se selecciona de:  W is selected from:
Figure imgf000077_0003
en la que W2a es un átomo de hidrógeno, átomo de halógeno, ciano, o metilo que puede estar sustituido con de uno a tres átomos de flúor.
Figure imgf000077_0003
wherein W 2a is a hydrogen, halogen, cyano, or methyl atom which may be substituted with one to three fluorine atoms.
En una realización particular, el compuesto de fórmula (V) o una sal o un éster farmacéuticamente aceptable del mismo, en la que W es uno cualquiera de los siguientes:
Figure imgf000078_0001
In a particular embodiment, the compound of formula (V) or a pharmaceutically acceptable salt or ester thereof, wherein W is any one of the following:
Figure imgf000078_0001
En una realización particular, el compuesto de fórmula (V) se selecciona de:  In a particular embodiment, the compound of formula (V) is selected from:
(a) ácido trans-4-(3-cloro-2-fluorofenoxi)-1-((6-(1 ,3-tiazol-2-ilamino)piridin-2- il)metil)ciclohexanocarboxílico;  (a) trans-4- (3-chloro-2-fluorophenoxy) -1 - ((6- (1,3-thiazol-2-ylamino) pyridin-2-yl) methyl) cyclohexanecarboxylic acid;
(b) ácido trans-4-(2-fluoro-3-(trifluorometil)fenoxi)-1-((6-(1 ,3-tiazol-2-ilamino)piridin-2- il)metil)ciclohexanocarboxílico; (b) trans-4- (2-fluoro-3- (trifluoromethyl) phenoxy) -1 - ((6- (1,3-thiazol-2-ylamino) pyridin-2-yl) methyl) cyclohexanecarboxylic acid;
(c) ácido trans-4-(2,3-diclorofenoxi)-1-((6-(1 ,3-tiazol-2-ilamino)piridin-2- il)metil)ciclohexanocarboxílico;  (c) trans-4- (2,3-dichlorophenoxy) -1 - ((6- (1,3-thiazol-2-ylamino) pyridin-2- yl) methyl) cyclohexanecarboxylic acid;
(d) ácido trans-4-(2-fluoro-3-(trifluorometil)fenoxi)-1-((6-(1 H-pirazol-3-ilamino)piridin-2- il)metil)ciclohexanocarboxílico;  (d) trans-4- (2-fluoro-3- (trifluoromethyl) phenoxy) -1 - ((6- (1 H-pyrazol-3-ylamino) pyridin-2- yl) methyl) cyclohexanecarboxylic acid;
(e) trans-4-(3-cloro-2-fluorofenoxi)-1-((6-(1 H-pirazol-3-ilamino)pirazin-2- il)metil)ciclohexancarboxamida;  (e) trans-4- (3-chloro-2-fluorophenoxy) -1 - ((6- (1 H-pyrazol-3-ylamino) pyrazin-2-yl) methyl) cyclohexancarboxamide;
(f) 5-(trans-4-(2-fluoro-3-(trifluorometil)fenoxi)-1-((6-(1 H-pirazol-3-ilamino)piridin-2- il)metil)ciclohexil)-1 ,3,4-oxadiazol-2(3H)-ona;  (f) 5- (trans-4- (2-fluoro-3- (trifluoromethyl) phenoxy) -1 - ((6- (1 H-pyrazol-3-ylamino) pyridin-2- yl) methyl) cyclohexyl) - 1,3,4-oxadiazol-2 (3H) -one;
(g) 5-(trans-4-(3-cloro-2-fluorofenoxi)-1-((6-(1 H-pirazol-3-ilamino)piridin-2- il)metil)ciclohexil)-1 ,3,4-oxadiazol-2(3H)-ona; (g) 5- (trans-4- (3-chloro-2-fluorophenoxy) -1 - ((6- (1 H-pyrazol-3-ylamino) pyridin-2- yl) methyl) cyclohexyl) -1, 3 , 4-oxadiazol-2 (3H) -one;
(h) 5-(trans-4-(3-cloro-2-fluorofenoxi)-1-((6-(1 H-pirazol-3-ilamino)pirazin-2- il)metil)ciclohexil)-1 ,3,4-oxadiazol-2(3H)-ona; o  (h) 5- (trans-4- (3-chloro-2-fluorophenoxy) -1 - ((6- (1 H-pyrazol-3-ylamino) pyrazin-2- yl) methyl) cyclohexyl) -1, 3 , 4-oxadiazol-2 (3H) -one; or
(i) 5-(trans-4-((2,3-diclorofenil)sulfonil)-1-((6-(1 H-pirazol-3-ilamino)piridin-2- il)metil)ciclohexil)-1 ,3,4-oxadiazol-2(3H)-ona;  (i) 5- (trans-4 - ((2,3-dichlorophenyl) sulfonyl) -1 - ((6- (1 H-pyrazol-3-ylamino) pyridin-2- yl) methyl) cyclohexyl) -1, 3,4-oxadiazol-2 (3H) -one;
o una sal o un éster farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt or ester thereof.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento WO 2007041358 tal como ENMD-2076. Compuestos de fórmula (I) tal como se dan a conocer en el documento WO 2007041358 se identifican en el presente documento con fórmula (VI):  In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2007041358 such as ENMD-2076. Compounds of formula (I) as disclosed in WO 2007041358 are identified herein with formula (VI):
Figure imgf000078_0002
Fórmula (VI) o un derivado o profármaco farmacéuticamente aceptable del mismo, en la que:
Figure imgf000078_0002
Formula (VI) or a pharmaceutically acceptable derivative or prodrug thereof, in which:
Rx y Ry se seleccionan independientemente del grupo que consiste en -T-R3 y -L-Z-R3;R x and R y are independently selected from the group consisting of -TR 3 and -LZR 3 ;
Q1 se selecciona del grupo que consiste en -CR6=CR6- y º , en la que dicho -Q 1 is selected from the group consisting of -CR 6 = CR 6 - and º , in which said -
CR6=CR6 - puede ser un doble enlace en cis o trans o una mezcla de los mismos; R1 es -T-(anillo D); CR 6 = CR 6 - can be a cis or trans double bond or a mixture thereof; R 1 is -T- (ring D);
Anillo D es un anillo monocíclico de 5-7 miembros o un anillo bicíclico de 8-10 miembros seleccionado del grupo que consiste en arilo, heteroarilo, heterociclilo y carbociclilo, teniendo dicho anillo de heteroarilo o heterociclilo 1-4 heteroátomos de anillo seleccionados del grupo que consiste en nitrógeno, oxígeno y azufre, en la que cada carbono sustituible del anillo del anillo D está sustituido independientemente por oxo, -T-R5, o -V-Z-R5, y cada nitrógeno sustituible del anillo del anillo D está sustituido independientemente por -R4; Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl and carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable ring D ring carbon is independently substituted by oxo, -TR 5 , or -VZR 5 , and each substitutable D ring ring nitrogen is independently substituted by -R 4 ;
T es un enlace de valencia o -(C(R6’)2)-A-; T is a valence bond or - (C (R 6 ' ) 2 ) -A-;
A es un enlace de valencia o una cadena de alquilideno C1-C3 en la que una unidad de metileno de dicha cadena de alquilideno C1-3 está reemplazada opcionalmente por -O-, -S-, -N(R4)-, -CO-, -CONH-, -NHCO-, -S02 -, -SO2NH-, -NHSO2 -, -C02 -, -OC(O)-, - OC(0)NH-, o -NHCO2-; A is a valence bond or an alkylidene chain C1-C 3 in which a methylene unit of said C 1-3 alkylidene chain is optionally replaced by -O-, -S-, -N (R 4) - , -CO-, -CONH-, -NHCO-, -S0 2 -, -SO2NH-, -NHSO2 -, -C0 2 -, -OC (O) -, - OC (0) NH-, or -NHCO 2 -;
Z es una cadena de alquilideno Ci-4; Z is a Ci -4 alkylidene chain;
L se selecciona del grupo que consiste en -O-, -S-, -SO-, -SO2-, -N(R6)S02 -, - S02N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6)-, -L is selected from the group consisting of -O-, -S-, -SO-, -SO2-, -N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -CO2-, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, -
N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(0)N(R6)-, -OC(0)N(R6)-, -C(R6)20-, -C(R6)2-, C(R6)2SO-, -C(R6)2SC>2-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(0)-, - C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N-0-, -C(R6)2N(R6)N(R6)-,N (R 6 ) S0 2 N (R 6 ) -, -N (R 6 ) N (R 6 ) -, -C (0) N (R 6 ) -, -OC (0) N (R 6 ) - , -C (R 6 ) 2 0-, -C (R 6 ) 2 -, C (R 6 ) 2 SO-, -C (R 6 ) 2 SC> 2 -, -C (R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) C (0) -, - C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) = NN (R 6 ) -, -C (R 6 ) = N-0-, -C (R 6 ) 2 N (R 6 ) N (R 6 ) -,
C(R6)2N(R6)S02N(R6)-, y -C(R6)2N(R6)CON(R6)-; C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) -, and -C (R 6 ) 2 N (R 6 ) CON (R 6 ) -;
R2 y R2 se seleccionan independientemente del grupo que consiste en -R y -T-W-R6, o R2 y R2’ tomados junto con sus átomos intervinientes forman un anillo insaturado o parcialmente insaturado de 5-8 miembros condensado que tiene 0-3 heteroátomos de anillo seleccionados del grupo que consiste en nitrógeno, oxígeno y azufre, en la que cada carbono sustituible del anillo de dicho anillo condensado formado por R2 y R2’ está sustituido independientemente por halo, oxo, -CN, -NO2, R7, o -V-R6, y cada nitrógeno sustituible del anillo de dicho anillo formado por R2 y R2’ está sustituido independientemente por -R4; R 2 and R 2 are independently selected from the group consisting of -R and -TWR 6 , or R 2 and R 2 ' taken together with their intervening atoms form a fused 5-8 membered unsaturated or partially unsaturated ring having 0- 3 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable carbon of the ring of said condensed ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO2, R 7 , or -VR 6 , and each substitutable nitrogen in the ring of said ring formed by R 2 and R 2 ' is independently substituted by -R 4 ;
R3 se selecciona del grupo que consiste en -R, -halo, -OR, -C(=0)R, -CO2R, -COCOR, -COCH2COR, -N02, -CN, -S(0)R, -S(0)2 R, -SR, -N(R4)2, -CON(R7)2, -S02N(R7)2, - OC(0)R, -N(R7)COR, -N(R7)C02(C1-6 alifático), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -R 3 is selected from the group consisting of -R, -halo, -OR, -C (= 0) R, -CO2R, -COCOR, -COCH2COR, -N0 2 , -CN, -S (0) R, - S (0) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -S0 2 N (R 7 ) 2 , - OC (0) R, -N (R 7 ) COR , -N (R 7 ) C0 2 (C 1 -6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -
N(R7)CON(R7)2, -N(R7)S02 N(R7)2, -N(R4)S02R, y -OC(0)N(R)2; N (R 7 ) CON (R 7 ) 2 , -N (R 7 ) S0 2 N (R 7 ) 2 , -N (R 4 ) S0 2 R, and -OC (0) N (R) 2 ;
cada R es independientemente hidrógeno o un grupo opcionalmente sustituido seleccionado del grupo que consiste en alifático C1-6, arilo Ce-io, un anillo de heteroarilo que tiene 5-10 átomos de anillo, y un anillo de heterociclilo que tiene 5-10 átomos de anillo; each R is independently hydrogen or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, Ce-io aryl, a heteroaryl ring having 5-10 ring atoms, and a heterocyclyl ring having 5-10 ring atoms;
cada R4 se selecciona independientemente del grupo que consiste en -R7, -COR7, - C02(alifático C1-6 opcionalmente sustituido), -CON(R7)2, y -SO2R7 ; each R 4 is independently selected from the group consisting of -R 7 , -COR 7 , - C0 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2, and -SO2R 7 ;
cada R5 se selecciona independientemente del grupo que consiste en -R, halo, - OR, - C(0)R, -CO2R, -COCOR, -N02, -CN, -S(0)R, -S02R, -SR, -N(R4)2, -CON(R4)2, - S02N(R4)2, -0C(0)R, -N(R4)COR, -N(R4)C02 (alifático Ci-e opcionalmente sustituido), - N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R, y -0C(=0)N(R4)2; each R 5 is independently selected from the group consisting of -R, halo, - OR, - C (0) R, -CO2R, -COCOR, -N0 2 , -CN, -S (0) R, -S0 2 R , -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , - S0 2 N (R 4 ) 2 , -0C (0) R, -N (R 4 ) COR, -N (R 4 ) C0 2 (optionally substituted aliphatic Ci-e), - N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) S0 2 N (R 4 ) 2 , - N (R 4 ) S0 2 R, and -0C (= 0) N (R 4 ) 2 ;
V se selecciona del grupo que consiste en -O-, -S-, -SO-, -S02-, - N(R6)S02-, - S02N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6)-, -V is selected from the group consisting of -O-, -S-, -SO-, -S0 2 -, - N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -C0 2 -, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, -
N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(0)N(R6)-, -0C(0)N(R6)-, -C(R6)20-, -C(R6)2S-, - C(R6)2SO-, -C(R6)2S02-, -C(R6)2S02N(R6)-, -C(R6)2N(R6), -C(R6)2N(R6)C(0)-, -N (R 6 ) S0 2 N (R 6 ) -, -N (R 6 ) N (R 6 ) -, -C (0) N (R 6 ) -, -0C (0) N (R 6 ) - , -C (R 6 ) 2 0-, -C (R 6 ) 2 S-, - C (R 6 ) 2 SO-, -C (R 6 ) 2 S0 2 -, -C (R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ), -C (R 6 ) 2 N (R 6 ) C (0) -, -
C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N-0-, C(R6)2N(R6)N(R6)-,C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) = NN (R 6 ) -, -C (R 6 ) = N-0-, C (R 6 ) 2 N (R 6 ) N (R 6 ) -,
C(R6)2N(R6)S02N(R6)-, y -C(R6)2N(R6)CON(R6)-; C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) -, and -C (R 6 ) 2 N (R 6 ) CON (R 6 ) -;
W se selecciona del grupo que consiste en -C(R6)20-, -C(R6)2S-, - C(R6)2SO-, - C(R6)2S02-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -CO-, -C02-, - C(R6)OC(0)-, - C(R6)0C(0)N(R6)-, -C(R6)2N(R6)CO-, -C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N- O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)S02N(R6)-, -C(R6)2N(R6)CON(R6)-, y -CON(R6)-; cada R6 se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático Ci-4 opcionalmente sustituido, o dos grupos R6 en el mismo átomo de nitrógeno pueden tomarse junto con el átomo de nitrógeno para formar un anillo de heterociclilo o heteroarilo de 3-6 miembros; W is selected from the group consisting of -C (R 6 ) 2 0-, -C (R 6 ) 2 S-, - C (R 6 ) 2 SO- , - C (R 6 ) 2 S0 2 -, - C (R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) -, -CO-, -C0 2 -, - C (R 6 ) OC (0) -, - C (R 6 ) 0C (0) N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (0) 0- , -C (R 6 ) = NN (R 6 ) -, -C (R 6 ) = N- O-, -C (R 6 ) 2 N (R 6 ) N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) CON (R 6 ) -, and -CON (R 6 ) -; each R 6 is independently selected from the group consisting of hydrogen and Ci- 4 optionally substituted aliphatic group, or two R 6 groups on the same nitrogen atom may be taken together with the nitrogen atom to form a heterocyclyl ring or heteroaryl 3-6 members;
cada R6’ se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático Ci-4, o dos R6 en el mismo átomo de carbono se toman juntos para formar un anillo carbocíclico de 3-8 miembros; each R 6 ' is independently selected from the group consisting of hydrogen and one Ci -4 aliphatic group, or two R 6s on the same carbon atom are taken together to form a 3-8 membered carbocyclic ring;
cada R6” se selecciona independientemente del grupo que consiste en hidrógeno, un grupo alifático Ci-4, halógeno, arilo opcionalmente sustituido, y heteroarilo opcionalmente sustituido, o dos R6” en átomos de carbono adyacentes se toman juntos para formar un anillo carbocíclico de 5-7 miembros; y each R 6 "is independently selected from the group consisting of hydrogen, an aliphatic group Ci- 4, halogen, optionally substituted aryl, and optionally substituted heteroaryl, or two R 6 'on adjacent carbon atoms are taken together to form a carbocyclic ring 5-7 members; Y
cada R7 se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático Ci-4 opcionalmente sustituido, o dos R7 en el mismo nitrógeno se toman junto con el nitrógeno para formar un anillo de heterociclilo o heteroarilo de 5-8 miembros. each R 7 is independently selected from the group consisting of hydrogen and an optionally substituted C 4 -aliphatic group, or two R 7's in the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
En una realización particular, el compuesto de fórmula (VI) se selecciona del grupo:  In a particular embodiment, the compound of formula (VI) is selected from the group:
Figure imgf000080_0001
80
Figure imgf000080_0001
80
Figure imgf000081_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000085_0001
Figure imgf000086_0001
86
Figure imgf000086_0001
86
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000089_0001
Figure imgf000090_0001
90 90
Figure imgf000091_0001
91
Figure imgf000091_0001
91
Figure imgf000092_0001
Figure imgf000092_0001
92 92
Figure imgf000093_0001
Figure imgf000094_0003
Figure imgf000093_0001
Figure imgf000094_0003
y sales farmacéuticamente aceptables del mismo.  and pharmaceutically acceptable salts thereof.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado bajo la fórmula (I) tal como se da a conocer en el documento WO 2007087276 tal como AMG- 900. Los compuestos de fórmula (I) tal como se da a conocer en el documento WO In a further embodiment, the AURK inhibitor is a compound encompassed under formula (I) as disclosed in WO 2007087276 such as AMG-900. Compounds of formula (I) as disclosed in the WO document
2007087276 se identifican en el presente documento con fórmula (Vil): 2007087276 are identified in the present document with formula (Vil):
Figure imgf000094_0001
Fórmula (Vi l) o estereoisómero, tautómero, solvato, sal, derivado o profármaco farmacéuticamente aceptable del mismo, en la que cada uno de A1 y A2, independientemente, es N o CR9, siempre que al menos uno de A1 y A2 es N;
Figure imgf000094_0001
Pharmaceutically acceptable formula (Vi l) or stereoisomer, tautomer, solvate, salt, derivative or prodrug thereof, wherein each of A 1 and A 2 , independently, is N or CR 9 , provided that at least one of A 1 and A 2 is N;
C1 es N o CR10; C 1 is N or CR 10 ;
C2 es N o CH; C 2 is N or CH;
D es  D is
Figure imgf000094_0002
Figure imgf000094_0002
en la que D1 es N o CR1 1 ; where D 1 is N or CR 1 1 ;
D2 es N o CR12; D 2 is N or CR 12 ;
D3 es N o CR2; D 3 is N or CR 2 ;
D4 es NR1 a, O, S o CR12; D 4 is NR 1 a , O, S or CR 12 ;
D5 es N o CR2; D 5 is N or CR 2 ;
R1 es H, OR14, SR14, OR15, SR15, NR14R , N R15R , (CHR15)nR14, (CHR15)nR15 o R15, en la que n es 0, 1 , 2, 3 ó 4; R 1 is H, OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R, NR 15 R, (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 , in where n is 0, 1, 2, 3 or 4;
Rla es H, CN o alquilo CMO; R a is H, CN or alkyl CMO;
alternativamente R1 tomado junto con cualquiera de R11 y R1a y los átomos de carbono o nitrógeno al que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N y S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de oxo, R15, SR14, OR14, SR15, OR15, OC(0)R15, COOR15, C(0)R15, C(0)NR15R15, NR14R15 o NR15R15; y alternatively R 1 taken together with either R 11 and R 1a and the carbon or nitrogen atoms to which they are attached form a 5- or 6-membered ring of partially or completely unsaturated carbon atoms optionally including 1-3 heteroatoms selected from O , N and S, and the ring optionally independently substituted with 1-3 oxo substituents, R 15 , SR 14 , OR 14 , SR 15 , OR 15 , OC (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or NR 15 R 15 ; Y
R2 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15,R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 ,
NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15),NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ),
0C(0)NR15R1S, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R13, NR15S(0)2NR14R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15 O R15; 0C (0) NR 15 R 1S , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 13 , NR 15 S (0 ) 2 NR 14 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 OR 15 ;
U es NR3, O, S, C(O), S(O), S02 o CR3R3; U is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
L2 es NR3, O, S, C(O), S(O), S02 o CR3R3; L 2 is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
Z es un primer anillo monocíclico completamente insaturado de 5-6 miembros, dicho primer anillo (1) formado de átomos de carbono que incluyen opcionalmente 1-3 heteroátomos seleccionados de O, N o S, (2) opcionalmente condensado con un segundo anillo monocíclico parcial o completamente saturado o completamente insaturado de 5-6 miembros formado por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y (3) en el que 0, 1 , 2 ó 3 átomos de cada uno de dicho primer y segundo anillo están opcionalmente sustituidos independientemente con 1-5 sustituyentes de R5; Z is a 5-6 membered fully unsaturated monocyclic first ring, said first ring (1) formed of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, (2) optionally fused with a second monocyclic ring partially or fully saturated or fully unsaturated 5-6 membered carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and (3) wherein 0, 1, 2 or 3 atoms each of said first and second rings are optionally independently substituted with 1-5 substituents of R 5 ;
cada uno de R3 y R4, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15,each of R 3 and R 4 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C ( 0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 ,
NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
alternativamente, cualquiera de R3 o R4, independientemente, tomados junto con R10 y los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R13, R14 o R15; alternatively, any of R 3 or R 4 , independently, taken together with R 10 and the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-3 substituents of R 13 , R 14 or R 15 ;
cada R5, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR13R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15,each R 5 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 13 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 ,
NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
cada de R6, R7 y R8, independientemente, es R13, R14 o R15; each of R 6 , R 7 and R 8 , independently, is R 13 , R 14 or R 15 ;
alternativamente, cualquiera de R6 o R8, independientemente, tomados junto con R7 y los átomos de carbono a los que se unen forman un anillo de átomos de carbono de 5 ó 6 miembros completamente saturado o parcial o completamente insaturado que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15; cada uno de R9, R10, R11 y R12, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, 0C(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15,alternatively, any of R 6 or R 8 , independently, taken together with R 7 and the carbon atoms to which they are attached form a fully or partially saturated or fully saturated 5 or 6 membered ring of carbon atoms optionally including 1 -3 hetero atoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ; each of R 9 , R 10 , R 11 and R 12 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0 ) R 15 , COOR 15 , 0C (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 ,
S(0)2NR15R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15 o R15; S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
R13 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, 0C(0)R14, 0C(0)R15, COOR14, COOR15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, C(0)C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR14),R 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , 0C (0) R 14 , 0C (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , C (0) C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ),
NR15(COOR15), NR15C(0)C(0)NR14R1 S, NR15C(0)C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15 O NR15S(0)2NR15R15; NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R 1 S , NR 15 C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 O NR 15 S (0) 2 NR 15 R 15 ;
R14 es un sistema de anillo monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros parcial o completamente insaturado, formado el sistema de anillos por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, los heteroátomos seleccionados de O, N o S, en los que 0, 1 , 2 ó 3 átomos de cada anillo están opcionalmente sustituidos independientemente con 1-5 sustituyentes de R15; y R15 es H, halo, haloalquilo, haloalcoxilo, oxo, CN, OH, SH, N02, NH2, acetilo, alquiloR 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered tricyclic system partially or completely unsaturated, the ring system being formed by carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-5 R 15 substituents; and R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2 , NH 2 , acetyl, alkyl
CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, CMO- alquilamino-, Ci-10-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO O sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros saturado o parcial o completamente insaturado, formado dicho sistema de anillos de átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, dichos heteroátomos seleccionados de O, N o S, en los que cada uno del alquilo CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, CMo-alquilamino-, CMo-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO y el anillo de dicho sistema de anillos está opcionalmente sustituido independientemente con 1-5 sustituyentes de halo, haloalquilo, CN, N02, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina, diisopropilamina, bencilo o fenilo; CMO, C 2 -i alkenyl o, C 2-i alkynyl or, C3-10 cycloalkyl, C4-10 cycloalkenyl, CMO-alkylamino-, Ci-10-dialkylamino-, alkoxy CMO, thioalkoxy CMO OR 5-monocyclic ring system -8 membered, 6-12 membered bicyclic or 7-14 membered saturated or partially or fully unsaturated tricyclic, said carbon atom ring system formed optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S, where each of CMO alkyl, C 2 -i alkenyl or, C 2 -i alkynyl or, C3-10 cycloalkenyl, C4 cycloalkenyl -10, C M o-alkylamino-, C M o-dialkylamino-, alkoxy CMO, thioalkoxy CMO and the ring of said ring system is optionally independently substituted with 1-5 substituents of halo, haloalkyl, CN, N0 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobuti lo, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;
siempre que (1) no más de uno de D1 , D2 y D3 es N, y (2) cada uno de L1 y L2, independientemente, se une al primer anillo de Z. provided that (1) no more than one of D 1 , D 2 and D 3 is N, and (2) each of L 1 and L 2 , independently, joins the first ring of Z.
En una realización particular, el compuesto de fórmula (Vil) en la que D es
Figure imgf000096_0001
In a particular embodiment, the compound of formula (Vil) in which D is
Figure imgf000096_0001
en la que D1 es N, D2 es CR12 y D3 es CH. where D 1 is N, D 2 is CR 12 and D 3 is CH.
En una realización particular, el compuesto de fórmula (Vil) en la que D es
Figure imgf000097_0001
In a particular embodiment, the compound of formula (Vil) in which D is
Figure imgf000097_0001
en la que D1 es CR11, D2 es N y D3 es CH. where D 1 is CR 11 , D 2 is N and D 3 is CH.
En una realización particular, el compuesto de fórmula (Vil) en la que  In a particular embodiment, the compound of formula (Vil) in which
C1 es CR10 y R10 es H, halo, haloalquilo, haloalcoxilo, CN, OH, SH, NO2, NH2, acetilo, alquilo CMO O alcoxilo CMO; C 1 is CR 10 and R 10 is H , halo, haloalkyl, haloalkoxy, CN, OH, SH, NO2, NH2, acetyl, CMO alkyl, or CMO alkoxy;
C2 es N; y C 2 is N; Y
R2 es H, halo, NO2, CN, alquilo CMO O alcoxilo CMO. R 2 is H, halo, NO2, CN, CMO alkyl, or CMO alkoxy.
En una realización particular, el compuesto de fórmula (Vil) en la que  In a particular embodiment, the compound of formula (Vil) in which
U es NR15, O, CHR15, S, C(O), S(O) o S02; y U is NR 15 , O, CHR 15 , S, C (O), S (O) or S0 2 ; Y
R2 es H, halo, NO2, CN, alquilo CMO o alcoxilo CMO. R 2 is H, halo, NO2, CN, CMO alkyl or CMO alkoxy.
En una realización particular, el compuesto de fórmula (Vil) en la que  In a particular embodiment, the compound of formula (Vil) in which
L2 es NR15, O o S; L 2 is NR 15 , O or S;
cada de R3, R4 y R9, independientemente, es H; each of R 3 , R 4 and R 9 , independently, is H;
C1 es CR10; y C 1 is CR 10 ; Y
Z es fenilo, piridilo, pirimidinilo, piridazinilo, pirazinilo, triazinilo, tiofenilo, furilo, pirrolilo, pirazolilo, tieno-pirazolilo, imidazolilo, triazolilo, tetrazolilo, tiazolilo, tiadiazolilo, oxazolilo, oxadiazolilo, isoxazolilo o isotiazolilo, en la que U y L2, juntos, se orientan en posición para entre sí en el anillo Z, en el que el anillo Z está opcionalmente sustituido con 1-5 sustituciones de R15. Z is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, or isothiazolyl or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazolyl, isothiazole, or isothiazole, isolyl, or isothiazole. 2 together are oriented in position to each other on the Z ring, where the Z ring is optionally substituted with 1-5 substitutions of R 15 .
En una realización particular, el compuesto de fórmula (Vil) en la que R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15. In a particular embodiment, the compound of formula (Vil) wherein R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms including optionally 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents from R 13 , R 14 or R 15 .
En una realización particular, el compuesto de fórmula (Vil) en la que  In a particular embodiment, the compound of formula (Vil) in which
cada uno de A1 y A2, independientemente, es N; y each of A 1 and A 2 , independently, is N; Y
R6 es fenilo, naftilo, piridilo, pirimidinilo, piridazinilo, piazinilo, triazinilo, quinolinilo, dihidroquinolinilo, tetrahidroquinolinilo, isoquinolinilo, tetrahidroisoquinolinilo, quinazolinilo, isoquinazolinilo, ftalazinilo, tiofenilo, furilo, tetrahidrofuranilo, pirrolilo, pirazolilo, tieno-pirazolilo, imidazolilo, triazolilo, tetrazolilo, tiazolilo, tiadiazolilo, benzotiazolilo, oxazolilo, oxadiazolilo, benzoxazolilo, benzoxadiazolilo, isoxazolilo, isotiazolilo, indolilo, azaindolilo, 2,3-dihidroindolilo, isoindolilo, indazolilo, benzofuranilo, benzotiofenilo, bencimidazolilo, imidazo-piridinilo, purinilo. benzotriazolilo, oxazolinilo, isoxazolinilo, tiazolinilo, pirrolidinilo, pirazolinilo, morfolinilo, piperidinilo, piperazinilo, piranilo, dioxozinilo, 2,3-dihidro-1 ,4-benzoxazinilo, 1 ,3-benzodioxolilo, ciclopropilo, ciclobutilo, azetidinilo, ciclopentilo, ciclohexilo, cicloheptilo o piranilo, cada uno de los cuales está opcionalmente sustituido independientemente con 1-5 sustituyentes de R15. En una realización particular, el compuesto de fórmula (Vil) en la que D es R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, piazinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, furyl, tetrayl , tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, pyridinyl, imidazolyl, benzofuranyl, benzothiofenyl, benzothiolyl, Benzotriazolyl, Oxazolinyl, Isoxazolinyl, Thiazolinyl, Pyrrolidinyl, Pyrazolinyl, Morpholinyl, Piperidinyl, Piperazinyl, Pyranyl, Dioxozinyl, 2,3-Dihydro-1, 4-Benzoxazinyl, Cyclopropyl, Cyclobutyl, Cyclopropyl, Cyclobutyl, Cyclopropyl cycloheptyl or pyranyl, each of which is optionally independently substituted with 1-5 substituents of R 15 . In a particular embodiment, the compound of formula (Vil) in which D is
Figure imgf000098_0001
Figure imgf000098_0001
En una realización particular, el compuesto de fórmula (Vil) que tiene una fórmula (Vil'):  In a particular embodiment, the compound of formula (Vil) having a formula (Vil '):
Figure imgf000098_0002
Fórmula (Vil’)
Figure imgf000098_0002
Formula (Vil ')
o estereoisómero, tautómero, solvato, sal, derivado o profármaco farmacéuticamente aceptable del mismo, en la que or a pharmaceutically acceptable stereoisomer, tautomer, solvate, salt, derivative or prodrug thereof, wherein
cada uno de A1 y A2, independientemente, es N o CR9, siempre que al menos uno de A1 y A2 es N; each of A 1 and A 2 , independently, is N or CR 9 , provided that at least one of A 1 and A 2 is N;
cada uno de B1 , B2, B3 y B4, independientemente, es N o CR5, siempre que no más de dos de B1 , B2, B3 y B4 son N; each of B 1 , B 2 , B 3 and B 4 , independently, is N or CR 5 , provided that no more than two of B 1 , B 2 , B 3 and B 4 are N;
C1 es N o CR10; C 1 is N or CR 10 ;
D1 es N o CR11 ; D 1 is N or CR 11 ;
D2 es N o CR12; D 2 is N or CR 12 ;
U es NR3, O, S o CR3R3; U is NR 3 , O, S, or CR 3 R 3 ;
L2 es NR3, O, S o CR3R3; L 2 is NR 3 , O, S or CR 3 R 3 ;
R1 es OR14, SR14, OR15, SR15, NR14R15, NR15R15, (CHR15)nR14, (CHR15)nR15 o R15; alternativamente R1 y R1’ tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N y S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de oxo, R15, SR14, OR14, SR15, OR15, 0C(0)R15, COOR15, C(0)R15, C(0)NR15R15, NR14R15 oR 1 is OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 1 'taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O , N and S , and the ring optionally independently substituted with 1-3 oxo substituents, R 15 , SR 14 , OR 14 , SR 15 , OR 15 , 0C (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or
NR1SR1S; NR1SR1S;
R2 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15),R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C ( 0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ),
0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR14R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15 O R15; 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0 ) 2 NR 14 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 OR 15 ;
cada uno de R3 y R4, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15 o R15; alternativamente, cualquiera de R3 o R4, independientemente, tomados junto con R10 y los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R13, R14 o R15; each of R 3 and R 4 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 or R 15 ; alternatively, any of R 3 or R 4 , independently, taken together with R 10 and the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-3 substituents of R 13 , R 14 or R 15 ;
cada R5 es, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, 0C(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15,each R 5 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , 0C (0 ) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 ,
NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
R6 es R13 o R14; R 6 is R 13 or R 14 ;
cada uno de R7 y R8, independientemente, es R13, R14 o R15; each of R 7 and R 8 , independently, is R 13 , R 14 or R 15 ;
alternativamente, cualquiera de R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono de 5 ó 6 miembros completamente saturado o parcial o completamente insaturado que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15; alternatively, any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully saturated or partially or fully unsaturated 5 or 6 membered carbon atom ring optionally including 1-3 heteroatoms selected from O , N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ;
cada uno de R9, R10, R11 y R12, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15 o R15; each of R 9 , R 10 , R 11 and R 12 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0 ) R 15 or R 15 ;
R13 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, OC(0)R14, OC(0)R15, COOR14, COOR15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, C(0)C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR14), NR15(COOR15), NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15 OR 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , OC (0) R 14 , OC (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , C (0) C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ), NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 O
NR15S(0)2NR15R15; NR 15 S (0) 2 NR 15 R 15 ;
R14 es un sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros parcial o completamente saturado o completamente insaturado, formado el sistema de anillos por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico oR 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic system partially or completely saturated or completely unsaturated, the ring system formed by carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or
1-9 heteroátomos si es tricíclico, los heteroátomos seleccionados de O, N o S, en la que 0, 1 , 2 ó 3 átomos de cada anillo están opcionalmente sustituidos independientemente con 1-5 sustituyentes de R15; 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-5 substituents of R 15 ;
R15 es H, halo, haloalquilo, haloalcoxilo, oxo, CN, OH, SH, N02, NH2, acetilo, alquilo CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, CMO- alquilamino-, Ci-10-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO O sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros saturado o parcial o completamente insaturado, dicho sistema de anillos formado por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, dichos heteroátomos seleccionados de O, N , o S, en los que cada uno del alquilo CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, CMo-alquilamino-, CMo-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO y el anillo de dicho sistema de anillos está opcionalmente sustituido independientemente con 1-5 sustituyentes de halo, haloalquilo, CN, N02, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina, diisopropilamina, bencilo o fenilo; y R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2 , NH 2 , acetyl, CMO alkyl, C 2 -i alkenyl or, C 2 -i alkynyl or C3-10 cycloalkenyl, cycloalkenyl C4-10, CMO- alkylamino-, Ci-10-dialkylamino-, alkoxy CMO, thioalkoxy CMO OR 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered tricyclic saturation system or partially or completely unsaturated, said ring system consisting of carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O , N, or S, in each of CMO alkyl, C 2 -i alkenyl or, C 2-i alkynyl or, C3-10 cycloalkyl, C4-10 cycloalkenyl, C M o-alkylamino-, C M o-dialkylamino-, CMO alkoxy, thioalkoxy CMO and the ring of said ring system is optionally independently substituted with 1-5 substituents of halo, haloalkyl, CN, N0 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; Y
n es 0, 1 , 2, 3 ó 4; n is 0, 1, 2, 3, or 4;
siempre que no más de uno de D1 y D2 es N. provided that not more than one of D 1 and D 2 is N.
En una realización particular, el compuesto de fórmula (Vil’) en la que  In a particular embodiment, the compound of formula (Vil ’) in which
cada uno de A1 y A2, independientemente, es N; each of A 1 and A 2 , independently, is N;
cada uno de B1 , B2, B3 y B4, independientemente, es N o CR5, siempre que no más de uno de B1 , B2, B3 y B4 es N; each of B 1 , B 2 , B 3 and B 4 , independently, is N or CR 5 , provided that not more than one of B 1 , B 2 , B 3 and B 4 is N;
C1 es CR10; C 1 is CR 10 ;
D1 es N o CR11 ; D 1 is N or CR 11 ;
D2 es N o CR12; D 2 is N or CR 12 ;
U es NH, O o S;  U is NH, O or S;
L2 es NH, O o S; siempre que ambos de U y L2 no sean ni O ni S; L 2 is NH, O or S; provided that both of U and L 2 are neither O nor S;
R1 es H, halo, haloalquilo, NO2, NH2, acetilo, alquilo CMO, alquenilo C2-10, alquinilo C2- 10, cicloalquilo C3-10, cicloalquenilo C4-10, Ci-io-alquilamino-, Ci-10-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO, NHR14, NHR15, OR15, SR15 O CH2R15; R 1 is H, halo, haloalkyl, NO 2, NH 2, acetyl, alkyl CM O alkenyl, C 2-10 alkynyl C 2-10, C 3-10 cycloalkyl, cycloalkenyl C 4-10, Ci-io-alkylamino -, Ci- 10 -dyalkylamino-, alkoxy CM O , thioalkoxy CM O , NHR 14 , NHR 15 , OR 15 , SR 15 O CH 2 R 15 ;
R2 es H, halo, NO2, CN, alquilo CMO O alcoxilo CMO; R 2 is H, halo, NO 2 , CN, CMO alkyl, or CMO alkoxy;
cada uno de R3 y R4, independientemente, es SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R1S o R15; each of R 3 and R 4 , independently, is SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 1S or R 15 ;
cada R5 es, independientemente, es SR15, OR15, NR15R15, C(0)R15, C(0)NR15R15, NR15C(0)R15, NR15C(0)NR15R15, NR15(COOR15), S(0)2R15, S(0)2NR15R15,each R 5 is independently SR 15 , OR 15 , NR 15 R 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 15 , NR 15 C (0) NR 15 R 15 , NR 15 (COOR 15 ), S (0) 2 R 15 , S (0) 2 NR 15 R 15 ,
NR15S(0)2NR15R15, NR15S(0)2R15, NR15C(0)C(0)NR14R15 O R15; R6 es R14; NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 15 , NR 15 C (0) C (0) NR 14 R 15 OR 15 ; R 6 is R 14 ;
cada uno de R7 y R8, independientemente, es R15; each of R 7 and R 8 , independently, is R 15 ;
alternativamente, cualquiera de R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13 o R15; y cada uno de R9, R10, R11 y R12, independientemente, es R15. alternatively, any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents on R 13 or R 15 ; and each of R 9 , R 10 , R 11 and R 12 , independently, is R 15 .
En una realización particular, el compuesto de fórmula (Vil’) en la que  In a particular embodiment, the compound of formula (Vil ’) in which
R1 es NR14R15, NR15R15, (CHR15)nR14, (CHR15)nR15or R15; alternativamente R1 y R11 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N y S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R15; R 1 is NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 11 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally independently substituted with 1-3 R 15 substituents;
R2 es H, halo, haloalquilo, CN, NO2, NH2, OH, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina, diisopropilamina, bencilo o fenilo; R 2 is H, halo, haloalkyl, CN, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine , isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;
cada de R3 y R4, independientemente, es H, halo, haloalquilo, CN3 NO2, NH2, OH, metilo, etoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, etila ina, di etila ina, etila ina, dietila ina, propila ina, isopropila ina, dipropila ina, diisopropila ina, bencilo o fenilo; each of R 3 and R 4 , independently, is H, halo, haloalkyl, CN 3 NO 2 , NH 2 , OH, methyl, ethoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, ethyla ina, di ethyla ina, ethyla ina, diethyla ina, propyla ina, isopropyl ina, dipropyl ina, diisopropyl ina, benzyl or phenyl;
cada R5 es, independientemente, es H, halo, haloalquilo, CN, NO2, NH2, OH, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere- butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina o diisopropilamina; each R 5 is independently H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, terebutyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, or diisopropylamine;
R6 es R13 o R14; R 6 is R 13 or R 14 ;
cada uno de R7 y R8, independientemente, es R15; each of R 7 and R 8 , independently, is R 15 ;
alternativamente, cualquiera de R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15; y alternatively, any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ; Y
cada uno de R9, R10, R1 1 y R12, independientemente, es H, halo, haloalquilo, CN, NO2, NH2, OH, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina o diisopropilamina. each of R 9 , R 10 , R 1 1 and R 12 , independently, is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl , butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine or diisopropylamine.
En una realización particular, el compuesto de fórmula (Vil’) en la que  In a particular embodiment, the compound of formula (Vil ’) in which
cada uno de A1 y A2, independientemente, es N; y each of A 1 and A 2 , independently, is N; Y
R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de 5 ó 6 miembros completamente insaturado de átomos de carbono que incluyen opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15. R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 .
En una realización particular, el compuesto de fórmula (Vil’) en la que R6 es fenilo, naftilo, piridilo, pirimidinilo, piridazinilo, piazinilo, triazinilo, quinolinilo, dihidroquinolinilo, tetrahidroquinolinilo, isoquinolinilo, tetrahidroisoquinolinilo, quinazolinilo, isoquinazolinilo, ftalazinilo, tiofenilo, furilo, tetrahidrofuranilo, pirrolilo, pirazolilo, tieno- pirazolilo, imidazolilo, triazolilo, tetrazolilo, tiazolilo, tiadiazolilo, benzotiazolilo, oxazolilo, oxadiazolilo, benzoxazolilo, benzoxadiazolilo, isoxazolilo, isotiazolilo, indolilo, azaindolilo, 2,3-dihidroindolilo, isoindolilo, indazolilo, benzofuranilo, benzotiofenilo, bencimidazolilo, imidazo-piridinilo, purinilo, benzotriazolilo, oxazolinilo, isoxazolinilo, tiazolinilo, pirrolidinilo, pirazolinilo, morfolinilo, piperidinilo, piperazinilo, piranilo, dioxozinilo, 2,3-dihidro-1 ,4-benzoxazinilo, 1 ,3-benzodioxolilo, ciclopropilo, ciclobutilo, azetidinilo, ciclopentilo, ciclohexilo, cicloheptilo o piranilo, cada de uno de los cuales está opcionalmente sustituido independientemente con 1-5 sustituyentes de R15. In a particular embodiment, the compound of formula (VII ') wherein R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, piazinilo, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl , furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, isozozolyl, isothiazolyl, indolyl, azololyl , benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydrazin -benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl or pyranil, each of u not of which is optionally independently substituted with 1-5 substituents of R 15 .
En una realización particular, el compuesto de fórmula (Vil’) en la que  In a particular embodiment, the compound of formula (Vil ’) in which
C1 es CH; C 1 is CH;
D1 es N; D 1 is N;
D2 es CR12 en la que R12 es H, halo, NO2, CN, alquilo CM O O alcoxilo CMO; D 2 is CR 12 wherein R 12 is H, halo, NO 2, CN, C MO alkyl or alkoxyl CMO;
U es NH3, O o S; U is NH 3 , O or S;
L2 es NH; R1 es H, halo, haloalquilo, acetilo, alquilo CMO O NHR15; L 2 is NH; R 1 is H, halo, haloalkyl, acetyl, alkyl CM O O NHR 15 ;
cada uno de R2, R3 y R4, independientemente, es H, halo, alquilo CMO O alcoxilo CMO; R6 es R14; y each of R 2 , R 3 and R 4 , independently, is H, halo, CMO-alkyl or CMO-alkoxy; R 6 is R 14 ; Y
R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13 o R15. R 7 and R 8 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents on R 13 or R 15 .
En una realización particular, el compuesto de fórmula (Vil) que tiene una fórmula (Vil”):  In a particular embodiment, the compound of formula (Vil) having a formula (Vil "):
Figure imgf000102_0001
fórmula (Vil”)
Figure imgf000102_0001
formula (Vil ”)
o estereoisómero, tautómero, solvato, sal, derivado o profármaco farmacéuticamente aceptable del mismo, en la que or a pharmaceutically acceptable stereoisomer, tautomer, solvate, salt, derivative or prodrug thereof, wherein
cada uno de A1 y A2, independientemente, es N o CR9, siempre que al menos uno de A1 y A2 es N; each of A 1 and A 2 , independently, is N or CR 9 , provided that at least one of A 1 and A 2 is N;
cada uno de B1 , B2, B3 y B4, independientemente, es N o CR5, siempre que no más de dos de B1 , B2, B3 y B4 son N; each of B 1 , B 2 , B 3 and B 4 , independently, is N or CR 5 , provided that no more than two of B 1 , B 2 , B 3 and B 4 are N;
C1 es N o CR10; C 1 is N or CR 10 ;
U es O, S, C(O), S(O), S02 o CR3R3; U is O, S , C (O), S (O), S0 2 or CR 3 R 3 ;
L2 es NR3, O, S o CR3R3; L 2 is NR 3 , O, S or CR 3 R 3 ;
R1 es OR14, SR14, OR15, SR15, NR14R15, NR15R15, (CHR15)nR14, (CHR15)nR15 o R15; alternativamente R1 y R11 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N y S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R15, SR14, OR14, SR15, OR15, OC(0)R15, COOR15, C(0)R15, C(0)NR15R15, NR14R15 oR 1 is OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R 15 , NR 15 R 15 , (CHR 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 ; alternatively R 1 and R 11 taken together with the carbon atoms to which they are attached form a 5- or 6-membered partially or completely unsaturated ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally independently substituted with 1-3 substituents of R 15 , SR 14 , OR 14 , SR 15 , OR 15 , OC (0) R 15 , COOR 15 , C (0) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or
NR15R15; NR 15 R 15 ;
R2 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR14R15,R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C ( 0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0 ) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 14 R 15 ,
NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15 O R15; NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 OR 15 ;
cada uno de R3 y R4, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15 o R15; each of R 3 and R 4 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 or R 15 ;
alternativamente, cualquiera de R3 o R4, independientemente, tomados junto con R10 y los átomos de carbono a los que se unen forman un anillo de átomos de carbono parcial o completamente insaturado de 5 ó 6 miembros que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o Ss y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R13, R14 o R15; alternatively, either R 3 or R 4 , independently, taken together with R 10 and the carbon atoms to which they are attached form a ring of carbon atoms partially or completely unsaturated 5 or 6 membered optionally including 1-3 heteroatoms selected from O, N or Ss and the ring optionally independently substituted with 1-3 substituents from R 13 , R 14 or R 15 ;
cada R5 es, independientemente, es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R1 S, COOR15, 0C(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15,each R 5 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 1 S , COOR 15 , 0C ( 0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 ,
NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15,NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 ,
NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
R6 es R13 o R14; R 6 is R 13 or R 14 ;
cada uno de R7 y R8, independientemente, es R13, R14 o R15; each of R 7 and R 8 , independently, is R 13 , R 14 or R 15 ;
alternativamente, cualquiera de R7 y R8 tomados junto con los átomos de carbono a los que se unen forman un anillo de átomos de carbono de 5 ó 6 miembros completamente saturado o parcial o completamente insaturado que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15; alternatively, any of R 7 and R 8 taken together with the carbon atoms to which they are attached form a fully saturated or partially or fully unsaturated 5 or 6 membered carbon atom ring optionally including 1-3 heteroatoms selected from O , N or S, and the ring optionally independently substituted with 1-4 substituents of R 13 , R 14 or R 15 ;
cada uno de R9, R10, R11 y R12, independientemente, es SR14, OR14, SR15, OR15, NR14R15, each of R 9 , R 10 , R 11 and R 12 , independently, is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 ,
NR15R15, C(0)R14, C(0)R15 o R15; NR 15 R 15 , C (0) R 14 , C (0) R 15 or R 15 ;
R13 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, OC(0)R14,R 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , OC (0) R 14 ,
OC(0)R15, COOR14, COOR15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, C(0)C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR14), NR15(COOR15), NR15C(0)C(0)NR14R15, NR15C(0)C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15 O NR15S(0)2NR15R15; OC (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , C (0) C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ), NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R 15 , NR 15 C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0 ) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0 ) 2 NR 14 R 15 O NR 15 S (0) 2 NR 15 R 15 ;
R14 es un sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros parcial o completamente saturado o completamente insaturado, formado el sistema de anillos por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico. o 1-9 heteroátomos si es tricíclico, los heteroátomos seleccionados de O, N o S, en los que 0, 1 , 2 ó 3 átomos de cada anillo están opcionalmente sustituidos independientemente con 1-3 sustituyentes de R15; R 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic system partially or completely saturated or completely unsaturated, the ring system formed by carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic. or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-3 substituents of R 15 ;
R15 es H, halo, haloalquilo, haloalcoxilo, oxo, CN, OH, SH, N02, NH2, acetilo, alquilo Ci- 10, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, CMO- alquilamino-, Ci-10-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO O sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros saturado o parcial o completamente insaturado, dicho sistema de anillos formado por átomos de carbono que incluyen opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, dichos heteroátomos seleccionados de O, N, o S, en los que cada uno del alquilo CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, Ci-10-alquilamino-, Ci-io-dialquilamino-, alcoxilo CMO, tioalcoxilo CMO y el anillo de dicho sistema de anillos está opcionalmente sustituido independientemente con 1-5 sustituyentes de halo, haloalquilo, CN, N02, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina, diisopropilamina, bencilo o fenilo; y n es 0, 1 , 2, 3 ó 4. R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2, NH 2, acetyl, alkyl Ci- 10 alkenyl or C 2 i, C 2 i alkynyl or C3-10 , C4-10 cycloalkenyl, CMO-alkylamino-, Ci-10-dialkylamino-, alkoxy CMO, thioalkoxy CMO OR 5-8 membered monocyclic, 6-12 membered bicyclic or 7-14 membered saturated or partial tricyclic ring system or completely unsaturated, said ring system consisting of carbon atoms optionally including 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O , N, or S , wherein each of the CMO alkyl, C 2 -i alkenyl or, C 2-i alkynyl or, C3-10 cycloalkyl, C4-10 cycloalkenyl, Ci-10-alkylamino-, Ci-io-dialkylamino-, CMO alkoxy , thioalkoxy CMO and the ring of said ring system is optionally independently substituted with 1-5 substituents of halo, haloalkyl, CN, N0 2 , NH 2 , OH, or xo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; Y n is 0, 1, 2, 3 or 4.
