WO2014124757A1 - Pyrrolotriazine derivatives as pi3k inhibitors - Google Patents

Pyrrolotriazine derivatives as pi3k inhibitors Download PDF

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WO2014124757A1
WO2014124757A1 PCT/EP2014/000432 EP2014000432W WO2014124757A1 WO 2014124757 A1 WO2014124757 A1 WO 2014124757A1 EP 2014000432 W EP2014000432 W EP 2014000432W WO 2014124757 A1 WO2014124757 A1 WO 2014124757A1
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group
amino
branched
linear
triazin
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PCT/EP2014/000432
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French (fr)
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Montserrat Erra Sola
Joan Taltavull Moll
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Almirall, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Phosphoinositide 3-Kinases are among the enzymes involved in early signalling events to a plethora of different types of stimuli.
  • PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns), Ptdlns-4-phosphate (Ptdlns4P), and Ptdlns-4,5-bisphosphate (Ptdlns(4,5)P2).
  • Ptdlns phosphatidylinositol
  • Ptdlns4P Ptdlns-4-phosphate
  • Ptdlns(4,5)P2 Ptdlns(4,5)P2
  • PI3K class I PI3K class II
  • class III PI3K class III
  • the best characterized is the PI3K class I with the preferential substrate Ptdlns- (4,5)P2. It englobes 4 different isoforms which originally were further subdivided into class IA (p1 10a, p110b, p110d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits.
  • p110a PI3Ka or PI3 a
  • p1 10b PI3Kb or ⁇ 3 ⁇
  • p110g PI3Kg or ⁇ 3 ⁇
  • p110d PI3Kd or PI3K5
  • PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli.
  • Pharmacological inhibition or genetic deficiency in active p110d has been shown to inhibit T cell proliferation and cytokine production in response to different stimuli such as anti-CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen- dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008).
  • B cell function is critically dependent on functional PI3Kd activity as demonstrated by suppressed B cell proliferation and cytokine release in vitro in response to anti-lgM (Bilancio A, Blood 107, 2006), toll like receptor agonists such as LPS and oligodeoxynucleotides (Dil N, Mol Immunol 46, 2009) or impaired ability to stimulate antigen-specific T cells (Al-Alwan M, Jl 2007) in the absence of functional p110d or pharmacological inhibition.
  • PI3Kg deficient mice display partially suppressed antibody production upon immunization (Garcon F, 2009; Durand CA, Jl 2009). Further studies have demonstrated an important role of PI3Kd in inhibition of T cell apoptosis and in TH17 differentiation (Haylock-Jacobs S, J. Autoimmun 2010).
  • mast cell degranulation was reduced in cells from mice with inactivated PI3Kd or by pharmacological inhibition of PI3Kd (AN K, Nature 431 :1007-1011 , 2004; Ali K, Journal of Immunology 180:2538-2544, 2008) and basophil activation via the FcE receptor is suppressed by pharmacological inhibition of PI3Kd (Lannutti BJ, Blood Oct. 2010).
  • PI3Kd inhibition inhibits migration of mouse neutrophils to fMLP in an under-agarose migration assay by inhibiting cell polarization and directional movement (Sadhu C, Jl 170, 2003) and mouse PI3Kd deficient or inhibitor treated neutrophils show slightly (25%) reduced in vitro chemotaxis to LTB4, whereas in vivo accumulation in the lung in response to LPS was reduced by more than 80%, indicating an important role of PI3Kd in endothelial cells for mediating PMN
  • TNF induced neutrophil infiltration to an air pouch in mice and elastase release is partially inhibited by a PI3Kd selective inhibitor (Sadhu C, Biochem Biophys Res Comm 308, 2003).
  • PI3Kd selective inhibitor Sadhu C, Biochem Biophys Res Comm 308, 2003.
  • TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005).
