WO2020049208A1 - Aurora cinasa comme cible pour traiter, prévenir ou soigner une infection par vih ou le sida - Google Patents

Aurora cinasa comme cible pour traiter, prévenir ou soigner une infection par vih ou le sida 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
ring
amino
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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

La présente invention concerne l'utilisation d'inhibiteurs d'aurora cinasa (AURK) pour traiter ou prévenir une infection par VIH ou le SIDA chez un sujet. La présente invention concerne en outre des compositions qui contiennent des inhibiteurs d'AURK et des combinaisons d'inhibiteurs d'AURK avec d'autres agents actifs utiles pour traiter ou prévenir une infection par VIH ou le SIDA chez un sujet.
PCT/ES2019/070596 2018-09-09 2019-09-09 Aurora cinasa comme cible pour traiter, prévenir ou soigner une infection par vih ou le sida WO2020049208A1 (fr)

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