En una realización particular, el compuesto de fórmula (Vil) se selecciona de:  In a particular embodiment, the compound of formula (Vil) is selected from:
2-(4-(4-((4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)amino)-1-ftalazinil)fenil)etanol; 2- (4- (4 - ((4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) amino) -1-phthalazinyl) phenyl) ethanol;
N-(5-((3-(2-(metilamino)-4-pirimidinil)-2-piridinil)oxi)-2-piridinil)-4-fenil-1 -ftalazinamina; N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-fenilfuro[2,3-d]piridazin-7-amina;N- (5 - ((3- (2- (methylamino) -4-pyrimidinyl) -2-pyridinyl) oxy) -2-pyridinyl) -4-phenyl-1 -phthalazinamine; N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4-phenylfuro [2,3-d] pyridazin-7-amine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(3-metil-5-isotiazolil)-1- ftalazinamina; N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (3-methyl-5-isothiazolyl) -1-phthalazinamine;
4-fenil-N-(4-((2-(4-piridinil)fenil)oxi)fenil)-1 -ftalazinamina;  4-phenyl-N- (4 - ((2- (4-pyridinyl) phenyl) oxy) phenyl) -1 -phthalazinamine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(2,6-bis(metiloxi)fenil)-1- ftalazinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (2,6-bis (methyloxy) phenyl) -1-phthalazinamine;
(1 R)-1-(4-(4-((4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)amino)-1- ftalazinil)fenil)etanol;  (1 R) -1- (4- (4 - ((4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) amino) -1-phthalazinyl) phenyl) ethanol;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4,5-dimetil-6-(4-metil-2-tienil)-3- piridazinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4,5-dimethyl-6- (4-methyl-2-thienyl) -3-pyridazinamine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-fenil-1-isoquinolinamina; N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4-phenyl-1-isoquinoline amine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(4-metil-2-tienil)-1- isoquinolinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-isoquinoline amine;
4-fenil-N-(6-((3-(2-((3-(1-piperidinil)propil)amino)-4-pirimidinil)-2-piridinil)oxi)-3-piridinil)- 1 -ftalazinamina;  4-phenyl-N- (6 - ((3- (2 - ((3- (1-piperidinyl) propyl) amino) -4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) - 1 -phthalazinamine ;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(6-metil-2-piridinil)-1- ftalazinamina; N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (6-methyl-2-pyridinyl) -1-phthalazinamine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-ciclohexil-1 -ftalazinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4-cyclohexyl-1-phthalazinamine;
N-(4-((3-(2-((3-(4-metil-1-piperazinil)propil)amino)-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(6- metil-2-piridinil)-1 -ftalazinamina;  N- (4 - ((3- (2 - ((3- (4-methyl-1-piperazinyl) propyl) amino) -4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (6- methyl -2-pyridinyl) -1 -phthalazinamine;
4-(6-metil-2-piridinil)-N-(4-((3-(2-((3-(1-piperazinil)propil)amino)-4-pirimidinil)-2- piridinil)oxi)fenil)-1 -ftalazinamina; 4- (6-methyl-2-pyridinyl) -N- (4 - ((3- (2 - ((3- (1-piperazinyl) propyl) amino) -4-pyrimidinyl) -2- pyridinyl) oxy) phenyl ) -1-phthalazinamine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(3-fluoro-1-piperidinil)-1- ftalazinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (3-fluoro-1-piperidinyl) -1-phthalazinamine;
4-(2-((4-((4-fenil-1-ftalazinil)amino)fenil)oxi)-3-piridinil)-1 ,3-dihidro-2H-pirrolo[2,3- b]piridin-2-ona;  4- (2 - ((4 - ((4-phenyl-1-phthalazinyl) amino) phenyl) oxy) -3-pyridinyl) -1, 3-dihydro-2H-pyrrolo [2,3- b] pyridin-2 -ona;
4-(4-metil-1 ,3-tiazol-2-il)-N-(4-((3-(5,6,7,8-tetrahidro-1 ,8-naftiridin-4-il)-2- piridinil)oxi)fenil)-1 -ftalazinamina;  4- (4-methyl-1,3-thiazol-2-yl) -N- (4 - ((3- (5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl) -2 - pyridinyl) oxy) phenyl) -1-phthalazinamine;
N-(4-((3-(2,3-dihidro-1 H-pirrolo[2,3-b]piridin-4-il)-2-piridinil)oxi)fenil)-4-fenil-1- ftalazinamina;  N- (4 - ((3- (2,3-dihydro-1 H-pyrrolo [2,3-b] pyridin-4-yl) -2-pyridinyl) oxy) phenyl) -4-phenyl-1- phthalazinamine ;
N-(6-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)-3-piridinil)-4-(5-metil-2-piridinil])-1- ftalazinamina; N- (6 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) -4- (5-methyl-2-pyridinyl]) - 1- phthalazinamine;
N-(4-((3-(5-fluoro-2-((3-(4-metil-1-piperazinil)propil)amino)-4-pirimidinil)-2- piridinil)oxi)fenil)-4-fenil-1 -ftalazinamina; N-(4-((3-(3-amino-1 H-pirazol-4-il)-2-piridinil)oxi)fenil)-4-(4-metilfenil)-1-ftalazinamina;N- (4 - ((3- (5-fluoro-2 - ((3- (4-methyl-1-piperazinyl) propyl) amino) -4-pyrimidinyl) -2- pyridinyl) oxy) phenyl) -4- phenyl-1-phthalazinamine; N- (4 - ((3- (3-amino-1 H-pyrazol-4-yl) -2-pyridinyl) oxy) phenyl) -4- (4-methylphenyl) -1-phthalazinamine;
N-(4-((3-(3-amino-1 H-pirazol-4-il)-2-piridinil)oxi)fenil)-4-(fenilmetil)-1-ftalazinamina;N- (4 - ((3- (3-amino-1 H-pyrazol-4-yl) -2-pyridinyl) oxy) phenyl) -4- (phenylmethyl) -1-phthalazinamine;
N-(4-((3-(3-amino-1 H-pirazol-4-il)-2-piridinil)oxi)fenil)-4-feniltien[2,3-d]piridazin-7- amina; N- (4 - ((3- (3-amino-1 H-pyrazol-4-yl) -2-pyridinyl) oxy) phenyl) -4-phenylthien [2,3-d] pyridazin-7-amine;
N-(4-((3-(3-amino-1 H-pirazol-4-il)-2-piridinil)oxi)-3-fluorofenil)-4-fenil-1-ftalazinamina;N- (4 - ((3- (3-amino-1 H-pyrazol-4-yl) -2-pyridinyl) oxy) -3-fluorophenyl) -4-phenyl-1-phthalazinamine;
N-(6-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)-3-piridinil)-4-(3-(metilsulfonil)fenil)-1 - ftalazina ina; N- (6 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) -4- (3- (methylsulfonyl) phenyl) -1-phthalazine ina;
N-(4((3-(2-((3-((2S,5S)-2,5-dimetil-4-morfolinil)propil)amino)-4-pirimidinil)-2- piridinil)oxi)fenil)-4-fenil-1 -ftalazinamina;  N- (4 ((3- (2 - ((3 - ((2S, 5S)) -2,5-dimethyl-4-morpholinyl) propyl) amino) -4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4-phenyl-1-phthalazinamine;
N-(6-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)-3-piridinil)-4-(4-metil-2-tienil)-1- ftalazinamina; N- (6 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine;
1-(4-((4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)amino)-1-ftalazinil)-3-piperidinol; 1- (4 - ((4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) amino) -1-phthalazinyl) -3-piperidinol;
2-(4-((6-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)-3-piridinil)amino)-1-ftalazinil)fenol;2- (4 - ((6 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) amino) -1-phthalazinyl) phenol;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(4-metil-2-tienil)-1 -ftalazinamina; dihidrogenofosfato de 2-(4-((6-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)-3- piridinil)amino)-1-ftalazinil)fenilo; N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1 -phthalazinamine; 2- (4 - ((6 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) -3-pyridinyl) amino) -1-phthalazinyl) phenyl dihydrogen phosphate;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(5-metil-2-piridinil)-1- ftalazinamina;  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -4- (5-methyl-2-pyridinyl) -1-phthalazinamine;
2-((4-((4-(4-metil-2-tienil)-1-ftalazinil)amino)fenil)oxi)-3,4’-bipiridin-2’-amina;  2 - ((4 - ((4- (4-methyl-2-thienyl) -1-phthalazinyl) amino) phenyl) oxy) -3,4'-bipyridin-2'-amine;
2-((4-((4-etil-6-fenil-3-piridazinil)amino)fenil)oxi)-3,4’-bipiridin-2’-amina; 2 - ((4 - ((4-ethyl-6-phenyl-3-pyridazinyl) amino) phenyl) oxy) -3,4'-bipyridin-2'-amine;
2-((4-((4-metil-6-(4-metil-1 ,3-tiazol-2-il)3piridazinil)amino)fenil)oxi)-3,4’-bipiridin-2’- amina;  2 - ((4 - ((4-methyl-6- (4-methyl-1, 3-thiazol-2-yl) 3pyridazinyl) amino) phenyl) oxy) -3,4'-bipyridin-2'-amine;
2-((4-((4-(2-(metiloxi)fenil)-1-ftalazinil)amino)fenil)oxi)-3,4’-bipiridin-2’-amina;  2 - ((4 - ((4- (2- (methyloxy) phenyl) -1-phthalazinyl) amino) phenyl) oxy) -3,4'-bipyridin-2'-amine;
N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-6-fenil-4-propil-3-piridazinamina; y N-(4-((2-(metiloxi)-6-(4-piridinil)fenil)oxi)fenil)-4-fenil-1 -ftalazinamina.  N- (4 - ((3- (2-amino-4-pyrimidinyl) -2-pyridinyl) oxy) phenyl) -6-phenyl-4-propyl-3-pyridazinamine; and N- (4 - ((2- (methyloxy) -6- (4-pyridinyl) phenyl) oxy) phenyl) -4-phenyl-1-phthalazinamine.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado en la fórmula (I) tal como se da a conocer en el documento US 2003069299 tal como hesperadina. Los compuestos de fórmula (I) tal como se da a conocer en el documento US 2003069299 se identifican en el presente documento con la fórmula (VIII):  In a further embodiment, the AURK inhibitor is a compound encompassed by formula (I) as disclosed in US2003069299 such as hesperadine. Compounds of formula (I) as disclosed in US2003069299 are identified herein by formula (VIII):
Figure imgf000105_0001
Figure imgf000105_0001
Fórmula (VIII) o una sal farmacéuticamente aceptable del mismo, en la que: Formula (VIII) or a pharmaceutically acceptable salt thereof, in which:
X es un átomo de oxígeno o azufre,  X is an oxygen or sulfur atom,
Ri es un átomo de hidrógeno, un grupo alcoxicarbonilo C 1-4 o alcanoílo C 2-4, Ri is a hydrogen atom, a C 1-4 alkoxycarbonyl group or C 2-4 alkanoyl,
R2 es un grupo alquilo Ci-e opcionalmente sustituido por uno o más átomos de halógeno o un grupo fenilo o un grupo alquenilo C2-6 opcionalmente sustituido por un grupo fenilo, en el que el resto de fenilo puede estar sustituido en cada caso por un átomo de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3 o alcoxilo C1-3, un grupo fenilo que puede estar mono o disustituido por átomos de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3 o alcoxilo C1-3, en el que los sustituyentes pueden ser idénticos o diferentes, R 2 is a Ci-e alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C 2-6 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety can be substituted in each case by a fluorine, chlorine, bromine or iodine, an alkyl group or C 1-3 alkoxy C1-3, a phenyl group which may be mono- or disubstituted by fluorine, chlorine, bromine or iodine, a group C 1-3 alkyl or alkoxy C 1-3, in which the substituents may be identical or different,
un grupo fenilo sustituido por un grupo trifluorometilo, carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, ciano, aminometilo, nitro o amino, a phenyl group substituted by a trifluoromethyl, carboxyl, C 1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
un grupo alquilo C4-6, cicloalquilo C3-7, trimetilfenilo o naftilo, a C 4-6 alkyl, C 3-7 cycloalkyl, trimethylphenyl or naphthyl group,
un grupo heteroaromático de 5 miembros opcionalmente sustituido por un grupo alquilo C1-3, que contiene, en el resto heteroaromático, a 5-membered heteroaromatic group optionally substituted by a C 1-3 alkyl group, containing, in the heteroaromatic moiety,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3, un átomo de oxígeno o azufre, an imino group optionally substituted by a C 1-3 alkyl group, an oxygen or sulfur atom,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3 y un átomo de oxígeno, azufre o nitrógeno, an imino group optionally substituted by a C 1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3 y dos átomos de nitrógeno, o un átomo de oxígeno o azufre y dos átomos de nitrógeno, y al que puede condensarse un anillo de fenilo a través de dos átomos de carbono adyacentes, o es un grupo heteroaromático de 6 miembros opcionalmente sustituido por un grupo alquilo C1-3, que contiene uno o dos heteroátomos en el resto heteroaromático y al que puede condensarse un anillo de fenilo a través de dos átomos de carbono adyacentes,an imino group optionally substituted by a C 1-3 alkyl group and two nitrogen atoms, or an oxygen or sulfur atom and two nitrogen atoms, and to which a phenyl ring can be condensed through two adjacent carbon atoms, o is a 6-membered heteroaromatic group optionally substituted by a C 1-3 alkyl group, which contains one or two heteroatoms in the heteroaromatic moiety and to which a phenyl ring can be fused through two adjacent carbon atoms,
R3 es un átomo de hidrógeno o un grupo alquilo C1-6, R 3 is a hydrogen atom or a C 1-6 alkyl group,
un grupo fenilo opcionalmente sustituido por un átomo de flúor, cloro o bromo, por un grupo alquilo C1-3, hidroxilo, alcoxilo C1-3, alquilsulfenilo C1-3, alquilsulfinilo C1-3, alquilsulfonilo C1-3, fenilsulfenilo, fenilsulfinilo, fenilsulfonilo, nitro, amino, alquilamino C1-3, di(alquil Ci-3)-amino, alcanoilamino C2-5 o N-(alquilamino Ci-3)alquilamino C2-5,a phenyl group optionally substituted by a fluorine, chlorine or bromine, an alkyl group C 1-3, hydroxy, alkoxy C 1-3, C 1-3 alkylsulfenyl, alkylsulfinyl C 1-3 alkylsulfonyl C 1-3, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, alkylamino C 1-3 -alkylamino, di (Ci- 3) alkylamino, alkanoylamino or C 2-5 N- (Ci- 3 alkylamino) C 2-5 alkylamino,
R4 es un grupo fenilo o naftilo opcionalmente sustituido por R7, que puede estar adicionalmente sustituido por un átomo de cloro o bromo o un grupo nitro, un grupo heteroaromático de 5 miembros que contiene un grupo imino, un átomo de oxígeno o azufre o un grupo imino, un átomo de oxígeno o azufre y uno o dos átomos de nitrógeno, o un grupo heteroaromático de 6 miembros que contiene uno, dos o tres átomos de nitrógeno, mientras que los grupos heteroaromáticos de 5 y 6 miembros anteriormente mencionados pueden estar adicionalmente sustituidos por un átomo de cloro o bromo o por un grupo metilo o en el que un anillo de fenilo puede condensarse con los grupos heteroaromáticos de 5 y 6 miembros anteriormente mencionados a través de 2 átomos de carbono adyacentes, o R 4 is a phenyl or naphthyl group optionally substituted by R 7 , which may be further substituted by a chlorine or bromine atom or a nitro group, a 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, while the aforementioned 5- and 6-membered heteroaromatic groups may be additionally substituted by a chlorine or bromine atom or by a methyl group or in which a phenyl ring can be condensed with the above mentioned 5- and 6-membered heteroaromatic groups through 2 adjacent carbon atoms, or
R5 y R6 en cada caso independientemente el uno del otro son átomos de hidrógeno o grupos alquilo C1-3, y R7 es un átomo de flúor, cloro, bromo o yodo o un grupo ciano, R 5 and R 6 in each case independently of each other are hydrogen atoms or C 1-3 alkyl groups, and R 7 is a fluorine, chlorine, bromine or iodine atom or a cyano group,
un grupo metoxilo o un grupo alcoxilo C2-3, que puede estar sustituido en la posición 2 ó 3 por un grupo amino, alquilamino C1-3, di(alquil Ci-3)-amino o cicloalquilenimino de 5 a 7 miembros, mientras que en cada caso un resto de alquilo en los grupos alquilamino y dialquilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo fenilo, un grupo trifluorometilo, nitro, amino, alquilamino C1-3, di(alquil Ci-3)-amino, alcanoilamino C2-5, N-(alquil Ci-3)-alcanoilamino C2-5, alquilsulfonilamino C1-5, N-(alquil Ci-3)-alquilsulfonilamino C1-5, fenilsulfonilamino, N- (alquil Ci-3)-fenilsulfonilamino, aminosulfonilo, alquilaminosulfonilo C1-3 o di(alquil C1-3)- aminosulfonilo, mientras que en cada caso un resto de alquilo en los grupos alquilamino y dialquilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, alquilaminocarbonilo C1-3, di(alquil Ci-3)-aminocarbonilo, 2- dimetilaminoetilaminocarbonilo o N-metil-(2-dimetilaminoetil)-aminocarbonilo y en cada caso el resto de alquilo de los grupos alcanoilamino o alquisulfonilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo fenilo, amino, alquilamino C1-3, di(alquil Ci-3)-amino o un cicloalquilenimino de 4 a 7 miembros, un grupo alquilamino C2-4 que está sustituido de manera terminal en la posición 2, 3 ó 4 por un grupo amino, alquilamino C1-3, di(alquil Ci-3)-amino, bencilamino, N-(alquil C1- 3)-bencilamino, alcanoilamino C2-5 o N-(alquil Ci-3)-alcanoilamino C2-5 y en el que adicionalmente el átomo de hidrógeno del amino puede reemplazarse por un grupo alcanoílo C2-5, benzoílo, alquilsulfonilo C1-5 o fenilsulfonilo, mientras que los últimos grupos mencionados alcanoílo C2-5 o alquilsulfonilo C1-5 en el resto de alquilo pueden estar sustituidos por un grupo fenilo, a methoxy group or a C 2-3 alkoxy group, which may be substituted in position 2 or 3 by an amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino or 5-7 membered cycloalkyleneimino group, while in each case an alkyl residue in the aforementioned alkylamino and dialkylamino groups may be additionally substituted by a phenyl group, a trifluoromethyl group, nitro, amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino, C 2-5 alkanoylamino, N- (Ci- 3- alkyl) -C 2-5- alkanoylamino, C 1-5 -alkylsulfonylamino, N- (Ci- 3- alkyl) -C 1-5 alkylsulfonylamino, N- (Ci-alkyl) 3 ) -phenylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl or di (C 1-3 alkyl) -aminosulfonyl, while in each case an alkyl residue in the aforementioned alkylamino and dialkylamino groups may be additionally substituted by a carboxyl group, C 1-3 alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, di (Ci- 3- alkyl) -amin ocarbonyl, 2- dimethylaminoethylaminocarbonyl or N-methyl- (2-dimethylaminoethyl) -aminocarbonyl and in each case the alkyl moiety of the aforementioned alkanoylamino or alkylsulfonylamino groups can be additionally substituted by a phenyl, amino, C 1-3 alkylamino group, di (Ci- 3- alkyl) -amino or a 4- to 7-membered cycloalkyleneimino, a C 2-4 alkylamino group which is terminally substituted in the 2, 3 or 4 position by an amino group, C 1-3 alkylamino, di (Ci- 3) alkylamino, benzylamino, N- (alkyl C 1-3) -benzylamino, C 2-5 alkanoylamino or N- (Ci- alkyl 3) C 2-5 alkanoylamino and further wherein the The hydrogen atom of the amino may be replaced by a C 2-5 alkanoyl, benzoyl, C 1-5 alkylsulfonyl or phenylsulfonyl group, while the last mentioned C 2-5 alkanoyl or C 1-5 alkylsulfonyl groups may be substituted by a phenyl group,
un grupo carbonilo que está sustituido por un grupo hidroxilo, alcoxilo C1-3, amino, alquilamino C1-3, N-(alquil Ci-5)-alquilamino C1-3 o cicloalquilenimino C5-7; a carbonyl group which is substituted by hydroxyl group, C1-3 alkoxy, amino, C1-3 alkylamino, N- (Ci- 5 alkyl) C1-3 alkylamino or C 5-7 cicloalquilenimino;
un grupo alquilo C1-3 que puede estar sustituido por un grupo amino, alquilamino C1-5, cicloalquilamino C5-7 o fenilo-alquilamino C1-3 que puede estar adicionalmente sustituido en el átomo de nitrógeno del amino en cada caso por un grupo alquilo C1-4, cicloalquilo C5-7 o alquenilo C2-4 o alquilo C1-4, mientras que el sustituyente de alquilo C1-4 anteriormente mencionado en cada caso puede estar adicionalmente mono, di o trisustituido por un grupo ciano, carboxilo, alcoxicarbonilo C1-3, alcanoílo C2-4, piridilo, imidazolilo, benzo[1 ,3]dioxol o fenilo, mientras que el grupo fenilo puede estar sustituido por átomos de flúor, cloro o bromo, por grupos metilo, metoxilo, trifluorometilo, ciano o nitro y los sustituyentes pueden ser idénticos o diferentes, o en la posición 2, 3 ó 4 por un grupo hidroxilo, a C1-3 alkyl group which may be substituted by an amino, C1-5 alkylamino, C5-7 cycloalkylamino or phenyl-C1-3 alkylamino group which may be additionally substituted in the nitrogen atom of the amino in each case by an alkyl group C1-4, C5-7 cycloalkyl or C2-4 alkenyl or C1-4 alkyl, while the aforementioned C1-4 alkyl substituent in each case may additionally be mono, di or trisubstituted by a cyano, carboxyl, C1 alkoxycarbonyl group -3, C2-4 alkanoyl, pyridyl, imidazolyl, benzo [1, 3] dioxol or phenyl, while the phenyl group can be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents can be identical or different, or in the 2, 3 or 4 position by a hydroxyl group,
un grupo alquilo C1-3 que está sustituido por un grupo hidroxilo, carboxilo, morfolino, tiomorfolino, 1-oxo-tiomorfolino, 1 ,1-dioxo-tiomorfolino, piperazino, N-(alquil C-1-3)- piperazino o N-bencil-piperazino, por un grupo cicloalquenilenimino de 5 a 7 miembros o por un grupo cicloalquilenimino de 4 a 7 miembros, mientras que los grupos cicloalquilenimino de 5 a 7 miembros anteriormente mencionados pueden estar sustituidos por uno o dos grupos alquilo C1-3, que en cambio pueden estar sustituidos de manera terminal por un grupo hidroxilo, amino o alcanoilamino C2-4, o por un grupo cicloalquilo C5-7 o fenilo y por un grupo hidroxilo, y en los grupos cicloalquilenimino anteriormente mencionados un grupo metileno adyacente al átomo de nitrógeno puede reemplazarse por un grupo carbonilo, a C1-3 alkyl group which is substituted by a hydroxyl, carboxyl, morpholino, thiomorpholine, 1-oxo-thiomorpholine, 1,1-dioxo-thiomorpholine, piperazine, N- (C-1-3 alkyl) -piperazine or N group -benzyl-piperazino, by a 5-7 membered cycloalkenyleneimino group or by a 4-7 membered cycloalkyleneimino group, whereas the aforementioned 5-7 membered cycloalkyleneimino groups may be substituted by one or two C1-3 alkyl groups, instead they may be terminally substituted by a C2-4 hydroxyl, amino or alkanoylamino group, or by a C5-7 cycloalkyl or phenyl group and by a hydroxyl group, and in the aforementioned cycloalkyleneimino groups a methylene group adjacent to the atom nitrogen can be replaced by a carbonyl group,
un grupo alquilo C1-3 que está sustituido por un grupo cicloalquilenimino de 5 a 7 miembros, mientras que un grupo fenilo opcionalmente mono o disustituido por átomos de flúor, cloro o bromo o por grupos metilo o metoxilo, en el que los sustituyentes pueden ser idénticos o diferentes, o un grupo oxazolo, imidazolo, tiazolo, piridino, pirazino o pirimidino opcionalmente sustituido por un átomo de flúor, cloro, bromo o yodo, por un grupo metilo, metoxilo o amino se condensa con los grupos cicloalquilenimino de 5 a 7 miembros anteriormente mencionados a través de 2 átomos de carbono adyacentes, mientras que los grupos fenilo monosustituidos anteriormente mencionados pueden estar adicionalmente sustituidos por un átomo de flúor, cloro o bromo, por un grupo metilo, metoxilo o nitro, o es un grupo imidazolilo o 1 H-alquilimidazolilo C1-3. an alkyl group which is substituted C1- 3 cicloalquilenimino group for 5 to 7 members, while a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine or by methyl or methoxy groups, wherein the substituents they may be identical or different, or an oxazolo, imidazolo, tiazolo, pyridine, pyrazine or pyrimidine group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or amino group is condensed with the cycloalkyleneimino groups of 5 a 7 members mentioned above through 2 adjacent carbon atoms, while the aforementioned monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, or is an imidazolyl group or 1 H-alkylimidazolyl C 1-3 .
En una realización particular, el compuesto de fórmula (VIII) en el que el grupo sulfonilamino de la fórmula R2— SO2NR6— se une a la posición 5 del grupo indolinona.In a particular embodiment, the compound of formula (VIII) in which the sulfonylamino group of formula R 2 -SO 2 NR 6 - is attached to position 5 of the indolinone group.
En una realización particular, el compuesto de fórmula (VIII) en el que: In a particular embodiment, the compound of formula (VIII) in which:
R3 es un grupo fenilo opcionalmente sustituido por un átomo de flúor, cloro o bromo, por un grupo alquilo C1-3, hidroxilo, alcoxilo C1-3, alquilsulfenilo C1-3, alquilsulfinilo C1-3, alquilsulfonilo C1-3, fenilsulfenilo, fenilsulfinilo, fenilsulfonilo, nitro, amino, alquilamino C1-3, di(alquil Ci-3)-amino, alcanoilamino C2-5 o N-(alquilamino Ci-3)alcanoilamino C2-5.R 3 is a phenyl group optionally substituted by a fluorine, chlorine or bromine, an alkyl group C 1-3, hydroxy, C 1-3 alkoxy, C 1-3 alkylsulfenyl, alkylsulfinyl C 1-3 alkylsulphinyl, C 1 -3, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, alkylamino C 1-3 -alkylamino, di (Ci- 3) alkylamino, alkanoylamino or C 2-5 N- (Ci- 3 alkylamino) C 2-5 alkanoylamino.
En una realización particular, el compuesto de fórmula (VIII) en el que: In a particular embodiment, the compound of formula (VIII) in which:
R2 es un grupo alquilo C1-3 opcionalmente sustituido por uno o más átomos de halógeno o un grupo fenilo o un grupo alquenilo C2-4 opcionalmente sustituido por un grupo fenilo, en el que el resto de fenilo en cada caso puede estar sustituido por un átomo de flúor, cloro, bromo o yodo o por un grupo alquilo C1-3 o alcoxilo C1-3. R 2 is a C 1-3 alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C 2-4 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety in each case can be substituted by a fluorine, chlorine, bromine or iodine atom or by a C 1-3 alkyl or C 1-3 alkoxy group.
En una realización particular, el compuesto de fórmula (VIII) en el que:  In a particular embodiment, the compound of formula (VIII) in which:
X es un átomo de oxígeno,  X is an oxygen atom,
R1 es un átomo de hidrógeno, R 1 is a hydrogen atom,
R2 es un grupo alquilo C1-3 opcionalmente sustituido por uno o más átomos de flúor o un grupo fenilo o un grupo alquenilo C2-4 opcionalmente sustituido por un grupo fenilo; un grupo fenilo que puede estar mono o disustituido por átomos de flúor, cloro, bromo o yodo, por grupos alquilo C1-3 o alcoxilo C1-3, en el que los sustituyentes pueden ser idénticos o diferentes, R 2 is a C 1-3 alkyl group optionally substituted by one or more fluorine atoms or a phenyl group or a C 2-4 alkenyl group optionally substituted by a phenyl group; a phenyl group which may be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-3 alkyl or C 1-3 alkoxy groups, in which the substituents may be identical or different,
un grupo fenilo sustituido por un grupo trifluorometilo, carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, ciano, aminometilo, nitro o amino, a phenyl group substituted by a trifluoromethyl, carboxyl, C 1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
un grupo alquilo C4-6, cicloalquilo C3-7, trimetilfenil o naftil, o a C 4-6 alkyl, C 3-7 cycloalkyl, trimethylphenyl or naphthyl group, or
grupo piridinilo, quinolilo, isoquinolilo, oxazolilo, isoxazolilo, imidazolilo o 1 -(alquil C1-3)- imidazolilo opcionalmente sustituido por un grupo alquilo C1-3, pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1 - (C 1-3 alkyl) -imidazolyl group optionally substituted by a C 1-3 alkyl group,
R3 es un átomo de hidrógeno o un grupo alquilo C1-4, o un grupo fenilo opcionalmente sustituido por un átomo de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3, alcoxilo C1-3, nitro o amino, R 3 is a hydrogen atom or an alkyl group C 1-4, or a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine, an alkyl group C 1-3, alkoxy C 1-3, nitro or amino,
R4 es un grupo fenilo opcionalmente sustituido por R7, R 4 is a phenyl group optionally substituted by R 7 ,
R5 y R6 en cada caso indican un átomo de hidrógeno, y R 5 and R 6 in each case indicate a hydrogen atom, and
R7 es un átomo de flúor, cloro, bromo o yodo, R 7 is a fluorine, chlorine, bromine or iodine atom,
un grupo metoxilo, nitro, ciano, carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, alquilaminocarbonilo C1-3, di(alquil Ci-3)-aminocarbonilo, fenilo-alquilaminocarbonilo C1- 3, N-(fenilo-alquil Ci-3)alquilaminocarbonilo C1-3 o cicloalquileniminocarbonilo de 5 a 7 miembros, a methoxy, nitro, cyano, carboxyl, C 1-3 alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, di (Ci- 3- alkyl) -aminocarbonyl, phenyl-C 1 -alkylaminocarbonyl group 3 , N- (phenyl-Ci- 3 -alkyl) C 1-3 alkylaminocarbonyl or 5-7 membered cycloalkyleneiminocarbonyl,
un grupo alquilo C1-3 que está sustituido por un grupo carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, alquilaminocarbonilo C1-3, di(alquil Ci-3)-aminocarbonilo, fenilo- alquilaminocarbonilo C1-3, N-(fenilo-alquil Ci-3)alquilaminocarbonilo C1-3, cicloalquileniminocarbonilo de 5 a 7 miembros, amino, alquilamino C1-3, di(alquil C1-3)- amino, fenilo-alquilamino C1-3, N-(fenilo-alquil Ci-3)alquilamino C1-3 o cicloalquilenimino de 5 a 7 miembros, C 1-3 alkyl group which is substituted by a carboxyl group, alkoxycarbonyl C 1-3 aminocarbonyl, C 1-3 -alkylamino, di (Ci- 3) alkylaminocarbonyl, phenyl- C 1-3 alkylaminocarbonyl, N- ( phenyl-Ci- 3 -alkyl) C 1-3 alkylaminocarbonyl, 5-7 membered cycloalkyleneiminocarbonyl, amino, C 1-3 alkylamino, di (C 1-3 alkyl) -amino, phenyl-C 1-3 alkylamino, N- ( phenyl-Ci-alkyl 3 ) C 1-3 alkylamino or 5-7 membered cycloalkyleneimino,
mientras que el grupo cicloalquilenimino de 5 a 7 miembros anteriormente mencionado puede estar sustituido por uno o dos grupos alquilo C1-3, que en cambio pueden estar sustituidos de manera terminal por un grupo hidroxilo, amino o alcanoilamino C2-4, y al mismo tiempo en los restos de cicloalquilenimino de 5 a 7 miembros anteriormente mencionado un grupo metileno en la posición 2 puede reemplazarse por un grupo carbonilo o en los restos de cicloalquilenimino de 6 y 7 miembros anteriormente mencionado un grupo metileno en la posición 4 puede reemplazarse por un átomo de oxígeno, por un grupo imino, N-(alquil Ci-3)-imino, N-(fenilo-alquil Ci-3)-imino o N- (alcoxicarbonil Ci-5)-imino, while the aforementioned 5-7 membered cycloalkyleneimino group may be substituted by one or two C 1-3 alkyl groups, which may instead be terminally substituted by a C 2-4 hydroxyl, amino or alkanoylamino group, and at At the same time, in the aforementioned 5 to 7-membered cycloalkyleneimino residues, a methylene group in position 2 can be replaced by a carbonyl group or in the aforementioned 6 and 7-membered cycloalkyleneimino residues, a methylene group in position 4 can be replaced by an oxygen atom, for an imino group, N- (Ci- 3- alkyl) -imino, N- (phenyl-Ci- 3 -alkyl) -imino or N- (Ci- 5- alkoxycarbonyl) -imino,
un grupo amino, alquilamino C1-3, fenilo-alquilamino C1-3, alcanoilamino C1-5, fenilo- alcanoilamino C1-4, alcoxicarbonilamino C1-5, fenilo-alcoxicarbonilamino C1-3, alquilsulfonilamino C1-5, fenilo-alquilsulfonilamino C1-3 o fenilsulfonilamino, en el que el átomo de hidrógeno del grupo amino puede reemplazarse por un grupo alquilo C1-3, mientras que el resto de alquilo C1-3 puede estar sustituido por un grupo carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, alquilaminocarbonilo C1-3, di(alquil C1-3)- aminocarbonilo, fenilo-alquilaminocarbonilo C1-3, N-(fenilo-alquil C1-3)- alquilaminocarbonilo C1-3, 2-dimetilaminoetilaminocarbonilo, N-metil-(2- dimetilaminoetil)-aminocarbonilo o cicloalquileniminocarbonilo C4-6 o en la posición 2 por un grupo amino, alquilamino C1-3, di(alquil Ci-3)-amino, fenilo-alquilamino C1-3, N- (fenilo-alquil Ci-3)-alquilamino C1-3, alcanoilamino C2-5, N-(alquil Ci-3)-alcanoilamino C2- 5, alcoxicarbonilamino C1-5 o N-(alcoxicarbonil Ci-5)-alquilamino C1-3. an amino group, C 1-3 alkylamino, phenyl-C 1-3 alkylamino, C 1-5 alkanoylamino, phenyl-C 1-4 alkanoylamino, C 1-5 alkoxycarbonylamino, C 1-3 phenyl-alkoxycarbonylamino, C 1- alkylsulfonylamino. 5 , phenyl-C 1-3 alkylsulfonylamino or phenylsulfonylamino, in which the hydrogen atom of the amino group can be replaced by a C 1-3 alkyl group, while the C 1-3 alkyl moiety can be substituted by a carboxyl group , C 1-3 alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, di (C 1-3 alkyl) -aminocarbonyl, phenyl-C 1-3 alkylaminocarbonyl, N- (phenyl-C 1-3 alkyl) -C 1- alkylaminocarbonyl 3 , 2-dimethylaminoethylaminocarbonyl, N-methyl- (2- dimethylaminoethyl) -aminocarbonyl or cycloalkyleneiminocarbonyl C 4-6 or in the 2-position by an amino group, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino, phenyl C 1-3 -alkylamino, N- (phenyl-Ci- 3 alkyl) C 1-3 alkylamino, C 2-5 alkanoylamino, N- (alkyl Ci- 3) alkanoylamino C 2-5 alkoxycarbonylamino , C 1 -5 or N- (Ci- 5- alkoxycarbonyl) -C 1-3 alkylamino.
En una realización particular, el compuesto de fórmula (VIII) en el que: In a particular embodiment, the compound of formula (VIII) in which:
R2 es un grupo alquilo C1-3 opcionalmente sustituido por un grupo fenilo, un grupo perfluoroalquilo C1-3 o un grupo fenilvinilo, R 2 is a C 1-3 alkyl group optionally substituted by a phenyl group, a C 1-3 perfluoroalkyl group or a phenylvinyl group,
un grupo fenilo que puede estar sustituido por un átomo de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3, alcoxilo C1-3, nitro, amino, ciano, cianometilo o aminometilo, un grupo alquilo C4-6, cicloalquilo C3-7, trimetilfenilo o naftilo, un grupo piridinilo, quinolilo, isoquinolilo, oxazolilo, isoxazolilo, imidazolilo o 1 -(alquil Ci-3)-imidazolilo opcionalmente sustituido por un grupo alquilo C1-3, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine, an alkyl group C 1-3, alkoxy C 1-3, nitro, amino, cyano, cyanomethyl or aminomethyl, an alkyl group C 4- 6 , C 3-7 cycloalkyl, trimethylphenyl or naphthyl, a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1 - (Ci- 3- alkyl) -imidazolyl group optionally substituted by a C 1-3 alkyl group,
R3 es un grupo fenilo opcionalmente sustituido por un átomo de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3, alcoxilo C1-3, nitro o amino, R 3 is a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine, an alkyl amino group C 1-3, alkoxy C 1-3, or nitro,
R4 es un grupo fenilo que puede estar sustituido por R7 y adicionalmente por un átomo de cloro o un grupo nitro, mientras que R 4 is a phenyl group which may be substituted by R 7 and additionally by a chlorine atom or a nitro group, while
R7 es un átomo de flúor, cloro, bromo o yodo, R 7 is a fluorine, chlorine, bromine or iodine atom,
un grupo metoxilo, nitro, ciano, carboxilo, metoxicarbonilo, aminocarbonilo, metilaminocarbonilo, dimetilaminocarbonilo, bencilaminocarbonilo, N-bencil- metilaminocarbonilo, pirrolidincarbonilo o piperidincarbonilo, un grupo metilo o etilo que puede estar sustituido por un grupo carboxilo, metoxicarbonilo, aminocarbonilo, metilaminocarbonilo, dimetilaminocarbonilo, bencilaminocarbonilo, N-bencil-metilaminocarbonilo, pirrolidincarbonilo, piperidincarbonilo, amino, metilamino, dimetilamino, bencilamino, N-bencilmetilamino, alcanoilamino C2-4, N-metil-alcanoilamino C2-4, terc-butiloxicarbonilamino, N-metil-terc- butiloxicarbonilamino, pirrolidino, pirrolidinmetilo, hidroxipirrolidinmetilo, hidroximetilpirrolidinmetilo, piperidino, dimetilpiperidino, 2-oxo-piperidino, piperazino, 4- metil-piperazino, 4-bencil-piperazino, 4-terc-butoxicarbonil-piperazino o morfolino, o un grupo amino, metilamino, etilamino, alcanoilamino C1-3, fenilacetilamino, terc butoxicarbonilamino, alquilsulfonilamino C1-4, fenil-metilsulfonilamino o fenilsulfonilamino, en el que el átomo de hidrógeno del grupo amino puede reemplazarse por un grupo metilo o etilo, mientras que el resto de metilo o etilo en cada caso puede estar sustituido por un grupo carboxilo, metoxicarbonilo, aminocarbonilo, metilaminocarbonilo o dimetilaminocarbonilo o el resto de etilo también puede estar sustituido en la posición 2 por un grupo amino, metilamino, dimetilamino, bencilalquilamino, N-bencil-metilamino, alcanoilamino C2-3, N-metil- alcanoilamino C2-3, terc-butiloxicarbonilamino o N-metil-terc-butiloxicarbonilamino.a methoxy, nitro, cyano, carboxyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzyl-methylaminocarbonyl, pyrrolidinecarbonyl or piperidinecarbonyl group, a methyl or ethyl group that may be substituted by a carboxyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzyl-methylaminocarbonyl, pyrrolidincarbonyl, piperidincarbonyl, amino, methylamino, dimethylamino, benzylamino, benzylamino, dimethylamino, benzylamino , N-methyl-alkanoylamino C2-4, tert-butyloxycarbonylamino, N-methyl-tert-butyloxycarbonylamino, pyrrolidine, pyrrolidinmethyl, hydroxypyrrolidinmethyl, hydroxymethylpyrrolidinmethyl, piperidino, dimethylpiperidino, 2-oxo-piperidino, piperazine benzyl-piperazino, 4-tert-butoxycarbonyl-piperazino or morpholino, or an amino, methylamino, ethylamino, C1-3 alkanoylamino, phenylacetylamino, tert-butoxycarbonylamino, C1-4 alkylsulfonylamino, or phenylsulfonylamino atom, in which the hydrogen from the amino group can be replaced by a methyl or ethyl group, while the rest of methyl or ethyl in each case can be substituted by a carboxyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or the ethyl moiety may also be substituted in position 2 by an amino, methylamino, dimethylamino, benzylakylamino, N-benzyl-methylamino, C2-3 alkanoylamino group, N- C2-3 methyl-alkanoylamino, tert-butyloxycarbonylamino or N-methyl-tert-butyloxycarbonylamino.
En una realización particular, el compuesto de fórmula (VIII) en el que R4 es un grupo fenilo sustituido en la posición 4 por R7. In a particular embodiment, the compound of formula (VIII) in which R4 is a phenyl group substituted in position 4 by R 7 .
En una realización particular, el compuesto de fórmula (VIII) que tiene la fórmula (Villa): In a particular embodiment, the compound of formula (VIII) having the formula (Villa):
Figure imgf000110_0001
Figure imgf000110_0001
Fórmula (Villa) en la que R7 se define como anteriormente. Formula (Villa) in which R 7 is defined as above.
En una realización particular, un compuesto de fórmula (Villa) en el que R7 se selecciona del grupo que consiste en: In a particular embodiment, a compound of formula (Villa) in which R 7 is selected from the group consisting of:
hidrógeno, (N-etilsulfonil)-N-(2-dimetilaminoetil)-aminocarbonilmetil)-amino, N- etilsulfonil-N-(N-(2-dimetilaminoetil-N-metil-amino-carbonilmetil)-amino, acetilamino, acetilaminometilo, amino, aminometilo, bencilaminocarbonilo, bencilaminocarbonilmetilo, carboxilo, carboximetilo, cloro, ciano, dimetilaminocarbonil- metilamino, dimetilaminoetilo, dimetilaminometilo, etoxicarbonilmetilo, etilsulfonilamino, formilamino, metoxicarbonilo, metilsulfonilamino, N-(2-(N-acetil-N-metil-amino)-etil)- etilsulfonilamino, N-(2-(N-acetil-N-metil-amino)-etil)-metilsulfonilamino, N-(2-(N-acetil- N-metil-amino)-etil)-propionilamino, N-(2-(N-acetil-N-metil-amino)-etilamino, N-(2-(N- bencil-N-metil-amino)-etil)-propionilamino, N-(2-acetilamino-etil)-N-acetil-amino, N-(2- acetilamino-etil)-N-etilsulfonil-amino, N-(2-acetilamino-etil)-N-metilsulfonil-amino, N-(2- acetilamino-etil)-N-propionil-amino, N-(2-aminoetil)-N-metilsulfonil-amino, N-(2- dimetilamino-etil)-N-acetil-amino, N-(2-dimetilamino-etil)-N-butilsulfonil-amino, N-(2- dimetilamino-etil)-N-metilsulfonil-amino, N-(2-dimetilamino-etil)-N-fenilsulfonil-amino, N- (2-dimetilamio-etil)-N-propilsulfonil-amino, N-(2-metilamino-etil)-acetilamino, N-(2- metilamino-etil)-N-metilsulfonil-amino, N-(2-metilamino-etil)-propionilamino, N-(2- propionilamino-etil)-N-propionil-amino, N-(aminocarbonil-metil)-N-metilsulfonil-amino, N-(dimetilamino-carbonilmetil)-N-(metilsulfonil-amino, N-(dimetilaminoetil)-N- metilsulfonil-amino, N-(metilaminocarbonil-metil)-N-metilsulfonil-amino, N-acetil-N-(2- (N-bencil-N-metil-amino)-etil-amino, N-acetil-N-(2-bencil-oxicarbonilamino-etil)-amino, N-carboxilmetil-N-metilsulfonil-amino, N-etilsulfonil-N-hidroxicarbonilmetil-amino, N- metil-N-acetil-amino, N-metil-N-etilsulfonil-amino, N-metil-N-formil-amino, N-metil-N- metilsulfonil-amino, N-metil-N-propionil-amino, propionilamino; y terc- butoxicarbonilamino. hydrogen, (N-ethylsulfonyl) -N- (2-dimethylaminoethyl) -aminocarbonylmethyl) -amino, N- ethylsulfonyl-N- (N- (2-dimethylaminoethyl-N-methyl-amino-carbonylmethyl) -amino, acetylamino, acetylaminomethyl, amino, aminomethyl, benzylaminocarbonyl, benzylaminocarbonylmethyl, carboxyl, carboxymethyl, chloro, cyano, dimethylaminocarbonyl-methylamino, dimethylaminoethyl, dimethylaminomethyl, ethoxycarbonylmethyl, ethylsulfonylamino, methylsulfonyl-methylsulfonylamino, methylsulfonilamino -ethyl) -ethylsulfonylamino, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -methylsulfonylamino, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -propionylamino, N- (2- (N-acetyl-N-methyl-amino) -ethylamino, N- (2- (N-benzyl-N-methyl-amino) -ethyl) -propionylamino, N- (2-acetylamino-ethyl) -N-acetyl-amino, N- (2- acetylamino-ethyl) -N-ethylsulfonyl-amino, N- (2-acetylamino-ethyl) -N-methylsulfonyl-amino, N- (2- acetylamino-ethyl) -N -propionyl-amino, N- (2-aminoethyl) -N-methylsulfonyl-amino, N- (2- dimethylamino-ethyl) -N-acetyl-amino, N- (2-dimethylamino-ethyl) -Nb utilsulfonyl-amino, N- (2- dimethylamino-ethyl) -N-methylsulfonyl-amino, N- (2-dimethylamino-ethyl) -N-phenylsulfonyl-amino, N- (2-dimethylamio-ethyl) -N-propylsulfonyl-amino, N- (2-methylamino- ethyl) -acetylamino, N- (2- methylamino-ethyl) -N-methylsulfonyl-amino, N- (2-methylamino-ethyl) -propionylamino, N- (2-propionylamino-ethyl) -N-propionyl-amino, N - (aminocarbonyl-methyl) -N-methylsulfonyl-amino, N- (dimethylamino-carbonylmethyl) -N- (methylsulfonyl-amino, N- (dimethylaminoethyl) -N- methylsulfonyl-amino, N- (methylaminocarbonyl-methyl) -N- methylsulfonyl-amino, N-acetyl-N- (2- (N-benzyl-N-methyl-amino) -ethyl-amino, N-acetyl-N- (2-benzyl-oxycarbonylamino-ethyl) -amino, N-carboxymethyl -N-methylsulfonyl-amino, N-ethylsulfonyl-N-hydroxycarbonylmethyl-amino, N-methyl-N-acetyl-amino, N-methyl-N-ethylsulfonyl-amino, N-methyl-N-formyl-amino, N-methyl -N- methylsulfonyl-amino, N-methyl-N-propionyl-amino, propionylamino, and tert-butoxycarbonylamino.