  • PI3Kg seems to affect primarily chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, Jl 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008), as well as degranulation and oxidative burst of innate immuce cells induced by GPCR mediated stimuli such as fMLP, IL-8 or C5a (Condliffe AM, Blood 106, 2005; Yum HK, Jl 167, 2001 ; Pinho V, Jl 179, 2007
  • PI3Kd or dual PI3Kd/PI3Kg pharmacological inhibition represents a promising approach for treating a variety of diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, e
  • COPD chronic
  • PI3Kd inhibition Puri KD, Blood 2004,103:3448
  • inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor
  • PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment associated with oxidative stress and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • PI3Kd selective inhibitor To Y, AJRCCM 182:897- 904, 2010.
  • in vitro induction of corticosteroid resistance by oxidative stress is prevented by PI3Kd inhibition (To Y, AJRCCM 2010).
  • lung macrophages display increased expression of PI3Kd and phosphorylation of its downstream effector Akt and non-selective PI3K or PI3Kd- selective inhibition restored the impaired inhibitory efficacy of dexamethasone in PBMC from COPD patients (To Y, AJRCCM 182:897-904, 2010; Marwick JA, JACI 125: 1 146-53, 2010).
  • PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
  • Soond DR Blood Jan 2010
  • PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
  • PI3Kd deficiency or pharmacological inhibition of PI3Kd attenuated T cell activation and function and reduced T cell numbers in the CNS suggesting a therapeutic benefit of PI3Kd inhibitor in multiple sclerosis and other Th17-mediated autoimmune diseases (Haylock-Jacobs S, J. Autoimmun 2010).
  • genetic deficiency or pharmacological inhibition of PI3Kd diminished joint erosion in a mouse model of inflammatory arthritis (Randis TM, Eur J Immunol 38, 2008).
  • PI3Kd overexpression seems to contribute to excessive vascular contraction and PI3Kd inhibition normalized vascular contractive responses in a mouse model of type I diabetes, suggesting a therapeutic potential of PI3Kd blockade to treat vascular dysfunction in diabetic patients (Pinho JF, Br. J.
  • pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition is effective in the treatment of cancers including but not restricted to leukemias, such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
  • leukemias such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
  • the selective PI3Kd inhibitor CAL-101 demonstrated anti-proliferative properties on different tumor cells in vitro and efficacy in cancer patients with a dysregulated PI3Kd activity, such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
  • a dysregulated PI3Kd activity such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
  • Conditions in which targeting of the PI3K pathway or modulation of the PI3 Kinases, particularly PI3Kd or PI3Kd/g, are contemplated to be therapeutically useful for the treatment or prevention of diseases including: respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune-mediated diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis,
  • neuropathic pain trigeminal neuralgia or central pain
  • myelo-dysplastic syndrome myeloproliferative disorders (MPDs)
  • cancer and hematologic malignancies leukemia, lymphomas and solid tumors (such as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non-small cell lung cancer and small-cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T
  • novel pyrrolotriazine derivatives for use in the treatment of conditions in which targeting of the PI3K pathway or inhibition of PI3 Kinases can be therapeutically useful.
  • the compounds described in the present invention are potent PI3K inhibitors, particularly PI3Kd or dual PK3Kd/g inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic derma
  • polycythemia vera essential thrombocythemia or mielofibrosis
  • cancer and
  • hematologic malignancies such as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non-small cell lung cancer and small-cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)).
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • the compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases such as neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g.
  • rheumatoid arthritis multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis and blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa; respiratory inflammation diseases (e.g.
  • asthma chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • idiopathic pulmonary fibrosis sarcoidosis
  • skin inflammatory diseases e.g., atopic dermatitis, contact dermatitis, eczema or psoriasis
  • premalignant and malignant skin conditions e.g. basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • AK actinic keratosis
  • neurological disorders and pain such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain
  • the compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic ker
  • W represents a direct bond or a linker selected from a -O-(CH 2 ) 0 -3- group, a -S-(CH 2 ) 0 - 3 - group, a -(CH 2 ) 1-4 - group, a -(CH 2 ) 0 . 3 -NR a -(CH 2 )o-3- group, a -(CH 2 ) 0 .3-NR a -C(O)-(CH 2 ) 0 . 3- group, a -0-(CH 2 ) 2 . 4 -N(*)R a group, a -(CH 2 ) 0 .
  • R a and R b each independently represents hydrogen, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0 -3-O-(linear or branched CVC 4 alkyl) group; and wherein (*) represents the point of attachment to R ;
  • R° represents a C 3 -C 10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH 2 group, a -CHF 2 group, a -CF 3 group or a linear or branched C ⁇ C alkyl group;
  • X represents a nitrogen atom or a -CR 6 group;
  • Ri represents a linear or branched Ci-C 6 alkyl group, a linear or branched C ⁇ -Ce hydroxyalkyl group, a -(CH 2 )o- 3 N(R d )R e group, a linear or branched C Ce haloalkyl group, a C 3 -C 10 cycloalkyl group, a C 3 -C 10 cycloalkenyl group, a phenyl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein R d and R e each independently represents hydrogen or a linear or branched Ci-C 4 alkyl group; and
  • cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -(CH 2 ) 1-3 CN group, a -(CH 2 ) 0- 3-0-(CH 2 )o.3-0-R 7 group, a -(CH 2 )o-3-0-(linear or branched C C 4 alkyl) group, a -(CH 2 ) 0 .3-O-(CH 2 ) 2 . 4 - NR 7 R 8 group, a -(CH 2 ) 0 . 3
  • heteroatom selected from O, S and N) group a -C(O)-(CH 2 ) 0 . 3 -NR 7 [CH(C 1 -C 2 alkyl)]o.3-(phenyl) group, a -C(0)-(CH 2 )o-3-NR7(CH 2 )o-3-(phenyl) group, a -C(O)- (CH 2 )o-3-NR7(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH 2 )o-3-NR 7 (CH 2 )o-3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o-3-NR 7 R 8 group, a -C(0)-(CH 2 )o-3-NR 7 -(CH 2 )
  • each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group, a linear or branched Ci-C 4 hydroxyalkyi group, a -(CH 2 )o-3-0-(linear or branched Ci- C 4 alkyl) group, a -C(0)-0-(linear or branched C ⁇ C 4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH 2 ) 0 - 3 -(linear or branched Ci-C 4 alkyl) group, a -C(O)-(CH 2 ) 0 .
  • 3 NR f R 9 group a -(CH 2 ) 0 . 3 N(R f )R 9 group, a -S(O) 2 (CH 2 ) 0 . 3(linear or branched CVC 4 alkyl) group, a -S(O) 2 (CH 2 ) 0 . 3 NR f R 9 group, a - NR f -S(0) 2 (CH 2 )o. 3 NR f R 9 group, a -NR f -S(0) 2 (CH 2 )o. 3 R 9 group, a -(CH 2 ) 0 . 3 - 0-(CH 2 ) 2 .
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C C 4 hydroxyalkyi group, a C 3 -C 4 cycloalkyi group, a CVC 4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group;
  • R 4 represents a hydrogen atom, a linear or branched C ⁇ C alkyl group, a CVC haloalkyi group, a linear or branched C C 4 hydroxyalkyi group, a C 3 -C 7 cycloalkyi group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl group), a -(CH 2 )o- 3 -S-(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N), a - (CH 2 )o-3-0-(CH 2 ) 0 -3-(phenyl group), a -(CH 2 ) 0-3 -0-(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N), a -(CH 2 ) 0-3 -0-(CH 2 )o-3-(5
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ! -C 4 alkyl group, a C ⁇ C 4 haloalkyi group, a linear or branched C C 4 hydroxyalkyl group or a C C 4 alkoxy group;
  • R 6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C 4 alkyl group; a C ! -C alkoxy group; a CrC 4 haloalkyi group; a linear or branched C C 4 hydroxyalkyl group; a C 3 -C 7 cycloalkyl group; a -(CH 2 ) 0 .