En una realización particular, el compuesto de fórmula (VIII) que tiene la fórmula (Vlllb):  In a particular embodiment, the compound of formula (VIII) having the formula (Vlllb):
Figure imgf000111_0001
Fórmula (VI 11 b) en la que R2 y R7 se definen como anteriormente.
Figure imgf000111_0001
Formula (VI 11 b) in which R 2 and R7 are defined as above.
En una realización particular, el compuesto de fórmula (VI 11 b) en el que R7 se selecciona del grupo que consiste en: In a particular embodiment, the compound of formula (VI 11 b) in which R 7 is selected from the group consisting of:
hidrógeno, (N-etilsulfonil)-N-(2-dimetilaminoetil)-aminocarbonilmetil)-amino, N- etilsulfonil-N-(N-(2-dimetilaminoetil)-N-metil-amino-carbonilmetil)-amino, acetilamino, acetilaminometilo, amino, aminometilo, bencilaminocarbonilo, bencilaminocarbonilmetilo, carboxilo, carboximetilo, cloro, ciano, dimetilaminocarbonil- metilamino, dimetilaminoetilo, dimetilaminometilo, etoxicarbonilmetilo, etilsulfonilamino, formilamino, metoxicarbonilo, metilsulfonilamino, N-(2-(N-acetil-N-metil-amino)-etil)- etilsulfonilamino, N-(2-(N-acetil-N-metil-amino)-etil)-metilsulfonilamino, N-(2-(N-acetil- N-metil-amino)-etil)-propionilamino, N-(2-(N-acetil-N-metil-amino)-etilamino, N-(2-(N- bencil-N-metil-amino)-etil)-propionilamino, N-(2-acetilamino-etil)-N-acetil-amino, N-(2- acetilamino-etil)-N-etilsulfonil-amino, N-(2-acetilamino-etil)-N-metilsulfonil-amino, N-(2- acetilamino-etil)-N-propionil-amino, N-(2-aminoetil)-N-metilsulfonil-amino, N-(2- dimetilamino-etil)-N-acetil-amino, N-(2-dimetilamino-etil)-N-butilsulfonil-amino, N-(2- dimetilamino-etil)-N-metilsulfonil-amino, N-(2-dimetilamino-etil)-N-fenilsulfonil-amino, N-hydrogen, (N-ethylsulfonyl) -N- (2-dimethylaminoethyl) -aminocarbonylmethyl) -amino, N- ethylsulfonyl-N- (N- (2-dimethylaminoethyl) -N-methyl-amino-carbonylmethyl) -amino, acetylamino, acetylaminomethyl , amino, aminomethyl, benzylaminocarbonyl, benzylaminocarbonylmethyl, carboxyl, carboxymethyl, chloro, cyano, dimethylaminocarbonyl-methylamino, dimethylaminoethyl, dimethylaminomethyl, ethoxycarbonylmethyl, ethylsulfonylamino, methylsulfonyl-methylsulfonylamino, methylsulfonylamino, methylsulfonylamino, methylsulfonylmethylansulfonylmethyl ) -ethyl) - ethylsulfonylamino, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -methylsulfonylamino, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -propionylamino , N- (2- (N-acetyl-N-methyl-amino) -ethylamino, N- (2- (N-benzyl-N-methyl-amino) -ethyl) -propionylamino, N- (2-acetylamino-ethyl ) -N-acetyl-amino, N- (2- acetylamino-ethyl) -N-ethylsulfonyl-amino, N- (2-acetylamino-ethyl) -N-methylsulfonyl-amino, N- (2- acetylamino-ethyl) - N-propionyl-amino, N- (2-aminoethyl) -N-methylsulfonyl-amino, N- (2- dimethylamino-ethyl) -N-acetyl-amino, N- (2-dimethylamino-ethyl) -N- butylsulfonyl-amino, N- (2-dimethylamino-ethyl) -N-methylsulfonyl-amino, N- (2-dimethylamino-ethyl) -N-phenylsulfonyl-amino, N-
(2-dimetilaminoetil)-N-propilsulfonil-amino, N-(2-metilamino-etil)-acetilamino, N-(2- metilamino-etil)-N-metilsulfonilamino, N-(2-metilamino-etil)-propionilamino, N-(2- propionilamino-etil)-N-propionil-amino, N-(aminocarbonil-metil)-N-metilsulfonil-amino, N-(dimetilamino-carbonilmetil)-N-(metilsulfonil-amino, N-(dimetilaminoetil)-N- metilsulfenil-amino, N-(metilaminocarbonil-metil)-N-metilsulfonil-amino, N-acetil-N-(2-(2-dimethylaminoethyl) -N-propylsulfonyl-amino, N- (2-methylamino-ethyl) -acetylamino, N- (2- methylamino-ethyl) -N-methylsulfonylamino, N- (2-methylamino-ethyl) -propionylamino, N- (2- propionylamino-ethyl) -N-propionyl-amino, N- (aminocarbonyl-methyl) -N-methylsulfonyl-amino, N- (dimethylamino-carbonylmethyl) -N- (methylsulfonyl-amino, N- (dimethylaminoethyl) -N- methylsulfenyl-amino, N- (methylaminocarbonyl-methyl) -N-methylsulfonyl-amino, N-acetyl-N- (2-
(N-bencil-N-metil-amino)-etil-amino, N-acetil-N-(2-bencil-oxicarbonilamino-etil)-amino, N-carboxilmetil-N-metilsulfonil-amino, N-metilsulfonil-N-hidroxicarbonilmetil-amino, N- metil-N-acetil-amino, N-metil-N-etilsulfonil-amino, N-metil-N-formil-amino, N-metil-N- metilsulfonil-amino, N-metil-N-propionil-amino, propionilamino y terc- butoxicarbonilamino; y (N-benzyl-N-methyl-amino) -ethyl-amino, N-acetyl-N- (2-benzyl-oxycarbonylamino-ethyl) -amino, N-carboxymethyl-N-methylsulfonyl-amino, N-methylsulfonyl-N- hydroxycarbonylmethyl-amino, N-methyl-N-acetyl-amino, N-methyl-N-ethylsulfonyl-amino, N-methyl-N-formyl-amino, N-methyl-N- methylsulfonyl-amino, N-methyl-N-propionyl-amino, propionylamino and tert-butoxycarbonylamino; Y
R2 se selecciona del grupo que consiste en:  R2 is selected from the group consisting of:
2-clorofenilo, 2-cianofenilo, 2-nitrofenilo, 2-fenileteno, 3-aminometilfenilo, 3- aminofenilo, 3-clorofenilo, 3-cianofenilo, 3-metoxifenilo, 3-metilfenilo, 3-nitrofenilo, 4- aminofenilo, 4-clorofenilo, 4-metoxifenilo, 4-metilfenilo, 4-nitrofenilo, bencilo, ciclopropilo, etilo, isopropilo, metilo, naftalin-1-ilo, naftalin-2-ilo, propilo y 2,4,6- trimetilfenilo.  2-chlorophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-phenylene, 3-aminomethylphenyl, 3- aminophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-methoxyphenyl, 3-nitrophenyl, 4- aminophenyl, 4- chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, cyclopropyl, ethyl, isopropyl, methyl, naphthalene-1-yl, naphthalene-2-yl, propyl, and 2,4,6-trimethylphenyl.
En una realización particular, el compuesto de fórmula (VIII) se selecciona del grupo que consiste en:  In a particular embodiment, the compound of formula (VIII) is selected from the group consisting of:
(Z)-3-{1-[4-(N-(2-aminoetil)-N-metilsulfonil-amino)-fenilamino]-1-fenil-metiliden}-5- fenilsulfonilamino-2-indolinona,  (Z) -3- {1- [4- (N- (2-aminoethyl) -N-methylsulfonyl-amino) -phenylamino] -1-phenyl-methylidene} -5- phenylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-(N-(2-dimetilaminoetil)-N-fenilsulfonil-amino)-fenilamino)-1-fenil-metiliden}-5- fenilsulfonilamino-2-indolinona,  (Z) -3- {1- [4- (N- (2-dimethylaminoethyl) -N-phenylsulfonyl-amino) -phenylamino) -1-phenyl-methylidene} -5-phenylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-(N-metil-N-acetil-amino)-fenilamino]-1-fenil-metiliden}-5-fenilsulfonilamino-2- indolinona, (Z) -3- {1- [4- (N-methyl-N-acetyl-amino) -phenylamino] -1-phenyl-methyliden} -5-phenylsulfonylamino-2- indolinone,
(Z)-3-(1-fenilamino-1-fenil-metiliden)-5-fenilsulfonilamino-2-indolinona,  (Z) -3- (1-phenylamino-1-phenyl-methylidene) -5-phenylsulfonylamino-2-indolinone,
(Z)-3-[1-(4-clorofenilamino)-1-fenil-metiliden]-5-fenilsulfonilamino-2-indolinona,  (Z) -3- [1- (4-chlorophenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-(N-(2-propionilamino-etil)-N-propionil-amino)-fenilamino]-1-fenil-metiliden}-5- fenilsulfonilamino-2-indolinona,  (Z) -3- {1- [4- (N- (2-propionylamino-ethyl) -N-propionyl-amino) -phenylamino] -1-phenyl-methylidene} -5- phenylsulfonylamino-2-indolinone,
(Z)-3-[1-(4-dimetilaminometil-fenilamino)-1-fenil-metiliden]-5-fenilsulfonilamino-2-indol, (Z) -3- [1- (4-dimethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indole,
(Z)-3-[1-(4-(N-metil-N-metilsulfonil-amino)-fenilamino)-1-fenil-metiliden]-5- fenilsulfonilamino-2-indolinona, (Z) -3- [1- (4- (N-methyl-N-methylsulfonyl-amino) -phenylamino) -1-phenyl-methyliden] -5- phenylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-dimetilaminometil-fenilamino]-1-fenil-metiliden}-5-etilsulfonilamino-2- indolinona,  (Z) -3- {1- [4-dimethylaminomethyl-phenylamino] -1-phenyl-methylidene} -5-ethylsulfonylamino-2- indolinone,
(Z)-3-{1-[4-(N-bencil-N-metil-aminometil)-fenilamino]-1-fenil-metiliden}-5- etilsulfonilamino-2-indolinona,  (Z) -3- {1- [4- (N-benzyl-N-methyl-aminomethyl) -phenylamino] -1-phenyl-methyliden} -5- ethylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-(2-dimetilamino-etil)-fenilamino]-1-fenil-metiliden}-5-etilsulfonilamino-2- indolinona,  (Z) -3- {1- [4- (2-dimethylamino-ethyl) -phenylamino] -1-phenyl-methyliden} -5-ethylsulfonylamino-2- indolinone,
(Z)-3-{1-[4-(bencilaminocarbonil)-fenilamino]-1-fenil-metiliden}-5-fenilsulfonilamino-2- indolinona, (Z) -3- {1- [4- (benzylaminocarbonyl) -phenylamino] -1-phenyl-methylidene} -5-phenylsulfonylamino-2- indolinone,
(Z)-3-{1-[4-(N-dimetilaminocarbonilmetil-N-acetil-amino)-fenilamino]-1-fenil-metiliden}- (Z) -3- {1- [4- (N-dimethylaminocarbonylmethyl-N-acetyl-amino) -phenylamino] -1-phenyl-methyliden} -
5-fenilsulfonilamino-2-indolinona, 5-phenylsulfonylamino-2-indolinone,
(Z)-3-{1-[4-(N-(2-dimetilamino-etil)-N-metilsulfonil-amino)-fenilamino)-1-fenil-metiliden}- 5-(N-metil-N-fenilsulfonil-amino)-2-indolinona,  (Z) -3- {1- [4- (N- (2-dimethylamino-ethyl) -N-methylsulfonyl-amino) -phenylamino) -1-phenyl-methyliden} - 5- (N-methyl-N-phenylsulfonyl -amino) -2-indolinone,
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
En una realización adicional, el inhibidor de AURK es un compuesto abarcado en la fórmula (I) tal como se da a conocer en el documento WO 2001021596 tal como ZM- 447439. Los compuestos de fórmula (I) tal como se dan a conocer en el documento WO 2001021596 se identifican en el presente documento con la fórmula (IX):
Figure imgf000113_0001
Fórmula (IX) o una sal, un éster, una amida o un profármaco del mismo; In a further embodiment, the AURK inhibitor is a compound encompassed by formula (I) as disclosed in WO 2001021596 such as ZM-447439. Compounds of formula (I) as disclosed in WO 2001021596 are identified herein with formula (IX):
Figure imgf000113_0001
Formula (IX) or a salt, an ester, an amide or a prodrug thereof;
en la que X es O, o S, S(O) o S(0)2 ,NH o NR12 en el que R12 es hidrógeno o alquilo Ci.where X is O, or S, S (O) or S (0) 2, NH or NR 12 where R 12 is hydrogen or Ci alkyl.
6; 6;
R5 se selecciona de un grupo NHC(0)0R9, NHC(0)R9, NHS(0)2R9 C(0)R9, C(0)0R9, S(0)R9, S(0)0R9, S(0)20R9, C(O)NR10R11, S(O)NR10R11, S(O)ONR10R11 R 5 is selected from a group NHC (0) 0R 9 , NHC (0) R 9 , NHS (0) 2 R 9 C (0) R 9 , C (0) 0R 9 , S (0) R 9 , S (0) 0R 9 , S (0) 2 0R 9 , C (O) NR 10 R 11 , S (O) NR 10 R 11 , S (O) ONR 10 R 11
en el que R9, R10 o R11 se seleccionan independientemente de hidrógeno, hidrocarbilo opcionalmente sustituido y heterociclilo opcionalmente sustituido, y R10 y R11 junto con el átomo de nitrógeno al que se unen pueden formar adicionalmente un anillo heterocíclico opcionalmente sustituido que contiene opcionalmente heteroátomos adicionales; wherein R 9 , R 10 or R 11 are independently selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 together with the nitrogen atom to which they are attached may additionally form an optionally substituted heterocyclic ring which optionally contains additional heteroatoms;
R6 es hidrógeno, hidrocarbilo opcionalmente sustituido o heterociclilo opcionalmente sustituido; R 6 is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
R7 y R8 se seleccionan independientemente de hidrógeno, halo, alquilo Ci-4, alcoxilo C1-4, alcoximetilo Ci-4, di(alcoxi Ci-4)-metilo, alcanoilo Ci-4, trifluorometilo, ciano, amino, alquenilo C2-5, alquinilo C2-s, un grupo fenilo, un grupo bencilo o un grupo heterocíclico de 5-6 miembros con 1-3 heteroátomos, seleccionado independientemente de O, S y N, cuyo grupo heterocíclico puede ser aromático o no aromático y puede estar saturado (unido a través de un átomo de carbono o nitrógeno de anillo) o insaturado (unido a través de un átomo de carbono de anillo), y cuyo grupo fenilo, bencilo o heterocíclico puede albergar en uno o más átomos de carbono de anillo hasta 5 sustituyentes seleccionados de hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro, alcanoilo C2.4, alcanoilamino Ci-4, alcoxicarbonilo Ci-4, alquilsulfanilo Ci-4, alquilsulfinilo Ci-4, alquilsulfonilo Ci-4, carbamoílo, N-alquilcarbamoílo Ci-4, N,N-di(alquil Ci-4)carbamoílo, aminosulfonilo, N- alquilaminosulfonilo Ci-4, N,N-di(alquil Ci-4)aminosulfonilo, alquilsulfonilamino Ci-4, y un grupo heterocíclico saturado seleccionado de morfolino, tiomorfolino, pirrolidinilo, piperazinilo, piperidinilo imidazolidinilo y pirazolidinilo, cuyo grupo heterocíclico saturado puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro y alcoxicarbonilo Ci-4, y R 7 and R 8 are independently selected from hydrogen, halo, Ci- 4- alkyl, Ci- 4- alkoxy, Ci- 4- alkoxymethyl, di (Ci- 4- alkoxy) -methyl, Ci- 4- alkanoyl, trifluoromethyl, cyano, amino, alkenyl C 2 -5, C 2 -s alkynyl, a phenyl group, a benzyl group, or a 5-6 membered heterocyclic group with 1-3 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which may or may not be aromatic aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl, benzyl or heterocyclic group can harbor one or more atoms of ring carbon to 5 substituents selected from hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C 04.02, alkanoylamino Ci- 4 alkoxycarbonyl Ci- 4 alkylsulfanyl Ci- 4 , alkylsulfinyl Ci- 4 , alkylsulfonyl Ci- 4 , carbamoyl, N-alkyl rbamoyl Ci- 4 , N, N-di (Ci- 4- alkyl) carbamoyl, aminosulfonyl, N-alkylaminosulfonyl-Ci- 4 , N, N-di (Ci- 4- alkyl) aminosulfonyl, alkylsulfonylamino-Ci- 4 , and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl, the saturated heterocyclic group of which may harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C1-3alkyl, C1-3alkoxyloxy, trifluoromethyl, cyano, amino, nitro and Ci- 4 alkoxycarbonyl, and
R1, R2, R3, R4 se seleccionan independientemente de halógeno, ciano, nitro, alquilsulfanilo C1-3, -N(OH)R13- (en el que R13 es hidrógeno o alquilo C1-3), o R15X1- (en el que X1 representa un enlace directo, -O-, -CH2-, -OCO-, carbonilo, -S-, -SO-, -S02-, - NR16CO-, -CONR16-, -S02NR16-, -NR17S02- O -NR18- (en el que R16, R17 y R18 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3), y R1 5 es hidrógeno, hidrocarbilo opcionalmente sustituido, heterociclilo opcionalmente sustituido o alcoxilo opcionalmente sustituido En una realización particular, el compuesto según la fórmula (IX) en el que al menos un grupo R1 , R2, R3, R4 es un grupo R15X1- y R15 es hidrógeno, un grupo hidrocarbilo opcionalmente sustituido seleccionado de alquilo, alquenilo, alquinilo, arilo, aralquilo, cicloalquilo, cicloalquenilo o cicloalquinilo, o combinaciones de los mismos; o un grupo heterociclilo opcionalmente sustituido de desde 4 hasta 20 átomos de anillo, al menos uno de los cuales es un heteroátomo tal como oxígeno, azufre o nitrógeno y en el que los sustituyentes opcionales comprenden al menos un grupo funcional seleccionado de nitro, ciano, halo, oxo, =CR78R79, C(0)xR77, OR77, S(0)yR77, NR78R79, C(0)NR78R79, 0C(0)NR78R79, =NOR77, -NR77C(0)xR78, -NR77CONR78R79, -N=CR78R79, S(0)yNR78R79 o -NR77S(0)yR78 en el que R77, R78 y R79 se seleccionan independientemente de hidrógeno, hidrocarbilo opcionalmente sustituido, heterociclilo opcionalmente sustituido o alcoxilo opcionalmente sustituido, o R78 y R79 juntos forman un anillo opcionalmente sustituido que contiene opcionalmente heteroátomos adicionales tales como oxígeno, nitrógeno, S, S(O) o S(0)2, en el que x es un número entero de 1 ó 2, y es 0 o un número entero de 1-3. R 1 , R 2 , R 3 , R 4 are independently selected from halogen, cyano, nitro, C1-3 alkylsulfanyl, -N (OH) R 13 - (where R 13 is hydrogen or C1-3 alkyl), or R 15 X 1 - (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -S0 2 -, - NR 16 CO-, -CONR 16 -, -S0 2 NR 16 -, -NR 17 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C1-3 alkyl or Ci-3 alkoxy -C 2 -3 alkyl), and R 1 5 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy In a particular embodiment, the compound according to formula (IX) in which at least one group R 1 , R 2 , R 3 , R 4 is a group R 15 X 1 - and R 15 is hydrogen, an optionally substituted hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, or combinations thereof; or an optionally substituted heterocyclyl group of from 4 to 20 ring atoms, at least one of which is a heteroatom such as oxygen, sulfur or nitrogen and in which the optional substituents comprise at least one functional group selected from nitro, cyano, halo, oxo, = CR 78 R 79 , C (0) x R 77 , OR 77 , S (0) and R 77 , NR 78 R 79 , C (0) NR 78 R 79 , 0C (0) NR 78 R 79 , = NOR 77 , -NR 77 C (0) x R 78 , -NR 77 CONR 78 R 79 , -N = CR 78 R 79 , S (0) and NR 78 R 79 or -NR 77 S (0) and R 78 wherein R 77 , R 78 and R 79 are independently selected from hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy, or R 78 and R 79 together form an optionally substituted ring containing optionally additional heteroatoms such such as oxygen, nitrogen, S, S (O) or S (0) 2 , where x is an integer of 1 or 2, and is 0 or an integer of 1-3.
En una realización particular, el compuesto según la fórmula (IX) en el que los grupos hidrocarbilo, heterociclilo o alcoxilo R77, R78 y R79 así como los anillos formados por R78 y R79 están opcionalmente sustituidos por halo, perhaloalquilo, mercapto, alquiltio, hidroxilo, carboxilo, alcoxilo, heteroarilo, heteroariloxilo, cicloalquilo, cicloalquenilo, cicloalquinilo, alqueniloxilo, alquiniloxilo, alcoxialcoxilo, ariloxilo (en el que el grupo arilo puede estar sustituido por halo, nitro o hidroxilo), ciano, nitro, amino, mono o dialquilamino, oximino o S(0)yR9° en el que y es tal como se definió anteriormente y R90 es un alquilo. In a particular embodiment, the compound according to formula (IX) in which the hydrocarbyl, heterocyclyl or alkoxy groups R 77 , R 78 and R 79 as well as the rings formed by R 78 and R 79 are optionally substituted by halo, perhaloalkyl, mercapto, alkylthio, hydroxyl, carboxyl, alkoxy, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may be substituted by halo, nitro or hydroxy), cyano, nitro, , mono or dialkylamino, oximino or S (0) and R 9 ° where y is as defined above and R 90 is an alkyl.
En una realización particular, el compuesto según la fórmula (IX) en el que al menos un grupo R1 , R2, R3 o R4 es un grupo X1 R15 y R15 se selecciona de uno de los siguientes veintidós grupos: In a particular embodiment, the compound according to formula (IX) in which at least one group R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 and R 15 is selected from one of the following twenty-two groups :
1) hidrógeno o alquilo Cis que puede no estar sustituido o que puede estar sustituido con uno o más grupos funcionales;  1) hydrogen or Cis alkyl which may be unsubstituted or which may be substituted with one or more functional groups;
2) -RaX2C(0)R19 (en el que X2 representa -O- o -NR20- (en el que R20 representa hidrógeno o alquilo opcionalmente sustituido con un grupo funcional) y R19 representa alquilo C1 -3, -NR21 R22 o -OR23 (en el que R21 , R22 y R23 que pueden ser el mismo o diferente cada uno representa hidrógeno o alquilo opcionalmente sustituido con un grupo funcional); 2) -R to X 2 C (0) R 19 (where X 2 represents -O- or -NR 20 - (where R 20 represents hydrogen or alkyl optionally substituted with a functional group) and R 19 represents alkyl C1 -3, -NR 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen or alkyl optionally substituted with a functional group);
3) -RbX3R24 (en el que X3 representa -O-, -C(O)-, -S-, -SO-, -SO2-, -OC(O)-, - NR25C(0)s-, -C(0)NR26-, -SO2NR27-, -NR28S02- O -NR29- (en el que R25, R26, R27, R28 y3) -R b X 3 R 24 (where X 3 represents -O-, -C (O) -, -S-, -SO-, -SO2-, -OC (O) -, - NR 25 C (0) s -, -C (0) NR 26 -, -SO2NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and
R29 cada uno independientemente representa hidrógeno o alquilo opcionalmente sustituido con un grupo funcional y s es 1 ó 2) y R24 representa hidrógeno, hidrocarbilo (tal como se define en el presente documento) o un grupo heterocíclico saturado, en el que los grupos hidrocarbilo o heterocíclico pueden estar opcionalmente sustituidos por uno o más grupos funcionales y los grupos heterocíclicos pueden estar adicionalmente sustituidos por un grupo hidrocarbilo; R 29 each independently represents hydrogen or alkyl optionally substituted with a functional group and s is 1 or 2) and R 24 represents hydrogen, hydrocarbyl (as defined herein) or a saturated heterocyclic group, in which the hydrocarbyl groups or heterocyclic can be optionally substituted by one or more functional groups and the heterocyclic groups can be additionally substituted by a hydrocarbyl group;
4) -RCX4RCX5R30 (en el que X4 y X5 que pueden ser el mismo o diferente son cada uno -O-, -C(O)-, -S-, -SO-, -SO2-, -OC(O)-, -NR31C(0)s-, -C(0)xNR32-, -SO2NR33-, -NR34S02- o -NR35- (en el que R31 , R32, R33, R34 y R35 cada uno independientemente representa hidrógeno o alquilo opcionalmente sustituido por un grupo funcional y s es 1 ó 2) y R30 representa hidrógeno o alquilo opcionalmente sustituido por un grupo funcional; 4) -R C X 4 R C X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -C (O) -, -S-, -SO- , -SO2-, -OC (O) -, -NR 31 C (0) s -, -C (0) x NR 32 -, -SO2NR 33 -, -NR 34 S0 2 - or -NR 35 - (in where R 31 , R 32 , R 33 , R 34 and R 35 each independently represents hydrogen or alkyl optionally substituted by a functional group and s is 1 or 2) and R 30 represents hydrogen or alkyl optionally substituted by a functional group;
5) R36 en el que R36 es un cicloalquilo C3-6 O anillo heterocíclico saturado (unido a través de carbono o nitrógeno), cuyo grupo cicloalquilo o heterocíclico puede estar sustituido por uno o más grupos funcionales o por un grupo hidrocarbilo o heterociclilo en el que el grupo hidrocarbilo o heterociclilo puede estar opcionalmente sustituido por uno o más grupos funcionales; 5) R 36 in which R 36 is a C3-6 cycloalkyl OR saturated heterocyclic ring (linked via carbon or nitrogen), the cycloalkyl or heterocyclic group of which may be substituted by one or more functional groups or by a hydrocarbyl or heterocyclyl group in which the hydrocarbyl or heterocyclyl group may optionally be substituted by one or more functional groups;
6) -RdR36 (en el que R36 es tal como se define anteriormente en el presente documento); 6) -R d R 36 (wherein R 36 is as defined herein above);
7) - ReR36 (en el que R36 es tal como se define anteriormente en el presente documento); 7) - R e R 36 (wherein R 36 is as defined herein above);
8) -RfR36 (en el que R36 es tal como se define anteriormente en el presente documento); 8) -R f R 36 (wherein R 36 is as defined herein above);
9) R37 (en el que R37 representa un grupo piridona, un grupo arilo o un grupo heterocíclico aromático (unido a través de carbono o nitrógeno) con 1-3 heteroátomos seleccionados de O, N y S, cuyo grupo piridona, arilo o heterocíclico aromático puede estar sustituido por uno o más grupos funcionales o por un grupo hidrocarbilo opcionalmente sustituido por uno o más grupos funcionales o grupos heterociclilo, o por un grupo heterociclilo opcionalmente sustituido por uno o más grupos funcionales o grupos hidrocarbilo; 9) R 37 (wherein R 37 represents a pyridone group, an aryl group, or an aromatic heterocyclic group (bonded via carbon or nitrogen) with 1-3 heteroatoms selected from O, N, and S, of which the pyridone group, aryl or aromatic heterocyclic may be substituted by one or more functional groups or by a hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or by a heterocyclyl group optionally substituted by one or more functional groups or hydrocarbyl groups;
10) -R9R37 (en el que R37 es tal como se define anteriormente en el presente documento); 10) -R 9 R 37 (wherein R 37 is as defined herein above);
11) -RhR37 (en el que R37 es tal como se define anteriormente en el presente documento); 11) -R h R 37 (wherein R 37 is as defined herein above);
12) -R'R37 (en el que R37 es tal como se define anteriormente en el presente documento); 12) -R'R 37 (wherein R 37 is as defined herein above);
13) -RjX6R37 (en el que X6 representa -O-, -S-, -SO-, -S02-, -OC(O)-, -NR42C(0)-, - C(0)NR43-, -S02NR44-, -NR45S02- O -NR46- (en el que R42, R43, R44, R45 y R46 cada uno independientemente representa hidrógeno o alquilo opcionalmente sustituido con un grupo funcional) y R37 es tal como se define anteriormente en el presente documento);13) -R j X 6 R 37 (where X 6 represents -O-, -S-, -SO-, -S0 2 -, -OC (O) -, -NR 42 C (0) -, - C (0) NR 43 -, -S0 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45 and R 46 each independently represents hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
14) -RkX7R37 (en el que X7 representa -O-, -C(O)-, -S-, -SO-, -SO -, -OC(O)-, - NR47C(0)-, -C(0)NR48-, -S02NR49-, -NR50SO2- O -NR51- (en el que R47, R48, R49, R50 y R51 cada uno independientemente representa hidrógeno o alquilo opcionalmente sustituido con un grupo funcional) y R37 es tal como se define anteriormente en el presente documento); 14) -R k X 7 R 37 (where X 7 represents -O-, -C (O) -, -S-, -SO-, -SO -, -OC (O) -, - NR 47 C (0) -, -C (0) NR 48 -, -S0 2 NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represents hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
15) -RmX8R37 (en el que X8 representa -O-, -C(O)-, -S-, -SO-, -S02-, -OC(O)-, -15) -R m X 8 R 37 (where X 8 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -OC (O) -, -
NR52C(0)-, -C(0)NR53-, -S02NR54-, -NR55S02- O -NR56- (en el que R52, R53, R54, R55 y R56 cada uno independientemente representa hidrógeno, hidrógeno o alquilo opcionalmente sustituido con un grupo funcional) y R37 es tal como se define anteriormente en el presente documento); NR 52 C (0) -, -C (0) NR 53 -, -S0 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (where R 52 , R 53 , R 54 , R 55 and R 56 each independently represents hydrogen, hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
16) -RnX9Rn’R37 (en el que X9 representa -O-, -C(O)-, -S-, -SO-, -S02-, -OC(O)-, -16) -R n X 9 R n ' R 37 (where X 9 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -OC (O) -, -
NR57C(0)-, -C(0)NR58-, -S02NR59-, -NR60SO2- O -NR61- (en el que R57, R58, R59, R60 y R61 cada uno independientemente representa hidrógeno, hidrógeno o alquilo opcionalmente sustituido con un grupo funcional) y R37 es tal como se define anteriormente en el presente documento); NR 57 C (0) -, -C (0) NR 58 -, -S0 2 NR 59 -, -NR 60 SO 2 - O -NR 6 1- (where R 57 , R 58 , R 59 , R 60 and R 61 each independently represent hydrogen, hydrogen or alkyl optionally substituted with a functional group) and R 37 is as defined herein above);
17) -RPX9-RP’R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); 17) -R P X 9 -R P ' R 36 (wherein X 9 and R 36 are as defined herein above);
18) alquenilo C2-s que puede no estar sustituido o que puede estar sustituido con uno o más grupos funcionales; 18) C 2 -s alkenyl which may be unsubstituted or which may be substituted with one or more functional groups;
19) alquinilo C2-s que puede no estar sustituido o que puede estar sustituido con uno o más grupos funcionales;  19) C2-s alkynyl which may be unsubstituted or which may be substituted with one or more functional groups;
20) -R^F^’R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); 20) -R ^ F ^ ' R 36 (where X 9 and R 36 are as defined herein above);
21) -RUX9RU’R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); y 21) -R U X 9 R U ' R 36 (wherein X 9 and R 36 are as defined herein above); Y
22) -RvR62(Rv’)q(X9)rR63 (en el que X9 es tal como se define anteriormente en el presente documento, q es 0 ó 1 , r es 0 ó 1 , y R62 es un grupo alquileno C1 -3 o un grupo cíclico seleccionado de grupo cicloalquilo o heterocíclico divalente, cuyo grupo alquileno C1 -3 puede estar sustituido por uno o más grupos funcionales y cuyo grupo cíclico puede estar sustituido por uno o más grupos funcionales o por un grupo hidrocarbilo opcionalmente sustituido por uno o más grupos funcionales o grupos heterociclilo, o por un grupo heterociclilo opcionalmente sustituido por uno o más grupos funcionales o grupos hidrocarbilo; y R63 es hidrógeno, alquilo C1-3, o un grupo cíclico seleccionado de grupo cicloalquilo o heterocíclico, cuyo grupo alquilo C1 -3 puede estar sustituido por uno o más grupos funcionales y cuyo grupo cíclico puede estar sustituido por uno o más grupos funcionales o por un grupo hidrocarbilo opcionalmente sustituido por uno o más grupos funcionales o grupos heterociclilo, o por un grupo heterociclilo opcionalmente sustituido por uno o más grupos funcionales o grupos hidrocarbilo ; 22) -R v R 62 (R v ' ) q (X 9 ) r R 63 (where X 9 is as defined herein above, q is 0 or 1, r is 0 or 1, and R 62 is a C1 -3 alkylene group or a cyclic group selected from a divalent cycloalkyl or heterocyclic group, whose C1-3 alkylene group may be substituted by one or more functional groups and whose cyclic group may be substituted by one or more functional groups or by a hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or by a heterocyclyl group optionally substituted by one or more functional groups or hydrocarbyl groups; and R 63 is hydrogen, C1-3 alkyl, or a cyclic group selected from cycloalkyl or heterocyclic group, whose C1 -3 alkyl group may be substituted by one or more functional groups and whose cyclic group may be substituted by one or more functional groups or by a hydrocarbyl group optionally substituted by one or more functional groups it is either heterocyclyl groups, or by a heterocyclyl group optionally substituted by one or more functional groups or hydrocarbyl groups;
y en el que Ra, Rb, Rc, Rc’, Rd, R9, Rj, Rn, Rn’ , Rp, Rp’, R1’, Ru’, Rv y Rv’ se seleccionan independientemente de grupos alquileno C1 -8 opcionalmente sustituidos por uno o más grupos funcionales sustituyentes, and in which R a , R b , R c , R c ' , R d , R 9 , R j , R n , R n' , R p , R p ' , R 1' , R u ' , R v and R v ' are independently selected from C1 -8 alkylene groups optionally substituted by one or more substituent functional groups,
Re, Rh, Rk y R‘ se seleccionan independientemente de grupos alquenileno C2-8 opcionalmente sustituidos por uno o más grupos funcionales, y Rf, R1, Rm y Ru se seleccionan independientemente de grupos alquinileno C2-8 opcionalmente sustituidos por uno o más grupos funcionales. R e , R h , R k and R 'are independently selected from C2-8 alkenylene groups optionally substituted by one or more functional groups, and R f , R 1 , R m and R u are independently selected from C2-8 alkynylene groups optionally substituted by one or more functional groups.