  • 3NR 7 R 8 group a -(CH ⁇ .s-O- inear or branched C C 4 alkyl group); a -(CH 2 ) 0-3 -OC(O)-( linear or branched C C 4 alkyl group); a -(CH 2 ) 0 . 3 -C(O)O-(linear or branched C C 4 alkyl group); a -C(O)-(CH 2 ) 0 - 3 -NR 7 R 8 group; or a -(CH 2 ) 0 - 3 -C(O)OH group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched CVC 4 alkyl group, a C C haloalkyi group, a linear or branched Ci-C 4 hydroxyalkyl group or a CVC 4 alkoxy group;
  • R 5 represents a moiety of formula (11-1 ), (II-2), (II-3), (II-4), (II-5), (II-6) or (II-7)
  • (*) represents the point of attachment of R 5 to the carbon atom bonded to R 4 and to the pyrrolotriazine group
  • Z represents a nitrogen atom or a -CH group
  • R9, R 1 1 , Ri 3, Ri 4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched Ci-C 4 alkyl group;
  • R 10 and R 12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C1-C4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a -0-(linear or branched C C 3 alkyl) group, a -(CH 2 ) 0-3 - C(O)-(CH 2 ) 0 -3-NR'R"group, a -(CH 2 ) 0 - 3 NR'R" group, a -(CH 2 ) 0 .
  • ⁇ L represents a direct bond or a linker selected from -0-(CH 2 )o-3-, -S-
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said compounds.
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
  • Phosphoinositide 3-Kinases in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders and pain; cardiovascular diseases; viral infection;
  • RA rheumatoid artritis
  • MS multiple sclerosis
  • amyotrophic lateral sclerosis Crohn's disease
  • ulcerative colitis systemic lupus erythematosis
  • autoimmune hemolytic anemia type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK).
  • COPD chronic obstructive pulmonary disease
  • COPD cystic fibrosis
  • CF cystic fibrosis
  • sarcoidosis atopic dermatitis
  • allergic rhinitis contact dermatitis
  • the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
  • PI3Ks Phosphoinositide 3-Kinases
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
  • PI3Ks Phosphoinositide 3-Kinases
  • the invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases;
  • inflammatory or autoimmune-mediated diseases include inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa,
  • C C 6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2- ethylbutyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
  • alkyl radical may be optionally substituted it is meant to include linear or branched alkyl radical as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1 , 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different.
  • Ci-C 4 haloalkyl group is an alkyl group, for example a Ci-C 4 or C C 2 alkyl group, which is bonded to one or more, preferably 1 , 2 or 3 halogen atoms.
  • said haloakyl group is chosen from -CCI 3 , -CHF 2 and -CF 3 .
  • C C 4 hydroxyalkyi embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted by one or more, preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
  • C r C 4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • C 3 -C 10 cycloalkyl embraces saturated monocyclic or polycyclic carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms.
  • An optionally substituted C 3 -Ci 0 cycloalkyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • the substituents may be the same or different.
  • the substituents on a C 3 -C 10 cycloalkyl group are themselves unsubstituted.
  • Polycyclic cycloalkyl radicals contains two or more fused cycloalkyl groups, preferably two cycloalkyl groups.
  • polycyclic cycloalkyl radicals are selected from decahydronaphthyl (decalyl), bicyclo[2.2.2]octyl, adamantly, camphyl or bornyl groups.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
  • C 3 -Ci 0 cycloalkenyl embraces partially unsaturated
  • carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms.
  • a C 3 -C 10 cycloalkenyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • substituents may be the same or different.
  • the substituents on a cycloalkenyl group are themselves unsubstituted.
  • 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 9- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • a 5- to 14- membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • a said optionally substituted 5- to 14- membered heteroaryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • substituents may be the same or different.
  • the substituents on a 5- to 14- membered heteroaryl radical are typically themselves unsubstituted.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2
  • the term monocyclic or bicyclic 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 5 -C 14 carbocyclic ring system, preferably C 5 -C 10 carbocyclic ring system, more preferably C 5 -C 9 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • a heterocyclyl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom. When a 5 to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
  • a said optionally substituted monocyclic or bicyclic 5- to 14-membered heterocyclyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. Typically, the substituents on a 5 to 14-membered heterocyclyl radical are themselves unsubstituted.