En una realización particular, el compuesto según la fórmula (IX) en el que al menos un grupo R1, R2, R3 o R4 es un grupo X1R15 y R15 se selecciona de uno de los siguientes veintidós grupos: In a particular embodiment, the compound according to formula (IX) in which at least one group R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 and R 15 is selected from one of the following twenty-two groups :
1) hidrógeno o alquilo Cis que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, oxiranilo, fluoro, cloro, bromo y amino (incluyendo alquilo Ci-3y trifluorometilo);  1) hydrogen or Cis alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, oxiranyl, fluoro, chloro, bromo and amino (including Ci-3alkyl and trifluoromethyl);
2) -RaX2C(0)R19 (en el que X2 representa -O- o -NR20- (en el que R20 representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3) y R19 representa alquilo C1-3, -NR21 R22 o -OR23 (en el que R21 , R22 y R23 que pueden ser el mismo o diferente cada uno representa hidrógeno, alquilo ¿1-5, hidroxilo-alquilo C1-5 O alcoxil Ci-3-alquilo C2-3));2) -R to X 2 C (0) R 19 (where X 2 represents -O- or -NR 20 - (where R 20 represents hydrogen, C 1-3 -alkyl or C- 3- alkoxy-C-alkyl 2-3 ) and R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, alkyl ¿ 1 -5 , hydroxy-C 1-5 -alkyl or C- 3- alkoxy-C 2-3- alkyl));
3) -RbX3R24 (en el que X3 representa -O-, -C(O)-, -S-, -SO-, -SO2-, -OC(O)-, - NR25C(0)s-, -NR25C(0)NR26-, -C(0)NR26-, -SO2NR27-, -NR28SO- o -NR29- (en el que3) -R b X 3 R 24 (where X 3 represents -O-, -C (O) -, -S-, -SO-, -SO2-, -OC (O) -, - NR 25 C (0) s -, -NR 25 C (0) NR 26 -, -C (0) NR 26 -, -SO2NR 27 -, -NR 28 SO- or -NR 29 - (where
R25, R26, R27, R28 y R29 cada uno independientemente representa hidrógeno, alquilo Ci- 3, hidroxilo-alquilo C1 -3 o alcoxil Ci-3-alquilo C2-3 y s es 1 ó 2) y R24 representa hidrógeno, alquilo C1-6, alquenilo C2-6 o un grupo cíclico seleccionado de ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, fenilo o un grupo heterocíclico de 5 a 6 miembros saturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo alquilo Ci-e puede albergar 1 , 2 ó 3 sustituyentes seleccionados de oxo, hidroxilo, halógeno, ciclopropilo, amino, alquilamino C1-4, dialquilamino C1-4, alquiltio C1- 4, alcoxilo C1-4 y cuyo grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, ciano, cianoalquilo C1-4, alquilo C1-4, hidroxialquilo C1-4, alcoxilo C1-4, alcoxil Ci-4-alquilo C1-4, alquilsulfonil Ci-4-alquilo C1-4, alcoxicarbonilo C1-4, aminoalquilo C1-4, alquilamino C1-4, di(alquil Ci-4)a ino, alquilamino Ci-4-alquilo C1-4, di(alquil Ci-4)amino-alquilo C1-4, alcanoílo C1-4, alquilamino Ci-4-alcoxilo C1-4, di(alquil Ci-4)amino-alcoxilo C1-4 y un grupo -(-0-)f(Rb’)gD (en el que f es 0 ó 1 , g es 0 ó 1 y el anillo D es un grupo cicloalquilo C3-6, un arilo o un grupo heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo cíclico puede albergar uno o más sustituyentes seleccionados de halo o alquilo C1-4)); R 25 , R 26 , R 27 , R 28 and R 29 each independently represent hydrogen, Ci-3alkyl, hydroxyl-C1 -3alkyl or Ci-3-C2-3alkyl and s is 1 or 2) and R 24 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, or a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S, and N, whose Ci-e alkyl group can harbor 1, 2 or 3 substituents selected from oxo, hydroxyl, halogen, cyclopropyl, amino, C1-4 alkylamino, C1-4 dialkylamino, alkylthio C 1-4, alkoxy C 1-4 cyclic group and which can accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, cyano , C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, Ci- 4 alkoxyl C 1-4 alkyl, Ci- 4 alkylsulfonyl C 1-4 alkyl, alkoxycarbonyl C 1 -4, aminoC 1-4 alkylamino C 1-4 -alkylamino, di (Ci- 4) ino, Ci- 4 alkylamino C 1-4 alkyl, di (Ci- 4) aminoC 1-4 , C 1-4 alkanoyl, alkylamino Ci- 4 -alkoxy C 1-4 -alkylamino, di (Ci- 4) alkoxy-C 1-4 amino and a group - (- 0-) f (R b ') g D ( wherein f is 0 or 1, g is 0 or 1 and ring D is a C 3-6 cycloalkyl group, an aryl or a 5-6 membered heterocyclic group saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, whose cyclic group can harbor one or more substituents selected from halo or C 1-4 alkyl));
4) -RCX4RCX5R30 (en el que X4 y X5 que pueden ser el mismo o diferente son cada uno -O-, -C(O)-, -S-, -SO-, -SO2-, -NR31C(0)s-, -C(0)xNR32-, -SO2NR33-, -NR34S02- o -NR35- (en el que R31, R32, R33, R34 y R35 cada uno independientemente representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 O alcoxil Ci-3-alquilo Ci-z 'j s es 1 ó 2) y R representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 O alcoxil Ci-3-alquilo C2-3); 4) -R C X 4 R C X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -C (O) -, -S-, -SO- , -SO 2 -, -NR 31 C (0) s -, -C (0) x NR 32 -, -SO 2 NR 33 -, -NR 34 S0 2 - or -NR 35 - (where R 31 , R 32, R 33, R 34 and R 35 each independently represents hydrogen, C 1-3 alkyl, hydroxy-C 1-3 alkyl or alkoxyl Ci- 3 alkyl Ci-z 'js is 1 or 2) and R represents hydrogen, C 1-3 -alkyl, hydroxyl-C 1-3 -alkyl or C- 3- alkoxy-C 2-3 -alkyl);
5) R36 (en el que R36 es un cicloalquilo de 4-6 miembros o anillo heterocíclico saturado (unido a través de carbono o nitrógeno) con 1 -2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo cicloalquilo o heterocíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, ciano, alquilo C1-4, hidroxilo-alquilo ¿1-4, ciano-alquilo C1-4, ciclopropilo, alquilsulfonil Ci-4-alquilo C1-4, alcoxicarbonilo C1-4, carboxamido, aminoalquilo C1-4, alquilamino C1-4, di(alquil C1- 4)amino, alquilamino Ci-4-alquilo C1-4, alcanoílo C1-4, di(alquil Ci-4)amino-alquilo C1-4, alquilamino Ci-4-alcoxilo C1-4, di(alquil Ci-4)amino-alcoxilo C1-4, nitro, amino, alcoxilo C1- 4, hidroxialcoxilo C1-4, carboxilo, trifluorometilo, -C(0)NR38R39, -NR40C(O)R41 (en el que5) R 36 (wherein R 36 is a 4-6 membered cycloalkyl or saturated heterocyclic ring (bonded via carbon or nitrogen) with 1 -2 heteroatoms, independently selected from O, S, and N, whose cycloalkyl group or Heterocyclic can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, cyano, C 1-4 alkyl, hydroxy-C 1-4 -alkyl, cyano-C 1-4 -alkyl, cyclopropyl, alkylsulfonyl C- 4- C 1- alkyl. 4 C 1-4 alkoxycarbonyl, carboxamido, C1-4 aminoalkyl, C1-4 alkylamino, di (alkyl C 1 - 4) amino, Ci- 4 alkylamino C 1-4 alkyl, C 1-4 alkanoyl, di (Ci- 4 alkyl) amino-C 1-4 alkyl, Ci- 4 alkylamino C 1-4 -alkoxy, di (Ci- 4) amino-C1-4 alkoxy, nitro, amino, alkoxy C 1-4, C 1-4 hydroxyalkoxy, carboxyl, trifluoromethyl, -C (0) NR 38 R 39 , -NR 40 C (O) R 41 (where
R38, R39, R40 y R41, que pueden ser el mismo o diferente, cada uno representa hidrógeno, alquilo C1-4, hidroxilo-alquilo C1-4 o alcoxil Ci-3-alquilo C2-3) y un grupo -(-O- )f(alquil Ci-4)g-anilloD (en el que f es 0 ó 1 , g es 0 ó 1 y el anillo D es un grupo cíclico seleccionado de cicloalquilo C3-6, arilo o grupo heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo cíclico puede albergar uno o más sustituyentes seleccionados de halo y alquilo C1-4); R 38, R 39, R 40 and R 41, which may be the same or different, each represents hydrogen, C 1-4 -alkyl, hydroxy-C 1-4 alkyl or alkoxyl C 2-3 Ci- 3 alkyl) and a group - (- O-) f (C 4 -alkyl) g- ring D (where f is 0 or 1, g is 0 or 1 and ring D is a cyclic group selected from C 3-6 cycloalkyl, aryl or 5-6 membered heterocyclic group saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, the cyclic group of which may harbor one or more substituents selected from halo and C 1-4 alkyl);
6) -RdR36 (en el que R36 es tal como se define anteriormente en el presente documento); 6) -R d R 36 (wherein R 36 is as defined herein above);
7) - ReR36 (en el que R36 es tal como se define anteriormente en el presente documento); 7) - R e R 36 (wherein R 36 is as defined herein above);
8) -Rf R36 (en el que R36 es tal como se define anteriormente en el presente documento); 8) -R f R 36 (wherein R 36 is as defined herein above);
9) R37 (en el que R37 representa un grupo piridona, un grupo fenilo o un grupo heterocíclico aromático de 5-6 miembros (unido a través de carbono o nitrógeno) con9) R 37 (where R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (bonded via carbon or nitrogen) with
1-3 heteroátomos seleccionados de O, N y S, cuyo grupo piridona, fenilo o heterocíclico aromático puede portar hasta 5 sustituyentes seleccionados de hidroxilo, nitro, halógeno, amino, alquilo C1-4, alcoxilo C1-4, hidroxialquilo C1-4, aminoalquilo C1-4, alquilamino C1-4, hidroxialcoxilo C1-4, oxo, cianoalquilo C1-4, ciclopropilo, alquilsulfonil Ci-4-alquilo C1-4, alcoxicarbonilo C1-4, di(alquil examino, alquilamino Ci-4-alquilo C1-4, alcanoílo C1-4, di(alquil Ci-4)amino-alquilo C1-4, alquilamino Ci-4-alcoxilo C1-4, di(alquil C1- 4)amino-alcoxilo C1-4, carboxilo, carboxamido, trifluorometilo, ciano, -C(0)NR38R39, - NR40C(O)R41 (en el que R38, R39, R40 y R41, que pueden ser el mismo o diferente, cada uno representa hidrógeno, alquilo C1-4, hidroxilo-alquilo C1-4 O alcoxil Ci-3-alquilo C2-3) y un grupo -(-O-)f(alquil Civ g-anilloD (en el que f es 0 ó 1 , g es 0 ó 1 y el anillo D es un grupo cíclico seleccionado de cicloalquilo C3-6, arilo o grupo heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, en el que el grupo cíclico puede albergar uno o más sustituyentes seleccionados de halo y alquilo Ci-4); 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic may carry selected from hydroxyl, nitro, halogen, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-5 hydroxyalkyl substituents -4, aminoC 1-4 alkylamino C 1-4 hydroxyalkoxy C 1-4 oxo, cyano - C 1-4 cyclopropyl, Ci- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, di ( alkyl examined, Ci- 4 alkylamino C 1-4 alkyl, C 1-4 alkanoyl, di (Ci- 4) amino-C 1-4 alkyl, Ci- 4 alkylamino C 1-4 -alkoxy, di (C 1 - 4) amino-C 1-4 -alkoxy, carboxyl, carboxamido, trifluoromethyl, cyano, -C (0) NR 38 R 39, - NR 40 C (O) R 41 (wherein R 38, R 39, R 40 and R 41, which may be the same or different, each represents hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and a group - (- O-) f (alkyl Civ g- ring D (where f is 0 or 1, g is 0 or 1 and ring D is a cyclic group selected from C3-6 cycloalkyl, aryl or heterocyclic group of 5-6 membered saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, in which the cyclic group may harbor one or more substituents selected from halo and Ci -4 alkyl);
10) -R9R37 (en el que R37 es tal como se define anteriormente en el presente documento); 10) -R 9 R 37 (wherein R 37 is as defined herein above);
1 1) -RhR37 (en el que R37 es tal como se define anteriormente en el presente documento); 1 1) -R h R 37 (wherein R 37 is as defined herein above);
12) -R'R37 (en el que R37 es tal como se define anteriormente en el presente documento); 12) -R'R 37 (wherein R 37 is as defined herein above);
13) -RjX6R37 (en el que X6 representa -O-, -C(O)-, -S-, -SO-, -S02-, -OC(O)-, - NR42C(0)-, -C(0)NR43-, -SO2NR44-, -NR45S02- O -NR46- (en el que R42, R43, R44, R45 y R46 cada uno independientemente representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 13) -R j X 6 R 37 (where X 6 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -OC (O) -, - NR 42 C (0) -, -C (0) NR 43 -, -SO2NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45 and R 46 each each independently represents hydrogen, C1-3 alkyl, hydroxy-C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 37 is as hereinbefore defined herein);
14) -RkX7R37 (en el que X7 representa -O-, -C(O)-, -S-, -SO-, -S02-, -NR47C(0)-, - C(0)NR48-, -SO2NR49-, -NR50SO2- O -NR51- (en el que R47, R48, R49, R50 y R51 cada uno independientemente representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento);14) -R k X 7 R 37 (where X 7 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -NR 47 C (0) -, - C (0) NR 48 -, -SO2NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represents hydrogen, C1-alkyl C1-3 alkoxyl or Ci- 3 C 2-3 alkyl) and R 37 -3, hydroxy-alkyl is as hereinbefore defined herein);
15) -RmX8R37 (en el que X8 representa -O-, -C(O)-, -S-, -SO-, -S02-, -NR52C(0)-, - C(0)NR53-, -SO2NR54-, -NR55S02- O -NR56- (en el que R52, R53, R54, R55 y R56 cada uno independientemente representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 16) -RnX9Rn’R37 (en el que X9 representa -O-, -C(O)-, -S-, -SO-, -S02-, -NR57C(0)-, -15) -R m X 8 R 37 (where X 8 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -NR 52 C (0) -, - C (0) NR 53 -, -SO 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (where R 52 , R 53 , R 54 , R 55 and R 56 each independently represents hydrogen, C 1-3 alkyl, hydroxy-C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 37 is as hereinbefore defined herein); 16) -R n X 9 R n ' R 37 (where X 9 represents -O-, -C (O) -, -S-, -SO-, -S0 2 -, -NR 57 C (0) -, -
C(0)NR58-, -SO2NR59-, -NR60SO2- O -NR61- (en el que R57, R58, R59, R60 y R61 cada uno independientemente representa hidrógeno, alquilo C1-3, hidroxilo-alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento);C (0) NR 58 -, -SO 2 NR 59 -, -NR 60 SO 2 - O -NR 61 - (where R 57 , R 58 , R 59 , R 60 and R 61 each independently represents hydrogen, C 1-3 alkyl, hydroxy-C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 37 is as hereinbefore defined herein);
17) -RPX9-RP’R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); 17) -R P X 9 -R P ' R 36 (wherein X 9 and R 36 are as defined herein above);
18) alquenilo C^ que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, fluoro, amino, alquilamino C1-4, carboxilo (y particularmente ásteres de alquilo de los mismos), N,N-di(alquil Ci-4)amino, aminosulfonilo, N-alquilaminosulfonilo Ci-4 y N,N-di(alquil Ci-4)aminosulfonilo; 18) C ^ alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro, amino, C1-4 alkylamino, carboxyl (and particularly alkyl esters thereof), N, N-di (Ci- 4- alkyl) amino, aminosulfonyl, C- 4 -N-alkylaminosulfonyl and N, N-di (Ci- 4- alkyl) aminosulfonyl;
19) alquinilo C2-5 que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, fluoro, amino, alquilamino Ci-4, N,N-di(alquil Ci-4)amino, aminosulfonilo, N-alquilaminosulfonilo Ci-4 y N,N-di(alquil C1- 4)aminosulfonilo; 19) C2-5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro, amino, Ci- 4- alkylamino, N, N-di (Ci- 4- alkyl) amino, aminosulfonyl, N -Ci- 4- alkylaminosulfonyl and N, N-di (C 1-4 -alkyl) aminosulfonyl;
20) -R^R^R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); 20) -R ^ R ^ R 36 (where X 9 and R 36 are as defined herein above);
21) -RUX9RU’R36 (en el que X9 y R36 son tal como se definen anteriormente en el presente documento); y 21) -R U X 9 R U ' R 36 (wherein X 9 and R 36 are as defined herein above); Y
22) - RvR62(Rv’)q(X9)rR63 (en el que X9 es tal como se define anteriormente en el presente documento, q es 0 ó 1 , r es 0 ó 1 , y R62 es un grupo alquileno C1-3 o un grupo cíclico seleccionado de ciclopropileno, ciclobutileno, ciclopentileno, ciclohexileno o un grupo heterocíclico de 5-6 miembros saturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, en el que el grupo alquileno C1-3 puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno y alcoxilo Ci-4 y en el que el grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, ciano, cianoalquilo C1-4, alquilo C1-4, hidroxialquilo C1-4, alcoxilo C1-4, alcoxil Ci-4-alquilo C1-4, alquilsulfonil Ci-4-alquilo C1-4, alcoxicarbonilo C1-4, aminoalquilo C1-4, alquilamino C1-4, di(alquil Ci-4)amino, alquilamino Ci-4-alquilo C1-4, di(alquil Ci-4)amino- alquilo C1-4, alquilamino Ci-4-alcoxilo C1-4, di(alquil Ci-4)amino-alcoxilo Ci-4 y un grupo - (-O-)f(alquil Ci-4)g-anillo D (en el que f es 0 ó 1 , g es 0 ó 1 y el anillo D es un grupo cíclico seleccionado de cicloalquilo C3-6, arilo o grupo heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo cíclico puede albergar uno o más sustituyentes seleccionados de halo y alquilo Ci-4);y R63 es hidrógeno, alquilo C1-3, o un grupo cíclico seleccionado de ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo y un grupo heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo alquilo C1-3 puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alcoxilo C1-4 y cuyo grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, ciano, cianoalquilo C1-4, alquilo C1-4, hidroxialquilo C1-4, alcoxilo C1-4, alcoxil Ci-4-alquilo C1-4, alquilsulfonil Ci-4-alquilo C1-4, alcoxicarbonilo C1-4, aminoalquilo C1-4, alquilamino C1-4, di(alquil examino, alquilamino Ci-4-alquilo C1-4, di(alquil Ci-4)amino-alquilo C1-4, alquilamino Ci-4-alcoxilo C1-4, di(alquil Ci-4)amino-alcoxilo C1-4 y un grupo -(-O-)f(alquil Ci-4)g-anilloD (en el que f es 0 ó 1 , g es 0 ó 1 y el anillo D es un grupo cíclico seleccionado de grupo cicloalquilo C3-6, arilo o heterocíclico de 5-6 miembros saturado o insaturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo cíclico puede albergar uno o más sustituyentes seleccionados de halo y alquilo Ci-4); 22) - R v R 62 (R v ' ) q (X 9 ) r R 63 (where X 9 is as defined herein above, q is 0 or 1, r is 0 or 1, and R 62 is a C1-3 alkylene group or a group cyclic selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, in which the C 1-3 alkylene group can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen and Ci- 4 alkoxy and which cyclic group may accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, cyano, C1-4 cyanoalkyl, C 1-4 alkyl, hydroxy C 1-4, alkoxy C 1-4, alkoxyl C 1-4 Ci- 4 alkyl, Ci- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, aminoC 1-4 alkylamino C 1-4, di (Ci- 4) amino, Ci- 4 alkylamino C 1-4 alkyl, di (Ci- 4) alkyl amino C 1-4 alkylamino C 1-4 -alkoxy Ci- 4 -alkylamino, di (Ci - 4 ) amino-C 4 -alkoxy and a group - (-O-) f (C 4 -alkyl) g- ring D (where f is 0 or 1, g is 0 or 1 and ring D is a selected cyclic group of C 3-6 cycloalkyl, aryl or o 5-6 membered heterocyclic group saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, the cyclic group of which may harbor one or more substituents selected from halo and C 4 -alkyl); and R 63 is hydrogen , C 1-3 alkyl, or a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and a 5-6 membered heterocyclic group saturated or unsaturated with 1-2 heteroatoms, independently selected from O, S and N, whose alkyl group C 1-3 can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C 1-4 alkoxy and whose cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, cyano, cyanoalkyl C 1-4 , alkyl C 1-4 hydroxyalkyl, C 1-4, alkoxy C 1-4, alkoxyl C 1-4 Ci- 4 alkyl, Ci- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, aminoC 1-4 , C 1-4 -alkylamino, di (alkyl I examine, Ci- 4- alkylamino -C 1-4 -alkyl, di (Ci-alkyl 4) amino-C 1-4 alkyl, Ci- 4 alkylamino C 1-4 -alkoxy, di (Ci- 4) amino-C 1-4 alkoxy and a group - (- O-) f (Ci- 4 alkyl ) g- ring D (where f is 0 or 1, g is 0 or 1 and ring D is a cyclic group selected from C 3-6 , aryl or 5-6 membered saturated or unsaturated cycloalkyl group 2 heteroatoms, independently selected from O, S, and N, the cyclic group of which can harbor one or more substituents selected from halo and Ci -4 alkyl);
y en el que Ra, Rb, Rb’, Rc, Rc’, Rd, R9, Rj, Rn, Rn’ Rp, Rp’, R1’, Ru’, Rv y R''’ se seleccionan independientemente de grupos alquileno Ci-e opcionalmente sustituidos por uno o más sustituyentes seleccionados de hidroxilo, halógeno, amino, and in which R a , R b , R b ' , R c , R c' , R d , R 9 , R j , R n , R n ' R p , R p' , R 1 ' , R u' , R v and R ''' are independently selected from Ci-e alkylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino,
Re, Rh, Rk y R* se seleccionan independientemente de grupos alquenileno C2-8 opcionalmente sustituidos por uno o más sustituyentes seleccionados de hidroxilo, halógeno, amino, y R* puede ser adicionalmente un enlace; R e , R h , R k and R * are independently selected from C 2-8 alkenylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino, and R * may additionally be a bond;
Rf, R', Rm y Ru se seleccionan independientemente de grupos alquinileno C2-5 opcionalmente sustituidos por uno o más sustituyentes seleccionados de hidroxilo, halógeno, amino. R f , R ', R m and R u are independently selected from C 2-5 alkynylene groups optionally substituted by one or more substituents selected from hydroxyl, halogen, amino.
En una realización particular, el compuesto según la fórmula (IX) en el que R1, R2, R3, R4 se seleccionan independientemente de, halo, ciano, nitro, trifluorometilo, alquilo Ci. 3, -NR13R14 (en el que R13 y R14, que pueden ser el mismo o diferente, cada uno representa hidrógeno o alquilo C1-3), o -X1R15 (en el que X1 representa un enlace directo, -O-, -CH2-, -OCO-, carbonilo, -S-, -SO-, -S02-, -NR16CO-, -CONR16-, -SO2NR16- , -NR17S02- O -NR18- (en el que R16, R17and R18 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3), y R15 se selecciona de uno de los siguientes grupos: In a particular embodiment, the compound according to formula (IX) in which R 1 , R 2 , R 3 , R 4 are independently selected from, halo, cyano, nitro, trifluoromethyl, Ci-alkyl. 3, -NR 13 R 14 (where R 13 and R 14 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or -X 1 R 15 (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -S0 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 S0 2 - O -NR 18 - (wherein R 16 , R 17 and R 18 each independently represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2-3 -alkyl), and R 15 is selected from one of the following groups:
1’) hidrógeno o alquilo C1-5 que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, fluoro o amino; 1 ') hydrogen or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro or amino;
2’) alquil CI-S-X2COR19 (en el que X2 representa -O- o -NR20- en el que R20 representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R1 9 representa alquilo C1-3, - NR1 21R22 o -OR23 (en el que R21, R22 y R23 que pueden ser el mismo o diferente cada uno representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3)); 2 ') alkyl CI- S -X 2 COR 19 (where X 2 represents -O- or -NR 20 - where R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 1 9 represents C 1-3 alkyl, - NR1 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, C 1-3 alkyl or C 3 -alkoxy-C 2-3 alkyl)) ;
3’) alquil Ci-s-X3R24 (en el que X3 representa -O-, -S-, -SO-, -SO2-, -OCO-, -NR25CO-, - CONR26-, -SO2NR27-, -NR28S02- O -NR29- (en el que R25, R26, R27, R28 y R29 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R24 representa hidrógeno, alquilo C1-3, ciclopentilo, ciclohexilo o un grupo heterocíclico de 5-6 miembros saturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo alquilo C1-3 puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno y alcoxilo C1-4 y cuyo grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-4, hidroxialquilo C1-4 y alcoxilo C1-4); 3 ') alkyl Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO-, -NR 25 CO-, - CONR 26 -, - SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represents hydrogen, C 1-3 -alkyl or C-alkoxy 3- C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, whose group C 1-3 alkyl can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and C 1-4 alkoxy and whose cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C 1-4 alkyl, hydroxyalkyl C 1-4 and C 1-4 alkoxy);
4’) alquil Ci-5-X4-alquil CI-5-X5R30 (en el que X4 y X5 que pueden ser el mismo o diferente son cada uno -O-, -S-, -SO-, -SO2-, -NR31CO-, -CONR32-, -SO2NR33-, - NR34SC>2- O -NR35- (en el que R31 , R32, R33, R34 y R35 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3) y R30 representa hidrógeno o alquilo C1-3); 4 ') alkyl Ci- 5 -X 4 -alkyl CI- 5 -X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -S-, -SO- , -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, - NR 34 SC> 2 - O -NR 35 - (where R 31 , R 32 , R 33 , R 34 and R 35 each independently represents hydrogen, C 1-3 -alkyl or C- 3- alkoxy-C 2-3 -alkyl and R 30 represents hydrogen or C 1-3 -alkyl);
5’) R36 (en el que R36 es un grupo heterocíclico de 5-6 miembros saturado (unido a través de carbono o nitrógeno) con 1-2 heteroátomos, seleccionados independientemente de O, S y N, en el que el grupo heterocíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-4, hidroxialquilo C1-4, alcoxilo C1-4, alcoxil Ci-4-alquilo Ci-4y alquilsulfonil Ci-4-alquilo C1-4); 5 ') R 36 (where R 36 is a saturated 5-6 membered heterocyclic group (bonded via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, where the group heterocyclic can accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, C 1-4 alkyl, hydroxy C 1-4, alkoxy C 1-4, alkoxyl Ci- 4 alkyl and Ci- 4 alkylsulfonyl Ci- 4 -C 1-4 );
6’) alquil C1-4-R36 (en el que R36 es tal como se define en (5’) anterior); 6 ') C 1-4 alkyl-R 36 (wherein R 36 is as defined in (5') above);
7’) alquenil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 7 ') C 2-5 -R 36 alkenyl (wherein R 36 is as defined in (5') above);
8’) alquinil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 8 ') C 2-5 alkynyl-R 36 (wherein R 36 is as defined in (5') above);
9’) R37 (en el que R37 representa un grupo piridona, un grupo fenilo o un grupo heterocíclico aromático de 5-6 miembros (unido a través de carbono o nitrógeno) con 1-3 heteroátomos seleccionados de O, N y S, en el que el grupo piridona, fenilo o heterocíclico aromático puede portar hasta 5 sustituyentes en un átomo de carbono disponible seleccionados de hidroxilo, halógeno, amino, alquilo C1-4, alcoxilo C1-4, hidroxialquilo C1-4, aminoalquilo C1-4, alquilamino C1-4, hidroxialcoxilo C1-4, carboxilo, trifluorometilo, ciano, -CONR38R39 y -NR40COR41 (en el que R38, R39, R40 y R41, que pueden ser el mismo o diferente, cada uno representa hidrógeno, alquilo C1-4 o alcoxil Ci-3-alquilo C2-3)); 9 ') R 37 (where R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S wherein the pyridone, phenyl or aromatic heterocyclic I may carry up to 5 substituents on available carbon atom selected from hydroxy, halogen, amino, C 1-4 alkyl, C 1-4 alkoxy, hydroxy C 1-4 aminoalkyl C 1-4 alkylamino C 1-4 hydroxyalkoxy C 04.01, carboxyl, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (wherein R 38, R 39, R 40 and R 41, which may be the same or different, each representing hydrogen, C 1-4 -alkyl or C- 3- alkoxy-C 2-3 alkyl));
10’) alquil C1-5-R37 (en el que R37 es tal como se define en (9’) anterior); 10 ') C 1-5 alkyl-R 37 (wherein R 37 is as defined in (9') above);
1 1‘) alquenil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 1 1 ') C 2-5 -R 37 alkenyl (wherein R 37 is as defined in (9') above);
12’) alquinil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 12 ') C 2-5 alkynyl-R 37 (wherein R 37 is as defined in (9') above);
13’) alquil Ci-s-X6R37 (en el que X6 representa -O-, -S-, -SO-, -SO2-, -NR42CO-, - CONR43-, -SO2NR44-, -NR45S02- O -NR46- (en el que R42, R43, R44, R45 y R46 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 13 ') alkyl Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, - CONR 43 -, -SO 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45, and R 46 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy-C-alkyl 2-3 ) and R 37 is as defined herein above);
14’) alquenil C2-s-X7R37 (en el que X7 representa -O-, -S-, -SO-, -SO2-, -NR47CO-, - CONR48-, -SO2NR49-, -NR50SO2- O -NR51- (en el que R47, R48, R49, R50 y R51 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define en (9’) anterior); 15’) alquinil C2-5-X8R37 (en el que X8 representa -O-, -S-, -SO-, -SO2-, -NR5CO-, - CONR53-, -SO2NR54-, -NR55S02- O -NR56- (en el que R52, R53, R54, R55 y R56 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 14 ') alkenyl C 2 -sX 7 R 37 (where X 7 represents -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, - CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represent hydrogen, C 1-3 alkyl or C 3 -alkoxy-alkyl C 2-3 ) and R 37 is as defined in (9 ') above); 15 ') C 2-5 alkynyl-X 8 R 37 (where X 8 represents -O-, -S-, -SO-, -SO 2 -, -NR 5 CO-, - CONR 53 -, -SO 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (where R 52 , R 53 , R 54 , R 55 and R 56 each independently represents hydrogen, C 1-3 -alkyl or C- 3- alkoxy -C 2-3 alkyl and R 37 is as defined herein above);
16’) alquil Ci-3-X9-alquil C1-3-R37 (en el que X9 representa -O-, -S-, -SO-, -SO2-, -16 ') C 3 -alkyl- 9- alkyl C 1-3 -R 37 (wherein X 9 represents -O-, -S-, -SO-, -SO 2 -, -
NR57CO-, -CONR58-, -SO2NR59-, -NR60SO2- O -NR61- (en el que R57, R58, R 59 R60 y R61 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); y NR 57 CO-, -CONR 58 -, -SO 2 NR 59 -, -NR 60 SO 2 - O -NR 61 - (where R 57 , R 58 , R 59 R 60 and R 61 each independently represents hydrogen , C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 37 is as hereinbefore defined herein); Y
17’) alquil Ci-3-X9-alquil C1-3-R36 (en el que X9 y R36 son tal como se definen en (5’) anterior). 17 ') Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
En una realización particular, el compuesto según la fórmula (IX) en el que R1 es hidrógeno y R4 es hidrógeno, halo, alquilo C1 -4 O alcoxilo C1 -4. In a particular embodiment, the compound according to formula (IX) in which R 1 is hydrogen and R 4 is hydrogen, halo, C 1-4 alkyl or C 1-4 alkoxy.
En una realización particular, el compuesto según la fórmula (IX) en el que al menos un grupo R2 o R3 comprende una cadena de al menos 3 átomos de carbono o heteroátomos opcionalmente sustituidos seleccionados de oxígeno, nitrógeno o azufre; en el que dicha cadena está preferiblemente sustituida por un grupo polar que ayuda a la solubilidad. In a particular embodiment, the compound according to formula (IX) in which at least one group R 2 or R 3 comprises a chain of at least 3 carbon atoms or optionally substituted heteroatoms selected from oxygen, nitrogen or sulfur; wherein said chain is preferably replaced by a polar group that aids in solubility.
En una realización particular, el compuesto según la fórmula (IX) en el que R3 es un grupo X1R15 en el que X1 es oxígeno y R15 incluye un grupo metileno directamente adyacente a X1. In a particular embodiment, the compound according to formula (IX) in which R 3 is a group X 1 R 15 in which X 1 is oxygen and R 15 includes a methylene group directly adjacent to X 1 .
En una realización particular, el compuesto según la fórmula (IX) en el que al menos uno de R1, R2, R3 o R4 es un grupo X1R15 que incluye grupos alquileno, alquenileno o alquinileno en puente Ra, Rb, Rb’, Rc, Rc’, Rd, R9, Rj, Rn, Rn’, Rp, R1’, Ru’, Rv, Rv’, Re, Rh, Rk, R‘, Rf, R', Rm y Ru y al menos uno de tales grupos incluye un sustituyente hidroxilo. En una realización particular, el compuesto según la fórmula (IX) en el que R5 es un grupo NHC(0)R9 o NHS(0)2R9 en el que R9 es tal como se define anteriormente en el presente documento. In a particular embodiment, the compound according to formula (IX) in which at least one of R 1 , R 2 , R 3 or R 4 is a group X 1 R 15 including alkylene, alkenylene or alkynylene groups in bridging R to , R b , R b ' , R c , R c' , R d , R 9 , R j , R n , R n ' , R p , R 1' , R u ' , R v , R v' , R e , R h , R k , R ', R f , R', R m and R u and at least one such group includes a hydroxyl substituent. In a particular embodiment, the compound according to formula (IX) in which R 5 is an NHC (0) R 9 or NHS (0) 2 R 9 group in which R 9 is as defined herein above. .
En una realización particular, el compuesto según la fórmula (IX) en el que R5 es un grupo C(0)R9, C(0)0R9, S(0)R9, S(0)0R9, S(0)20R9, C(O)NR10R11, S(O)NR10R11 o S(O)ONR10R11 en el que R9, R10 y R11 son tal como se definen anteriormente en el presente documento. In a particular embodiment, the compound according to formula (IX) in which R 5 is a group C (0) R 9 , C (0) 0R 9 , S (0) R 9 , S (0) 0R 9 , S (0) 2 0R 9 , C (O) NR 10 R 11 , S (O) NR 10 R 11 or S (O) ONR 10 R 11 where R 9 , R 10 and R 11 are as defined above in the present document.
En una realización particular, el compuesto según la fórmula (IX) en el que R9, R10 o R11 se seleccionan independientemente de arilo opcionalmente sustituido con uno o más grupos funcionales; In a particular embodiment, the compound according to formula (IX) wherein R 9 , R 10 or R 11 are independently selected from aryl optionally substituted with one or more functional groups;
cicloalquilo C3-6 opcionalmente sustituido con uno o más grupos funcionales; C 3-6 cycloalkyl optionally substituted with one or more functional groups;
aralquilo opcionalmente sustituido con uno o más grupos funcionales y en el que la parte de arilo puede comprender además uno o más sustituyentes alquilo; aralkyl optionally substituted with one or more functional groups and in which the aryl part may further comprise one or more alkyl substituents;
heterociclilo opcionalmente sustituido con uno o más grupos funcionales alquilo, alquenilo o alquinilo; heterocyclyl optionally substituted with one or more alkyl, alkenyl or alkynyl functional groups;
alquilo opcionalmente sustituido por un grupo funcional o un grupo cicloalquilo o heterociclilo en el que el grupo cicloalquilo o heterociclilo pueden estar ellos mismos opcionalmente sustituidos con uno o más grupos funcionales o alquilo; alkyl optionally substituted by a functional group or a cycloalkyl or heterocyclyl group in which the cycloalkyl or heterocyclyl group may themselves be optionally substituted with one or more functional or alkyl groups;
alquenilo opcionalmente sustituido por un grupo funcional o un grupo arilo o heterociclilo en el que el grupo arilo o heterociclilo puede estar opcionalmente sustituido con uno o más grupos funcionales o alquilo; y alkenyl optionally substituted by a functional group or an aryl group or heterocyclyl in which the aryl or heterocyclyl group may be optionally substituted with one or more functional or alkyl groups; Y
alquinilo opcionalmente sustituido por un grupo funcional o un grupo arilo o heterociclilo en el que el grupo arilo o heterociclilo puede estar opcionalmente sustituido con uno o más grupos funcionales o grupos alquilo. alkynyl optionally substituted by a functional group or an aryl or heterocyclyl group in which the aryl or heterocyclyl group may be optionally substituted with one or more functional groups or alkyl groups.
En una realización particular, el compuesto según la fórmula (IX) tiene la fórmula (IXa)  In a particular embodiment, the compound according to formula (IX) has formula (IXa)
Figure imgf000122_0001
Fórmula (IXa) o una sal, un éster, una amida o un profármaco del mismo;
Figure imgf000122_0001
Formula (IXa) or a salt, an ester, an amide or a prodrug thereof;
en la que X, R1 , R2, R3, R4, R6, R7 y R8 son tal como se definen anteriormente en el presente documento en la fórmula (IX); wherein X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined herein above in formula (IX);
Z es C(O) o S(0)2, y Z is C (O) or S (0) 2, and
R64 es un hidrocarbilo opcionalmente sustituido o heterociclilo opcionalmente sustituido. R 64 is an optionally substituted hydrocarbyl or optionally substituted heterocyclyl.
En una realización particular, el compuesto según la fórmula (IXa) tiene la fórmula (IXb)  In a particular embodiment, the compound according to the formula (IXa) has the formula (IXb)
Figure imgf000122_0002
Fórmula (IXb) o una sal, un éster o una amida del mismo;
Figure imgf000122_0002
Formula (IXb) or a salt, an ester or an amide thereof;
en la que X es O, o S, S(O) o S(0)2 o NR8 en el que R8 es hidrógeno o alquilo C1-6;where X is O, or S, S (O) or S (0) 2 or NR 8 where R 8 is hydrogen or C 1-6 alkyl;
Z es C(O) o S(0)2, Z is C (O) or S (0) 2,
R65 es un hidrocarbilo opcionalmente sustituido o heterociclilo opcionalmente sustituido; R 65 is an optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
R7 y R8 se seleccionan independientemente de hidrógeno, halo, alquilo C1-4, alcoxilo C1-4, alcoximetilo C1-4, di(alcoxil Ci-4)metilo, alcanoílo Ci-4, trifluorometilo, ciano, amino, alquenilo C2-5, alquinilo C2-5, un grupo fenilo, un grupo bencilo o un grupo heterocíclico de 5-6 miembros con 1-3 heteroátomos, seleccionados independientemente de O, S yR 7 and R 8 are independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (alkoxyl Ci- 4) methyl, alkanoyl Ci- 4, trifluoromethyl, cyano, amino alkenyl, C 2-5 alkynyl , C 2-5, a phenyl group, a benzyl group or a heterocyclic group 5-6 membered with 1-3 heteroatoms, independently selected from O, S, and
N, cuyo grupo heterocíclico puede ser aromático o no aromático y puede estar saturado (unido a través de un átomo de carbono o nitrógeno de anillo) o insaturado (unido a través de un átomo de carbono de anillo), y cuyo grupo fenilo, bencilo o heterocíclico puede albergar en uno o más átomos de carbono de anillo hasta 5 sustituyentes seleccionados de hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro, alcanoílo C2-4, alcanoilamino C1-4, alcoxicarbonilo C1-4, alquilsulfanilo C1-4, alquilsulfinilo C1-4, alquilsulfonilo C1-4, carbamoílo, N-alquilcarbamoílo C1-4, N,N-di(alquil Ci-4)carbamoílo, aminosulfonilo, N- alquilaminosulfonilo C1-4, N,N-di(alquil Ci-4)aminosulfonilo, alquilsulfonilamino C1-4, y un grupo heterocíclico saturado seleccionado de morfolino, tiomorfolino, pirrolidinilo, piperazinilo, piperidinilo, imidazolidinilo y pirazolidinilo, en el que el grupo heterocíclico saturado puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro y alcoxicarbonilo C1-4, y N, whose heterocyclic group can be aromatic or non-aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl group, benzyl or heterocyclic can hold one or more ring carbon atoms of up to 5 substituents selected from hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C 2-4 alkanoylamino C 1-4 alkoxycarbonyl C 1-4 alkylsulfanyl C 1-4 alkylsulfinyl C 1-4 alkylsulfonyl C 1-4, carbamoyl, N-alkylcarbamoyl C 1-4 N, N-di ( alkyl Ci- 4) carbamoyl, aminosulfonyl, alkylaminosulfonyl C 1-4 N-, N, N-di (Ci- 4) aminosulfonyl, alkylsulfonylamino C 1-4, and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl , piperidinyl, imidazolidinyl and pyrazolidinyl, in which the saturated heterocyclic group p ou accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy, alkanoyloxy C 1-3, trifluoromethyl, cyano, amino, nitro and C1-4alkoxycarbonyl, and
en la que R1 , R2, R3 y R4 se seleccionan independientemente de, halo, ciano, nitro, trifluorometilo, alquilo C1-3, -NR13R14 (en el que R13 y R14, que pueden ser el mismo o diferente, cada uno representa hidrógeno o alquilo C1-3), o -X1 R15 (en el que X1’ representa un enlace directo, -O-, -CH2-, -OCO-, carbonilo, -S-, -SO-, -SO2-, -NR16CO-, -CONR16-, -SO2NR16-, -NR17S02- O -NR18- (en el que R16, R17 y R18 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3), y R15 se selecciona de uno de los siguientes grupos: wherein R 1 , R 2 , R 3 and R 4 are independently selected from, halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (where R 13 and R 14 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or -X 1 R 15 (where X 1 'represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl , -S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 15 is selected from one of the following groups:
1’) hidrógeno o alquilo C1-5 que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, fluoro o amino; 1 ') hydrogen or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro or amino;
2’) alquil CI-S-X2COR19 (en el que X2 representa -O- o -NR20- en el que R20 representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R19 representa alquilo C1-3, - NR121 R22 o -OR23 (en el que R21 , R22 y R23 que pueden ser el mismo o diferente cada uno representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3)); 2 ') alkyl CI- S -X 2 COR 19 (where X 2 represents -O- or -NR 20 - where R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 19 represents C 1-3 alkyl, - NR1 21 R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, C 1-3 alkyl O Ci- 3 alkoxyl C 2-3 alkyl));
3’) alquil Ci-s-X3R24 (en el que X3 representa -O-, -S-, -SO-, -SO2-, -OCO-, NR25CO-, - CONR26-, -SO2NR27-, -NR28S02- O -NR29- (en el que R25, R26, R27, R28 y R29 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R24 representa hidrógeno, alquilo C1-3, ciclopentilo, ciclohexilo o un grupo heterocíclico de 5-6 miembros saturado con 1-2 heteroátomos, seleccionados independientemente de3 ') alkyl Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO-, NR 25 CO-, - CONR 26 -, -SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy -C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from
O, S y N, en el que el grupo alquilo C1-3 puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno y alcoxilo C1-4 y en el que el grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-4, hidroxialquilo Ci-4y alcoxilo C1-4); O, S and N, in which the C1-3 alkyl group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and C1-4 alkoxy and in which the cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C1-4 alkyl, Ci- 4 hydroxyalkyl and C1-4 alkoxy);
4’) alquil Ci-5-X4-alquil CI-5-X5R30 (en el que X4 y X5 que pueden ser el mismo o diferente son cada uno -O-, -S-, -SO-, -SO2-, -NR31CO-, -CONR32-, -SO2NR33-, - NR34S02- O -NR35- (en el que R31 , R32, R33, R34 y R35 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3) y R30 representa hidrógeno o alquilo C1-3); 4 ') alkyl Ci- 5 -X 4 -alkyl CI- 5 -X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -S-, -SO- , -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, - NR 34 S0 2 - O -NR 35 - (where R 31 , R 32 , R 33 , R 34 and R 35 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 30 represents hydrogen or C 1-3 alkyl);
5’) R36 (en el que R36 es un grupo heterocíclico de 5-6 miembros saturado (unido a través de carbono o nitrógeno) con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo heterocíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-4, hidroxialquilo C1-4, alcoxilo C1-4, alcoxil Ci-4-alquilo Ci-4 y alquilsulfonil Ci-4-alquilo C1-4); 5 ') R 36 (where R 36 is a saturated 5-6 membered heterocyclic group (bonded via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxyl, alkoxyl Ci-4-alkyl and Ci - 4 alkylsulfonyl-Ci-4 alkyl C1-4);
6’) alquil C1-5-R36 (en el que R36 es tal como se define en (5’) anterior); 7’) alquenil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 6 ') C1-5 alkyl R 36 (wherein R 36 is as defined in (5') above); 7 ') C2-5-R 36 alkenyl (wherein R 36 is as defined in (5') above);
8’) alquinil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 8 ') C2-5-R 36 alkynyl (wherein R 36 is as defined in (5') above);
9’) R37 (en el que R37 representa un grupo piridona, un grupo fenilo o un grupo heterocíclico aromático de 5-6 miembros (unido a través de carbono o nitrógeno) con 1-3 heteroátomos seleccionados de O, N y S, cuyo grupo piridona, fenilo o heterocíclico aromático puede portar hasta 5 sustituyentes en un átomo de carbono disponible seleccionados de hidroxilo, halógeno, amino, alquilo C1 -4, alcoxilo C1 -4, hidroxialquilo C1 -4, aminoalquilo C1 -4, alquilamino C1 -4, hidroxialcoxilo C1 -4, carboxilo, trifluorometilo, ciano, -CONR38R39 y -NR40COR41 (en el que R38, R39, R40 y R41 , que pueden ser el mismo o diferente, cada uno representa hidrógeno, alquilo C1 -4 o alcoxil Ci-3-alquilo C2-3)); 9 ') R 37 (where R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S , whose pyridone, phenyl or aromatic heterocyclic group can carry up to 5 substituents on an available carbon atom selected from hydroxyl, halogen, amino, C1-4alkyl, C1-4alkoxy, hydroxyalkylC1-4, aminoalkylC1-4, alkylaminoC1 -4, C1-4 hydroxyalkoxy, carboxyl, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (where R 38 , R 39 , R 40 and R 41 , which may be the same or different, each one represents hydrogen, C1-4alkyl or Ci-3-alkoxyC2-3alkyl));
10’) alquil C1 -5-R37 (en el que R37 es tal como se define en (9’) anterior); 10 ') C 1 -5-alkyl R 37 (wherein R 37 is as defined in (9') above);
1 1’) alquenil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 1 1 ') C2-5-R 37 alkenyl (wherein R 37 is as defined in (9') above);
12’) alquinil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 12 ') C2-5-alkynyl R 37 (wherein R 37 is as defined in (9') above);
13’) alquil Ci-s-X6R37 (en el que X6 representa -O-, -S-, -SO-, -SO2-, -NR42CO-, -13 ') alkyl Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -
CONR43-, -SO2NR44-, -NR45S02- O -NR46- (en el que R42, R43, R44, R45 y R46 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); CONR 43 -, -SO 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45 and R 46 each independently represents hydrogen, C 1- alkyl 3 or Ci- 3 alkoxyl C 2-3 alkyl) and R 37 is as hereinbefore defined herein);
14’) alquenil C2-s-X7R37 (en el que X7 representa -O-, -S-, -SO-, -SO2-, -NR47CO-, - CONR48-, -SO2NR49-, -NR50SO2- O -NR51- (en el que R47, R48, R49, R50 y R51 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define en (9’) anterior); 14 ') alkenyl C 2 -sX 7 R 37 (where X 7 represents -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, - CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represent hydrogen, C 1-3 alkyl or C 3 -alkoxy-alkyl C 2-3 ) and R 37 is as defined in (9 ') above);
15’) alquinil C2-s-X8R37 (en el que X8 representa -O-, -S-, -SO-, -SO2-, -NR52CO-, - CONR53-, -SO2NR54-, -NR55S02- O -NR56- (en el que R52, R53, R54, R55 y R56 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 15 ') alkynyl C 2 -sX 8 R 37 (where X 8 represents -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, - CONR 53 -, -SO 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (wherein R 52 , R 53 , R 54 , R 55, and R 56 each independently represent hydrogen, C 1-3 alkyl, or Ci- 3- alkoxy-alkyl C 2-3 ) and R 37 is as defined herein above);
16’) alquil Ci-3-X9-alquil C1-3-R37 (en el que X9 representa -O-, -S-, -SO-, -SO2-, - NR57CO-, -CONR58-, -SO2NR59-, -NR60SO2- O -NR61- (en el que R57, R58, R59, R60 y R61 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); y 16 ') Ci-3-X 9 -alkyl-C1-3-alkyl- 37 (in which X 9 represents -O-, -S-, -SO-, -SO2-, - NR 57 CO-, -CONR 58 -, -SO2NR 59 -, -NR 60 SO 2 - O -NR 61 - (where R 57 , R 58 , R 59 , R 60 and R 61 each independently represents hydrogen, C1-3-alkyl or C-alkoxy 3-C2-3alkyl) and R 37 is as defined herein above); Y
17’) alquil Ci-3-X9-alquil C1-3-R36 (en el que X9 y R36 son tal como se definen en (5’) anterior). 17 ') Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
En una realización particular, el compuesto según la fórmula (IX) tiene la fórmula (IXc)  In a particular embodiment, the compound according to formula (IX) has formula (IXc)
Figure imgf000124_0001
Fórmula (IXc) o una sal, un éster, una amida o un profármaco del mismo;
Figure imgf000124_0001
Formula (IXc) or a salt, an ester, an amide, or a prodrug thereof;
en la que X, R1, R2, R3, R4, R6, R7 y R8 son tal como se definen anteriormente en el presente documento; where X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined herein above;
Y es C, S o S(O),  Y is C, S or S (O),
R65 es un grupo R9, OR9 o NR10R11 en el que R9, R10 y R11 son tal como se definen anteriormente en el presente documento. R 65 is a group R 9 , OR 9 or NR 10 R 11 in which R 9 , R 10 and R 11 are as defined herein above.
En una realización particular, el compuesto según la fórmula (IX) tiene la fórmula (IXd)  In a particular embodiment, the compound according to formula (IX) has formula (IXd)
Figure imgf000125_0001
Figure imgf000125_0001
Fórmula (IXd)  Formula (IXd)
o una sal, un éster o una amida del mismo; or a salt, an ester or an amide thereof;
en la que X es O, o S, S(O) o S(0)2, o NR8 en el que R8 es hidrógeno o alquilo C1-6;wherein X is O, or S, S (O) or S (0) 2, or NR 8 wherein R 8 is hydrogen or C1- 6 alkyl;
Y es C, S o S(O), Y is C, S or S (O),
R65 es un grupo R9, OR9 o NR10R11 en el que R9, R10 y R11 se seleccionan independientemente de hidrógeno, hidrocarbilo opcionalmente sustituido y heterociclilo opcionalmente sustituido, y R10 y R11 pueden formar, junto con el átomo de nitrógeno al que se unen, un anillo heterocíclico opcionalmente sustituido que contiene opcionalmente heteroátomos adicionales, R 65 is a group R 9 , OR 9 or NR 10 R 11 in which R 9 , R 10 and R 11 are independently selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 can, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring optionally containing additional heteroatoms,
R6 y R7 se seleccionan independientemente de hidrógeno, halo, alquilo Ci-4, alcoxilo C1-4, alcoximetilo Ci-4, di(alcoxil Ci-4)metilo, alcanoílo Ci-4, trifluorometilo, ciano, amino, alquenilo C2-5, alquinilo C2-5, un grupo fenilo, un grupo bencilo o un grupo heterocíclico de 5-6 miembros con 1-3 heteroátomos, seleccionados independientemente de O, S y N, en el que el grupo heterocíclico puede ser aromático o no aromático y puede estar saturado (unido a través de un átomo de carbono o nitrógeno de anillo) o insaturado (unido a través de un átomo de carbono de anillo), y cuyo grupo fenilo, bencilo o heterocíclico puede albergar en uno o más átomos de carbono de anillo hasta 5 sustituyentes seleccionados de hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro, alcanoílo C2-4, alcanoilamino Ci-4, alcoxicarbonilo Ci-4, alquilsulfanilo Ci-4, alquilsulfinilo Ci-4, alquilsulfonilo Ci-4, carbamoílo, N-alquilcarbamoílo Ci-4, N,N-di(alquil Ci-4)carbamoílo, aminosulfonilo, N- alquilaminosulfonilo Ci-4, N,N-di(alquil Ci-4)aminosulfonilo, alquilsulfonilamino Ci-4, y un grupo heterocíclico saturado seleccionado de morfolino, tiomorfolino, pirrolidinilo, piperazinilo, piperidinilo imidazolidinilo y pirazolidinilo, cuyo grupo heterocíclico saturado puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro y alcoxicarbonilo Ci-4, y R1, R2, R3, R4 se seleccionan independientemente de, halo, ciano, nitro, trifluorometilo, alquilo C1-3, -NR13R14 (en el que R13 y R14, que pueden ser el mismo o diferente, cada uno representa hidrógeno o alquilo ¿1-3), o -X1R15 (en el que X1 representa un enlace directo, -O-, -CH2-, -OCO-, carbonilo, -S-, -SO-, -S02-, -NR16CO-, -CONR16-, -SO2NR16- , -NRI7S02- O -NR18- (en el que R16, R17 y R18 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3), y R15 se selecciona de uno de los siguientes grupos: R 6 and R 7 are independently selected from hydrogen, halo, Ci- 4, C1-4alkoxy, Ci- 4 alkoxymethyl, di (alkoxyl Ci- 4) methyl, alkanoyl Ci- 4, trifluoromethyl, cyano, amino, C2 -5, C2-5 alkynyl, a phenyl group, a benzyl group or a 5-6 membered heterocyclic group with 1-3 heteroatoms, independently selected from O, S and N, wherein the heterocyclic group may or may not be aromatic aromatic and can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl, benzyl or heterocyclic group can harbor one or more atoms of ring carbon to 5 substituents selected from hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C2- 4 alkanoylamino Ci- 4 alkoxycarbonyl Ci- 4 Ci- 4 alkylsulfanyl, alkylsulfinyl Ci- 4 alkylsulfonyl Ci- 4, carbamoyl, N-a lquilcarbamoílo Ci- 4, N, N-di (Ci- 4) carbamoyl, aminosulphonyl, N- alkylaminosulfonyl Ci- 4, N, N-di (Ci- 4) aminosulfonyl, alkylsulfonylamino Ci- 4, and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl, the saturated heterocyclic group of which may harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C1-3alkyl, C1-3alkoxyloxy, trifluoromethyl, cyano, amino, nitro and Ci- 4 alkoxycarbonyl, and R 1 , R 2 , R 3 , R 4 are independently selected from, halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (where R 13 and R 14 , which may be the same or different, each represents hydrogen or? 1-3 alkyl), or -X 1 R 15 (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S- , -SO-, -S0 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR I7 S0 2 - O -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 15 is selected from one of the following groups:
1’) hidrógeno o alquilo C1 -5 que puede no estar sustituido o que puede estar sustituido con uno o más grupos seleccionados de hidroxilo, fluoro o amino;  1 ') hydrogen or C1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxyl, fluoro or amino;
2’) alquil CI-S-X2COR19 (en el que X2 representa -O- o -NR20- en el que R20 representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3) y R19 representa alquilo C1-3, -NR12IR22 o -OR23 (en el que R21 , R22 y R23 que pueden ser el mismo o diferente cada uno representa hidrógeno, alquilo ¿1-3 o alcoxil Ci-3-alquilo C2-3)); 2 ') alkyl CI- S -X 2 COR 19 (in which X 2 represents -O- or -NR 20 - in which R 20 represents hydrogen, C 1-3 -alkyl or Ci- 3- alkoxy-C 2- alkyl 3 ) and R 19 represents C 1-3 alkyl, -NR1 2I R 22 or -OR 23 (where R 21 , R 22 and R 23 which may be the same or different each represent hydrogen, alkyl 1-3 alkoxyl or C 2-3 -alkyl Ci- 3));
3’) alquil Ci-s-X3R24(en el que X3 representa -O-, -S-, -SO-, -SO2-, -OCO-,-NR25CO-, - CONR26-, -SO2NR27-, -NR28S02- O -NR29- (en el que R25, R26, R27, R28 y R29 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R24 representa hidrógeno, alquilo C1-3, ciclopentilo, ciclohexilo o un grupo heterocíclico de 5-6 miembros saturado con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo alquilo C1-3 puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno y alcoxilo Ci-4 y en el que el grupo cíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-4, hidroxialquilo C1-4 y alcoxilo C1-4); 3 ') alkyl Ci-sX 3 R 24 (where X 3 represents -O-, -S-, -SO-, -SO 2 -, -OCO -, - NR 25 CO-, - CONR 26 -, - SO 2 NR 27 -, -NR 28 S0 2 - O -NR 29 - (where R 25 , R 26 , R 27 , R 28 and R 29 each independently represents hydrogen, C 1-3 -alkyl or C-alkoxy 3- C 2-3 alkyl) and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6 membered heterocyclic group saturated with 1-2 heteroatoms, independently selected from O, S and N, whose group C 1-3 alkyl can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen and Ci- 4 alkoxy and in which the cyclic group can harbor 1 or 2 substituents selected from oxo, hydroxyl, halogen, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy);
4’) alquil Ci-5-X4-alquil CI-5-X5R30 (en el que X4 y X5 que pueden ser el mismo o diferente son cada uno -O-, -S-, -SO-, -SO2-, -NR31CO-, -CONR32-, -SO2NR33-, - NR34S02- O -NR35- (en el que R31, R32, R33, R34 y R35 cada uno independientemente representa hidrógeno, alquilo C1-3 O alcoxil Ci-3-alquilo C2-3) y R30 representa hidrógeno o alquilo C1-3); 4 ') alkyl Ci- 5 -X 4 -alkyl CI- 5 -X 5 R 30 (where X 4 and X 5 which may be the same or different are each -O-, -S-, -SO- , -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, - NR 34 S0 2 - O -NR 35 - (where R 31 , R 32 , R 33 , R 34 and R 35 each independently represents hydrogen, C 1-3 alkyl or alkoxyl Ci- 3 C 2-3 alkyl) and R 30 represents hydrogen or C 1-3 alkyl);
5’) R36 (en el que R36 es un grupo heterocíclico de 5-6 miembros saturado (unido a través de carbono o nitrógeno) con 1-2 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo heterocíclico puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo Ci-4, hidroxialquilo Ci-4, alcoxilo C1-4, alcoxil Ci-4-alquilo Ci-4y alquilsulfonil Ci-4-alquilo Ci-4); 5 ') R 36 (where R 36 is a 5-6 membered heterocyclic group saturated (linked via carbon or nitrogen) with 1-2 heteroatoms, independently selected from O, S, and N, the heterocyclic group of which can harbor 1 or 2 substituents selected from oxo, hydroxy, halogen, Ci -4 alkyl, Ci -4 hydroxyalkyl, C1-4 alkoxyl, alkoxyl alkyl Ci-4-Ci- 4 alkylsulfonyl and Ci-4-alkyl Ci -4);
6’) alquil C1-5-R36 (en el que R36 es tal como se define en (5’) anterior); 6 ') C1-5 alkyl R 36 (wherein R 36 is as defined in (5') above);
7’) alquenil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 7 ') C2-5-R 36 alkenyl (wherein R 36 is as defined in (5') above);
8’) alquinil C2-5-R36 (en el que R36 es tal como se define en (5’) anterior); 8 ') C2-5-R 36 alkynyl (wherein R 36 is as defined in (5') above);
9’) R37 (en el que R37 representa un grupo piridona, un grupo fenilo o un grupo heterocíclico aromático de 5-6 miembros (unido a través de carbono o nitrógeno) con 1-3 heteroátomos seleccionados de O, N y S, en el que el grupo piridona, fenilo o heterocíclico aromático puede portar hasta 5 sustituyentes en un átomo de carbono disponible seleccionados de hidroxilo, halógeno, amino, alquilo Ci-4, alcoxilo Ci-4, hidroxialquilo Ci-4, aminoalquilo Ci-4, alquilamino Ci-4, hidroxialcoxilo Ci-4, carboxilo, trifluorometilo, ciano, -CONR38R39 y -NR40COR41 (en el que R38, R39, R40 y R41, que pueden ser el mismo o diferente, cada uno representa hidrógeno, alquilo Ci-4 o alcoxil Ci-3-alquilo C2-3)); 9 ') R 37 (where R 37 represents a pyridone group, a phenyl group or a 5-6 membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S wherein the pyridone, phenyl or aromatic heterocyclic I may carry up to 5 substituents on available carbon atom selected from hydroxy, halogen, amino, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 hydroxyalkyl, aminoalkyl Ci -4 , Ci -4 alkylamino, Ci -4 hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -CONR 38 R 39 and -NR 40 COR 41 (wherein R 38, R 39, R 40 and R 41, which may be the same or different, each represents hydrogen, Ci -4 alkyl or alkoxyl Ci-3-alkyl C 2-3));
10’) alquil C1-5-R37 (en el que R37 es tal como se define en (9’) anterior); 1 1’) alquenil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 10 ') C1-5-alkyl 37 (wherein R 37 is as defined in (9') above); 1 1 ') C2-5-R 37 alkenyl (wherein R 37 is as defined in (9') above);
12’) alquinil C2-5-R37 (en el que R37 es tal como se define en (9’) anterior); 12 ') C2-5-alkynyl R 37 (wherein R 37 is as defined in (9') above);
13’) alquil Ci-s-X6R37 (en el que X6 representa -O-, -S-, -SO-, -SO2-, -NR42CO-, - CONR43-, -SO2NR44-, -NR45S02- O -NR46- (en el que R42, R43, R44, R45 y R46 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 13 ') alkyl Ci-sX 6 R 37 (where X 6 represents -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, - CONR 43 -, -SO 2 NR 44 -, -NR 45 S0 2 - O -NR 46 - (where R 42 , R 43 , R 44 , R 45, and R 46 each independently represent hydrogen, C 1-3 alkyl, or C 3 -alkoxy-C-alkyl 2-3 ) and R 37 is as defined herein above);
14’) alquenil C2-s-X7R37 (en el que X7 representa -O-, -S-, -SO-, -SO2-, -NR47CO-, - CONR48-, -SO2NR49-, -NR50SO2- O -NR51- (en el que R47, R48, R49, R50 y R51 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define en (9’) anterior); 14 ') alkenyl C 2 -sX 7 R 37 (where X 7 represents -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, - CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - O -NR 51 - (where R 47 , R 48 , R 49 , R 50 and R 51 each independently represent hydrogen, C 1-3 alkyl or C 3 -alkoxy-alkyl C 2-3 ) and R 37 is as defined in (9 ') above);
15’) alquinil C2-s-X8R37 (en el que X8 representa -O-, -S-, -SO-, -SO2-, -NR52CO-, - CONR53-, -SO2NR54-, -NR55S02- O -NR56- (en el que R52, R53, R54, R55 y R56 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); 15 ') alkynyl C 2 -sX 8 R 37 (where X 8 represents -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, - CONR 53 -, -SO 2 NR 54 -, -NR 55 S0 2 - O -NR 56 - (wherein R 52 , R 53 , R 54 , R 55, and R 56 each independently represent hydrogen, C 1-3 alkyl, or Ci- 3- alkoxy-alkyl C 2-3 ) and R 37 is as defined herein above);
16’) alquil Ci-3-X9-alquil C1-3-R37 (en el que X9 representa -O-, -S-, -SO-, -SO2-, -16 ') Ci-3-X 9 -alkyl C1-3-R-alkyl 37 (where X 9 represents -O-, -S-, -SO-, -SO2-, -
NR57CO-, -CONR58-, -SO2NR59-, -NR60SO2- O -NR61- (en el que R57, R58, R59, R60 y R61 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxil Ci-3-alquilo C2-3) y R37 es tal como se define anteriormente en el presente documento); y NR 57 CO-, -CONR 58 -, -SO2NR 59 -, -NR 60 SO 2 - O -NR 61 - (where R 57 , R 58 , R 59 , R 60 and R 61 each independently represents hydrogen, C1-3alkyl or Ci-3alkoxy-C2-3alkyl) and R 37 is as defined herein above); Y
17’) alquil Ci-3-X9-alquil C1-3-R36 (en el que X9 y R36 son tal como se definen en (5’) anterior). 17 ') Ci-3-X 9 -alkyl-C1-3-R-alkyl- 36 (wherein X 9 and R 36 are as defined in (5') above).
En una realización particular, el compuesto según la fórmula (IXa) o una sal, un éster, una amida o un profármaco del mismo, siempre que  In a particular embodiment, the compound according to formula (IXa) or a salt, an ester, an amide or a prodrug thereof, provided that
(i) en el que R1 , R4, R6, R7 y R8 son todos hidrógeno y R2 y R3 son ambos hidrógeno o ambos metoxilo, R64 es distinto de fenilo; (i) where R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are both hydrogen or both methoxy, R 64 is other than phenyl;
(ii) en el que R1 , R4, R6, R7 y R8 son todos hidrógeno y R2 y R3 son metoxilo, y Z es C(O), R64 es distinto de metilo; (ii) where R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are methoxy, and Z is C (O), R 64 is other than methyl;
(iii) en el que R1 , R2, R3, R4, R6, R7 y R8 son todos hidrógeno, X es oxígeno, R6 es 4- metil-1-piperazinilo y Z es C(O), R64 es distinto de metilo. (iii) where R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are all hydrogen, X is oxygen, R 6 is 4-methyl-1-piperazinyl and Z is C (O ), R 64 is other than methyl.
i) En una realización particular, el compuesto según la fórmula (IXb) o una sal, un éster, una amida o un profármaco del mismo, siempre queen el que R1 , R4 , R7 y R8 son todos hidrógeno y R2 y R3 son ambos hidrógeno o ambos metoxilo, R64 es distinto de fenilo; y i) In a particular embodiment, the compound according to formula (IXb) or a salt, an ester, an amide or a prodrug thereof, provided that R 1 , R 4 , R 7 and R 8 are all hydrogen and R 2 and R 3 are both hydrogen or both methoxy, R 64 is other than phenyl; Y
ii) en el que R1 , R4, R6, R7 y R8 son todos hidrógeno y R2 y R3 son metoxilo, y Z es C(O), R64 es distinto de metilo. ii) where R 1 , R 4 , R 6 , R 7 and R 8 are all hydrogen and R 2 and R 3 are methoxy, and Z is C (O), R 64 is other than methyl.
En una realización particular, el compuesto según la fórmula (IX) tiene la siguiente fórmula
Figure imgf000128_0001
In a particular embodiment, the compound according to formula (IX) has the following formula
Figure imgf000128_0001
o una sal, un éster, una amida o un profármaco del mismo, or a salt, an ester, an amide or a prodrug thereof,
en la que R1, R4, R6, R7, R8, R64, Z y X son tal como se definen para la fórmula (IXa) y R2’ y R3’ son los grupos R2 y R3 respectivamente, siempre que al menos uno de dichos grupos y preferiblemente R3 sea un grupo de subfórmula X1-R15 en la que X1 es tal como se define anteriormente, y R15 es un grupo R15 tal como se define anteriormente en la fórmula (IX), siempre que sea distinto de metilo. wherein R 1 , R 4 , R 6 , R 7 , R 8 , R 64 , Z and X are as defined for formula (IXa) and R 2 ' and R 3' are the groups R 2 and R 3 respectively, provided that at least one of said groups and preferably R 3 is a group of sub-formula X 1 -R 15 in which X 1 is as defined above, and R 15 is a group R 15 as defined above in formula (IX), provided it is other than methyl.
En una realización particular, el compuesto según la fórmula (IX) tiene la siguiente fórmula  In a particular embodiment, the compound according to formula (IX) has the following formula
Figure imgf000128_0002
Figure imgf000128_0002
o una sal, un éster o una amida del mismo; or a salt, an ester or an amide thereof;
en la que R1, R4, R6, R7, R8, X, Z y R64 son tal como se definen para la fórmula (IXb) y R2’ y R3’ son los grupos R2 y R3 tal como se define para la fórmula (IXb) respectivamente, siempre que al menos uno de dichos grupos y preferiblemente R3 sea un grupo de subfórmula X1-R15 en la que X1 es tal como se define para la fórmula (IXb), y R15 es un grupo R15 tal como se define para la fórmula (IXb), siempre que sea distinto de metilo. wherein R 1 , R 4 , R 6 , R 7 , R 8 , X, Z and R 64 are as defined for formula (IXb) and R 2 ' and R 3' are the groups R 2 and R 3 as defined for formula (IXb) respectively, provided that at least one of said groups and preferably R 3 is a group of sub-formula X 1 -R 15 where X 1 is as defined for formula (IXb ), and R 15 is a group R 15 as defined for formula (IXb), provided it is other than methyl.
En una realización particular, el compuesto según la fórmula (IX) tiene la siguiente fórmula  In a particular embodiment, the compound according to formula (IX) has the following formula
Figure imgf000128_0003
o una sal, un éster, una amida o un profármaco del mismo,
Figure imgf000128_0003
or a salt, an ester, an amide or a prodrug thereof,
en la que X, Y, R1 , R4, R6, R7, R8 son tal como se definen para la fórmula (IX), R65 es tal como se define para la fórmula (IXc), y R68 y R69 son equivalentes a R2 y R3 tal como se define anteriormente para la fórmula (IX) excepto que al menos uno de R68 o R69 es un grupo de subfórmula X1 R15 en la que R15 es tal como se define anteriormente para la fórmula (IX), siempre que cuando dicho uno de R68 o R69 sea morfolino propoxilo, el otro no sea un grupo de subfórmula (18) tal como se define para la fórmula (IX); y además siempre que cuando dicho uno de R68 o R69 sea metoxietoxilo, el otro no sea metoxilo. wherein X, Y, R 1 , R 4 , R 6 , R 7 , R 8 are as defined for formula (IX), R 65 is as defined for formula (IXc), and R 68 and R 69 are equivalent to R 2 and R 3 as defined above for formula (IX) except that at least one of R 68 or R 69 is a group of sub-formula X 1 R 15 in which R 15 is as is defined above for formula (IX), provided that said one of R 68 or R 69 is morpholinopropoxy, the other is not a sub-formula group (18) as defined for formula (IX); and further provided that when said one of R 68 or R 69 is methoxyethoxy, the other is not methoxy.
En una realización particular, el compuesto según la fórmula (IX) tiene la siguiente fórmula In a particular embodiment, the compound according to formula (IX) has the following formula
Figure imgf000129_0001
Figure imgf000129_0001
o una sal, un éster o una amida del mismo, or a salt, an ester or an amide thereof,
en la que X, Y, R1 , R4, R6, R7, R8 son tal como se definen para la fórmula (IXd), R65 es tal como se define para la fórmula (IXd), y R68 y R69 son equivalentes a R2 y R3 tal como se define para la fórmula (IXd) excepto que al menos uno de R68 o R69 es un grupo de subfórmula X1 R15 en la que R15 es tal como se define para la fórmula (IXd), siempre que cuando dicho uno de R68 o R69 sea morfolino propoxilo, el otro no sea un grupo de subfórmula (18) tal como se define para la fórmula (IXd); y además siempre que cuando dicho uno de R68 o R69 sea metoxietoxilo, el otro no sea metoxilo. wherein X, Y, R 1 , R 4 , R 6 , R 7 , R 8 are as defined for formula (IXd), R 65 is as defined for formula (IXd), and R 68 and R 69 are equivalent to R 2 and R 3 as defined for formula (IXd) except that at least one of R 68 or R 69 is a group of sub-formula X 1 R 15 where R 15 is as defines for formula (IXd), provided that when said one of R 68 or R 69 is morpholino propoxy, the other is not a group of sub-formula (18) as defined for formula (IXd); and further provided that when said one of R 68 or R 69 is methoxyethoxy, the other is not methoxy.
En las formulas anteriores, X es preferiblemente NH y X1 es oxígeno. In the above formulas, X is preferably NH and X 1 is oxygen.
En una realización adicional, el inhibidor de AURK se selecciona de un compuesto de fórmula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) o (IX) tal como se definió anteriormente. En una realización adicional, el inhibidor de AURK comprende ARNip anti-AURK (por ejemplo, ARNip que selecciona como diana AURKB), barasertib, tozasertib, alisertib, mesilato de SNS-314, MK-5108, ENMD-2076, AMG-900, hesperadina, ZM-447439 o una combinación de los mismos. Preferiblemente, el ARNip de AURK comprende cualquiera de SEQ ID NO: 1-4, una variante funcionalmente equivalente de las mismas, o una combinación de al menos cualesquiera de dos secuencias seleccionadas del grupo que consiste en SEQ ID NO: 1-4 o sus variantes equivalentes funcionales. En una versión preferida de esta realización, el inhibidor de AURK comprende barasertib, tozasertib o una combinación de los mismos. Lo más preferiblemente, el inhibidor de AURK es barasertib.  In a further embodiment, the AURK inhibitor is selected from a compound of formula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) or (IX ) as defined above. In a further embodiment, the AURK inhibitor comprises anti-AURK siRNA (eg, siRNA that targets AURKB), barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG-900, hesperadine, ZM-447439 or a combination thereof. Preferably, the AURK siRNA comprises any of SEQ ID NO: 1-4, a functionally equivalent variant thereof, or a combination of at least any of two sequences selected from the group consisting of SEQ ID NO: 1-4 or their equivalent functional variants. In a preferred version of this embodiment, the AURK inhibitor comprises barasertib, tozasertib, or a combination thereof. Most preferably, the AURK inhibitor is barasertib.
El tratamiento beneficioso o los efectos preventivos de los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención en relación a la infección por VIH o los síntomas del SIDA incluyen, por ejemplo, la prevención o el retraso de la infección inicial de un sujeto expuesto al VIH, la reducción de la carga viral en un sujeto infectado con VIH, la prolongación de la fase asintomática de la infección por VIH, el mantenimiento de unas cargas virales bajas en sujetos infectados por VIH cuyos niveles virales se han reducido a través de terapia antirretroviral (TAR), aumentando los niveles de células T CD4 o reduciendo la disminución en células T CD4, tanto específicas como no específicas de VIH-1 , en sujetos no tratados con fármacos y en sujetos tratados con AT, aumentando la salud y la calidad de vida globales en un sujeto con SIDA y prolongando la esperanza de vida de un sujeto con SIDA. Un médico o veterinario puede comparar el efecto del tratamiento con el estado del sujeto antes el tratamiento, o con el estado esperado de un sujeto no tratado, para determinar si el tratamiento es eficaz en la inhibición del SIDA. En una realización preferida, los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención se usan para la prevención de la infección por VIH o SIDA. En otra realización preferida, los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención se usan para el tratamiento de la infección por VIH o SIDA. Por tanto, los inhibidores de AURK de la presente invención serán adecuados para la inclusión en los protocolos de ART comúnmente aplicados a los pacientes con VIH o SIDA. The beneficial treatment or preventive effects of AURK inhibitors, active agents, compositions and additional combinations of the invention in relation to HIV infection or AIDS symptoms include, for example, the prevention or delay of initial infection of a subject exposed to HIV, the reduction of viral load in an HIV-infected subject, prolongation of the asymptomatic phase of HIV infection, maintenance of low viral loads in HIV-infected subjects whose viral levels have been reduced through antiretroviral therapy (ART), by increasing levels of CD4 T cells or reducing the decrease in CD4 T cells, both HIV-1 specific and nonspecific, in subjects not treated with drugs and in subjects treated with AT, increasing overall health and quality of life in a subject with AIDS and prolonging the life expectancy of a subject with AIDS. A physician or veterinarian may compare the effect of the treatment with the condition of the subject prior to treatment, or with the expected state of an untreated subject, to determine if the treatment is effective in inhibiting AIDS. In a preferred embodiment, the AURK inhibitors, active agents, compositions, and additional combinations of the invention are used for the prevention of HIV infection or AIDS. In another preferred embodiment, the AURK inhibitors, active agents, compositions, and additional combinations of the invention are used for the treatment of HIV infection or AIDS. Therefore, the AURK inhibitors of the present invention will be suitable for inclusion in ART protocols commonly applied to patients with HIV or AIDS.
Los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención pueden ser útiles en el tratamiento de la infección por VIH o SIDA. Mientras todos los sujetos que pueden estar afectados con VIH o sus equivalentes puedan tratarse de esta manera (por ejemplo, chimpancés, macacos, babuinos o humanos), los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención se refieren particularmente a sus usos terapéuticos en seres humanos. A menudo, puede requerirse más de una administración para lograr el efecto terapéutico deseado; el protocolo exacto (dosificación y frecuencia) pueden establecerse mediante procedimientos clínicos convencionales.  Additional AURK inhibitors, active agents, compositions, and combinations of the invention may be useful in the treatment of HIV infection or AIDS. While all subjects who may be affected with HIV or their equivalents can be treated in this manner (eg, chimpanzees, macaques, baboons, or humans), the AURK inhibitors, active agents, compositions, and additional combinations of the invention are particularly concerned with its therapeutic uses in humans. Often, more than one administration may be required to achieve the desired therapeutic effect; the exact protocol (dosage and frequency) can be established using conventional clinical procedures.
La presente invención se refiere además a la reducción o eliminación de los síntomas asociados con la infección por VIH o SIDA. Estos incluyen síntomas asociados con la fase sintomática leve de la infección por VIH, incluyendo, por ejemplo, zóster, erupción cutánea e infecciones de uñas, llagas orales, infección de nariz y garganta recurrente y pérdida de peso. Además, los síntomas adicionales asociados con la fase sintomática principal de la infección por VIH incluyen, por ejemplo, candidosis oral y vaginal (Candida), diarrea persistente, pérdida de peso, tos persistente y tuberculosis reactivada o infecciones por herpes recurrentes, tales como herpes labial (herpes simple). Otros síntomas de SIDA avanzado que pueden tratarse según la presente invención incluyen, por ejemplo, diarrea, náuseas y vómitos, candidosis y llagas orales, infecciones vaginales persistentes, recurrentes y cáncer cervical, linfadenopatía generalizada persistente (PGL), infecciones graves de la piel, condilomas y tiña, infecciones respiratorias, neumonía, especialmente neumonía por Pneumocystis carinii (PCP), herpes zóster (o zóster), problemas del sistema nervioso, tales como dolores, entumecimiento u“hormigueos” en la manos y pies, anomalías neurológicas, sarcoma de Kaposi, linfoma, tuberculosis u otras infecciones oportunistas similares.  The present invention further relates to the reduction or elimination of symptoms associated with HIV infection or AIDS. These include symptoms associated with the mild symptomatic phase of HIV infection, including, for example, zoster, rash and nail infections, oral sores, recurrent nose and throat infection, and weight loss. In addition, additional symptoms associated with the main symptomatic phase of HIV infection include, for example, oral and vaginal thrush (Candida), persistent diarrhea, weight loss, persistent cough, and reactivated tuberculosis or recurrent herpes infections, such as herpes labial (herpes simplex). Other symptoms of advanced AIDS that can be treated according to the present invention include, for example, diarrhea, nausea and vomiting, candidiasis and oral sores, persistent, recurrent vaginal infections and cervical cancer, persistent generalized lymphadenopathy (PGL), severe skin infections, condylomas and ringworm, respiratory infections, pneumonia, especially Pneumocystis carinii pneumonia (PCP), herpes zoster (or zoster), nervous system problems such as pain, numbness or "tingling" in the hands and feet, neurological abnormalities, sarcoma of Kaposi, lymphoma, tuberculosis, or other similar opportunistic infections.
En otra realización preferida, los inhibidores, las composiciones y combinaciones de AURK de la invención se administran a un sujeto infectado por VIH o un sujeto expuesto al VIH junto con al menos un agente activo adicional (agente terapéutico). Preferiblemente, el agente terapéutico se indica comúnmente para la prevención o el tratamiento de VIH o SIDA. Los agentes terapéuticos adecuados incluyen, pero no se limitan a, fármacos que forman parte de los protocolos de la terapia antirretroviral (TAR) actual y la terapia antirretroviral altamente activa (TARVAA) tales como inhibidor de la transcriptasa inversa de no nucleósidos (por ejemplo, efavirenz, nevirapina, delavirdina, etravirina, rilpivirina), inhibidores de la transcriptasa inversa de análogos de nucleósidos (por ejemplo, zidovudina, tenofovir, lamivudina, emtricitabina) e inhibidores de la proteasa (por ejemplo, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir), denominados a continuación en el presente documento independientemente o conjuntamente como“antirretroviral(es) del VIH” o simplemente “antirretroviral(es)”. En una versión de esta realización, los inhibidores, las composiciones y combinaciones de AURK de la invención se administran antes de que se aplique cualquier antirretroviral del VIH al sujeto. En aún otra versión, los inhibidores, las composiciones y combinaciones de AURK de la invención se administran después de que se haya aplicado el antirretroviral del VIH al sujeto, tal como, por ejemplo, después de la interrupción de un protocolo de TAR o TARVAA y antes de reanudar sus regímenes. In another preferred embodiment, the AURK inhibitors, compositions and combinations of the invention are administered to a subject infected with HIV or a subject exposed to HIV together with at least one additional active agent (therapeutic agent). Preferably, the therapeutic agent is commonly indicated for the prevention or treatment of HIV or AIDS. Suitable therapeutic agents include, but are not limited to, drugs that are part of the protocols for current antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) such as non-nucleoside reverse transcriptase inhibitor (eg. efavirenz, nevirapine, delavirdine, etravirine, rilpivirine), nucleoside analog reverse transcriptase inhibitors (eg, zidovudine, tenofovir, lamivudine, emtricitabine) and protease inhibitors (eg, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir), Continued herein independently or jointly as "HIV antiretroviral (s)" or simply "antiretroviral (s)". In one version of this embodiment, the AURK inhibitors, compositions and combinations of the invention are administered before any HIV antiretroviral is applied to the subject. In yet another version, the AURK inhibitors, compositions and combinations of the invention are administered after the HIV antiretroviral has been applied to the subject, such as, for example, after discontinuation of a TAR or HAART protocol and before resuming their regimes.
En otra realización, el agente activo adicional es un agente reversor de latencia. Preferiblemente, el agente reversor de latencia comprende una histona desacetilasa (inhibidor de HDAC). Más preferiblemente, el inhibidor de HDAC comprende panobinostat, vorinostat o una combinación de los mismos.  In another embodiment, the additional active agent is a latency reversing agent. Preferably, the latency reversing agent comprises a histone deacetylase (HDAC inhibitor). More preferably, the HDAC inhibitor comprises panobinostat, vorinostat, or a combination thereof.
3. Composiciones que contienen inhibidores de AURK y combinaciones de inhibidores de AURK con otros agentes activos  3. Compositions containing AURK inhibitors and combinations of AURK inhibitors with other active agents
En un aspecto adicional, la presente invención se refiere a una composición que comprende al menos un inhibidor de AURK de la invención formulado con un portador farmacéuticamente aceptable. Dichas composiciones farmacéuticas se usan para tratar VIH o SIDA en un sujeto o prevenir la infección por VIH en un sujeto no infectado. En una realización, la composición comprende un compuesto de fórmula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) o (IX) tal como se define anteriormente o una combinación de los mismos. En una realización, la composición comprende un ARNip anti-AURK (por ejemplo, ARNip que selecciona como diana AURKB), barasertib, tozasertib, alisertib, mesilato de SNS-314, MK-5108, ENMD-2076, AMG-900, hesperadina, ZM-447439 o una combinación de los mismos. Preferiblemente, el ARNip de AURK comprende cualquiera de SEQ ID NO:1-4, una variante funcionalmente equivalente de las mismas, o una combinación de al menos cualesquiera de dos secuencias seleccionadas del grupo que consiste en SEQ ID NO:1-4 o sus variantes equivalentes funcionales. En una versión preferida de esta realización, el inhibidor de AURK comprende barasertib, tozasertib o una combinación de los mismos. Lo más preferiblemente, el inhibidor de AURK es barasertib.  In a further aspect, the present invention relates to a composition comprising at least one AURK inhibitor of the invention formulated with a pharmaceutically acceptable carrier. Such pharmaceutical compositions are used to treat HIV or AIDS in a subject or to prevent HIV infection in an uninfected subject. In one embodiment, the composition comprises a compound of formula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) or (IX) as defined above or a combination thereof. In one embodiment, the composition comprises an anti-AURK siRNA (eg, siRNA targeting AURKB), barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG-900, hesperadine, ZM-447439 or a combination thereof. Preferably, the AURK siRNA comprises any of SEQ ID NO: 1-4, a functionally equivalent variant thereof, or a combination of at least any of two sequences selected from the group consisting of SEQ ID NO: 1-4 or their equivalent functional variants. In a preferred version of this embodiment, the AURK inhibitor comprises barasertib, tozasertib, or a combination thereof. Most preferably, the AURK inhibitor is barasertib.
En otra realización de este aspecto, se administra una combinación de al menos un inhibidor de AURK y al menos un agente activo adicional a un sujeto que lo necesita para tratar o prevenir una infección por VIH o SIDA. En una versión de esta realización, la combinación se administra conjuntamente en la misma composición. En otra versión de esta realización, la combinación se administra de manera separada y secuencial. Preferiblemente, se permiten al menos 24 horas entre la administración del inhibidor de AURK y el agente activo adicional. Más preferiblemente, la combinación comprende un inhibidor de AURK, un ARNip anti-AURK y un agente activo adicional. Preferiblemente, el agente activo adicional es un fármaco antirretroviral del VIH o un agente reversor de latencia. Preferiblemente, el agente reversor de latencia comprende una histona desacetilasa (inhibidor de HDAC). Más preferiblemente, el inhibidor de HDAC comprende panobinostat, vorinostat o una combinación de los mismos. La preparación de las composiciones y combinaciones de la invención se conoce en la técnica. Véase Remington: The Science and Practice of Pharmacy, 21a ed. (Pharmaceutical Press, Filadelfia, PA, EEUU, 2011). Preferiblemente, el portador es adecuado para administración parenteral (por ejemplo, intravenosa, intramuscular, subcutánea, espinal o epidérmica) (por ejemplo, mediante inyección o infusión). Dependiendo de la vía de administración, el agente activo de la invención puede recubrirse de un material para proteger al agente de la acción de condiciones que puedan inactivar al agente. In another embodiment of this aspect, a combination of at least one AURK inhibitor and at least one additional active agent is administered to a subject who needs it to treat or prevent HIV infection or AIDS. In one version of this embodiment, the combination is administered together in the same composition. In another version of this embodiment, the combination is administered separately and sequentially. Preferably, at least 24 hours are allowed between the administration of the AURK inhibitor and the additional active agent. More preferably, the combination comprises an AURK inhibitor, an anti-AURK siRNA, and an additional active agent. Preferably, the additional active agent is an HIV antiretroviral drug or a dormancy reversal agent. Preferably, the latency reversing agent comprises a histone deacetylase (HDAC inhibitor). More preferably, the HDAC inhibitor comprises panobinostat, vorinostat, or a combination thereof. The preparation of the compositions and combinations of the invention is known in the art. See Remington: The Science and Practice of Pharmacy, 21 ed. (Pharmaceutical Press, Philadelphia, PA, USA, 2011). Preferably, the carrier is suitable for parenteral (eg, intravenous, intramuscular, subcutaneous, spinal, or epidermal) administration (eg, by injection or infusion). Depending on the route of administration, the active agent of the invention can be coated with a material to protect the agent from the action of conditions that can inactivate the agent.
Las composiciones y combinaciones de la presente invención pueden administrarse mediante una variedad de métodos conocidos en la técnica. Tal como apreciará el experto en la técnica, la vía o el modo de administración variará dependiendo de los resultados deseados. Los agentes activos de la invención pueden prepararse con portadores que protejan al agente frente a la liberación rápida, tal como una formulación de liberación controlada, incluyendo implantes, parches transdérmicos y sistemas de administración microencapsulados. Pueden usarse polímeros biodegradables, biocompatibles, tales como acetato de etileno y vinilo, polianhídridos, ácido poliglicólico, colágeno, poliortoésteres y ácido poliláctico. Se conocen muchos métodos para la preparación de tales formulaciones en la técnica. Véase Robinson J, et al., editores, “Sustained and Controlled Release Drug Delivery Systems” (Marcel Dekker, Inc., Nueva York, NY, EEUU, 1978).  The compositions and combinations of the present invention can be administered by a variety of methods known in the art. As will be appreciated by one skilled in the art, the route or mode of administration will vary depending on the desired results. The active agents of the invention can be prepared with carriers that protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene and vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are known in the art. See Robinson J, et al., Editors, "Sustained and Controlled Release Drug Delivery Systems" (Marcel Dekker, Inc., New York, NY, USA, 1978).
Para administrar un agente activo de la invención mediante determinadas vías de administración, puede ser necesario recubrir el agente con, o coadministrar el agente con, un material para prevenir su inactivación o para asegurar su apropiada distribución in vivo. Por ejemplo, el agente puede administrarse a un sujeto en un portador apropiado (por ejemplo, liposoma) o un diluyente. Los diluyentes farmacéuticamente aceptables incluyen, pero no se limitan a, solución salina y disoluciones acuosas de tampón. Los liposomas incluyen emulsiones CGF agua en aceite en agua así como liposomas convencionales. Véase Strejan G, et al., J. Neuroimmunol. 1984; 7:27-41. Se conocen muchos métodos de fabricación de liposomas en la técnica. Véanse los documentos US 4.522.81 1 , US 5.374.548 y US 5.399.331. Los liposomas pueden comprender uno o más restos que se transportan de manera selectiva a células u órganos específicos y potencian así la administración dirigida del fármaco. Los restos de direccionamiento a modo de ejemplo incluyen folato o biotina, manósidos y receptor de la proteína A tensioactivo. En una realización de la invención, los agentes activos de la invención se formulan en liposomas; en una realización más preferida, los liposomas incluyen un resto de direccionamiento. En una realización lo más preferida, los agentes activos en los liposomas se administran mediante inyección en bolo.  To administer an active agent of the invention by certain routes of administration, it may be necessary to coat the agent with, or co-administer the agent with, a material to prevent its inactivation or to ensure its proper distribution in vivo. For example, the agent can be administered to a subject in an appropriate carrier (eg, liposome) or a diluent. Pharmaceutically acceptable diluents include, but are not limited to, saline and aqueous buffer solutions. Liposomes include CGF water-in-oil-in-water emulsions as well as conventional liposomes. See Strejan G, et al., J. Neuroimmunol. 1984; 7: 27-41. Many methods of manufacturing liposomes are known in the art. See US 4,522.81 1, US 5,374,548 and US 5,399,331. Liposomes can comprise one or more residues that are selectively transported to specific cells or organs and thus enhance targeted drug delivery. Exemplary targeting moieties include folate or biotin, mannosides, and surfactant protein A receptor. In one embodiment of the invention, the active agents of the invention are formulated into liposomes; in a more preferred embodiment, the liposomes include a targeting moiety. In a most preferred embodiment, the active agents in the liposomes are administered by bolus injection.
Los portadores farmacéuticamente aceptables incluyen disoluciones o dispersiones acuosas estériles y polvos estériles para la preparación extemporánea de disoluciones o dispersiones inyectables estériles. El uso de tales medios en la preparación de las composiciones y combinaciones de la invención se contempla en el presente documento en cuanto a que su uso no es incompatible con los agentes activos de la invención. También pueden incorporarse compuestos activos complementarios en las composiciones y combinaciones de la invención.  Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media in the preparation of the compositions and combinations of the invention is contemplated herein in that their use is not incompatible with the active agents of the invention. Complementary active compounds can also be incorporated into the compositions and combinations of the invention.
Las composiciones y combinaciones de la invención son normalmente estériles y estables en las condiciones de fabricación y almacenamiento. Una composición y combinación según la invención puede formularse como una disolución, microemulsión, liposoma u otra estructura ordenada adecuada para la concentración de agente activo. El portador puede ser un disolvente o medio de dispersión que contiene, por ejemplo, agua, etanol, poliol (por ejemplo, glicerol, propilenglicol, polietilenglicol líquido) o mezclas adecuadas de los mismos. La fluidez apropiada puede mantenerse, por ejemplo, usando un recubrimiento tal como lecitina, reduciendo la desviación en el tamaño de partículas y usando tensioactivos. En muchos casos, será preferible incluir agentes isotónicos, tales como, por ejemplo, azúcares, polialcoholes (por ejemplo, manitol, sorbitol) o cloruro de sodio en la composición. La absorción prolongada de las composiciones inyectables puede lograrse incluyendo en la composición o combinación compuestos que retrasen la absorción (por ejemplo, sales de monoestearato, gelatina). The compositions and combinations of the invention are normally sterile and stable under manufacturing and storage conditions. A composition and combination according to the invention can be formulated as a solution, microemulsion, liposome or other ordered structure suitable for the concentration of active agent. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), or suitable mixtures thereof. Proper fluidity can be maintained, for example, by using a coating such as lecithin, reducing deviation in particle size and using surfactants. In many cases, it will be preferable to include isotonic agents, such as, for example, sugars, polyalcohols (for example, mannitol, sorbitol) or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition or combination compounds that delay absorption (eg, monostearate salts, gelatin).
Pueden prepararse disoluciones inyectables estériles incorporando el agente activo de la invención en la cantidad requerida en un disolvente apropiado con uno o una combinación de los componentes enumerados anteriormente, tal como se requiera, seguido por esterilización-microfiltración. Generalmente, las dispersiones se preparan incorporando el agente activo en un vehículo estéril que contiene un medio de dispersión básico y los otros componentes requeridos de los enumerados anteriormente. En el caso de polvos estériles para la preparación de disoluciones inyectables estériles, los métodos de preparación preferidos son secado a vacío y secado por congelación (es decir, liofilización) que producen un polvo del principio activo más cualquier componente deseado adicional a partir de una disolución filtrada previamente esterilizada del mismo.  Sterile injectable solutions can be prepared by incorporating the active agent of the invention in the required amount in an appropriate solvent with one or a combination of the components listed above, as required, followed by sterilization-microfiltration. Generally, dispersions are prepared by incorporating the active agent into a sterile vehicle that contains a basic dispersion medium and the required other components from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying (i.e. lyophilization) which produce a powder of the active ingredient plus any additional desired components from a solution. Filtered previously sterilized thereof.
Los regímenes de dosificación se ajustan para proporcionar la respuesta deseada óptima (por ejemplo, una respuesta terapéutica). Por ejemplo, puede administrarse un único bolo, pueden administrarse varias dosis divididas a lo largo del tiempo o la dosis puede reducirse o aumentarse proporcionalmente, tal como indiquen las exigencias de la situación terapéutica.  Dosage regimens are adjusted to provide the optimal desired response (eg, a therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be reduced or increased proportionally, as indicated by the demands of the therapeutic situation.
Es especialmente ventajoso formular composiciones parenterales en forma unitaria de dosificación para facilitar la administración y uniformidad de la dosificación. La forma unitaria de dosificación tal como se usa en el presente documento se refiere a unidades discretas físicamente adecuadas como dosificaciones unitarias para los sujetos que van a tratarse; cada unidad contiene una cantidad predeterminada de agente activo calculada para producir el efecto terapéutico deseado junto con el portador farmacéutico requerido. La especificación para las formas unitarias de dosificación de la invención se dictan mediante y directamente son dependientes de las características únicas del agente activo y el efecto terapéutico particular que va a conseguirse.  It is especially advantageous to formulate parenteral compositions in dosage unit form to facilitate administration and uniformity of dosage. The unit dosage form as used herein refers to physically suitable discrete units as unit dosages for the subjects to be treated; each unit contains a predetermined amount of active agent calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active agent and the particular therapeutic effect to be achieved.
Las composiciones y combinaciones de la invención pueden comprender antioxidantes farmacéuticamente aceptables. Los ejemplos de antioxidantes farmacéuticamente aceptables incluyen, pero no se limitan a, antioxidantes solubles en agua (por ejemplo, ácido ascórbico, clorhidrato de cisteína, bisulfato de sodio, metabisulfito de sodio, sulfito de sodio), antioxidantes solubles en aceite (por ejemplo, palmitato de ascorbilo, hidroxianisol butilado (BHA), hidroxitolueno butilado (BHT), lecitina, galato de propilo, alfa-tocoferol) y agentes quelantes metálicos (por ejemplo, ácido cítrico, ácido etilendiaminotetraacético (EDTA), sorbitol, ácido tartático, ácido fosfórico). Las formulaciones de las composiciones farmacéuticas de la invención incluyen las adecuadas para la administración oral, nasal, tópica (por ejemplo, bucal y sublingual), rectal, vaginal o parenteral. Las formulaciones pueden presentarse convenientemente en forma de dosificación unitaria y pueden prepararse mediante cualquier método conocido en la técnica. La cantidad de agente activo que puede combinarse con un material portador para producir una forma de dosificación única variará dependiendo del sujeto que va a tratarse y del modo particular de administración. La cantidad de agente activo que puede combinarse con un material portador para producir una forma de dosificación única será generalmente esa cantidad de la composición que produzca un efecto terapéutico. Generalmente, esta cantidad oscilará entre aproximadamente el 0,001% y aproximadamente el 90% de agente activo, preferiblemente entre aproximadamente el 0,005% y aproximadamente el 70% y, lo más preferiblemente, entre aproximadamente el 0,01% y aproximadamente el 30%. The compositions and combinations of the invention may comprise pharmaceutically acceptable antioxidants. Examples of pharmaceutically acceptable antioxidants include, but are not limited to, water soluble antioxidants (eg, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite), oil soluble antioxidants (eg, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol) and metal chelating agents (eg citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid ). Formulations of the pharmaceutical compositions of the invention include those suitable for oral, nasal, topical (eg, buccal and sublingual), rectal, vaginal, or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method known in the art. The amount of active agent that can be combined with a carrier material to produce a single dosage form will vary depending on the subject to be treated and the particular mode of administration. The amount of active agent that can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition that produces a therapeutic effect. Generally, this amount will range from about 0.001% and about 90% active agent, preferably between about 0.005% and about 70%, and most preferably between about 0.01% and about 30%.
Las composiciones y combinaciones de la presente invención que son adecuadas para la administración vaginal también incluyen formulaciones de óvulos vaginales, tampones, cremas, geles, pastas, espumas o pulverizadores que contienen tales portadores que son apropiados tal como se conoce en la técnica. Las formas de dosificación para la administración tópica o transdérmica de composiciones de esta invención incluyen polvos, pulverizadores, pomadas, pastas, cremas, lociones, geles, disoluciones, parches e inhalatorios. El agente activo de la invención puede mezclarse en condiciones estériles con un portador farmacéuticamente aceptable y con cualquier conservante, tampón o propelente que pueda requerirse.  Compositions and combinations of the present invention that are suitable for vaginal administration also include formulations of vaginal ovules, tampons, creams, gels, pastes, foams or sprays containing such carriers that are appropriate as is known in the art. Dosage forms for topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active agent of the invention can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservative, buffer or propellant that may be required.
Las composiciones y combinaciones de la invención también pueden contener adyuvantes tales como conservantes, agentes humectantes, agentes emulsionantes y agentes de dispersión. La prevención de la presencia de microorganismos puede asegurarse mediante tanto procedimientos de esterilización como la inclusión de diversos agentes antibacterianos y antifúngicos (por ejemplo, parabeno, clorobutanol, ácido sórbico de fenol). También puede ser deseable incluir agentes isotónicos (por ejemplo, azúcares, cloruro de sodio) en las composiciones y combinaciones.  The compositions and combinations of the invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The prevention of the presence of microorganisms can be ensured by both sterilization procedures and the inclusion of various antibacterial and antifungal agents (for example, paraben, chlorobutanol, phenolic sorbic acid). It may also be desirable to include isotonic agents (eg, sugars, sodium chloride) in the compositions and combinations.
Los niveles de dosificación actuales de los agentes activos en las composiciones y combinaciones de la invención pueden variarse para lograr la respuesta terapéutica deseada en un sujeto. El nivel de dosificación seleccionado dependerá de una variedad de factores farmacocinéticos que incluyen la actividad del agente particular de la invención empleado, su cantidad, la vía de administración, el tiempo de administración, la tasa de excreción o expresión del agente activo particular empleado, la duración del tratamiento, otros fármacos, compuestos o materiales usados en combinación con las composiciones farmacéuticas particulares empleadas, la edad, el sexo, el peso, el estado, la salud general y la historia clínica previa del sujeto que va a tratarse y otros factores similares conocidos en las técnicas médicas. Un médico o veterinario que tiene la experiencia habitual en la técnica puede determinar fácilmente y prescribir la cantidad terapéuticamente eficaz requerida del/de los agente(s) activo(s). Por ejemplo, el médico o veterinario puede empezar con dosis de los agentes activos de la invención empleados en la composición farmacéutica a niveles menores que los requeridos para lograr el efecto terapéutico deseado y aumentar la dosificación de manera gradual hasta que se logre el efecto deseado. En general, una dosis diaria adecuada de una composición de la invención será esa cantidad del agente activo que sea la dosis eficaz más baja para producir un efecto terapéutico. Tal dosis eficaz dependerá generalmente de los factores descritos anteriormente. Se prefiera que la administración sea parenteral, más preferiblemente intravenosa, intramuscular, intraperitoneal o subcutánea. Si se desea, la dosis diaria eficaz de una composición farmacéutica puede administrarse como dos, tres, cuatro, cinco, seis o más subdosis aplicadas de manera separada a intervalos apropiados a lo largo del día, opcionalmente, en formas de dosificación unitaria. Mientras sea posible que un agente activo de la invención se administre solo, se prefiere administrar dicho agente como una composición farmacéutica. The current dosage levels of the active agents in the compositions and combinations of the invention can be varied to achieve the desired therapeutic response in a subject. The selected dosage level will depend on a variety of pharmacokinetic factors including the activity of the particular agent of the invention employed, its amount, the route of administration, the time of administration, the rate of excretion or expression of the particular active agent employed, the duration of treatment, other drugs, compounds or materials used in combination with the particular pharmaceutical compositions used, age, sex, weight, condition, general health and previous medical history of the subject to be treated and other similar factors known in medical techniques. A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the required therapeutically effective amount of the active agent (s). For example, the physician or veterinarian may start with doses of the active agents of the invention employed in the pharmaceutical composition at lower levels than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the active agent that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Administration is preferred to be parenteral, more preferably intravenous, intramuscular, intraperitoneal, or subcutaneous. If desired, the effective daily dose of a pharmaceutical composition can be administered as two, three, four, five, six or more subdoses applied separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for an active agent of the invention to be administered alone, it is preferred to administer said agent as a pharmaceutical composition.
Las composiciones y combinaciones de la invención pueden administrarse con dispositivos médicos conocidos en la técnica. Por ejemplo, en una realización preferida, la composición farmacéutica de la invención puede administrarse con un dispositivo de inyección hipodérmico sin aguja. Véanse los documentos US 5.399.163, US 5.383.851 , US 5.312.335, US 5.064.413, US 4.941.880, US 4.790.824 o US 4.596.556. Los ejemplos de implantes y módulos bien conocidos útiles en la presente invención incluyen, pero no se limitan a, bombas de infusión para dispensar medicamentos a diferentes velocidades (por ejemplo, el documento US 4.447.233 (no implantable, velocidad controlada), el documento US 4.447.224 (implantable, velocidad variable), el documento US 4.487.603 (implantable, velocidad controlada)), dispositivos para administrar medicamentos a través de la piel (por ejemplo, el documento US 4.486.194) y sistemas osmóticos de administración de fármacos (por ejemplo, los documentos US 4.439.196 y US 4.475.196). Se conocen muchos otros tales implantes, sistemas y módulos de administración por los expertos en la técnica. The compositions and combinations of the invention can be administered with medical devices known in the art. For example, in a preferred embodiment, the pharmaceutical composition of the invention can be administered with a needleless hypodermic injection device. See US 5,399,163, US 5,383,851, US 5,312,335, US 5,064,413, US 4,941,880, US 4,790,824 or US 4,596,556. Examples of well known implants and modules useful in the present invention include, but are not limited to, infusion pumps for dispensing medications at different rates (eg, US 4,447,233 (non-implantable, controlled rate), US Pat. US 4,447,224 (implantable, variable speed), US 4,487,603 (implantable, controlled speed)), devices for delivering medications through the skin (eg, US 4,486,194) and osmotic delivery systems of drugs (eg, US 4,439,196 and US 4,475,196). Many other such implants, systems and delivery modules are known to those skilled in the art.