  • Examples of monocyclic or bicyclic 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro- oxazolyl, 2-benzofuran-1(3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza- tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl,
  • a monocyclic or bicyclic 5- to 14-membered heterocyclyl radical carries 2 or more substituents
  • the substituents may be the same or different.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted".
  • substituents can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • substituents When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
  • halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
  • a halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine.
  • halo when used as a prefix has the same meaning.
  • any reference to a compound of formula (I) throughout the present specification includes a reference to any isomer, polymorph, pharmaceutically acceptable salt, N-oxide, isotope, solvate or prodrug of such compound of formula (I).
  • Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the compounds of Formula (I) as described and claimed encompass the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereoisomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • Oki (Oki, M; Topics in Stereochemistry 1983, 1) defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual atropisomers (an atropisomer "substantially free" of tis corresponding enantionmer) and stereoisomer-enriched mixtures, i.e. mixtures of atropisomers.
  • Atropisomers Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization.
  • an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other.
  • Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetric catalyst derived from proline) in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other.
  • CBS Corey-Bakshi-Shibata
  • the compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula (I). Polymorphs
  • the compounds of formula (I) may exist in different physical forms, i.e. amorphous and crystalline forms.
  • the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism.
  • Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula (I), including all polymorphic forms (“polymorphs”) or amorphous forms thereof, are included within the scope of the invention.
  • Pharmaceutically acceptable salts are included within the scope of the invention.
  • the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • pharmaceutically acceptable salt embraces salts with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid) and the like.
  • Salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, po!yamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine
  • X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the invention also includes isotopically-labeled derivatives of the compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11 C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3H, and carbon-14, 14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 1 1 C, 18F, 150 and 13N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled derivatives of the compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled derivatives include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds.
  • Prodrugs of the compounds described herein are also within the scope of the invention.
  • certain derivatives of the compounds of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • PI3Kd inhibitor generally refers to a compound that inhibits the activity of the PI3Kd isoform more effectively than other isoforms of the PI3 family.
  • PI3Kd/g inhibitor generally refers to a compound that inhibits the activity of both the PI3Kd isoform and the PI3Kg isoform more effectively than other isoforms of the PI3K family.
  • the relative efficacies of compounds as inhibitors of an enzyme activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results.
  • the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC 50 .”
  • IC 5 o determinations can be accomplished using conventional techniques known in the art. In general, an IC 50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC 50 value.
  • a PI3Kd inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC 50 ) with respect to PI3Kd that is at least of less than about 100 ⁇ , preferably of less than about 50 ⁇ , more preferably of less than about 20 ⁇ , even more preferably of less than about 10 ⁇ PI3K HTRF assay (as described in Gray et al.
  • W represents a direct bond or a linker selected from a-O-(CH 2 ) 0 -3- group, a -S- (CH 2 ) 0 - 3 - group, a -(CH 2 )i. 4 - group, a -(CH 2 ) 0 - 3 - NR a -(CH 2 ) 0 -3- group, a -(CH 2 ) 0 . 3 -NR a -C(0)-(CH 2 )o-3- group, a -0-(CH 2 ) 2 .
  • R a and R b each independently represents hydrogen, a linear or branched C1-C4 alkyl group or a -(CH 2 ) 0 -3-O-(linear or branched C ⁇ C A alkyl) group; and wherein (*) represents the point of attachment to R ⁇ and wherein R° represents a phenyl group or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N.
  • X represents a nitrogen atom or a -CR 6 group.
  • X represents a -CR 6 .
  • R a and R each independently represent a hydrogen atom or a linear or branched C ⁇ -C alkyl group.
  • R a and R b each independently represent a hydrogen atom, a methyl group or an ethyl group.