Las composiciones y combinaciones de la invención deben ser estériles y fluidas en la medida en que la composición sea administrable mediante una jeringa. Además de agua, el portador puede ser una solución salina tamponada isotónica, etanol, poliol (por ejemplo, glicerol, propilenglicol, polietilenglicol líquido) y mezclas adecuadas de los mismos. La fluidez apropiada puede mantenerse, por ejemplo, usando un recubrimiento tal como lecitina, mediante el mantenimiento del tamaño de partícula requerido en el caso de dispersión y mediante el uso de tensioactivos. En muchos casos, se prefiere incluir agentes isotónicos, tales como, por ejemplo, azúcares, polialcoholes (por ejemplo, manitol, sorbitol) y cloruro de sodio en la composición. La absorción a largo plazo de las composiciones inyectables puede lograrse incluyendo un agente que retrase la absorción (por ejemplo, monoestearato de aluminio, gelatina) en la composición o combinación. The compositions and combinations of the invention must be sterile and fluid to the extent that the composition is administrable by syringe. In addition to water, the carrier may be isotonic buffered saline, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it is preferred to include isotonic agents, such as, for example, sugars, polyalcohols (for example, mannitol, sorbitol) and sodium chloride in the composition. Long-term absorption of injectable compositions can be achieved by including an agent that delays absorption (eg, aluminum monostearate, gelatin) in the composition or combination.
4. Kits  4. Kits
En un aspecto adicional, la presente invención se refiere a kits que comprenden al menos uno de los inhibidores de AURK, agentes activos, composiciones y combinaciones adicionales de la invención o mezclas de los mismos. Los componentes de los kits de la invención pueden envasarse opcionalmente en envases adecuados y marcarse para la prevención o el tratamiento de VIH o SIDA o sus estados relacionados. Los componentes de los kits pueden almacenarse en envases unitarios o de dosis múltiple como una disolución acuosa, preferiblemente estéril, o como una formulación liofilizada, preferiblemente estéril, para reconstitución. Los envases pueden estar formados por una variedad de materiales tales como vidrio o plástico y pueden tener un orificio de acceso estéril (por ejemplo, el envase puede ser una bolsa de disolución intravenosa o un vial que tiene un tapón perforable mediante una aguja de inyección hipodérmica). Los kits pueden comprender además más envases que comprenden un portador farmacéuticamente aceptable. Además pueden incluir otros materiales deseables desde el punto de vista comercial y de uso, que incluyen, pero no se limitan a, tampones, diluyentes, filtros, agujas, jeringas, medio de cultivo para una o más de las células huésped adecuadas u otros agentes activos. Los kits pueden contener instrucciones incluidas normalmente en los paquetes comerciales de productos terapéuticos que contienen información, por ejemplo, sobre las indicaciones, uso, dosificación, fabricación, administración, contraindicaciones o advertencias en cuanto al uso de tales productos terapéuticos.  In a further aspect, the present invention relates to kits comprising at least one of the AURK inhibitors, active agents, compositions and additional combinations of the invention or mixtures thereof. The components of the kits of the invention can optionally be packaged in suitable containers and labeled for the prevention or treatment of HIV or AIDS or its related conditions. Kit components can be stored in unit or multiple dose containers as an aqueous solution, preferably sterile, or as a lyophilized, preferably sterile formulation for reconstitution. The packages can be made of a variety of materials such as glass or plastic and can have a sterile access hole (for example, the package can be an intravenous solution bag or a vial that has a cap that can be pierced by a hypodermic injection needle. ). The kits may further comprise more packages comprising a pharmaceutically acceptable carrier. They may also include other commercially desirable and useable materials, including, but not limited to, buffers, diluents, filters, needles, syringes, culture media for one or more of the appropriate host cells or other agents. assets. The kits may contain instructions normally included in commercial packages of therapeutic products that contain information, for example, on the indications, use, dosage, manufacture, administration, contraindications or warnings regarding the use of such therapeutic products.
Todas las publicaciones mencionadas en el presente documento se incorporan en su totalidad como referencia. Teniendo ahora la invención descrita de manera general, la misma será entendida más fácilmente a través de la referencia a los siguientes ejemplos, que se proporcionan a modo de ilustración y no se pretende que sean limitantes de la presente invención, a menos que se especifique.  All publications mentioned herein are incorporated by reference in their entirety. Having now the invention generally described, it will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention, unless specified.
Procedimientos generales  General procedures
1. Células Se obtuvieron células mononucleares de sangre periférica (PBMC) de capas leucocíticas de donantes sanos (Banco Catalán de Sangre y Tejidos, Barcelona, ES, http://www.bancsang.net/en/index.html) mediante centrifugación por gradiente de densidad Ficoll-Paque y se usaron para purificación nueva de linfocitos T CD4+, monocitos o linfocitos T CD4+ indiferenciados mediante selección negativa (StemCell Technologies Inc., Cambridge, R.U.). Se confirmó la pureza de las poblaciones mediante citometría de flujo. Se mantuvieron linfocitos T CD4+ en medio RPMI 1640 completo complementado con suero bovino fetal inactivado por calor al 10% (FBS; Gibco, Thermo Fisher Scientific, Waltham, MA, EE.UU.), penicilina 100 U/ml y estreptomicina 100 mg/ml (Gibco, Thermo Fisher Scientific, Waltham, MA, EE.UU.). Se cultivaron monocitos en medio de cultivo completo (medio RPMI 1640) complementado con suero bovino fetal inactivado por calor al 10% (FBS; Gibco) y penicilina/estreptomicina (Gibco, Thermo Fisher Scientific, Waltham, MA, EE.UU.) y se diferenciaron en macrófagos derivados de monocitos (MDM) durante 4 días en presencia de factor estimulante de colonias de monocitos (M-CSF, PeproTech EC, Ltd. , Londres, R.U.) a 100 ng/ml. Se activaron células T CD4+ con fitohemaglutinina (PHA) (4 mg/ml, Sigma-Aldrich Co., Saint Louis, MO, EE.UU.) en presencia de interleucina-2 (IL-2) (16 U/ml, Roche Diagnostics GmbH, Manheim, DE) durante 3 días o se dejaron sin tratar con IL-2. 1. cells Peripheral blood mononuclear cells (PBMC) from buffy coats were obtained from healthy donors (Banco Catalán de Sangre y Tejidos, Barcelona, ES, http://www.bancsang.net/en/index.html) by means of density gradient centrifugation Ficoll-Paque and used for fresh purification of CD4 + T cells, monocytes, or undifferentiated CD4 + T cells by negative selection (StemCell Technologies Inc., Cambridge, UK). The purity of the populations was confirmed by flow cytometry. CD4 + T cells were maintained in complete RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum (FBS; Gibco, Thermo Fisher Scientific, Waltham, MA, USA), penicillin 100 U / ml and streptomycin 100 mg / ml (Gibco, Thermo Fisher Scientific, Waltham, MA, USA). Monocytes were grown in complete culture medium (RPMI 1640 medium) supplemented with 10% heat inactivated fetal bovine serum (FBS; Gibco) and penicillin / streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and they differentiated into monocyte derived macrophages (MDM) for 4 days in the presence of monocyte colony stimulating factor (M-CSF, PeproTech EC, Ltd., London, UK) at 100 ng / ml. CD4 + T cells were activated with phytohemagglutinin (PHA) (4 mg / ml, Sigma-Aldrich Co., Saint Louis, MO, USA) in the presence of interleukin-2 (IL-2) (16 U / ml, Roche Diagnostics GmbH, Manheim, DE) for 3 days or left untreated with IL-2.
Se obtuvieron las líneas de células humanas ACH-2 y células 9.2 de clon Jurkat (J-Lat) del Programa de Reactivos para SIDA, Institutos Nacionales de la Salud (Bethesda, MD, EE.UU.). Todas las líneas celulares se hicieron crecer en medio RPMI 1640, complementado con suero bovino fetal inactivado por calor al 10% (FCS, Gibco, Thermo Fisher Scientific, Waltham, MA, EE.UU.) y antibióticos penicilina 100 U/ml, estreptomicina 100 mg/ml (Life Technologies, Thermo Fisher Scientific, Waltham, MA, EE.UU.) y se mantuvieron a 37°C en un incubador con el 5% de CO2. Human ACH-2 cell lines and 9.2 cells were obtained from Jurkat clone (J-Lat) from the AIDS Reagent Program, National Institutes of Health (Bethesda, MD, USA). All cell lines were grown in RPMI 1640 medium, supplemented with 10% heat inactivated fetal bovine serum (FCS, Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and 100 U / ml penicillin antibiotics, streptomycin. 100 mg / ml (Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA) and maintained at 37 ° C in a 5% CO2 incubator.
2. Virus  2. Viruses
Se pseudotipó el clon NL4-3 de VIH-1 deficiente en envuelta que codifica para el sitio de entrada de ribosomas interno (I RES)— proteína fluorescente verde (GFP) (NL4-3- GFP) con proteína G del virus de la estomatitis vesicular (VEV-G) mediante cotransfección de células T HEK293 usando polietilenimina (Polysciences, Inc., Warrington, PA, EE.UU.). Tres días después de la transfección, los sobrenadantes se recogieron, se filtraron y se almacenaron a -80°C. Se concentraron las reservas virales usando concentrador Lenti-X (Clontech Laboratories, Inc., Mountain Vista, CA, EE.UU.). Se valoraron los virus mediante infección de células TZM seguido por cuantificación con GFP mediante citometría de flujo.  The envelope-deficient HIV-1 clone NL4-3 encoding the internal ribosome entry site (I RES) - green fluorescent protein (GFP) (NL4-3-GFP) was pseudotyped with the G protein of stomatitis virus Vesicular (VEV-G) by HEK293 T cell cotransfection using polyethyleneimine (Polysciences, Inc., Warrington, PA, USA). Three days after transfection, supernatants were collected, filtered, and stored at -80 ° C. Viral stocks were concentrated using Lenti-X concentrator (Clontech Laboratories, Inc., Mountain Vista, CA, USA). Viruses were assessed by TZM cell infection followed by GFP quantification by flow cytometry.
El Dr. O. T. Keppler (Instituto de Virología Médica, Universidad de Francfort, Francfort, Alemania) proporcionó amablemente un clon que expresaba NL4-3 de VIH-1 modificado para unirse a Vpx (NL4-3*GFP). Se cotransfectó NL4-3*GFP con un plásmido que codifica para Vpx (SIVmac239) en células T HEK293 para producir reservas virales. Tres días después de la transfección, los sobrenadantes se recogieron, se filtraron y se concentraron usando concentrador Lenti-X (Clontech Dr. O. T. Keppler (Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany) kindly provided a clone expressing HIV-1 NL4-3 modified to bind Vpx (NL4-3 * GFP). NL4-3 * GFP was cotransfected with a Vpx-encoding plasmid (SIVmac239) in HEK293 T cells to produce viral stores. Three days after transfection, supernatants were collected, filtered, and concentrated using Lenti-X concentrator (Clontech
Laboratories, Inc., Mountain Vista, CA, EE.UU.) y se almacenaron a -80 °C. Laboratories, Inc., Mountain Vista, CA, USA) and stored at -80 ° C.
3. Compuestos  3. Compounds
Todos los agentes activos sometidos a prueba estaban disponibles en catálogos comerciales: se adquirieron barasertib, MK-5108, BML-277, LY2603618, palbociclib, MK-1775, acitretina de Selleck Chemicals, se adquirió vorinostat (VOR) de Prochifar S.r.l. y se adquirió panobinostat (PNB) de LC Laboratories. Se adquirió el agente antirretroviral 3-azido-3-desoxitimidina (zidovudina; AZT) de Sigma-Aldrich Co., (Saint Louis, MO, EE.UU.)· Se adquirió la biblioteca de 424 compuestos anticancerosos de Selleck Chemicals (Houston, TX, EE.UU.)· Todos los compuestos se resuspendieron en DMSO y se almacenaron a -20°C hasta su uso. All active agents tested were available in commercial catalogs: barasertib, MK-5108, BML-277, LY2603618, palbociclib, MK-1775, acitretin from Selleck Chemicals were purchased, vorinostat (VOR) was purchased from Prochifar Srl and purchased panobinostat (PNB) from LC Laboratories. Agent was purchased antiretroviral 3-azido-3-deoxythymidine (zidovudine; AZT) from Sigma-Aldrich Co., (Saint Louis, MO, USA) · The library of 424 anticancer compounds was purchased from Selleck Chemicals (Houston, TX, USA. ) · All compounds were resuspended in DMSO and stored at -20 ° C until use.
4. Generación de células infectadas de manera latente 4. Generation of latently infected cells
Se generaron células infectadas de manera latente (J-Hig) siguiendo un protocolo modificado descrito por Li et al. En resumen, se generaron células después de la infección aguda de células Jurkat con un virus NL4-3-GFP pseudotipado como VEV y se mantuvieron en cultivo durante 10 días para permitir el desgaste de células infectadas de manera productiva.  Latently infected cells (J-Hig) were generated following a modified protocol described by Li et al. Briefly, cells were generated after acute infection of Jurkat cells with a pseudotyped NL4-3-GFP virus such as VEV and maintained in culture for 10 days to allow for the wear of infected cells productively.
Se generaron células T CD4+ primarias infectadas de manera latente según el modelo de latencia de células T primarias polarizadas con citocina con pocas modificaciones. En resumen, se activaron células T CD4+ indiferenciadas con anticuerpos aCD3/aCD28 (1 mg/ml cada uno; BD Biosciences, Madrid, ES) y se complementaron con TGFpi (10 mg/ml; Peprotech EC, Ltd. , Londres, R.U.), alL-12 (2 mg/ml) y alL-4 (1 mg/ml; Peprotech EC, Ltd., Londres, R.U.). Se reemplazó medio complementado con rlL-2 (30 lU/ml, Roche) cada 3 días. Después de 7 días de activación, se infectaron células T CD4+ con un NL4-3*GFP de unión a Vpx mediante espinoculación (1200xg, 1 h 30 min a 37°C) y células infectadas de manera latente/negativas para GFP clasificadas tres días después usando un citómetro de flujo FACSAria II (BD Latently infected primary CD4 + T cells were generated according to the cytokine polarized primary T cell latency model with little modification. Briefly, undifferentiated CD4 + T cells were activated with aCD3 / aCD28 antibodies (1 mg / ml each; BD Biosciences, Madrid, ES) and supplemented with TGFpi (10 mg / ml; Peprotech EC, Ltd., London, UK) , alL-12 (2 mg / ml) and alL-4 (1 mg / ml; Peprotech EC, Ltd., London, UK). Medium supplemented with rLL-2 (30 lU / ml, Roche) was replaced every 3 days. After 7 days of activation, CD4 + T cells were infected with a Vpx binding NL4-3 * GFP by spinoculation (1200xg, 1 hr 30 min at 37 ° C) and GFP negative / latent infected cells classified three days then using a FACSAria II flow cytometer (BD
Biosciences, San José, CA, EE.UU.). Las células se dejaron sin tratar durante la noche antes del tratamiento farmacológico. Biosciences, San José, CA, USA). Cells were left untreated overnight prior to drug treatment.
5. Ensayos de reactivación de VIH-1 en células que expresan GFP  5. HIV-1 Reactivation Assays in GFP-Expressing Cells
Se incubaron células infectadas de manera latente J-Hig con la biblioteca de 424 compuestos anticancerosos, fármacos MK-5108 y HDACi durante 24 h. Se determinaron los aciertos como los compuestos cuya reactivación era igual o mayor que la reactivación media para panobinostat a 0,16 mM más/menos 2 desviaciones estándar. Para corroborar el efecto de reactivación de barasertib en células primarias, también se trataron células T CD4+ indiferenciadas infectadas de manera latente con los fármacos durante 24 h antes de evaluar su capacidad de reactivación.  J-Hig latently infected cells were incubated with the library of 424 anticancer compounds, MK-5108 drugs, and HDACi for 24 h. The hits were determined as the compounds whose reactivation was equal to or greater than the mean reactivation for panobinostat at 0.16 mM plus / minus 2 standard deviations. To corroborate the reactivation effect of barasertib in primary cells, latent-infected undifferentiated CD4 + T cells were also treated for 24 h before evaluating their reactivation capacity.
Para evaluar el efecto de las combinaciones farmacológicas, se incubaron células J- Hig y la línea celular establecida J-Lat, que albergan un provirus de VIH que contiene la proteína fluorescente verde (GFP) ORF en lugar de nef y una mutación de desplazamiento de marco en env, con barasertib en combinación con vorinostat o panobinostat durante 24 h antes del análisis.  To assess the effect of drug combinations, J-Hig cells and the established J-Lat cell line, harboring an HIV provirus containing the green fluorescent protein (GFP) ORF rather than nef, and a displacement mutation were incubated. frame in env, with barasertib in combination with vorinostat or panobinostat for 24 h before analysis.
En todos los casos, se evaluó la actividad de reactivación mediante citometría de flujo como el porcentaje de células GFP+ en comparación con los estados no tratados. In all cases, reactivation activity was evaluated by flow cytometry as the percentage of GFP + cells compared to untreated states.
6. Determinación de CAp24 en sobrenadantes de cultivo 6. Determination of CAp24 in culture supernatants
Se cultivaron células ACH-2, un modelo latente de células T con una copia proviral integrada, durante 48 h en presencia de HDACi, acitretina o barasertib y se midió la reactivación mediante la producción de antígeno CAp24 contra VIH usando Genscreen VIH-1 Ag ELISA (BioRad Laboratories, Inc., Hércules, CA, EE.UU.) según las instrucciones del fabricante.  ACH-2 cells, a latent model of T cells with an integrated proviral copy, were cultured for 48 h in the presence of HDACi, acitretin or barasertib and reactivation was measured by production of CAp24 antigen against HIV using Genscreen HIV-1 Ag ELISA (BioRad Laboratories, Inc., Hercules, CA, USA) according to the manufacturer's instructions.
7. Detección de ARN viral en sobrenadante de cultivo  7. Detection of viral RNA in culture supernatant
Además, la reactivación de VIH-1 en células T CD4+ indiferenciadas infectadas de manera latente se midió mediante ARN viral en el sobrenadante. Se aisló ARN total usando el mini kit de ARN viral QlAamp® (Qiagen, Hilden, Alemania), tal como recomienda el fabricante, y se retrotranscribió a ADNc mediante PrimeScript RT Master Mix (Perfect Real Time) (Takara Bio USA, Inc., MountainView, CA, EE.UU.). Se determinó la cuantificación de reactivación de VIH-1 usando una reacción en cadena de la polimerasa cuantitativa de dos etapas (qPCR). En resumen, se ejecutaron las muestras en ADNc usando TaqMan Universal Master Mix II (Applied Biosystems, Thermo Fisher Scientific Inc., Waltham, MA, EE.UU.) en un sistema de PCR en tiempo real 7500 (Applied Biosystems, Thermo Fisher Scientific Inc., Waltham, MA, EE.UU.) instrumento de PCR en tiempo real I. Se usaron el siguiente cebador y conjunto de sondas para regiones conservadas del 5’LTR de ARNm de VIH-1 : cebador directo (5 - 3’) GACGCAGGACTCGGCTTG; cebador inverso (5’-3’) ACTGACGCTCTCGCACCC y sonda (5’-3’) FAM-TTTGGCGTACTCACCAGTCGCCG-TAMRA. Las condiciones de ciclado fueron las siguientes: 50°C durante 2 min seguido por 95°C durante 10 min para activación de la polimerasa, seguido por 50 ciclos de 95°C durante 15 s y 60°C durante 1 min. Se realizó una curva de calibración desde 106 hasta 102 copias de 5’LTR de VIH-1 usando ADN de ACH-2 y se ejecutó en paralelo con muestras para cuantificar los números de copias de ARN absolutos presentes en el sobrenadante de células T CDD4+ indiferenciadas infectadas de manera latente. Furthermore, the reactivation of HIV-1 in undifferentiated CD4 + T cells infected with Latent way was measured by viral RNA in the supernatant. Total RNA was isolated using the QlAamp® Viral RNA Mini Kit (Qiagen, Hilden, Germany), as recommended by the manufacturer, and back-transcribed to cDNA using PrimeScript RT Master Mix (Perfect Real Time) (Takara Bio USA, Inc., MountainView, CA, USA). Quantification of HIV-1 reactivation was determined using a two-step quantitative polymerase chain reaction (qPCR). Briefly, samples were run on cDNA using TaqMan Universal Master Mix II (Applied Biosystems, Thermo Fisher Scientific Inc., Waltham, MA, USA) on a 7500 real-time PCR system (Applied Biosystems, Thermo Fisher Scientific Inc., Waltham, MA, USA) Real-time PCR instrument I. The following primer and probe set were used for conserved regions of the 5'LTR of HIV-1 mRNA: forward primer (5 - 3 ' ) GACGCAGGACTCGGCTTG; reverse primer (5'-3 ') ACTGACGCTCTCGCACCC and probe (5'-3') FAM-TTTGGCGTACTCACCAGTCGCCG-TAMRA. The cycling conditions were as follows: 50 ° C for 2 min followed by 95 ° C for 10 min for polymerase activation, followed by 50 cycles of 95 ° C for 15 s and 60 ° C for 1 min. A calibration curve of 10 6 to 10 2 copies of HIV-1 5'LTR was performed using ACH-2 DNA and run in parallel with samples to quantify the absolute RNA copy numbers present in the T cell supernatant Latently infected undifferentiated CDD4 +.
8. Ensayos de interferencia de ARN 8. RNA interference tests
Se transfectaron células J-Hig con ARNip mediante nucleofección. En resumen, se transfectaron 50 pmol del ARNip correspondiente (AURKB ON-TARGETplus SMARTpool, Dharmacon, Thermo-Scientific, Waltham, MA, EE.UU. y ThermoFisher Scientific) usando un kit de nucleofección V (Lonza, Basel, Suiza) siguiendo las instrucciones del fabricante. Las células se dejaron sin tratar durante 24 h antes de añadir los HDACi vorinostat y panobinostat o barasertib. 24 h después de la adición de fármaco, se midió la reactivación mediante citometría de flujo (LSRII, BD Biosciences) como el porcentaje de células GFP+ en comparación con células no interferidas sin tratar.  J-Hig cells were transfected with siRNA by nucleofection. In summary, 50 pmol of the corresponding siRNA (AURKB ON-TARGETplus SMARTpool, Dharmacon, Thermo-Scientific, Waltham, MA, USA and ThermoFisher Scientific) were transfected using a nucleofection V kit (Lonza, Basel, Switzerland) following the manufacturer's instructions. Cells were left untreated for 24 h before adding HDACi vorinostat and panobinostat or barasertib. 24 h after drug addition, reactivation was measured by flow cytometry (LSRII, BD Biosciences) as the percentage of GFP + cells compared to untreated, uninterrupted cells.
Para la cuantificación de ARNm relativa de eficacia de silenciamiento, se extrajo ARN de células transfectadas a 24 h y 48 h después de la transfección usando el kit NucleoSpin RNA XS (Magerey-Nagel), tal como recomienda el fabricante e incluyendo la etapa de tratamiento de ADNasa I. Se realizó transcriptasa inversa usando Primescript RT Master Mix (Clontech). Se midieron los niveles relativos de ARNm de todos los genes mediante RT-PCR cuantitativa de dos etapas y se normalizaron con la expresión de ARNm de GAPDH usando el método DDCt. Se adquirieron cebadores y sondas de ADN de Life Technologies (ensayos de expresión génica TaqMan): GAPDH (ref. Hs02758991_g1), AURKA (ref. Hs01582072) y AURKB (ref. Hs00945858). For relative mRNA quantification of silencing efficiency, RNA was extracted from transfected cells at 24 h and 48 h after transfection using the NucleoSpin RNA XS kit (Magerey-Nagel), as recommended by the manufacturer and including the treatment step of DNase I. Reverse transcriptase was performed using Primescript RT Master Mix (Clontech). Relative mRNA levels of all genes were measured by two-step quantitative RT-PCR and normalized to GAPDH mRNA expression using the DDCt method. DNA primers and probes were purchased from Life Technologies (TaqMan Gene Expression Assays): GAPDH (ref. Hs02758991_g1), AURKA (ref. Hs01582072) and AURKB (ref. Hs00945858).
Para determinar los niveles de proteínas de células de silenciamiento, se lisaron las células 48 h después de la transfección y se almacenaron los extractos de proteínas para análisis de inmunotransferencia de tipo Western.  To determine the levels of silencing cell proteins, cells were lysed 48 h after transfection and protein extracts were stored for Western blot analysis.
9. Inmunotransferencia  9. Immunoblotting
Se enjuagaron las células en solución salina tamponada con fosfato helada (PBS) y se prepararon los extractos en tampón de lisis (Tris HCI 50 mM pH 7,5, EDTA 1 mM, EGTA 1 mM, Na3V04 1 mM, b-glicerofosfato de sodio 10 mM, NaF 50 mM, pirofosfato de sodio 5 mM, sacarosa 270 mM y Tritón X-100 al 1 %) complementados con inhibidor de proteasa (Roche) y fluoruro de fenilmetilsulfonilo 1 mM. Se sometieron los lisados a SDS-PAGE y se transfirieron a una membrana de PVDF (ImmunolonP, Thermo). Se usaron los siguientes anticuerpos para inmunotransferencia: anticuerpos secundarios conjugados con peroxidasa de rábano anti-conejo y anti-ratón (1 :5000; Pierce); anticuerpo anti-Hsp90 humano (1 :1000; BD Biosciences); anticuerpo anti-SAMHD1 humano (1 :2500; Abcam); anticuerpo anti-fosfo-SAMHD1 humano (T592) (1 :1000; proporcionado amablemente por O. Keppler, Universidad de Francfort); anticuerpo anti-pRB humano (1 :1000; Cell Signalling); anticuerpo anti-fosfo— pRB humano (S807/811) (1 :1000; Cell Signalling). Cells were rinsed in ice cold phosphate buffered saline (PBS) and extracts were prepared in lysis buffer (50 mM Tris HCI pH 7.5, 1 mM EDTA, 1 mM EGTA, Na 3 V0 4 1 mM, b- 10mM sodium glycerophosphate, 50mM NaF, 5mM sodium pyrophosphate, 270mM sucrose and 1% Triton X-100) supplemented with protease inhibitor (Roche) and 1mM phenylmethylsulfonyl fluoride. Lysates were subjected to SDS-PAGE and transferred to a PVDF membrane (ImmunolonP, Thermo). The following antibodies were used for immunoblotting: secondary antibodies anti-rabbit and anti-mouse horseradish peroxidase conjugates (1: 5000; Pierce); anti-human Hsp90 antibody (1: 1000; BD Biosciences); anti-human SAMHD1 antibody (1: 2500; Abcam); human anti-phospho-SAMHD1 antibody (T592) (1: 1000; kindly provided by O. Keppler, University of Frankfurt); anti-human pRB antibody (1: 1000; Cell Signaling); anti-phospho-human pRB antibody (S807 / 811) (1: 1000; Cell Signaling).
10. Actividad antiviral de compuestos  10. Antiviral activity of compounds
Se incubaron células T CD4+ y MDM diferenciadas en M-CSF con fármacos antivirales 24 h antes de la infección. Se infectaron de manera aguda macrófagos M-CSF y células T CD4+ con un virus NL4-3-GFP pseudotipado como VEV. En células T CD4+, la infección se realizó mediante espinoculación (1200xg, 1 h 30 min a 37°C) para potenciar la tasa de infección. Se midió la replicación viral y la actividad antiviral en todos los casos dos días después mediante citometría de flujo (LSRII, BD Biosciences).  Differentiated CD4 + and MDM T cells in M-CSF were incubated with antiviral drugs 24 h prior to infection. M-CSF macrophages and CD4 + T cells were acutely infected with a pseudotyped NL4-3-GFP virus such as VEV. In CD4 + T cells, infection was performed by spinoculation (1200xg, 1 hr 30 min at 37 ° C) to enhance the infection rate. Viral replication and antiviral activity were measured in all cases two days later by flow cytometry (LSRII, BD Biosciences).
11. Evaluación del ciclo celular mediante citometría de flujo 11. Evaluation of the cell cycle by flow cytometry
Para análisis del ciclo celular, se suspendieron células en saponina al 0,03% (Sigma- Aldrich Co., Saint Louis, MO, EE.UU.) en PBS y luego se incubaron en 7- aminoactinomicina D 20 mM (7AAD; Sigma-Aldrich Co., Saint Louis, MO, EE.UU.) durante 30 min a temperatura ambiente en la oscuridad, seguido por 5 min a 4°C. Entonces, se añadió pironina Y (Sigma-Aldrich Co., Saint Louis, MO, EE.UU.) a una concentración final de 1 ,5 mg/ml y se incubaron adicionalmente las células a 4°C durante 15 min. Se realizó citometría de flujo en un citómetro de flujo LSRII (BD Biosciences). Se analizaron los datos usando el software FlowJo (BD Biosciences). For cell cycle analysis, cells were suspended in 0.03% saponin (Sigma-Aldrich Co., Saint Louis, MO, USA) in PBS and then incubated in 20mM 7-aminoactinomycin D (7AAD; Sigma -Aldrich Co., Saint Louis, MO, USA) for 30 min at room temperature in the dark, followed by 5 min at 4 ° C. Then, pyronine Y (Sigma-Aldrich Co., Saint Louis, MO, USA) was added to a final concentration of 1.5 mg / ml and the cells were further incubated at 4 ° C for 15 min. Flow cytometry was performed on an LSRII flow cytometer (BD Biosciences). Data were analyzed using FlowJo software (BD Biosciences).
12. Ensayos de viabilidad celular 12. Cell viability assays
Se realizó medición de la citotoxicidad celular en macrófagos M-CSF mediante un método colorimétrico basado en tetrazolio [3-(4,5-dimetiltiazo-2-il)-2,5— difeniltetrazolio, método MTT] Se realizaron ensayos de viabilidad para determinar la actividad antiviral en células T CD4+ primarias mediante citometría de flujo, es decir, las células se separaron como vivas o muertas, según citometría de flujo FSC y parámetros SSC. Para la evaluación de la viabilidad celular en líneas celulares infectadas de manera latente, se tiñeron las células durante 30 minutos con el kit de tinción LIVE/DEAD™ Fixable Near-IR Dead Cell (Invitrogen, Thermo Fischer Scientific) en PBS según las instrucciones del fabricante. Las células se lavaron y se fijaron en formaldehído al 1 %. Se realizó citometría de flujo en un citómetro de flujo FACS LSRII (BD Biosciences). Se analizaron los datos usando el software FlowJo (BD Biosciences). Measurement of cellular cytotoxicity in M-CSF macrophages was performed using a tetrazolium-based colorimetric method [3- (4,5-dimethylthiazo-2-yl) -2,5— diphenyltetrazolium, MTT method]. Viability tests were performed to determine antiviral activity in primary CD4 + T cells by flow cytometry, that is, cells were separated as alive or dead, according to FSC flow cytometry and SSC parameters. For evaluation of cell viability in latently infected cell lines, cells were stained for 30 minutes with the LIVE / DEAD ™ Fixable Near-IR Dead Cell Staining Kit (Invitrogen, Thermo Fischer Scientific) in PBS according to the instructions of the maker. Cells were washed and fixed in 1% formaldehyde. Flow cytometry was performed on a FACS LSRII flow cytometer (BD Biosciences). Data were analyzed using FlowJo software (BD Biosciences).
13. Evaluación del índice de combinación  13. Evaluation of the combination index
Se realizó clasificación de barasertib e interacción de HDACi como sinérgico, aditivo o antagónico en J-Hig y J-Lat clon 9.2 mediante el cálculo del índice de combinación (Cl) usando el software libre CompuSyn®.  Barasertib classification and HDACi interaction as synergistic, additive or antagonistic in J-Hig and J-Lat clone 9.2 were performed by calculating the combination index (Cl) using the free software CompuSyn®.
Ejemplo 1 Example 1
Inhibidores de AURK como posibles agentes reversores de latencia  AURK inhibitors as possible latency reversing agents
Se compararon 425 compuestos anticancerosos contra los inhibidores de HDAC panobinostat (PNB) y vorinostat (VOR), dos agentes de reversión de latencia (LRA) bien conocidos, para evaluar sus efectos como reactivadores de VIH-1 latentes. Los experimentos se realizaron en las células latentes J-Hig donde ambos HDACi indujeron reactivación de manera dependiente de la dosis. De los 425 compuestos sometidos a prueba, 15 agentes activos se consideraron aciertos, puesto que su reactivación relativa puntuó por encima de la de panobinostat a 0,16 mM más/menos dos desviaciones estándar. Véase la figura 1A. Los 46 compuestos por debajo del límite de acierto, pero cuya reactivación relativa era al menos 1 ,4 veces mayor que la condición sin tratar, se consideraron pseudoaciertos. Véase la figura 1 B. 425 anticancer compounds were compared against HDAC inhibitors panobinostat (PNB) and vorinostat (VOR), two well-known latency reversal agents (LRA), to assess their effects as latent HIV-1 reactivators. Experiments were performed on dormant J-Hig cells where both HDACi they induced reactivation in a dose-dependent manner. Of the 425 compounds tested, 15 active agents were considered correct, since their relative reactivation scored above that of panobinostat at 0.16 mM plus / minus two standard deviations. See figure 1A. The 46 compounds below the hit limit, but whose relative reactivation was at least 1.4 times greater than the untreated condition, were considered pseudo-hits. See figure 1 B.
La clasificación de compuestos de acierto por su diana mostró que una mayoría eran agentes dirigidos a HDAC (7 compuestos), mientras que la segunda diana más común era la familia de aurora cinasas (AURK) (3 compuestos). Véase la figura 2A. Cuando se añaden los pseudoaciertos a la clasificación, la familia de HDAC prevaleció como la diana más común (9 compuestos), mientras que la familia de AURK quedó en cuarta posición (7 compuestos). Véase la figura 2B.  Sorting target compounds by their target showed that a majority were HDAC targeting agents (7 compounds), while the second most common target was the aurora kinase family (AURK) (3 compounds). See figure 2A. When pseudo-hits were added to the classification, the HDAC family prevailed as the most common target (9 compounds), while the AURK family ranked fourth (7 compounds). See figure 2B.
El examen de todos los agentes activos anti-AURK presentes en la matriz de 425 compuestos mostró 12 productos, 3 de los cuales se clasificaron como aciertos, 4 como pseudoaciertos, 4 como fuera del intervalo y 1 como no clasificado puesto que su color interfería con los espectros de citometría de flujo. Véase la tabla 1. Todos los compuestos anti-AURK sometidos a prueba mostraron diferente especificidad hacia los miembros de la familia de AURK, siendo barasertib (S1147) el acierto más específico y potente anti-aurora cinasa B (AURKB) del ensayo.  Examination of all the anti-AURK active agents present in the 425 compound matrix showed 12 products, 3 of which were classified as hits, 4 as pseudo-hits, 4 as out-of-range and 1 as unclassified since their color interfered with flow cytometry spectra. See Table 1. All tested anti-AURK compounds showed different specificity towards members of the AURK family, with barasertib (S1147) being the most specific and potent anti-aurora kinase B (AURKB) test hit.
Tabla 1  Table 1
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000140_0001
Figure imgf000141_0001
aCI5o, concentración inhibitoria máxima media, o la concentración necesaria para inducir el 50% de inhibición de la diana para el fármaco indicado. CI50 refleja la fuerza funcional del inhibidor. bK¡, constante de inhibición, o la concentración necesaria para reducir la actividad de esa enzima a la mitad. K¡ refleja la afinidad de unión de un compuesto hacia su diana. CK¡ ap, K¡ aparente. Para inhibidores no competitivos, K¡ aparente es igual que K¡, mientras que para inhibidores competitivos, la K¡ aparente dependerá de la concentración del sustrato de la enzima. aCI 5 o, mean maximum inhibitory concentration, or the concentration necessary to induce 50% inhibition of the target for the indicated drug. IC 50 reflects the functional strength of the inhibitor. b K, constant of inhibition, or the concentration necessary to reduce the activity of that enzyme in half. K, reflects the binding affinity of a compound towards its target. C K¡ ap, K¡ apparent. For non-competitive inhibitors, apparent K, is the same as K, while for competitive inhibitors, the apparent K, will depend on the concentration of the enzyme substrate.
Ejemplo 2  Example 2
Los inhibidores de AURK inducen reactivación en líneas celulares y células primarias La actividad dependiente de la dosis de barasertib y MK-5108, el pseudoacierto con la mayor especificidad y potencia para aurora cinasa A (AURKA), se sometió a ensayo en células J-Hig. Véase la figura 3A. Se usaron los HDACi panobinostat y vorinostat como controles, junto con DMSO a la misma concentración final, y acitretina, un compuesto antipsoriasis descartado como LRA en vista de estudios previos. Aunque el control de DMSO no mostró ninguna reactivación, se observaron células GFP+ en las células tratadas con tanto inhibidores de HDAC como de AURK. Tal como se esperaba, la acitretina no indujo ninguna reactivación significativa.  AURK inhibitors induce reactivation in cell lines and primary cells Dose-dependent activity of barasertib and MK-5108, the pseudo-certainty with the highest specificity and potency for aurora kinase A (AURKA), was assayed in J-Hig cells . See figure 3A. HDACi panobinostat and vorinostat were used as controls, along with DMSO at the same final concentration, and acitretin, an antipsoriasis compound ruled out as LRA in view of previous studies. Although the DMSO control did not show any reactivation, GFP + cells were observed in cells treated with both HDAC and AURK inhibitors. As expected, acitretin did not induce any significant reactivation.
La capacidad de reactivación de los compuestos anteriores se sometió a ensayo en el modelo de células latentes ACH-2 usando las mismas concentraciones que las sometidas a prueba previamente. Véase la figura 3B. Ambos HDACi indujeron reactivación, tal como se esperaba, ya que la presencia de CAp24 en sus sobrenadantes celulares se verificó. En el caso de los compuestos anti-AURK, el nivel de reactivación de barasertib y MK-5108 era comparable al de vorinostat a 0,8 ó 0,35 mM. La actividad de MK-5108 era mayor que la de barasertib en el modelo celular ACH-2, en oposición a los resultaos obtenidos con las células J-Hig.  The reactivation capacity of the above compounds was tested in the ACH-2 dormant cell model using the same concentrations as previously tested. See figure 3B. Both HDACi induced reactivation, as expected, since the presence of CAp24 in their cell supernatants was verified. In the case of the anti-AURK compounds, the level of reactivation of barasertib and MK-5108 was comparable to that of vorinostat at 0.8 or 0.35 mM. MK-5108 activity was higher than that of barasertib in the ACH-2 cell model, as opposed to the results obtained with J-Hig cells.
Para evaluar la capacidad de reactivación de los inhibidores de AURK en células primarias, se cultivaron células T CD4+ indiferenciadas infectadas de manera latente en presencia de barasertib. Se usaron DMSO y aCD3aCD28 como controles negativos y positivos, respectivamente. Véase la figura 4A. Los HDACi vorinostat y panobinostat también se incluyeron en el experimento como controles para la reactivación. Aunque la reactivación en estas células no fue demasiado alta, tal como se observó con el control aCD3aCD28, barasertib logró la misma cantidad de reactivación con poca citotoxicidad. Por otro lado, ambos HDACi vorinostat y panobinostat provocaron una marcada disminución en la viabilidad celular sin inducir ninguna reactivación significativa. Véase la figura 4C. Se observó alguna reactivación con vorinostat a 1 mM, mientras que la viabilidad celular estaba por encima del 75%.To assess the reactivation capacity of AURK inhibitors in primary cells, latently infected undifferentiated CD4 + T cells were cultured in the presence of barasertib. DMSO and aCD3aCD28 were used as negative and positive controls, respectively. See figure 4A. The HDACi vorinostat and panobinostat were also included in the experiment as controls for reactivation. Although the reactivation in these cells was not too high, as observed with the aCD3aCD28 control, barasertib achieved the same amount of reactivation with little cytotoxicity. On the other hand, both HDACi vorinostat and panobinostat caused a marked decrease in cell viability without inducing any significant reactivation. See figure 4C. Some reactivation with vorinostat was observed at 1 mM, while cell viability was above 75%.
Alternativamente, la capacidad de reversión de latencia de los agentes activos anteriores se analizó cuantificando ARN viral en el sobrenadante de las células T CDD4+ indiferenciadas infectadas de manera latente primarias. Véase la figura 4B. Tal como se observa mediante citometría de flujo, aCD3aCD28 indujo la producción de ARN viral así como vorinostat a 1 mM. Además, también se analizó la reactivación inducida por barasertib a 1 mM. Aunque la reactivación inducida por barasertib no fue tan alta como la de los controles, se detectó más ARN viral que en las células tratadas con DMSO. Tal como se notifica en el ensayo de citometría de flujo, panobinostat a O,dmM no indujo ninguna reactivación. Alternatively, the latency reversal capacity of the above active agents was analyzed by quantifying viral RNA in the supernatant of the primary latently infected undifferentiated CDD4 + T cells. See figure 4B. As seen by flow cytometry, aCD3aCD28 induced viral RNA production as well as vorinostat at 1 mM. In addition, barasertib-induced reactivation at 1 mM was also analyzed. Although the barasertib-induced reactivation was not as high as that of the controls, more viral RNA was detected than in the DMSO-treated cells. As reported in the flow cytometric assay, panobinostat at O, dmM did not induce any reactivation.
Ejemplo 3  Example 3
Efecto sinérgico de la combinación de HDAC e inhibidores de AURK sobre la reversión de latencia  Synergistic effect of the combination of HDAC and AURK inhibitors on latency reversal
Después de evaluar el efecto de reactivación de compuestos anti-AURK por sí mismos, también se sometió a prueba su efecto combinado con LRA conocidos tales como panobinostat y vorinostat. Diferentes concentraciones de los HDACi se incubaron con o sin barasertib durante 24 h tanto en células J-Hig como en células 9.2 de clon J-Lat. After evaluating the reactivation effect of anti-AURK compounds on their own, their combined effect with known LRAs such as panobinostat and vorinostat was also tested. Different concentrations of HDACi were incubated with or without barasertib for 24 h in both J-Hig cells and 9.2 J-Lat clone cells.
Se observó un aumento significativo en el porcentaje de reactivación cuando se empleó una combinación de barasertib y un HDACi en el modelo de células J-Hig. Véase la figura 5A y 5B. Además, cuando se añadió barasertib a células 9.2 de clon J- Lat incubadas con panobinostat o vorinostat, también aumentaron las tasas de reactivación, aunque barasertib no podía inducir reactivación por sí mismo en esta línea celular. Véanse las figuras 5C y 5D. A significant increase in the percentage of reactivation was observed when a combination of barasertib and HDACi was used in the J-Hig cell model. See figure 5A and 5B. Furthermore, when barasertib was added to J-Lat clone 9.2 cells incubated with panobinostat or vorinostat, reactivation rates also increased, although barasertib was unable to induce reactivation by itself in this cell line. See Figures 5C and 5D.
Se observó un punto de reactivación óptimo tanto en las líneas de células J-Hig como J-Lat cuando un aumento marginal en la cantidad del HDACi (por ejemplo panobinostat) o barasertib al cultivo no afectó a la reactivación. Sin embargo, este punto óptimo sólo se alcanzó cuando se empleó una combinación de barasertib y un HDACi. El uso separado de cualquiera de los dos compuestos no logró un nivel de reactivación comparable. Además, el análisis de índice de combinación (Cl) calculado reveló que la combinación de barasertib y un HDACi no tenía un efecto aditivo sino uno sinérgico sobre la reactivación de VIH-1. Véanse las tablas 2 y 3. Se obtuvieron valores de Cl usando el software CompuSyn® (ComboSyn, Inc., Nueva York, NY, EE.UU., http://www.combosyn.com/index.html, mayo de 2018). Cl>1 indica una interacción antagonista; Cl=1 indica interacción aditiva; Cl<1 indica interacción sinérgica. Tabla 2, índice de combinación (Cl) entre barasertib y HDACi en células J- Hig. Tabla 3, índice de combinación (Cl) entre barasertib y HDACi en células 9.2 J-Lat. An optimal reactivation point was observed in both the J-Hig and J-Lat cell lines when a marginal increase in the amount of HDACi (eg panobinostat) or barasertib to the culture did not affect reactivation. However, this optimum point was only reached when a combination of barasertib and HDACi was used. Separate use of either compound did not achieve a comparable level of reactivation. Furthermore, the calculated combination index (Cl) analysis revealed that the combination of barasertib and an HDACi did not have an additive effect but a synergistic effect on reactivation of HIV-1. See Tables 2 and 3. Cl values were obtained using CompuSyn® software (ComboSyn, Inc., New York, NY, USA, http://www.combosyn.com/index.html, May 2018 ). Cl> 1 indicates an antagonistic interaction; Cl = 1 indicates additive interaction; Cl <1 indicates synergistic interaction. Table 2, combination index (Cl) between barasertib and HDACi in J-Hig cells. Table 3, combination index (Cl) between barasertib and HDACi in 9.2 J-Lat cells.
Tabla 2
Figure imgf000142_0001
Figure imgf000143_0001
Table 2
Figure imgf000142_0001
Figure imgf000143_0001
Tabla 3  Table 3
Figure imgf000143_0002
Figure imgf000143_0002
Ejemplo 4  Example 4
La interferencia de AURKB es suficiente para desencadenar reactivación de VIH-1AURKB interference is sufficient to trigger reactivation of HIV-1
Para verificar si el efecto de reactivación de barasertib se debía a la inhibición directa de su diana AURKB, se reguló por disminución la expresión de aurora cinasa B en células J-Hig usando ARNip dirigido contra AURKB. Véase la figura 6A. Tal como se observa en la condición sin tratar, el silenciamiento de AURKB induce la reactivación de provirus latente en comparación con las células no tratadas en la simulación y los controles no de direccionamiento (NT). Tal como se observó previamente con barasertib, el efecto del silenciamiento de AURKB se aumentó cuando estaba en combinación con un HDACi tal como panobinostat o vorinostat. To verify whether the reactivation effect of barasertib was due to direct inhibition of its target AURKB, the expression of aurora kinase B in J-Hig cells was downregulated using siRNA directed against AURKB. See figure 6A. As seen in the untreated condition, AURKB silencing induces reactivation of latent provirus compared to untreated cells in the mock and non-targeting (NT) controls. As previously observed with barasertib, the effect of AURKB silencing was increased when in combination with an HDACi such as panobinostat or vorinostat.
Los niveles de ARNm de AURK se cuantificaron mediante PCR en tiempo real en el momento en el que se añadieron los agentes activos (24 h tras la interferencia) y cuando se realizó un ensayo de citometría de flujo (48 h tras la interferencia). Los niveles de ARNm de AURKB fueron menores que en la simulación y los controles de ARNip NT en ambos casos, lo que muestra una regulación por diminución eficaz de AURKB. Véase la figura 6B.  AURK mRNA levels were quantified by real-time PCR at the time the active agents were added (24 h after interference) and when a flow cytometry assay was performed (48 h after interference). AURKB mRNA levels were lower than in the simulation and siRNA NT controls in both cases, showing effective down-regulation of AURKB. See figure 6B.
Ejemplo 5 Example 5
Los inhibidores de AURK tienen efecto protector frente a infección por VIH-1  AURK inhibitors have a protective effect against HIV-1 infection
Se evaluaron los efectos de compuestos anti-AURK en células no infectadas primarias antes de la infección aguda. Se incubaron células T CD4+ primarias y macrófagos derivados de monocitos con compuestos anti-AURK 24 h antes de la infección. Véase la figura 7A y 7B. Se usó el agente antirretroviral 3-azido-3-desoxitimidina (zidovudina; AZT) como control positivo en ambos casos, junto con palbociclib y MK-1775. Como controles negativos, se usó LY2603618 anti-cinasa de control 1 (Chk1) en macrófagos y se empleó BML-277 anti-cinasa de control 2 (Chk2) en células T CD4+. Tal como se esperaba, AZT, palbociclib y MK-1775 bloquearon la infección por VIH en ambos casos. Ninguno de los compuestos anti-cinasa de control indujo ningún cambio significativo. Por otro lado, ambos fármacos anti-aurora cinasas, MK-5108 y barasertib, redujeron la tasa de infección viral. Barasertib, el más potente de los dos, era especialmente eficaz en la reducción de la tasa de infección en células T CD4+. The effects of anti-AURK compounds on primary uninfected cells were evaluated prior to acute infection. Primary CD4 + T cells and monocyte derived macrophages were incubated with anti-AURK compounds 24 h prior to infection. See figure 7A and 7B. The antiretroviral agent 3-azido-3-deoxythymidine (zidovudine; AZT) was used as a positive control in both cases, along with palbociclib and MK-1775. How negative controls, LY2603618 anti-kinase control 1 (Chk1) was used in macrophages and BML-277 anti-kinase control 2 (Chk2) was used in CD4 + T cells. As expected, AZT, palbociclib, and MK-1775 blocked HIV infection in both cases. None of the control anti-kinase compounds induced any significant change. On the other hand, both anti-aurora kinase drugs, MK-5108 and barasertib, reduced the rate of viral infection. Barasertib, the more powerful of the two, was especially effective in reducing the infection rate in CD4 + T cells.
Para estudiar adicionalmente la ruta afectada por inhibidores de AURK, se evaluó la expresión de proteínas mediante inmunotransferencia de tipo Western en células T CD4+. Véase la figura 7C. Palbociclib y MK-1775 se usaron como controles. Tanto palbociclib como MK-1775 indujeron la desfosforilación y activación de SAMHD1 , un factor de restricción de VIH conocido, y la degradación de la proteína de retinoblastoma (pRB). En cambio, aunque ambos inhibidores de AURK presentaron actividad anti-VIH, las células T CD4+ tratadas con los inhibidores de AURK barasertib y MK-5108 mostraron los mismos niveles de proteínas que las no tratadas.  To further study the pathway affected by AURK inhibitors, protein expression was assessed by Western blotting on CD4 + T cells. See figure 7C. Palbociclib and MK-1775 were used as controls. Both palbociclib and MK-1775 induced dephosphorylation and activation of SAMHD1, a known HIV restriction factor, and degradation of the retinoblastoma protein (pRB). In contrast, although both AURK inhibitors exhibited anti-HIV activity, CD4 + T cells treated with the AURK inhibitors barasertib and MK-5108 showed the same protein levels as the untreated ones.
Además, el efecto de inhibidores de AURK sobre la progresión del ciclo celular en macrófagos y células T CD4+ se sometió a ensayo analizando su contenido en ARN/ADN. Se usó palbociclib como control. Véase la figura 8A y 8B. En comparación con los estados no tratados, palbociclib promovió la detención del ciclo celular en las fases G0-G1 , tal como se observa claramente en células T CD4+. Los inhibidores de cinasa de control BML-277 y LY2603618 no mostraron ningún efecto sobre el perfil del ciclo celular. Ambos inhibidores de AURK, MK-5108 y barasertib detuvieron las células en las fases G2-M en células T CD4+ y macrófagos.  Furthermore, the effect of AURK inhibitors on cell cycle progression in macrophages and CD4 + T cells was tested by analyzing their RNA / DNA content. Palbociclib was used as a control. See figure 8A and 8B. Compared to untreated states, palbociclib promoted cell cycle arrest in G0-G1 phases, as clearly seen in CD4 + T cells. Control kinase inhibitors BML-277 and LY2603618 showed no effect on cell cycle profile. Both AURK inhibitors, MK-5108 and barasertib stopped cells in G2-M phases in CD4 + T cells and macrophages.

Claims

REIVINDICACIONES
1. Método de tratamiento o prevención de una infección por VIH o SIDA que comprende administrar una cantidad terapéuticamente eficaz de un inhibidor de aurora cinasa (AURK) a un sujeto que lo necesita.  1. A method of treating or preventing an HIV or AIDS infection which comprises administering a therapeutically effective amount of an aurora kinase inhibitor (AURK) to a subject in need.
2. Método según la reivindicación 1 , en el que la AURK es una AURK de clase B.2. The method of claim 1, wherein the AURK is a class B AURK.
3. Método según una cualquiera de las reivindicaciones anteriores, en el que el inhibidor de AURK comprende un compuesto de fórmula (I), (II), (III), (IV), (V), (VI), (Vil), (VIII) o (IX), o una combinación de los mismos: 3. Method according to any one of the preceding claims, in which the AURK inhibitor comprises a compound of formula (I), (II), (III), (IV), (V), (VI), (Vil) , (VIII) or (IX), or a combination thereof:
Figure imgf000145_0001
Fórmula (I)
Figure imgf000145_0001
Formula (I)
o una sal farmacéuticamente aceptable del mismo;  or a pharmaceutically acceptable salt thereof;
en la que A es heteroarilo de 5 miembros que contiene un átomo de nitrógeno y opcionalmente contiene uno o dos átomos de nitrógeno adicionales;  wherein A is 5-membered heteroaryl containing one nitrogen atom and optionally containing one or two additional nitrogen atoms;
X es O, S, S(O), S(0)2 o NR 14; X is O, S, S (O), S (0) 2 or NR 14 ;
m es 0, 1 , 2 ó 3;  m is 0, 1, 2 or 3;
Z es un grupo seleccionado de— NR1 R2, fosfonooxilo, cicloalquilo C3-6 cuyo cicloalquilo C3-6 está sustituido por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo, y un anillo de 4 a 7 miembros unido a través de un átomo de carbono que contiene un átomo de nitrógeno y que opcionalmente contiene un átomo de nitrógeno adicional, en el que el anillo puede estar saturado, parcialmente saturado o insaturado, en el que el anillo está sustituido en el carbono o nitrógeno por fosfonooxilo o alquilo Ci-4 sustituido por fosfonooxilo, y en el que el anillo está opcionalmente sustituido adicionalmente en el carbono o nitrógeno por 1 , 2 ó 3 grupos halo o alquilo Ci-4; Z is a group selected from— NR 1 R 2 , phosphonooxy, C3-6 cycloalkyl whose C3-6 cycloalkyl is substituted by phosphonooxy or Ci -4 alkyl substituted by phosphonoxy, and a 4- to 7-membered ring attached through an atom carbon containing one nitrogen atom and optionally containing a nitrogen atom additional, wherein the ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by fosfonooxilo or alkyl Ci - 4 substituted by phosphonooxy, and wherein the ring is optionally further substituted at carbon or nitrogen by 1, 2 or 3 halo or Ci -4 alkyl groups;
R1 es un grupo seleccionado de— COR8,— CONR8R9 y alquilo Ci-e cuyo alquilo C1 -6 está sustituido por fosfonooxilo y opcionalmente sustituido adicionalmente por 1 ó 2 grupos halo o metoxilo; R 1 is a group selected from - COR 8 , - CONR 8 R 9 and Ci-e alkyl whose C 1 -6 alkyl is substituted by phosphonooxyl and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 es un grupo seleccionado de hidrógeno, — COR10, — CONR10R11 y alquilo C1 -6 cuyo alquilo Ci-e está opcionalmente sustituido por 1 , 2 ó 3 grupos halo o alcoxilo Ci-4 o— S(0)pR11 (donde p es 0, 1 ó 2) o fosfonooxilo, o R2 es un grupo seleccionado de alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6 y cicloalquil C3-6- alquilo Ci-4; R 2 is a group selected from hydrogen, - COR 10 , - CONR 10 R 11 and C1 -6 alkyl whose Ci-e alkyl is optionally substituted by 1, 2 or 3 halo groups or Ci- 4 alkoxy or S (0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and C3-6 cycloalkyl-Ci -4 alkyl;
o R1 y R2 junto con el nitrógeno al que se unen forman un anillo de 4 a 7 miembros que contiene opcionalmente un átomo de nitrógeno adicional cuyo anillo puede estar saturado, insaturado o parcialmente saturado en el que el anillo está sustituido en el carbono o nitrógeno por un grupo seleccionado de fosfonooxilo y alquilo Ci-4 cuyo alquilo Ci-4 está sustituido por fosfonooxilo o— NR8R9, y en el que el anillo está opcionalmente sustituido adicionalmente en el carbono o nitrógeno por 1 , 2 ó 3 grupos halo o alquilo Ci-4; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing an additional nitrogen atom the ring of which may be saturated, unsaturated or partially saturated in which the ring is carbon-substituted or nitrogen by a group selected from phosphonooxy and Ci -4 alkyl whose Ci -4 alkyl is substituted by phosphonooxy or— NR 8 R 9 , and wherein the ring is optionally further substituted at carbon or nitrogen by 1, 2 or 3 halo or Ci -4 alkyl groups;
R3 es un grupo seleccionado de hidrógeno, halo, ciano, nitro, alcoxilo Ci-e, alquilo Ci-6,— OR12,— CHR12R13,— 0C(0)R12,— C(0)R12,— NR12C(0)R13,— C(0)NR12R13,— NR12S02R13 y— NR12R13; R 3 is a group selected from hydrogen, halo, cyano, nitro, Ci-e - alkoxy, Ci- 6 alkyl, - OR 12, - CHR 12 R 13, - 0C (0) R 12, - C (0) R 12 , - NR 12 C (0) R 13 , - C (0) NR 12 R 13 , - NR 12 S0 2 R 13 and - NR 12 R 13 ;
R4 es hidrógeno o un grupo seleccionado de alquilo Ci-4, heteroarilo, alquil Ci-4- heteroarilo, arilo y alquil Ci-4-arilo cuyo grupo está opcionalmente sustituido por 1 , 2 ó 3 sustituyentes seleccionados de halo, metilo, etilo, ciclopropilo y etinilo;R 4 is hydrogen or a group selected from Ci- 4- alkyl, heteroaryl, Ci- 4- alkyl-heteroaryl, aryl and Ci- 4- aryl-alkyl the group of which is optionally substituted by 1, 2 or 3 substituents selected from halo, methyl, ethyl , cyclopropyl and ethynyl;
R5 se selecciona de hidrógeno, alquilo Ci-4, alquenilo C2-4, alquinilo C2-4, cicloalquilo C3-6 y cicloalquil C3-6-alquilo Ci-4; R 5 is selected from hydrogen, Ci -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl C 3-6 cycloalkyl C 3-6 -alkyl Ci -4;
R6 y R7 se seleccionan independientemente de hidrógeno, halo, alquilo Ci-4, cicloalquilo C3-6, hidroxilo y alcoxilo Ci-4; R 6 and R 7 are independently selected from hydrogen, halo, Ci -4 alkyl, C 3-6 cycloalkyl, hydroxyl and Ci -4 alkoxy;
R8 es alquilo Ci-4 sustituido por fosfonooxilo y opcionalmente sustituido adicionalmente por 1 ó 2 grupos halo o metoxilo; R 8 is Ci- 4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 se selecciona de hidrógeno y alquilo Ci-4; R 9 is selected from hydrogen and Ci -4 alkyl;
R10 se selecciona de hidrógeno y alquilo Ci-4 (opcionalmente sustituido por halo, alcoxilo Ci-4, S(0)q (donde q es 0, 1 ó 2) o fosfonooxilo); R 10 is selected from hydrogen and Ci -4 alkyl (optionally substituted by halo, Ci -4 alkoxy, S (0) q (where q is 0, 1, or 2) or phosphonooxy);
R11, R12, R13 y R14 se seleccionan independientemente de hidrógeno, alquilo Ci. 4 y heterociclilo; R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, Ci alkyl. 4 and heterocyclyl;
Figure imgf000146_0001
Figure imgf000146_0001
Fórmula (II)  Formula (II)
en la que: in which:
Q y T se seleccionan cada uno independientemente de oxígeno, azufre o N(R); cada R se selecciona independientemente de hidrógeno o un grupo alifático Ci. 6 opcionalmente sustituido, en el que: Q and T are each independently selected from oxygen, sulfur, or N (R); each R is independently selected from hydrogen or an aliphatic group Ci. 6 optionally substituted, in which:
dos R unidos al mismo atomo de nitrógeno se toman opcionalmente junto con el nitrógeno para formar un anillo monocíclico de 3-7 miembros o bicíclico de 8- 10 miembros saturado, parcialmente insaturado o completamente insaturado opcionalmente sustituido que tiene de 0 a 3 heteroátomos, además del nitrógeno unido al mismo, independientemente seleccionados de nitrógeno, oxígeno o azufre; two Rs attached to the same nitrogen atom are optionally taken together with the nitrogen to form an optionally substituted saturated, partially unsaturated or fully unsaturated 3-7 membered or 8-10 membered bicyclic ring having 0 to 3 heteroatoms, in addition of the nitrogen bound thereto, independently selected from nitrogen, oxygen or sulfur;
Rx es U-R5; R x is UR 5 ;
R5 se selecciona de halógeno, N02, CN, R o Ar; R 5 is selected from halogen, N0 2 , CN, R or Ar;
cada U se selecciona independientemente de un enlace de valencia o una cadena de alquilideno C1-4, en la que: each U is independently selected from a valence bond or a C1-4 alkylidene chain, in which:
hasta dos unidades de metileno de U están reemplazadas opcional e independientemente por— O— , — S— , — SO— , — SO2— , — N(R)SC>2— , — S02N(R)— ,— N(R)— ,— C(O)— ,— C02— ,— N(R)C(0)— ,— N(R)C(0)0— ,— N(R)CON(R)— , — N(R)S02N(R)— , — N(R)N(R)— , — C(0)N(R)— , —Up to two methylene units of U are optionally and independently replaced by— O—, - S—, - SO—, - SO2—, - N (R) SC> 2—, - S0 2 N (R) -, - N (R) -, - C (O) -, - C0 2 -, - N (R) C (0) -, - N (R) C (0) 0—, - N (R) CON (R) - , - N (R) S0 2 N (R) -, - N (R) N (R) -, - C (0) N (R) -, -
0C(0)N(R)— ,— C(R)=NN(R)— o— C(R)=N— O— ; 0C (0) N (R) -, - C (R) = NN (R) - o— C (R) = N— O—;
cada Ar se selecciona independientemente de un anillo opcionalmente sustituido seleccionado de un anillo monocíclico de 3-7 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0 a 4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre; each Ar is independently selected from an optionally substituted ring selected from a 3-7 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated, or fully unsaturated having 0 to 4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur ;
R* es— N(R1)2,— OR1 O— SR1; R * is— N (R 1 ) 2 , - OR 1 O— SR 1 ;
cada R1 se selecciona independientemente de R o un anillo monocíclico de 3-8 miembros, bicíclico de 8-10 miembros o tricíclico de 10-12 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, y en el que: each R 1 is independently selected from R or a 3-8 membered monocyclic, 8-10 membered bicyclic or 10-12 membered tricyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, independently selected from nitrogen , oxygen or sulfur, and in which:
cada R1 está opcional e independientemente sustituido por hasta cuatro sustituyentes independientemente seleccionados de R2; each R1 is optionally and independently substituted by up to four independently selected substituents from R 2 ;
cada R2 se selecciona independientemente de— R3,— OR3,— SR3,— CN,— N02, oxo, halógeno,— N(R3)2,— C(0)R3,— OC(0)R3,— CO2R3,— SO2R3,— S02N(R3)2, — N(R3)S02R3, — C(0)NR(R3), — C(0)N(R3)2, — OC(0)NR(R3), — 0C(0)N(R3)2,— NR3C(0)R3,— NR3C(0)N(R3)2 O— NR3C02(R3); each R 2 is independently selected from— R 3 , - OR 3 , - SR 3 , - CN, - N0 2 , oxo, halogen, - N (R 3 ) 2 , - C (0) R 3 , - OC (0 ) R 3 , - CO2R 3 , - SO2R 3 , - S0 2 N (R 3 ) 2 , - N (R 3 ) S0 2 R 3 , - C (0) NR (R 3 ), - C (0) N (R 3 ) 2 , - OC (0) NR (R 3 ), - 0C (0) N (R 3 ) 2 , - NR 3 C (0) R 3 , - NR 3 C (0) N (R 3 ) 2 O— NR 3 C0 2 (R 3 );
cada R3 se selecciona independientemente de R o Ar; each R 3 is independently selected from R or Ar;
Rz1 se selecciona de un grupo alifático Ci-e o un anillo monocíclico de 3-8 miembros, bicíclico de 8-10 miembros o tricíclico de 10-12 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos, independientemente seleccionados de oxígeno, nitrógeno o azufre, en el que: R z1 is selected from a Ci-e aliphatic group or a 3-8 membered monocyclic, 8-10 membered bicyclic or 10-12 membered saturated, partially unsaturated or fully unsaturated tricyclic ring having 0-4 heteroatoms, independently selected from oxygen, nitrogen or sulfur, in which:
Rz1 está sustituido con de 0-4 grupos R2 independientemente seleccionados;R z1 is substituted with 0-4 independently selected R 2 groups;
Rz2 es un grupo alifático C 1 -6 o un anillo monocíclico de 3-8 miembros o bicíclico de 8-10 miembros saturado, parcialmente insaturado o completamente insaturado que tiene de 0-4 heteroátomos, independientemente seleccionados de nitrógeno, oxígeno o azufre, en el que: R z2 is a C 1-6 aliphatic group or a 3-8 membered monocyclic or 8-10 membered bicyclic ring saturated, partially unsaturated or fully unsaturated having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, in which:
Rz2 está sustituido por 0-4 sustituyentes independientemente seleccionados de oxo o U-R5; o una sal farmacéuticamente aceptable del mismo; R z2 is substituted by 0-4 substituents independently selected from oxo or UR 5 ; or a pharmaceutically acceptable salt thereof;
Figure imgf000148_0001
Figure imgf000148_0001
Fórmula (III)  Formula (III)
o una sal farmacéuticamente aceptable del mismo, en la que: or a pharmaceutically acceptable salt thereof, in which:
Ra se selecciona del grupo que consiste en alifático C1-3, fluoroalifático C1-3, — R1, -T-R1,— R2 y -T-R2; R a is selected from the group consisting of C1-3 aliphatic, C1-3 fluoroaliphatic, - R 1 , -TR 1 , - R 2 and -TR 2 ;
T es una cadena de alquileno C1-3 opcionalmente sustituida con fluoro; T is a C 1-3 alkylene chain optionally substituted with fluoro;
R1 es un grupo arilo, heteroarilo o heterociclilo opcionalmente sustituido; R 1 is an optionally substituted aryl, heteroaryl or heterocyclyl group;
R2 se selecciona del grupo que consiste en halo,— CºC— R3,— CH=CH— R3, — N(R4)2 y— OR; R 2 is selected from the group consisting of halo, - C ° C - R 3 , - CH = CH - R 3 , - N (R 4 ) 2 and - OR;
R3 es hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; R 3 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
cada R4 es independientemente hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; o dos R4 en el mismo átomo de nitrógeno, tomados junto con el átomo de nitrógeno, forman un anillo de heteroarilo de 5 a 6 miembros o heterociclilo de 4 a 8 miembros opcionalmente sustituido que tiene, además del átomo de nitrógeno, de 0-2 heteroátomos de anillo seleccionados de N, O y S; each R 4 is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4's on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0- 2 ring heteroatoms selected from N, O and S;
R5 es hidrógeno o un grupo alifático, arilo, heteroarilo o heterociclilo opcionalmente sustituido; y R 5 is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; Y
Rb se selecciona del grupo que consiste en fluoro, cloro,— CH3,— CF3,— OH, — OCH3,— OCF3,— OCH2CH3 y— OCH2CF3 ;
Figure imgf000149_0002
Fórmula (IV): R b is selected from the group consisting of fluoro, chloro, - CH 3 , - CF 3 , - OH, - OCH 3 , - OCF 3 , - OCH2CH3 and - OCH2CF3;
Figure imgf000149_0002
Formula (IV):
o derivado farmacéuticamente aceptable del mismo; or a pharmaceutically acceptable derivative thereof;
en la que uno de— es un doble enlace, si lo permite la valencia; where one of— is a double bond, if valence allows;
uno de X1 y X2 es S, el otro es — C(RX1)— ; en el que RX1 es hidrógeno, halógeno, ciano, nitro o un resto alifático, heteroalifático, alicíclico, heteroalicíclico, aromático o heteroaromático; one of X 1 and X 2 is S, the other is - C (R X1 ) -; wherein R X1 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, or heteroaromatic moiety;
W1 es O, S, NRW1 o— C(=0)NRW1 en el que RW1 es hidrógeno, alquilo inferior, cicloalquilo C3-6, heteroalquilo inferior, heterociclilo, arilo, heteroarilo, - (alquil)arilo, -(alquil)heteroarilo o acilo; o RW1 junto con un átomo de carbono presente en Alk, forma un anillo heterocíclico de 5 a 6 miembros opcionalmente sustituido; W 1 is O, S, NR W1 or— C (= 0) NR W1 where R W1 is hydrogen, lower alkyl, C3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl; or R W1 together with a carbon atom present in Alk, forms an optionally substituted 5- to 6-membered heterocyclic ring;
Alki es una cadena de alquileno C1 -6 o alquenileno C2-6 sustituida o no sustituida en la que hasta dos unidades de metileno no adyacentes están reemplazadas opcional e independientemente por — C(=0)— , — CO2— , — (=0)C(=0)— , — C(=0) N RL1A— , — N RL1AN RL1 B— , — N RL1AN RL1 BC(=0)— , — N RL1AC(=0)— , — RU AC02— , — N RL1 AC(=0) N RL1 B— , — S(=0)— , — S02— , — N RUAS02— , — S02NRL1A— , — NRL1AS02NRL1 B— , —O—, — S— o— NRL1A— ; en la que cada aparición de RL1A y RL1 B es independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, heterociclilo, arilo, heteroarilo o acilo;
Figure imgf000149_0001
Alki is a substituted or unsubstituted C1 -6 alkylene or C2-6 alkenylene chain in which up to two non-adjacent methylene units are optionally and independently replaced by - C (= 0) -, - CO2—, - (= 0 ) C (= 0) -, - C (= 0) NR L1A -, - NR L1A NR L1 B -, - NR L1A NR L1 B C (= 0) -, - NR L1A C (= 0) -, - R UA C0 2 -, - NR L1 A C (= 0) NR L1 B -, - S (= 0) -, - S0 2 -, - NR UA S0 2 -, - S0 2 NR L1A -, - NR L1A S0 2 NR L1 B -, —O—, - S— or— NR L1A -; wherein each occurrence of R L1A and R L1 B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, or acyl;
Figure imgf000149_0001
RW4 y RG2 son independientemente hidrógeno, alquilo inferior, heteroalquilo inferior, heterociclilo, arilo, heteroarilo, -(alquil)arilo, -(alquil)heteroarilo o acilo;R W4 and R G2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, - (alkyl) aryl, - (alkyl) heteroaryl or acyl;
Y es un anillo de fenilo o tiazolilo opcionalmente sustituido; Y is an optionally substituted phenyl or thiazolyl ring;
Z es un resto alifático, heteroalifático, alicíclico, heteroalicíclico, aromático o heteroaromático;  Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic residue;
con la condición de que (a) RX1 no sea Q1 , Q2 o Q3, en el que with the proviso that (a) R X1 is not Q 1 , Q 2 or Q 3 , in which
Q1 es— (CR1AR1 B)mCºC— (CR1AR1 B)tR1 c, — (CR1AR1 B)mCºC— (CR1AR1 B)tR1 c, — C=NOR1 D o— X3R1 D en el que m es un número entero desde 0 hasta 3, t es un número entero desde 0 hasta 5 y X3 es un grupo divalente derivado de azetidina, oxetano o un grupo carbocíclico C3-4; Q 1 is— (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) t R 1 c , - (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) t R 1 c , - C = NOR 1 D or— X 3 R 1 D where m is an integer from 0 to 3, t is an integer from 0 to 5, and X 3 is a divalent group derived from azetidine, oxetane, or a carbocyclic group C3-4;
Q2 es — (CR1AR1 B)mCºC— (CR1AR1 B)kR1 E, — (CR1AR1 B)mCºC(CR1AR1 B)k en el que k es un número entero desde 1 hasta 3 y m es un número entero desde 0 hasta 3; y Q 2 is - (CR 1A R 1 B ) m CºC— (CR 1A R 1 B ) k R 1 E , - (CR 1A R 1 B ) m CºC (CR 1A R 1 B ) k in which k is a integer from 1 to 3 and m is an integer from 0 to 3; Y
Q3 es— (CR1AR1 B)tR1 c, en el que t es un número entero desde 0 hasta 5 y el punto de unión a R1 C es a través de un átomo de carbono del grupo R1 C ; en el que R1A y R1 B son independientemente H o alquilo Ci-e; R1C es un anillo monocíclico no aromático opcionalmente sustituido, un anillo bicíclico condensado o en puente o un anillo espirocíclico; R1 E es— NR1AR1 D o— OR1 D; R1 D es R1 F,— C(=0)R1 F,— S02R1 F,— C(=0)N(R1 F)2,— S02N(R1 F)2 o— C02R1 F, en el que R1 F es H, alquilo C1-6, (CR1AR1 B)t(arilo Ce-io) o —Q 3 is— (CR 1A R 1 B ) t R 1 c , where t is an integer from 0 to 5 and the point of attachment to R 1 C is through a carbon atom of the group R 1 C ; in the that R 1A and R 1 B are independently H or Ci-e alkyl; R 1C is an optionally substituted non-aromatic monocyclic ring, a fused or bridged bicyclic ring or a spirocyclic ring; R 1 E is— NR 1A R 1 D or— OR 1 D ; R 1 D is R 1 F , - C (= 0) R 1 F , - S0 2 R 1 F , - C (= 0) N (R 1 F ) 2 , - S0 2 N (R 1 F ) 2 or - C0 2 R 1 F , where R 1 F is H, C1-6 alkyl, (CR 1A R 1 B ) t (aryl Ce-io) or -
(CR1AR1 B)t(heterocíclico de 4-10 miembros); y (CR 1A R 1 B ) t (4-10 membered heterocyclic); Y
(b) en uno cualquiera o más de los siguientes grupos, las variables mencionadas no se producen simultáneamente tal como se define:  (b) in any one or more of the following groups, the mentioned variables do not occur simultaneously as defined:
(i)— W1-Alkr es— OCH2— O— N(R)CH2— , en el que R es H o alquilo Ci-8; Y es fenilo; y Z es un cicloalquilo, heterociclilo, arilo o heteroarilo de 5-10 miembros; (i) - W 1 -Alkr is - OCH 2 - O - N (R) CH 2 -, where R is H or Ci- 8 alkyl; Y is phenyl; and Z is a 5-10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl;
(ii) RX1 es hidrógeno, halógeno, alquilo Ci-4 o alcoxilo Ci-4;— W1-Alkr es— NH- alquilo C1-6,— O-alquilo Ci-e,— NH-heteroalquilo Ci-e o— O-heteroalquilo Ci-e; L2-Z es— X— Rx en el que X es— NR— o— NHC(=0)— , y Rx es cicloalquilo C3-10, morfolinilo, fenilo, fenilo-alquilo Ci-4 o fenilo-alquenilo C2-3; y (ii) R X1 is hydrogen, halogen, Ci -4 alkyl or Ci -4 alkoxy; - W 1 -Alkr is- NH- C1-6alkyl, - O-Ci-e alkyl, - NH-Ci-e or heteroalkyl - O-heteroalkyl Ci-e; L 2 -Z is— X— R x where X is— NR— or— NHC (= 0) -, and R x is C 3-10 cycloalkyl, morpholinyl, phenyl, phenyl-Ci -4 alkyl or phenyl- C 2-3 alkenyl; Y
(iii) uno de X1 y X2 es S, el otro es CR^ en el que R^ es hidrógeno, alquilo Ci-4 o fenilo opcionalmente sustituido con halógeno, (halo)alquilo Ci-4 o (halo)alcoxilo Ci-4; — W1-Alkr es— NR-alquilo Ci-e, — O-alquilo C1-6- o— S- alquilo C1 -6 en el que R es hidrógeno, alquilo Ci-4, acilo Ci-4; Y es fenilo; L2-Z es un cadena hidrocarbonada saturada o insaturada de alquilo CM2 que incluye—(iii) one of X 1 and X 2 is S, the other is CR ^ where R ^ is hydrogen, Ci- 4- alkyl or phenyl optionally substituted with halogen, (halo) Ci- 4- alkyl or (halo) Ci-alkoxy. -4 ; - W 1 NR-alkyl -Alkr is- Ci-e, - O-alkyl S- o- 1-6 C1 -6 wherein R is hydrogen, Ci -4 alkyl, Ci -4 acyl; Y is phenyl; L 2 -Z is a C M2 alkyl saturated or unsaturated hydrocarbon chain including—
NR— y opcionalmente sustituida con halo-alcoxilo Ci-4, cicloalquilo C3-8, cicloalquenilo C3-8, acilo Ci-4, fenoxilo, fenilo o feniltio ; NR— and optionally substituted with halo-Ci -4 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, Ci -4 acyl, phenoxy, phenyl or phenylthio;
Figure imgf000150_0001
Figure imgf000150_0001
Fórmula (V)  Formula (V)
en la que: in which:
R1 es un átomo de hidrógeno, F, CN, COORai , CONRa2Ra2’, NRa3CORa3’,R 1 is a hydrogen atom, F, CN, COOR ai , CONR a2 R a2 ' , NR a3 COR a3' ,
CONRa4ORa4’, NRa5CONRa5’Ra5 , NRa6COORa6 , S02NRa7Ra7’, NRasS02Ra8 , CORag, S02Raio, N02, ORai i o NRai2Rai2 , en el que: CONR a4 OR a4 ' , NR a5 CONR a5' R a5 , NR a6 COOR a6 , S0 2 NR a7 R a7 ' , NR a sS0 2 R a8 , COR ag , S0 2 R ai o, N0 2 , OR ai i o NR ai2 Rai 2 , in which:
Raí , Ra3, Ra4, Ras, Ra6 y Ras son cada uno independientemente un átomo de hidrógeno o alquilo inferior; R ai , R a3 , R a4 , R a s, R a6 and R a s are each independently a hydrogen or lower alkyl atom;
Ra2, Ra2 , Ras , Ras , Ra7, Ra7 , Rai2 y Rai2 son cada uno independientemente un átomo de hidrógeno o alquilo inferior que pueden estar sustituidos con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente >, en el que <grupo sustituyente > es un átomo de halógeno, hidroxilo, nitro, ciano, amino, carbamoílo, aminosulfonilo, imino, alquilamino inferior, dialquilamino inferior, alquilsulfonilo inferior, alquilsulfonilamino inferior, alcoxilo inferior, alcoxicarbonilo inferior, alcoxicarbonilamino inferior, alcanoílo inferior, alcanoiloxilo inferior, alquiltio inferior y carboxilo; siempre que, sin embargo, R32 y F ; Ras’ y Ras”; Ra7 y Ra7’; Rai2 y Rai2 cada uno independientemente, junto con el átomo de nitrógeno al que se unen, puedan formar un grupo heterocíclico alifático de 5 miembros o aromático o 6 miembros que puede estar sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente l_2>, en el que <grupo sustituyente l_2> es un átomo de halógeno, hidroxilo, amino e hidroximetilo;Ra2, Ra2, Ras, Ras, Ra7, R to 7, Rai2 and Rai2 are each independently a hydrogen or lower alkyl atom which may be substituted with one or more of the same or different substituents selected from <substituent group>, in where <substituting group> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl, aminosulfonyl, imino, lower alkylamino, dialkylamino, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; provided that without However, R 3 2 and F; Ras ' and Ras ” ; Ra7 and Ra7 ' ; Rai2 and Rai2 each independently, together with the nitrogen atom to which they are attached, may form a 5-membered aliphatic or aromatic or 6-membered heterocyclic group that may be substituted with one or more of the same or different substituents selected from <group l_2 substituent>, where <l_2 substituent group> is a halogen, hydroxyl, amino and hydroxymethyl atom;
Ra3 , Ra4 , Ra6 , Ras , Ra9, Raio y Ran son cada uno independientemente un átomo de hidrógeno o alquilo inferior que puede sustituirse con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente >; o Ri es un alquilo inferior que puede sustituirse con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente M>, en el que <grupo sustituyente M> es un átomo de halógeno, hidroxilo, nitro, ciano, amino, carbamoílo, aminosulfonilo, imino, alquilamino inferior, dialquilamino inferior, alquilsulfonilo inferior, alquilsulfonilamino inferior, alcoxilo inferior, alcoxicarbonilo inferior, alcoxicarbonilamino inferior, alcanoílo inferior, alcanoiloxilo inferior, alquiltio inferior y carboxilo; o Ra3, Ra4, Ra6, Ras, R a9 , Raio and R a n are each independently a hydrogen or lower alkyl atom which can be substituted with one or more of the same or different substituents selected from <substituent group>; or Ri is a lower alkyl which can be substituted with one or more of the same or different substituents selected from <substituent group M>, in which <substituent group M> is a halogen, hydroxyl, nitro, cyano, amino, carbamoyl atom , aminosulfonyl, imino, lower alkylamino, dialkylamino lower, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; or
Ri es un grupo heterocíclico seleccionado de los siguientes, en los que Yi e Y2 son el mismo y diferente, y cada uno es un átomo de hidrógeno o alquilo inferior que puede estar sustituido:  Ri is a heterocyclic group selected from the following, where Yi and Y2 are the same and different, and each is a hydrogen or lower alkyl atom that may be substituted:
Figure imgf000151_0001
Figure imgf000151_0001
R2 es O, S, SO, SO2, NH, NRb, o CRCI RC2 en el que Rb es un alquilo inferior que puede estar sustituido, y Rd y RC2, que pueden ser el mismo o diferente, son un átomo de hidrógeno o alquilo inferior; R2 is O, S, SO, SO2, NH, NR b , or CR C IR C 2 in which R b is a lower alkyl that may be substituted, and R d and R C 2, which may be the same or different , are a hydrogen or lower alkyl atom;
R3 es un fenilo que puede estar sustituido;  R3 is a phenyl that can be substituted;
X2 es CH, CX2a o N en el que: X2 is CH, CX2 a or N where:
X2a es un alquilo inferior; o X2 a is lower alkyl; or
X2a es un sustituyente seleccionado de <grupo sustituyente Ai>, o alquilo inferior que está sustituido con uno o más de los mismos o diferentes sustituyentes seleccionados de <grupo sustituyente Ai>, en el que <grupo sustituyente Ai> es átomo de halógeno; ciano; hidroxilo; alquilamino inferior; dialquilamino inferior; alcoxilo inferior que puede estar sustituido con uno o más grupos hidroxilo; alquiltio inferior; y alquilsulfonilo inferior; o X2 a is a substituent selected from <substituent group Ai>, or lower alkyl which is substituted with one or more of the same or different substituents selected from <substituent group Ai>, in which <substituent group Ai> is halogen atom; cyano; hydroxyl; lower alkylamino; lower dialkylamino; lower alkoxy that may be substituted with one or more hydroxyl groups; lower alkylthio; and lower alkylsulfonyl; or
X2a es COORxl , CONRX2RX3,X2a is COORxl, CONRX2R X3 ,
NHCORxi , NHCONRX2RX3, NHSC>2NRX2RX3, NRX4RX5 O CH2NRX4RX5, en el que: Rxi es un átomo de hidrógeno o alquilo inferior que puede estar sustituido;NHCORxi, NHCONRX2RX3, NHSC> 2NRX2RX3, NR X4 R X5 OR CH 2 NR X4 R X5 , where: R xi is a hydrogen or lower alkyl atom that may be substituted;
RX2 y Rxs, que pueden ser el mismo o diferente, son cada uno un átomo de hidrógeno, alquilo inferior que puede estar sustituido o cicloalquilo que puede estar sustituido; o alternativamente Rx2 y Rx3, junto con el átomo de nitrógeno al que se unen, forman un grupo heterocíclico alifático de 5 ó 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido; y R X 2 and R x s, which may be the same or different, are each a hydrogen atom, lower alkyl that can be substituted or cycloalkyl that can be substituted; or alternatively R x2 and R x3 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; Y
RX4 y RX5, que pueden ser el mismo o diferente, son un átomo de hidrógeno, alquilo inferior que puede estar sustituido, o cicloalquilo que puede estar sustituido; o R X 4 and R X 5, which may be the same or different, are a hydrogen atom, lower alkyl that can be substituted, or cycloalkyl that can be substituted; or
X2a es un grupo heterocíclico alifático de 5 a 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido, en el que los dos átomos de hidrógeno que están unidos al mismo átomo de carbono del grupo heterocíclico alifático pueden estar sustituidos con oxo y los dos átomos de carbono vecinos que constituyen el anillo heterocíclico alifático pueden formar un doble enlace; o un alquilo inferior que está sustituido con el grupo heterocíclico alifático; o X 2a is a 5- to 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted, in which the two hydrogen atoms that are attached to the same carbon atom of the heterocyclic group aliphatic can be substituted with oxo and the two neighboring carbon atoms that make up the aliphatic heterocyclic ring can form a double bond; or a lower alkyl that is substituted with the aliphatic heterocyclic group; or
X2a es un grupo heterocíclico aromático de 5 a 6 miembros que contiene al menos un átomo seleccionado de N, O y S y que puede estar sustituido; o un alquilo inferior que está sustituido con el grupo heterocíclico aromático; X 2a is a 5- to 6-membered aromatic heterocyclic group containing at least one atom selected from N, O and S and which may be substituted; or a lower alkyl that is substituted with the aromatic heterocyclic group;
W es el siguiente residuo:
Figure imgf000152_0001
W is the following residue:
Figure imgf000152_0001
en el que: in which:
Wi es CH, N, NH, O o S;  Wi is CH, N, NH, O or S;
W2 es CH, CW2a, N, NW2b, O o S, en el que W2a y W2b son cada uno independientemente un átomo de hidrógeno, átomo de halógeno, ciano, alquilo inferior que tiene de uno a dos átomos de carbono, cicloalquilo que tiene de tres a cinco átomos de carbono, o alquilo inferior que tiene de uno a dos átomos de carbono que puede estar sustituido con uno o más átomos de halógeno; W 2 is CH, CW 2a , N, NW 2b , O, or S, where W 2a and W 2b are each independently a hydrogen atom, halogen atom, cyano, lower alkyl having one to two atoms of carbon, cycloalkyl having three to five carbon atoms, or lower alkyl having one to two carbon atoms that may be substituted with one or more halogen atoms;
W3 es C o N ; y W 3 is C or N; Y
al menos uno de W1 , W2 y W3 es un átomo de carbono; sin embargo, dos de W1, W2 y W3 no son simultáneamente O y S, at least one of W1, W 2, and W3 is a carbon atom; however two of W1, W 2 and W3 are not simultaneously O and S,
o una sal o un áster farmacéuticamente aceptable del mismo; or a pharmaceutically acceptable salt or ester thereof;
Figure imgf000152_0002
Fórmula (VI) o un derivado o profármaco farmacéuticamente aceptable del mismo, en la que:
Figure imgf000152_0002
Formula (VI) or a pharmaceutically acceptable derivative or prodrug thereof, in which:
Rx y Ry se seleccionan independientemente del grupo que consiste en -T-R3 y - 1-Z-R3; R x and R y are independently selected from the group consisting of -TR 3 and - 1-ZR 3 ;
Q1 se selecciona del grupo que consiste en -CR6=CR6- y º , en el que dicho -CR6=CR6- puede ser un doble enlace en cis o trans o una mezcla de los mismos; Q 1 is selected from the group consisting of -CR 6 = CR 6 - and ° , wherein said -CR 6 = CR 6 - can be a cis- or trans-double bond or a mixture thereof;
R1 es -T-(anillo D); R 1 is -T- (ring D);
Anillo D es un anillo monocíclico de 5-7 miembros o un anillo bicíclico de 8-10 miembros seleccionado del grupo que consiste en arilo, heteroarilo, heterociclilo y carbociclilo, teniendo dicho anillo de heteroarilo o heterociclilo 1- 4 heteroátomos de anillo seleccionado del grupo que consiste en nitrógeno, oxígeno y azufre, en el que cada carbono sustituible del anillo del anillo D está sustituido independientemente por oxo, -T-R5 o -V-Z-R5, y cada nitrógeno sustituible del anillo del anillo D está sustituido independientemente por -R4;Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl and carbocyclyl, said ring heteroaryl or heterocyclyl having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable ring D ring carbon is independently substituted by oxo, -TR 5 or -VZR 5 , and each substitutable D ring ring nitrogen is independently substituted by -R 4 ;
T es un enlace de valencia o -(C(R6’)2)-A-; T is a valence bond or - (C (R 6 ' ) 2) -A-;
A es un enlace de valencia o una cadena de alquilideno C1-C3 en la que una unidad de metileno de dicha cadena de alquilideno C1-3 está reemplazada opcionalmente por -O-, -S-, -N(R4)-, -CO-, -CONH-, -NHCO-, -S02-, -SO2NH-, - NHSO2-, -CO2-, -OC(0 )-, -OC(0)NH- o -NHCO2-; A is a valence bond or a C 1 -C 3 alkylidene chain in which a methylene unit of said C 1-3 alkylidene chain is optionally replaced by -O-, -S-, -N (R 4 ) -, -CO-, -CONH-, -NHCO-, -S0 2 -, -SO 2 NH-, - NHSO2-, -CO2-, -OC (0) -, -OC (0) NH- or -NHCO2 -;
Z es una cadena de alquilideno C1-4; Z is a C 1-4 alkylidene chain;
L se selecciona del grupo que consiste en -O-, -S-, -SO-, -SO2-, -N(R6)S02-, - S02N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6)-, - N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(0)N(R6)-, -OC(0)N(R6)-, -C(R6)20-, -C(R6)2-, C(R6)2SO-, -C(R6)2SC>2-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(0)-, -L is selected from the group consisting of -O-, -S-, -SO-, -SO2-, -N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -CO2-, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, - N (R 6 ) S0 2 N (R 6 ) -, -N (R 6 ) N (R 6 ) -, -C (0) N (R 6 ) -, -OC (0) N (R 6 ) -, -C ( R 6 ) 2 0-, -C (R 6 ) 2 -, C (R 6 ) 2 SO-, -C (R 6 ) 2 SC> 2 -, -C (R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) C (0) -, -
C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N-0-, -C(R6)2N(R6)N(R6)-, -C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) = NN (R 6 ) -, -C (R 6 ) = N-0-, -C (R 6 ) 2 N (R 6 ) N (R 6 ) -, -
C(R6)2N(R6)S02N(R6)- y -C(R6)2N(R6)CON(R6)-; C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) - and -C (R 6 ) 2 N (R 6 ) CON (R 6 ) -;
R2 y R2’ se seleccionan independientemente del grupo que consiste en -R y -T- W-R6, o R2 y R2’ tomados junto con sus átomos intervinientes forman un anillo insaturado o parcialmente insaturado de 5-8 miembros condensado que tieneR 2 and R 2 ' are independently selected from the group consisting of -R and -T- WR 6 , or R 2 and R 2' taken together with their intervening atoms form a fused 5-8 membered unsaturated or partially unsaturated ring which have
0-3 heteroátomos de anillo seleccionados del grupo que consiste en nitrógeno, oxígeno y azufre, en el que cada carbono sustituible del anillo de dicho anillo condensado formado por R2 y R2’ está sustituido independientemente por halo, oxo, -CN, -NO2, R7 o -V-R6, y cada nitrógeno sustituible del anillo de dicho anillo formado por R2 y R2’ está sustituido independientemente por -R4; 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in which each substitutable carbon of the ring of said condensed ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, - NO2, R 7 or -VR 6 , and each substitutable nitrogen in the ring of said ring formed by R 2 and R 2 ' is independently substituted by -R 4 ;
R3 se selecciona del grupo que consiste en -R, -halo, -OR, -C(=0)R, -CO2R, - COCOR, -COCH2COR, -N02, -CN, -S(0)R, -S(0)2R, -SR, -N(R4)2, -CON(R7)2, - S02N(R7)2, -OC(0)R, -N(R7)COR, -N(R7C02(alifático Ci-e), -N(R4)N(R4)2, - C=NN(R4)2, -C=N-OR, -N(R7)CON(R7)2, -N(R7)S02N(R7)2, -N(R4)S02R y - OC(0)N(R)2; R 3 is selected from the group consisting of -R, -halo, -OR, -C (= 0) R, -CO2R, - COCOR, -COCH2COR, -N0 2 , -CN, -S (0) R, - S (0) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , - S0 2 N (R 7 ) 2 , -OC (0) R, -N (R 7 ) COR , -N (R 7 C0 2 (aliphatic Ci-e), -N (R 4 ) N (R 4 ) 2 , - C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , -N (R 7 ) S0 2 N (R 7 ) 2 , -N (R 4 ) S0 2 R and - OC (0) N (R) 2 ;
cada R es independientemente hidrógeno o un grupo opcionalmente sustituido seleccionado del grupo que consiste en alifático C1-6, arilo C6-10, un anillo de heteroarilo que tiene 5-10 átomos de anillo y un anillo de heterociclilo que tiene 5-10 átomos de anillo; cada R4 se selecciona independientemente del grupo que consiste en -R7, - COR7, -C02(alifático Ci-e opcionalmente sustituido), -CON(R7)2 y -SO2R7; each R is independently hydrogen or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms and a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from the group consisting of -R 7 , - COR 7 , -C0 2 (optionally substituted Ci-e aliphatic), -CON (R 7 ) 2 and -SO2R 7 ;
cada R5 se selecciona independientemente del grupo que consiste en -R, halo, -OR, -C(0)R, -CO2R, -COCOR, -N02, -CN, -S(0)R, -S02R, -SR, -N(R4)2, - CON(R4)2, -S02N(R4)2, -0C(0)R, -N(R4)COR, -N(R4)C02(alifático C -each R 5 is independently selected from the group consisting of -R, halo, -OR, -C (0) R, -CO2R, -COCOR, -N0 2 , -CN, -S (0) R, -S0 2 R , -SR, -N (R 4 ) 2 , - CON (R 4 ) 2 , -S0 2 N (R 4 ) 2 , -0C (0) R, -N (R 4 ) COR, -N (R 4 ) C0 2 (aliphatic C -
6 opcionalmente sustituido), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, 6 optionally substituted), -N (R 4 ) N (R 4 ) 2, -C = NN (R 4 ) 2, -C = N-OR,
N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R y -0C(=0)N(R4)2; N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) S0 2 N (R 4 ) 2 , -N (R 4 ) S0 2 R and -0C (= 0) N (R 4 ) 2 ;
V se selecciona del grupo que consiste en -O-, -S-, -SO-, -SO2-, -N(R6)S02-, - S02N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6)-, - N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(0)N(R6)-, -0C(0)N(R6)-, -C(R6)20-, -C(R6)2S- , -C(R6)2SO-, -C(R6)2S02-, -C(R6)2S02N(R6)-, -C(R6)2N(R6), -C(R6)2N(R6)C(0)-, - C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N-0-, C(R6)2N(R6)N(R6)-, -V is selected from the group consisting of -O-, -S-, -SO-, -SO2-, -N (R 6 ) S0 2 -, - S0 2 N (R 6 ) -, -N (R 6 ) -, -CO-, -CO2-, -N (R 6 ) CO-, -N (R 6 ) C (0) 0-, -N (R 6 ) CON (R 6 ) -, - N (R 6 ) S0 2 N (R 6 ) -, -N (R 6 ) N (R 6 ) -, -C (0) N (R 6 ) -, -0C (0) N (R 6 ) -, -C ( R 6 ) 2 0-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 S0 2 -, -C (R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ), -C (R 6 ) 2 N (R 6 ) C (0) -, - C (R 6 ) 2 N (R 6 ) C (0 ) 0-, -C (R 6 ) = NN (R 6 ) -, -C (R 6 ) = N-0-, C (R 6 ) 2 N (R 6 ) N (R 6 ) -, -
C(R6)2N(R6)S02N(R6)- y -C(R6)2N(R6)CON(R6)-; C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) - and -C (R 6 ) 2 N (R 6 ) CON (R 6 ) -;
W se selecciona del grupo que consiste en -C(R6)20-, -C(R6)2S-, -C(R6)2SO-, - C(R6)2S02-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-, -C(R6)0C(0)-, - C(R6)0C(0)N(R6)-, -C(R6)2N(R6)CO-, -C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, - C(R6)=N-0-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)S02N(R6)-, -C(R6)2N(R6)CON(R6)- y -CON(R6)-; W is selected from the group consisting of -C (R 6 ) 2 0-, -C (R 6 ) 2S-, -C (R 6 ) 2SO-, - C (R 6 ) 2 S0 2 -, -C ( R 6 ) 2 S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) -, -CO-, -CO2-, -C (R 6 ) 0C (0) -, - C ( R 6 ) 0C (0) N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) = NN (R 6 ) -, - C (R 6 ) = N-0-, -C (R 6 ) 2 N (R 6 ) N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) S0 2 N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) CON (R 6 ) - and -CON (R 6 ) -;
cada R6 se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático C1 -4 opcionalmente sustituido, o dos grupos R6 en el mismo átomo de nitrógeno pueden tomarse junto con el átomo de nitrógeno para formar un anillo de heterociclilo o heteroarilo de 3-6 miembros; each R 6 is independently selected from the group consisting of hydrogen and an optionally substituted C1-4 aliphatic group, or two R 6 groups on the same nitrogen atom may be taken together with the nitrogen atom to form a heterocyclyl or heteroaryl ring of 3-6 members;