  • Ri represents a linear or branched C C 6 alkyl group, a linear or branched C ⁇ -C 6 hydroxyalkyl group, a -(CH 2 ) 0 - 3 N(R d )R e group, a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein R d and R e each independently represents hydrogen or a linear or branched C C 4 alkyl group; and
  • cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C ⁇ C hydroxyalkyi group, a C3-C4 cycloalkyl group, a -(CH 2 )i.
  • heteroatom selected from O, S and N heteroatom selected from O, S and N
  • alkyl [0 . 3 -(phenyl) group, a -C(O)-(CH 2 ) 0 . 3 -NR 7 (CH 2 ) 0 - 3 -(phenyl) group, a -C(O)- (CH 2 ) 0 . 3 -NR 7 (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH 2 ) 0 - 3 -NR 7 (CH 2 ) 0 .
  • a hydroxyl group unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group, a linear or branched C C 4 hydroxyalkyi group, a -(CH 2 ) 0 . 3 -O-(linear or branched C C 4 alkyl) group, a -C(0)-0-(linear or branched d-d alkyl) group, a - C(0)-OH group, a -C(O)-(CH 2 ) 0 - 3 -(linear or branched d alkyl) group, a -C(0)-(CH 2 )o.
  • 3 NR f R 9 group a -(CH 2 ) 0 . 3 N(R f )R 9 group, a -S(O) 2 (CH 2 ) 0 . 3(linear or branched C C 4 alkyl) group, a -S(O) 2 (CH 2 ) 0 - 3 NR f R 9 group, a - NR f -S(0) 2 (CH 2 )o. 3 NR f R 9 group, a -NR f -S(O) 2 (CH 2 ) 0 - 3 R 9 group, a -(CH 2 ) 0 .
  • Ri represents a Iinear or branched C -C 6 alkyl group, a Iinear or branched Ci-C 6 hydroxyalkyl group, a -(CH 2 )o-3N(R d )R e group, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, a 1 ,4-azathianyl group, a thiomorpholinyl 1 ,1-dioxide group, a 2,5- diazabicyclo[2.2.1 ]heptan-2-yl group, a 2,5-diazabicyclo[2.2.1 ]octan-2-yl group, a pyr
  • cycloalkyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1 ,4-azathianyl, thiomorpholinyl 1 ,1- dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1 ]octan-2-yl, pyrrolidinyl-2-one or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a Iinear or branched (VC 4 alkyl group, a C C 4 haloalkyl group, a Iinear or branched C C hydroxyalkyl group, a C 3 -C 4 cycloalkyl group,
  • each phenyl, pyridinyl, pyrrolidinyl, piperazinyl or piperidinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a Iinear or branched C C alkyl group, a Iinear or branched C C 4 hydroxyalkyl group, a -(CH 2 ) 0 .
  • the compound of formula (I) represents a linear or branched C C 6 alkyl group, a linear or branched C C 6 hydroxyalkyl group, C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group; wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C 1 -C4 alkyl group or a C 3 -C 7 cycloalkyl group.
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C 1 -C4 alkyl group or a C 3 -C 7 cycloalkyl group.
  • in the compound of formula (I) preferably represents a linear or branched Ci-C 6 alkyl group, a linear or branched C C 6 hydroxyalkyl group, a C 3 -C 7 cycloalkyi group, a phenyl group, a pyridyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group; wherein the cycloalkyi, phenyl, pyridyl, piperidin
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0 . 3 -O-(CH 2 ) 2-4 -NR 7 R 8 group.
  • R 2 represents a hydrogen atom, a halogen atom or a linear or branched C C 4 alkyl group.
  • R 2 represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. More preferably R 2 represents a hydrogen atom.
  • R 3 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C C alkyl group, a C C 4 haloalkyl group, or a linear or branched C C 4 hydroxyalkyl group.
  • R 3 represents a hydrogen atom, a halogen atom or a linear or branched C C 4 alkyl group. More preferably R 3 represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. Even more preferred, R 3 represents a hydrogen atom.