cada R6’ se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático C1-4, o dos R6 en el mismo átomo de carbono se toman juntos para formar un anillo carbocíclico de 3-8 miembros; each R 6 ' is independently selected from the group consisting of hydrogen and a C 1-4 aliphatic group, or two R6s on the same carbon atom are taken together to form a 3-8 membered carbocyclic ring;
cada R6” se selecciona independientemente del grupo que consiste en hidrógeno, un grupo alifático C1 -4, halógeno, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido, o dos R6” en en átomos de carbono adyacentes se toman juntos para formar un anillo carbocíclico de 5-7 miembros; y each R 6 " is independently selected from the group consisting of hydrogen, a C1-4 aliphatic group, halogen, optionally substituted aryl and optionally substituted heteroaryl, or two R 6" en at adjacent carbon atoms are taken together to form a carbocyclic ring 5-7 members; Y
cada R7 se selecciona independientemente del grupo que consiste en hidrógeno y un grupo alifático C1 -4 opcionalmente sustituido, o dos R7 en el mismo nitrógeno se toman junto con el nitrógeno para formar un anillo de heterociclilo o heteroarilo de 5-8 miembros; each R 7 is independently selected from the group consisting of hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 7's in the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
Figure imgf000154_0001
Fórmula (Vil) o estereoisómero, tautómero, solvato, sal, derivado o profármaco farmacéuticamente aceptable del mismo, en la que cada uno de A1 y A2 es, independientemente, N o CR9, siempre que al menos uno de A1 y A2 sea N;
Figure imgf000154_0001
Pharmaceutically acceptable formula (Vil) or stereoisomer, tautomer, solvate, salt, derivative or prodrug thereof, wherein each of A 1 and A 2 is, independently, N or CR 9 , provided that at least one of A 1 and A 2 is N;
C1 es N o CR10; C2 es N o CH; C 1 is N or CR 10 ; C 2 is N or CH;
D es D is
Figure imgf000155_0001
Figure imgf000155_0001
en el que D1 es N o CR1 1 ; wherein D 1 is N or CR 1 1 ;
D2 es N o CR12; D 2 is N or CR 12 ;
D3 es N o CR2; D 3 is N or CR 2 ;
D4 es NR1 a, O, S o CR12; D 4 is NR 1 a , O, S or CR 12 ;
D5 es N o CR2; D 5 is N or CR 2 ;
R1 es H, OR14, SR14, OR15, SR15, N R14R15, N R15R15, (CH R15)nR14, (CHR15)nR15 o R15, en el que n es 0, 1 , 2, 3 ó 4; R 1 is H, OR 14 , SR 14 , OR 15 , SR 15 , NR 14 R 15 , NR 15 R 15 , (CH R 15 ) n R 14 , (CHR 15 ) n R 15 or R 15 , where n is 0, 1, 2, 3, or 4;
R1 a es H, CN o alquilo CMO; R 1 a is H, CN or CMO alkyl;
alternativamente R1 tomado junto con cualquiera de R1 1 y R1 a y los átomos de carbono o nitrógeno a los que se unen forman un anillo parcial o completamente insaturado de 5 ó 6 miembros de átomos de carbono que incluye opcionalmente 1 -3 heteroátomos seleccionados de O, N y S, y el anillo opcionalmente sustituido independientemente con 1 -3 sustituyentes de oxo, R15, SR14, OR14, SR15, OR15, OC(0)R15, COOR15, C(0)R15, C(0)NR15R15, NR14R15 o NR15R15; y alternatively R 1 taken together with either R 1 1 and R 1 a and the carbon or nitrogen atoms to which they are attached form a partially or completely unsaturated 5 or 6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally independently substituted with 1-3 oxo substituents, R 15 , SR 14 , OR 14 , SR 15 , OR 15 , OC (0) R 15 , COOR 15 , C (0 ) R 15 , C (0) NR 15 R 15 , NR 14 R 15 or NR 15 R 15 ; Y
R2 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14,R 2 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 ,
NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15,NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 ,
NR15(COOR15), OC(0)NR15R1 S, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R13, NR15S(0)2NR14R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15 O R15; NR 15 (COOR 15 ), OC (0) NR 15 R1 S, S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R13 , NR 15 S (0) 2 NR 14 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 OR 15 ;
U es NR3, O, S, C(O), S(O), S02 o CR3R3; U is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
L2 es NR3, O, S, C(O), S(O), S02 o CR3R3; L 2 is NR 3 , O, S, C (O), S (O), S0 2 or CR 3 R 3 ;
Z es un primer anillo monocíclico completamente insaturado de 5-6 miembros, dicho primer anillo (1 ) formado de átomos de carbono que incluye opcionalmente 1 -3 heteroátomos seleccionados de O, N o S, (2) opcionalmente condensado con un segundo anillo monocíclico parcial o completamente saturado o completamente insaturado de 5-6 miembros formado de átomos de carbono que incluye opcionalmente 1 -3 heteroátomos seleccionados de O, N o S, y (3) en el que 0, 1 , 2 ó 3 átomos de cada uno de dicho primer y segundo anillo está opcionalmente sustituido independientemente con 1 -5 sustituyentes de R5; Z is a 5-6 membered fully unsaturated monocyclic first ring, said first ring (1) formed of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, (2) optionally fused with a second monocyclic ring partially or completely saturated or fully unsaturated 5-6 membered carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and (3) wherein 0, 1, 2 or 3 atoms each of said first and second ring is optionally independently substituted with 1-5 substituents of R 5 ;
cada uno de R3 y R4 es, independientemente, SR14, OR14, SR15, OR15, N R14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15,each of R 3 and R 4 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C ( 0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S ( 0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 ,
NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
alternativamente, cualquiera de R3 o R4, independientemente, tomado junto con R10 y los átomos de carbono a los que se unen forman un anillo parcial o completamente insaturado de 5 ó 6 miembros de átomos de carbono que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-3 sustituyentes de R13, R14 o R15; alternatively, any of R 3 or R 4 , independently, taken together with R 10 and the carbon atoms to which they are attached form a partially or completely unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-3 substituents of R 13 , R 14 or R 15 ;
cada R5 es, independientemente, SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15,each R 5 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 ,
C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15,C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 ,
NR15C(0)NR15R15, NR15C(0)C(0)R15, NR15(COOR15), 0C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR13R15, NR15S(0)2NR15R15, NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15,NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NR 15 (COOR 15 ), 0C (0) NR 15 R 15 , S (0) 2 R 14 , S ( 0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR13R 15 , NR 15 S (0) 2 NR 15 R 15 , NR 15 S (0) 2 R 14 , NR 15 S ( 0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 ,
NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
cada uno de R6, R7 y R8 es, independientemente, R13, R14 o R15; R 6 , R 7 and R 8 are each independently R 13 , R 14 or R 15 ;
alternativamente, cualquiera de R6 o R8, independientemente, tomado junto con R7 y los átomos de carbono a los que se unen forman un anillo de 5 ó 6 miembros completamente saturado o parcial o completamente insaturado de átomos de carbono que incluye opcionalmente 1-3 heteroátomos seleccionados de O, N o S, y el anillo opcionalmente sustituido independientemente con 1-4 sustituyentes de R13, R14 o R15; alternatively, any of R 6 or R 8 , independently, taken together with R 7 and the carbon atoms to which they are attached form a fully saturated or partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 -3 heteroatoms selected from O, N or S, and the ring optionally independently substituted with 1-4 substituents from R 13 , R 14 or R 15 ;
cada uno de R9, R10, R11 y R12 es, independientemente, SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, COOR15, OC(0)R15, C(0)C(0)R15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14, NR15C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15, NR15C(0)C(0)R15, NRIS(COOR15), 0C(0)NR15R15,each of R 9 , R 10 , R 11 and R 12 is independently SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0 ) R 15 , COOR 15 , OC (0) R 15 , C (0) C (0) R 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 , NR 15 C (0) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 , NR 15 C (0) C (0) R 15 , NRIS (COOR 15 ), 0C (0) NR 15 R 15 ,
S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15, NR15S(0)2NR15R15,S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 , NR 15 S (0) 2 NR 15 R 15 ,
NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15, NR15C(0)C(0)NR14R15,NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 , NR 15 C (0) C (0) NR 14 R 15 ,
NR15C(0)C(0)NR15R15 o R15; NR 15 C (0) C (0) NR 15 R 15 or R 15 ;
R13 es SR14, OR14, SR15, OR15, NR14R15, NR15R15, C(0)R14, C(0)R15, 0C(0)R14 0C(0)R15, COOR14, COOR15, C(0)NR14R15, C(0)NR15R15, NR15C(0)R14 NR15C(0)R15, C(0)C(0)R15, NR15C(0)NR14R15, NR15C(0)NR15R15 NR15C(0)C(0)R15, NR15(COOR14), NR15(COOR15), NR15C(0)C(0)NR14R1 SR 13 is SR 14 , OR 14 , SR 15 , OR 15 , NR 14 R 15 , NR 15 R 15 , C (0) R 14 , C (0) R 15 , 0C (0) R 14 0C (0) R 15 , COOR 14 , COOR 15 , C (0) NR 14 R 15 , C (0) NR 15 R 15 , NR 15 C (0) R 14 NR 15 C (0) R 15 , C (0) C (0 ) R 15 , NR 15 C (0) NR 14 R 15 , NR 15 C (0) NR 15 R 15 NR 15 C (0) C (0) R 15 , NR 15 (COOR 14 ), NR 15 (COOR 15 ), NR 15 C (0) C (0) NR 14 R1 S
NR15C(0)C(0)NR15R15, S(0)2R14, S(0)2R15, S(0)2NR14R15, S(0)2NR15R15 NR15S(0)2R14, NR15S(0)2R15, NR15S(0)2NR14R15 O NR15S(0)2NR15R15; NR 15 C (0) C (0) NR 15 R 15 , S (0) 2 R 14 , S (0) 2 R 15 , S (0) 2 NR 14 R 15 , S (0) 2 NR 15 R 15 NR 15 S (0) 2 R 14 , NR 15 S (0) 2 R 15 , NR 15 S (0) 2 NR 14 R 15 O NR 15 S (0) 2 NR 15 R 15 ;
R14 es un sistema de anillos monocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros parcial o completamente saturado o completamente insaturado, incluyendo opcionalmente el sistema de anillos de átomos de carbono formado opcionalmente 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, los heteroátomos seleccionados de O, N o S, en el que 0, 1 , 2 ó 3 átomos de cada anillo están opcionalmente sustituidos independientemente con 1-5 sustituyentes de R15; y R 14 is a 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic system partially or completely saturated or completely unsaturated, optionally including the optionally formed carbon atom ring system 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, N, or S, where 0, 1, 2, or 3 atoms of each ring are optionally independently substituted with 1-5 substituents of R 15 ; Y
R15 es H, halo, haloalquilo, haloalcoxilo, oxo, CN, OH, SH, N02, NH2, acetilo, alquilo CMO, alquenilo C2-io, alquinilo C2-io, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino CMO, dialquilamino CMO, alcoxilo CMO, tioalcoxilo CMO O un sistema de anillos onocíclico de 5-8 miembros, bicíclico de 6-12 miembros o tricíclico de 7-14 miembros saturado o parcial o completamente insaturado, incluyendo opcionalmente dicho sistema de anillos formado de átomos de carbono 1-3 heteroátomos si es monocíclico, 1-6 heteroátomos si es bicíclico o 1-9 heteroátomos si es tricíclico, dichos heteroátomos seleccionados de O, N o S, en el que cada uno del alquilo CMO, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino CMO, dialquilamino CMO, alcoxilo CMO, tioalcoxilo CMO y anillo de dicho sistema de anillos está opcionalmente sustituido independientemente con 1-5 sustituyentes de halo, haloalquilo, CN,R 15 is H, halo, haloalkyl, haloalkoxy, oxo, CN, OH, SH, N0 2 , NH 2 , acetyl, CMO alkyl, C 2 -i alkenyl or, C 2 -i alkynyl or C3-10 cycloalkenyl, cycloalkenyl C4-10, CMO alkylamino, CMO dialkylamino, CMO alkoxy, CMO thioalkoxy OR a 5-8 membered, 6-12 membered bicyclic or 7-14 membered tricyclic saturated or partially or fully unsaturated ring system, optionally including said formed ring system carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O, N or S, where each of the CMO-alkyl, C2-alkenyl 10, C2-10 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, CMO alkylamino, CMO dialkylamino, CMO alkoxy, CMO thioalkoxy and ring of said ring system is optionally independently substituted with 1-5 substituents of halo, haloalkyl, CN ,
N02, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, ciclopropilo, butilo, isobutilo, tere-butilo, metilamina, dimetilamina, etilamina, dietilamina, propilamina, isopropilamina, dipropilamina, diisopropilamina, bencilo o fenilo; N0 2 , NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tere-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, or phenyl;
siempre que (1) no más de uno de D1, D2 y D3 sea N, y (2) cada uno de U y L2 se una, independientemente, al primer anillo de Z provided that (1) no more than one of D 1 , D 2 and D 3 is N, and (2) each of U and L 2 independently joins the first ring of Z
Figure imgf000157_0001
Figure imgf000157_0001
Fórmula (VIII)  Formula (VIII)
o una sal farmacéuticamente aceptable del mismo, en la que: or a pharmaceutically acceptable salt thereof, in which:
X es un átomo de oxígeno o azufre,  X is an oxygen or sulfur atom,
R1 es un átomo de hidrógeno, un grupo alcoxicarbonilo C 1-4 o alcanoilo C 2-4,R 1 is a hydrogen atom, a C 1-4 alkoxycarbonyl group or C 2-4 alkanoyl,
R2 es un grupo alquilo Ci-e opcionalmente sustituido por uno o más átomos de halógeno o un grupo fenilo o un grupo alquenilo C2-6 opcionalmente sustituido por un grupo fenilo, en el que el resto de fenilo puede estar sustituido en cada caso por un átomo de flúor, cloro, bromo o yodo, por un grupo alquilo C1-3 o alcoxilo C1-3, R 2 is a Ci-e alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C2-6 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety can be substituted in each case by a fluorine, chlorine, bromine or iodine atom, for a C1-3 alkyl or C1-3 alkoxy group,
un grupo fenilo que puede estar mono o disustituido por átomos de flúor, cloro, bromo o yodo, por grupo alquilo C1-3 o alcoxilo C1-3, en el que los sustituyentes pueden ser idénticos o diferentes, a phenyl group which may be mono or substituted by fluorine, chlorine, bromine or iodine atoms, by C1-3alkyl or C1-3alkoxy group, in which the substituents may be identical or different,
un grupo fenilo sustituido por un grupo trifluorometilo, carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, ciano, aminometilo, nitro o amino, a phenyl group substituted by a trifluoromethyl, carboxyl, C1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
un grupo alquilo C4-6, cicloalquilo C3-7, trimetilfenilo o naftilo, a C4-6 alkyl, C3-7 cycloalkyl, trimethylphenyl or naphthyl group,
un grupo heteroaromático de 5 miembros opcionalmente sustituido por un grupo alquilo C1-3, que contiene, en el resto heteroaromático, a 5-membered heteroaromatic group optionally substituted by a C1-3 alkyl group, containing, in the heteroaromatic moiety,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3, un átomo de oxígeno o azufre, an imino group optionally substituted by a C1-3 alkyl group, an oxygen or sulfur atom,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3 y un átomo de oxígeno, azufre o nitrógeno, an imino group optionally substituted by a C 1-3 alkyl group and an atom oxygen, sulfur or nitrogen,
un grupo imino opcionalmente sustituido por un grupo alquilo C1-3 y dos átomos de nitrógeno, o un átomo de oxígeno o azufre y dos átomos de nitrógeno, y al que puede condensarse un anillo de fenilo a través de dos átomos de carbono adyacentes, an imino group optionally substituted by a C 1-3 alkyl group and two nitrogen atoms, or an oxygen or sulfur atom and two nitrogen atoms, and to which a phenyl ring can be condensed through two adjacent carbon atoms,
o es un grupo heteroaromático de 6 miembros opcionalmente sustituido por un grupo alquilo C1-3, que contiene uno o dos heteroátomos en el resto heteroaromático y al que puede condensarse un anillo de fenilo a través de dos átomos de carbono adyacentes, o is a 6-membered heteroaromatic group optionally substituted by a C 1-3 alkyl group, which contains one or two heteroatoms in the heteroaromatic moiety and to which a phenyl ring can be fused through two adjacent carbon atoms,
R3 es un átomo de hidrógeno o un grupo alquilo C1-6, R 3 is a hydrogen atom or a C 1-6 alkyl group,
un grupo fenilo opcionalmente sustituido por un átomo de flúor, cloro o bromo, por un grupo alquilo C1-3, hidroxilo, alcoxilo C1-3, alquilsulfenilo C1-3, alquilsulfinilo C1-3, alquilsulfonilo C1-3, fenilsulfenilo, fenilsulfinilo, fenilsulfonilo, nitro, amino, alquilamino C1-3, di(alquil Ci-3)-amino, alcanoilamino C2-5 o N- (alquilamino Ci-3)alquilamino C2-5, a phenyl group optionally substituted by a fluorine, chlorine or bromine, an alkyl group C 1-3, hydroxy, alkoxy C 1-3, C 1-3 alkylsulfenyl, alkylsulfinyl C 1-3 alkylsulfonyl C 1-3, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, alkylamino C 1-3 -alkylamino, di (Ci- 3) alkylamino, alkanoylamino or C 2-5 N- (Ci- 3 alkylamino) C 2-5 alkylamino,
R4 es un grupo fenilo o naftilo opcionalmente sustituido por R7, que puede estar adicionalmente sustituido por un átomo de cloro o bromo o un grupo nitro, un grupo heteroaromático de 5 miembros que contiene un grupo imino, un átomo de oxígeno o azufre o un grupo imino, un átomo de oxígeno o azufre y uno o dos átomos de nitrógeno, o un grupo heteroaromático de 6 miembros que contiene uno, dos o tres átomos de nitrógeno, mientras que los grupos heteroaromáticos de 5 y 6 miembros anteriormente mencionados pueden estar adicionalmente sustituidos por un átomo de cloro o bromo o por un grupo metilo o en el que un anillo de fenilo puede condensarse con los grupos heteroaromáticos de 5 y 6 miembros anteriormente mencionados a través de 2 átomos de carbono adyacentes, o R 4 is a phenyl or naphthyl group optionally substituted by R 7 , which may be further substituted by a chlorine or bromine atom or a nitro group, a 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, while the aforementioned 5- and 6-membered heteroaromatic groups may be additionally substituted by a chlorine or bromine atom or by a methyl group or in which a phenyl ring can be condensed with the above mentioned 5- and 6-membered heteroaromatic groups through 2 adjacent carbon atoms, or
R5 y R6 en cada caso independientemente el uno del otro son átomos de hidrógeno o grupos alquilo C 1-3, y R 5 and R 6 in each case independently of each other are hydrogen atoms or C 1-3 alkyl groups, and
R7 es un átomo de flúor, cloro, bromo o yodo o un grupo ciano, R 7 is a fluorine, chlorine, bromine or iodine atom or a cyano group,
un grupo metoxilo o un grupo alcoxilo C2-3, que puede estar sustituido en la posición 2 ó 3 por un grupo amino, alquilamino C1-3, di(alquil Ci-3)-amino o cicloalquilenimino de 5 a 7 miembros, mientras que en cada caso un resto de alquilo en los grupos alquilamino y dialquilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo fenilo, un grupo trifluorometilo, nitro, amino, alquilamino C1-3, di(alquil Ci-3)-amino, alcanoilaminoa methoxy group or a C 2-3 alkoxy group, which may be substituted in position 2 or 3 by an amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino or 5-7 membered cycloalkyleneimino group, while in each case an alkyl residue in the aforementioned alkylamino and dialkylamino groups may be additionally substituted by a phenyl group, a trifluoromethyl group, nitro, amino, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino, alkanoylamino
C2-5, N-(alquil Ci-3)-alcanoilamino C2-5, alquilsulfonilamino C1-5, N-(alquil C1-3)- alquilsulfonilamino C1-5, fenilsulfonilamino, N-(alquil Ci-3)-fenilsulfonilamino, aminosulfonilo, alquilaminosulfonilo C1-3 o di(alquil Ci-3)-aminosulfonilo, mientras que en cada caso un resto de alquilo en los grupos alquilamino y dialquilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo carboxilo, alcoxicarbonilo C1-3, aminocarbonilo, alquilaminocarbonilo C1-3, di(alquil Ci-3)-aminocarbonilo, 2- dimetilaminoetilaminocarbonilo o N-metil-(2-dimetilaminoetil)-aminocarbonilo y en cada caso el resto de alquilo de los grupos alcanoilamino o alquilsulfonilamino anteriormente mencionados puede estar adicionalmente sustituido por un grupo fenilo, amino, alquilamino C1-3, di(alquil Ci-3)-amino o un cicloalquilenimino de 4 a 7 miembros, un grupo alquilamino C2-4 que está sustituido de manera terminal en la posición 2, 3 ó 4 por un grupo amino, alquilamino C1-3, di(alquil Ci-3)-amino, bencilamino, N-(alquil Ci-3)-bencilamino, alcanoilamino C2-5 o N-(alquil Ci-3)-alcanoilamino C2- 5 y en el que adicionalmente el átomo de hidrógeno del amino puede reemplazarse por un grupo alcanoilo C2-5, benzoílo, alquilsulfonilo o fenilsulfonilo C1-5, mientras que los últimos grupos mencionados alcanoilo C2-5 o alquilsulfonilo C1-5 en el resto de alquilo pueden estar sustituidos por un grupo fenilo, C 2-5 , N- (Ci- 3- alkyl) -C 2-5- alkanoylamino, C 1-5 alkylsulfonylamino, N- (C 1-3 alkyl) -C 1-5 alkylsulfonylamino, phenylsulfonylamino, N- (Ci-alkyl 3 ) -phenylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl or di (Ci- 3- alkyl) -aminosulfonyl, while in each case an alkyl residue in the aforementioned alkylamino and dialkylamino groups may be additionally substituted by a carboxyl, alkoxycarbonyl group C 1-3 , aminocarbonyl, C 1-3 alkylaminocarbonyl, di (Ci- 3- alkyl) -aminocarbonyl, 2- dimethylaminoethylaminocarbonyl or N-methyl- (2-dimethylaminoethyl) -aminocarbonyl and in each case the rest of the alkyl of the alkanoylamino groups or alkylsulfonylamino mentioned above may be additionally substituted by a phenyl, amino, C 1-3 alkylamino group, di (Ci- 3- alkyl) -amino or a 4- to 7-membered cycloalkyleneimino group, a C 2-4 alkylamino group which is terminally substituted at the 2, 3 or 4 position by an amino group, C 1-3 alkylamino, di (Ci- 3- alkyl) -amino, benzylamino, N- (Ci-alkyl 3) -benzylamino, C 2-5 alkanoylamino or N- (alkyl Ci- 3) alkanoylamino C 2-5 and further wherein the hydrogen atom of the amino may be replaced by C 2-5 alkanoyl group, benzoyl, alkylsulfonyl or C 1-5 phenylsulfonyl, while the last mentioned C 2-5 alkanoyl or C 1-5 alkylsulfonyl groups in the alkyl moiety may be substituted by a phenyl group,
un grupo carbonilo que está sustituido por un grupo hidroxilo, alcoxilo C1-3, amino, alquilamino C1-3, N-(alquil Ci-5)-alquilamino C1-3 o cicloalquilenimino C5-7; un grupo alquilo C1-3 que puede estar sustituido por un grupo amino, alquilamino C1-5, cicloalquilamino C5-7 o fenilo-alquilamino C1-3 que puede estar adicionalmente sustituido en el átomo de nitrógeno del amino en cada caso por un grupo alquilo C1-4, cicloalquilo C5-7 o alquenilo C2-4 o alquilo C1-4, mientras que el sustituyente alquilo C1-4 anteriormente mencionado en cada caso puede estar adicionalmente mono, di o trisustituido por un grupo ciano, carboxilo, alcoxicarbonilo C1-3, alcanoilo C2-4, piridilo, imidazolilo, benzo[1 ,3]dioxol o fenilo, mientras que el grupo fenilo puede estar sustituido por átomos de flúor, cloro o bromo, por grupos metilo, metoxilo, trifluorometilo, ciano o nitro y los sustituyentes pueden ser idénticos o diferentes, o en la posición 2, 3 ó 4 por un grupo hidroxilo, a carbonyl group which is substituted by a hydroxyl, C1-3 alkoxy, amino, C1-3 alkylamino, N- (Ci-5 alkyl) -C1-3alkylamino or C5-7 cycloalkyleneimino group; a C1-3 alkyl group which may be substituted by an amino, C1-5 alkylamino, C5-7 cycloalkylamino or phenyl-C1-3 alkylamino group which may be additionally substituted in the nitrogen atom of the amino in each case by an alkyl group C1-4, C5-7 cycloalkyl or C2-4 alkenyl or C1-4 alkyl, while the aforementioned C1-4 alkyl substituent in each case may additionally be mono, di or trisubstituted by a cyano, carboxyl, C1- alkoxycarbonyl group 3, C2-4 alkanoyl, pyridyl, imidazolyl, benzo [1, 3] dioxol or phenyl, while the phenyl group can be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents may be identical or different, or in the 2, 3 or 4 position by a hydroxyl group,
un grupo alquilo C1 -3 que está sustituido por un grupo hidroxilo, carboxilo, morfolino, tiomorfolino, 1-oxo-tiomorfolino, 1 ,1-dioxo-tiomorfolino, piperazino, N- (alquil C-i-3)-piperazino o N-bencil-piperazino, por un grupo cicloalquenilenimino de 5 a 7 miembros o por un grupo cicloalquilenimino de 4 a 7 miembros, mientras que los grupos cicloalquilenimino de 5 a 7 miembros anteriormente mencionados pueden estar sustituidos por uno o dos grupos alquilo C1-3, que en cambio pueden estar sustituidos de manera terminal por un grupo hidroxilo, amino o alcanoilamino C2-4, o por un grupo cicloalquilo C5-7 o fenilo y por un grupo hidroxilo, y en los grupos cicloalquilenimino anteriormente mencionados puede reemplazarse un grupo metileno adyacente al átomo de nitrógeno por un grupo carbonilo, a C1 -3 alkyl group which is substituted by a hydroxyl, carboxyl, morpholino, thiomorpholino, 1-oxo-thiomorpholino, 1,1-dioxo-thiomorpholino, piperazino, N- (Ci-3-alkyl) -piperazino or N-benzyl group -piperazino, by a cycloalkenyleneimino group of 5 to 7 members or by a cycloalkyleneimino group of 4 to 7 members, while the cycloalkyleneimino groups of 5 to 7 members mentioned above may be substituted by one or two C1-3 alkyl groups, which in Instead, they may be terminally substituted by a hydroxy, amino or C2-4 alkanoylamino group, or by a C5-7 cycloalkyl or phenyl group and by a hydroxyl group, and in the aforementioned cycloalkyleneimino groups, a methylene group adjacent to the atom may be replaced nitrogen by a carbonyl group,
un grupo alquilo C1-3 que está sustituido por un grupo cicloalquilenimino de 5 a 7 miembros, mientras que un grupo fenilo opcionalmente mono o disustituido por átomos de flúor, cloro o bromo o por grupos metilo o metoxilo, en el que los sustituyentes pueden ser idénticos o diferentes, o un grupo oxazolo, imidazolo, tiazolo, piridino, pirazino o pirimidino opcionalmente sustituido por un átomo de flúor, cloro, bromo o yodo, por un grupo metilo, metoxilo o amino se condensa con los grupos cicloalquilenimino de 5 a 7 miembros anteriormente mencionados a través de 2 átomos de carbono adyacentes, mientras que los grupos fenilo monosustituidos mencionados anteriormente pueden estar adicionalmente sustituidos por un átomo de flúor, cloro o bromo, por un grupo metilo, metoxilo o nitro, o es un grupo imidazolilo o 1 H-alquilimidazolilo C1-3;
Figure imgf000160_0001
Fórmula (IX) a C1-3 alkyl group which is substituted by a 5-7 membered cycloalkyleneimino group, while a phenyl group optionally mono or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, in which the substituents can be identical or different, or an oxazolo, imidazolo, tiazolo, pyridine, pyrazine or pyrimidine group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or amino group is condensed with cycloalkyleneimino groups from 5 to 7 aforementioned members through 2 adjacent carbon atoms, while the aforementioned monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, or is an imidazolyl group or 1 H-C1-3alkylimidazolyl;
Figure imgf000160_0001
Formula (IX)
o una sal, un éster, una amida o un profármaco del mismo; or a salt, an ester, an amide, or a prodrug thereof;
en la que X es O o S, S(O) o S(0)2, NH o NR12 en el que R12 es hidrógeno o alquilo Ci-e; where X is O or S, S (O) or S (0) 2 , NH or NR 12 where R 12 is hydrogen or Ci-e alkyl;
R5 se selecciona de un grupo NHC(0)OR9, NHC(0)R9, NHS(0)2R9, C(0)R9, C(0)OR9, S(0)R9, S(0)OR9, S(0)20R9, C(O)NR10R11 , S(O)NR10R11 ,R 5 is selected from a group NHC (0) OR 9 , NHC (0) R 9 , NHS (0) 2R 9 , C (0) R 9 , C (0) OR 9 , S (0) R 9 , S (0) OR 9 , S (0) 20R 9 , C (O) NR 10 R 11 , S (O) NR 10 R 11 ,
S(O)ONR10R11 ; S (O) ONR 10 R 11 ;
en la que R9, R10 o R11 se seleccionan independientemente de hidrógeno, hidrocarbilo opcionalmente sustituido y heterociclilo opcionalmente sustituido, y R10 y R1 1 junto con el átomo de nitrógeno al que se unen puede formar adicionalmente un anillo heterocíclico opcionalmente sustituido que contiene opcionalmente heteroátomos adicionales; wherein R 9 , R 10 or R 11 are independently selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 1 1 together with the nitrogen atom to which they are attached may additionally form an optionally substituted heterocyclic ring optionally containing additional heteroatoms;
R6 es hidrógeno, hidrocarbilo opcionalmente sustituido o heterociclilo opcionalmente sustituido; R 6 is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
R7 y R8 se seleccionan independientemente de hidrógeno, halo, alquilo Ci-4, alcoxilo C1-4, alcoximetilo Ci-4, di(alcoxi Ci-4)metilo, alcanoílo Ci-4, trifluorometilo, ciano, amino, alquenilo C2-5, alquinilo C2-5, un grupo fenilo, un grupo bencilo o un grupo heterocíclico de 5-6 miembros con 1-3 heteroátomos, seleccionados independientemente de O, S y N, cuyo grupo heterocíclico puede ser aromático o no aromático y puede estar saturado (unido a través de un átomo de carbono o nitrógeno de anillo) o insaturado (unido a través de un átomo de carbono de anillo), y cuyo grupo fenilo, bencilo o heterocíclico puede albergar en uno o más átomos de carbono de anillo hasta 5 sustituyentes seleccionados de hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro, alcanoílo C2-4, alcanoilamino Ci-4, alcoxicarbonilo Ci-4, alquilsulfanilo Ci-4, alquilsulfinilo Ci-4, alquilsulfonilo Ci-4, carbamoílo, N- alquilcarbamoílo Ci-4, N,N-di(alquil Ci-4)-carbamoílo, aminosulfonilo, N- alquilaminosulfonilo Ci-4, N,N-di(alquilo Ci-4)-aminosulfonilo, alquilsulfonilamino Ci-4 y un grupo heterocíclico saturado seleccionado de morfolino, tiomorfolino, pirrolidinilo, piperazinilo, piperidinilo, imidazolidinilo y pirazolidinilo, cuyo grupo heterocíclico saturado puede albergar 1 ó 2 sustituyentes seleccionados de oxo, hidroxilo, halógeno, alquilo C1-3, alcoxilo C1-3, alcanoiloxilo C1-3, trifluorometilo, ciano, amino, nitro y alcoxicarbonilo Ci-4, y R7 and R8 are independently selected from hydrogen, halo, Ci- 4 alkoxy C 1-4 alkoxymethyl Ci- 4, di (Ci- 4 alkoxy) methyl, Ci- 4 alkanoyl, trifluoromethyl, cyano, amino, alkenyl C 2 -5 , C 2-5 alkynyl, a phenyl group, a benzyl group or a 5-6 membered heterocyclic group with 1-3 heteroatoms, independently selected from O, S and N, the heterocyclic group of which may be aromatic or non-aromatic and it can be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked through a ring carbon atom), and whose phenyl, benzyl or heterocyclic group can harbor one or more carbon atoms of ring to 5 substituents selected from hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, alkanoyl C2- 4 alkanoylamino Ci- 4 alkoxycarbonyl Ci- 4 , Ci- 4 alkylsulfanyl, alkylsulfinyl Ci- 4 alkylsulfonyl Ci- 4, carbamoyl, N- Ci- 4- alkylcarbamoyl, N, N-di (Ci- 4- alkyl) -carbamoyl, aminosulfonyl, N-Ci- 4- alkylaminosulfonyl, N, N-di (Ci- 4- alkyl) -aminosulfonyl, alkylsulfonylamino-Ci- 4 and a heterocyclic group saturated selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl, which saturated heterocyclic group may accommodate 1 or 2 substituents selected from oxo, hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy, alkanoyloxy C 1 -3 , trifluoromethyl, cyano, amino, nitro, and Ci- 4- alkoxycarbonyl, and
R1 , R2, R3, R4 se seleccionan independientemente de halógeno, ciano, nitro, alquilsulfanilo C1-3, -N(OH)R13- (en el que R13 es hidrógeno o alquilo C1-3), o R15X1- (en el que X1 representa un enlace directo, -O-, -CH2-, -OCO-, carbonilo, -S-, -SO-, -SO2-, -NR16CO-, -CONR16-, -SO2NR16-, -NR17S02- o -NR18- (en el que R16, R17 y R18 cada uno independientemente representa hidrógeno, alquilo C1-3 o alcoxi Ci-3-alquilo C2-3), y R15 es hidrógeno, hidrocarbilo opcionalmente sustituido, heterociclilo opcionalmente sustituido o alcoxilo opcionalmente sustituido; R 1 , R 2 , R 3 , R 4 are independently selected from halogen, cyano, nitro, C 1-3 alkylsulfanyl, -N (OH) R 13 - (where R 13 is hydrogen or C 1-3 alkyl) , or R 15 X 1 - (where X 1 represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -SO 2 -, -NR 16 CO -, -CONR 16 -, -SO 2 NR 16 -, -NR 17 S0 2 - or -NR 18 - (where R 16 , R 17 and R 18 each independently represents hydrogen, alkyl C 1-3 or Ci- 3- alkoxy-C 2-3 alkyl, and R 15 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy;
o una sal farmacéuticamente aceptable del mismo.  or a pharmaceutically acceptable salt thereof.
4. Método según una cualquiera de las reivindicaciones anteriores, en el que el inhibidor de AURK comprende ARNip anti-AURK, barasertib, tozasertib, alisertib, mesilato de SNS-314, MK-5108, ENMD-2076, AMG-900, hesperadina, ZM-447439 o una combinación de los mismos. Method according to any one of the preceding claims, in which the AURK inhibitor comprises anti-AURK siRNA, barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG-900, hesperadin, ZM-447439 or a combination thereof.
5. Método según una cualquiera de las reivindicaciones anteriores, en el que el inhibidor de AURK se administra mediante una vía seleccionada del grupo que consiste en administración tópica, oral y parenteral.  Method according to any one of the preceding claims, in which the AURK inhibitor is administered by a route selected from the group consisting of topical, oral and parenteral administration.
6. Método según la reivindicación 5, en el que la administración parenteral comprende la administración intravenosa y subcutánea o la administración a través de implantes.  The method according to claim 5, wherein the parenteral administration comprises intravenous and subcutaneous administration or administration through implants.
7. Método según una cualquiera de las reivindicaciones anteriores, en el que el sujeto está sometiéndose a terapia antirretroviral. Method according to any one of the preceding claims, in which the subject is undergoing antiretroviral therapy.
8. Composición que comprende al menos un inhibidor de AURK para su uso en el tratamiento o la prevención de una infección por VIH o SIDA.  8. Composition comprising at least one AURK inhibitor for use in treating or preventing HIV infection or AIDS.
9. Combinación que comprende al menos un inhibidor de AURK y al menos un agente activo adicional para su uso en el tratamiento o la prevención de una infección por VIH o SIDA.  9. Combination comprising at least one AURK inhibitor and at least one additional active agent for use in treating or preventing HIV infection or AIDS.
10. Composición o combinación según una cualquiera de las reivindicaciones 8 ó 9, en la que la AURK es una AURK de clase B.  10. Composition or combination according to any one of claims 8 or 9, wherein the AURK is a class B AURK.
11. Composición o combinación según una cualquiera de las reivindicaciones 8 ó 9, en la que el inhibidor de AURK comprende un compuesto de fórmula (I), (II), 11. Composition or combination according to any one of claims 8 or 9, wherein the AURK inhibitor comprises a compound of formula (I), (II),
(III), (IV), (V), (VI), (Vil), (VIII) o (IX) tal como se define en la reivindicación 3 o una combinación de los mismos. (III), (IV), (V), (VI), (Vil), (VIII) or (IX) as defined in claim 3 or a combination thereof.
12. Composición o combinación según una cualquiera de las reivindicaciones 8 a 11 , en la que el inhibidor de AURK comprende ARNip anti-AURK, barasertib, tozasertib, alisertib, mesilato de SNS-314, MK-5108, ENMD-2076, AMG-900, hesperadina, ZM-447439 o una combinación de los mismos.  12. Composition or combination according to any one of claims 8 to 11, wherein the AURK inhibitor comprises anti-AURK siRNA, barasertib, tozasertib, alisertib, SNS-314 mesylate, MK-5108, ENMD-2076, AMG- 900, hesperadine, ZM-447439 or a combination thereof.
13. Combinación según una cualquiera de las reivindicaciones 9 a 12, en la que el agente activo adicional es un fármaco antirretroviral.  13. A combination according to any one of claims 9 to 12, wherein the additional active agent is an antiretroviral drug.
14. Combinación según una cualquiera de las reivindicaciones 9 a 12, en la que el agente activo adicional es un agente reversor de latencia.  14. A combination according to any one of claims 9 to 12, wherein the additional active agent is a latency reversing agent.
15. Combinación según la reivindicación 14, en la que el agente reversor de latencia comprende una histona desacetilasa (inhibidor de HDAC).  15. The combination according to claim 14, wherein the latency reversing agent comprises a histone deacetylase (HDAC inhibitor).
16. Combinación según la reivindicación 15, en la que el inhibidor de HDAC comprende panobinostat, vorinostat o una combinación de los mismos.  16. The combination according to claim 15, wherein the HDAC inhibitor comprises panobinostat, vorinostat or a combination thereof.
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Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
US5399331A (en) 1985-06-26 1995-03-21 The Liposome Company, Inc. Method for protein-liposome coupling
WO2001021596A1 (en) 1999-09-21 2001-03-29 Astrazeneca Ab Quinazoline derivatives and their use as pharmaceuticals
US20030069299A1 (en) 2000-11-01 2003-04-10 Rainer Walter Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
US20040049032A1 (en) 2002-06-20 2004-03-11 Jean-Damien Charrier Processes for preparing substituted pyrimidines
US20060035908A1 (en) 2004-07-16 2006-02-16 Willard Lew Thienopyrimidines useful as Aurora kinase inhibitors
US20060116357A1 (en) 2002-12-24 2006-06-01 Heron Nicola M Phosphonooxy quinazoline derivatives and their pharmaceutical use
WO2007041358A2 (en) 2005-09-30 2007-04-12 Miikana Therapeutics, Inc. Substituted pyrazole compounds
WO2007087276A1 (en) 2006-01-23 2007-08-02 Amgen Inc. Aurora kinase modulators and method of use
WO2008026768A1 (en) 2006-08-31 2008-03-06 Banyu Pharmaceutical Co., Ltd Novel aminopyridine derivatives having aurora a selective inhibitory action
US20080167292A1 (en) 2006-11-16 2008-07-10 Millennium Pharmaceuticals, Inc. Compounds for inhibiting mitotic progression
WO2012146936A1 (en) * 2011-04-28 2012-11-01 Cxr Biosciences Limited Pyrrolnitrin derivatives
US20140187540A1 (en) * 2011-02-15 2014-07-03 The Johns Hopkins University Compounds and methods of use thereof for treating neurodegenerative disorders
US20150164906A1 (en) * 2012-05-23 2015-06-18 The Johns Hopkins University Compounds and methods of use thereof for treating neurodegenerative disorders
WO2016135046A1 (en) * 2015-02-24 2016-09-01 Academisch Medisch Centrum Inhibitors of raf1, mst1, and pkl1 for use in the treatment of a retrovirus

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US5399331A (en) 1985-06-26 1995-03-21 The Liposome Company, Inc. Method for protein-liposome coupling
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
US5399163A (en) 1992-07-24 1995-03-21 Bioject Inc. Needleless hypodermic injection methods and device
WO2001021596A1 (en) 1999-09-21 2001-03-29 Astrazeneca Ab Quinazoline derivatives and their use as pharmaceuticals
US20030069299A1 (en) 2000-11-01 2003-04-10 Rainer Walter Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
US20040049032A1 (en) 2002-06-20 2004-03-11 Jean-Damien Charrier Processes for preparing substituted pyrimidines
US20060116357A1 (en) 2002-12-24 2006-06-01 Heron Nicola M Phosphonooxy quinazoline derivatives and their pharmaceutical use
US20060035908A1 (en) 2004-07-16 2006-02-16 Willard Lew Thienopyrimidines useful as Aurora kinase inhibitors
WO2007041358A2 (en) 2005-09-30 2007-04-12 Miikana Therapeutics, Inc. Substituted pyrazole compounds
WO2007087276A1 (en) 2006-01-23 2007-08-02 Amgen Inc. Aurora kinase modulators and method of use
WO2008026768A1 (en) 2006-08-31 2008-03-06 Banyu Pharmaceutical Co., Ltd Novel aminopyridine derivatives having aurora a selective inhibitory action
US20080167292A1 (en) 2006-11-16 2008-07-10 Millennium Pharmaceuticals, Inc. Compounds for inhibiting mitotic progression
US20140187540A1 (en) * 2011-02-15 2014-07-03 The Johns Hopkins University Compounds and methods of use thereof for treating neurodegenerative disorders
WO2012146936A1 (en) * 2011-04-28 2012-11-01 Cxr Biosciences Limited Pyrrolnitrin derivatives
US20150164906A1 (en) * 2012-05-23 2015-06-18 The Johns Hopkins University Compounds and methods of use thereof for treating neurodegenerative disorders
WO2016135046A1 (en) * 2015-02-24 2016-09-01 Academisch Medisch Centrum Inhibitors of raf1, mst1, and pkl1 for use in the treatment of a retrovirus

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
"Short Protocols in Molecular Biology", 2002, JOHN WILEY AND SONS, INC.
"Sustained and Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
"UniProt", Database accession no. P01730
ADLER M ET AL., BRIT. MED. J., vol. 294, 1987, pages 1145 - 1147
ALTSCHUL S ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
ALTSCHUL S ET AL., MET. ENZYMOL., vol. 266, 1996, pages 460 - 480
ALTSCHUL S ET AL., NUC. ACIDS RES., vol. 25, 1977, pages 3389 - 3402
ALTSCHUL S ET AL.: "BLAST Manual", 2001, NCBI NLM NIH
ARCHIN N ET AL., NATURE, vol. 487, 2012, pages 482 - 485
AUER H, NATURE BIOTECHNOL., vol. 24, 2006, pages 41 - 43
BENNI VARGAS ET AL: "Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 63, no. 2, 29 January 2019 (2019-01-29), US, pages e01744 - 18, XP055656409, ISSN: 0066-4804, DOI: 10.1128/AAC.01744-18 *
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1146618-41-8
CHOMONT N ET AL., NAT MED, vol. 15, no. 8, 2009, pages 893 - 900
CHUN T ET AL., PROC NAT ACAD SCI USA, vol. 94, 1997, pages 13193 - 13197
FENG L ET AL., BIOCHEMISTRY, vol. 39, no. 50, 2000, pages 15399 - 15409
FINZI D ET AL., NAT MED, vol. 5, 1999, pages 512 - 517
FINZI D ET AL., SCIENCE, vol. 278, 1997, pages 1295 - 1300
HERMANKOVA M ET AL., J VIROL, vol. 77, 2003, pages 7383 - 7392
HUMPHREYS D ET AL., PROTEIN EXPR. PURIF., vol. 20, no. 2, 2000, pages 252 - 264
JORGE MENESES NUNES ET AL: "Modulation of epigenetic factors during the early stages of HIV-1 infection in CD4+ T cells in vitro", VIROLOGY, vol. 523, 2 August 2018 (2018-08-02), AMSTERDAM, NL, pages 41 - 51, XP055656668, ISSN: 0042-6822, DOI: 10.1016/j.virol.2018.07.026 *
KARLIN S ET AL., PROC. NATI. ACAD. SCI. USA, vol. 87, 1990, pages 2264 - 2268
KARLIN S ET AL., PROC. NATI. ACAD. SCI. USA, vol. 90, 1993, pages 5873 - 5877
NARUM D ET AL., INFECT. IMMUN., vol. 69, no. 12, 2001, pages 7250 - 7253
NEEDLEMAN S ET AL., J. MOL. BIOL., vol. 48, 1970, pages 443 - 453
OUTCHKOUROV N ET AL., PROTEIN EXPR. PURIF., vol. 24, no. 1, 2002, pages 18 - 24
PEARSON W ET AL.: "Proc. Nati. Acad. Sci. USA", vol. 85, 1988, pages: 2444 - 2448
SILICIANO J ET AL., NAT MED, vol. 9, 2003, pages 727 - 728
SMITH T ET AL., ADV. APPL. MATH., vol. 2, 1981, pages 482 - 489
STRAIN M ET AL., PROC NAT ACAD SCI USA, vol. 100, 2003, pages 4819 - 4824
STREJAN G ET AL., J. NEUROIMMUNOL., vol. 7, 1984, pages 27 - 41
WEI D ET AL., PLOS PATHOG, vol. 10, no. 4, 2014, pages e1004071

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