  • R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a -(CH 2 ) 0 . 3 -S-(CH 2 ) 0 . 3 -(phenyl) group, a -(CH 2 ) 0 -3-O-(CH 2 ) 0 - 3 -(phenyl) group, or a -(CH 2 ) 0 . 3 -(phenyl) group; wherein the phenyl group is
  • a halogen atom unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C alkyl group, a Ci-C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group or a C C 4 alkoxy group.
  • R 4 represents a hydrogen atom, a branched C C 4 alkyl group or a -(CH 2 )o- 3-(phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C 4 alkyl group. More preferably R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, or a -(CH 2 ) 0 -3-(phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups. Even more preferably R 4 represents a hydrogen atom or a linear or branched C C 4 alkyl group. Most preferably, R 4 represents a hydrogen atom, a methyl group or an ethyl group.
  • R 6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C C alkyl group, a C C 4 haloalkyl group, or a linear or branched C C 4 hydroxyalkyl group.
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group. More preferably, R 6 represents a hydrogen atom, a halogen atom, hydroxyl group, a cyano group or a methyl group.
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C ! -C 4 alkyl group, a C C haloalkyl group, a linear or branched Ci-C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C 4 alkyl group, a ( C 4 haloalkyl group, a linear or branched C C hydroxyalkyl group or a C r C 4 alkoxy group.
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C ⁇ C 3 alkyl group, a linear or branched C C 3 hydroxyalkyl group, a C 3 -C cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C C 4 alkoxy groups. More preferably, R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C r C 3 alkyl group, a linear or branched C C 3 hydroxyalkyl group or a C 3 -C 7 cycloalkyi group.
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C ⁇ C 4 alkyl group, a C 3 -C 7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C 4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C ⁇ C 4 hydroxyalkyi group or a C ⁇ C 4 alkoxy group.
  • R 7 and R 8 each independently preferably represent a hydrogen atom, a linear or branched ( C 3 alkyl group, a C 3 -C 4 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C ⁇ C 4 alkoxy groups. More preferably, R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C 4 alkyl group or a C 3 -C 7 cycloalkyl group.
  • R 5 represents a moiety of formula (11-1 ), (II-2), (II-3), (II-4), (II-5), (II-6) or (II-7)
  • R 9, R 10 , R11, R 1 2, Ri3, Ri 4 , Ri5, Z and L are as defined above.
  • R 5 represents a moiety of formula (11-1), (II- 2), (II-3), (II-4), (II-5), (II-6) or (II-7)
  • Z represents a nitrogen atom or a -CH group
  • R 9i Rn , R 13 R 14 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 4 alkyl group;
  • R 10 and R 12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a -0-(linear or branched C ⁇ -Cz alkyl) group, a -(CH 2 )o-3- C(O)-(CH 2 ) 0 -3-NR'R"group, a -(CH 2 ) 0 .
  • substituents selected from a halogen atom, hydroxyl group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a -0-(linear or branched C ⁇ -Cz alkyl) group, a -(CH 2 )o-3
  • ⁇ L represents a direct bond or a linker selected from -0-(CH 2 )o-3-, -S-
  • R 5 represents a moiety of formula (11-1 ), (II-2
  • ⁇ (*) represents the point of attachment of R 5 to the carbon atom bonded to R and to the pyrrolotriazine group
  • R 9i R , R 13i R 14 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 3 alkyl group;
  • ⁇ Rio and R 12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
  • phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxyl group, a linear or branched 0 ⁇ 0 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a -0-(linear or branched C C 3 alkyl) group, a -(CH 2 )o-3-C(0)-(CH 2 ) o.
  • R' represents a hydrogen atom or a linear or branched C C 3 alkyl group
  • R" represents a hydrogen atom, a linear or branched ( C 3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched ( C 4 alkyl group;
  • R 5 represents a moiety of formula (11-1), (II-2 -5), (II-6) or (II-7)
  • Z represents a nitrogen atom
  • R 9 , Rn R 13i R 14 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 3 alkyl group;
  • R 10 and R 12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
  • phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched CV C 4 alkyl group, a linear or branched Ci-C 4 hydroxyalkyl group, a - 0-(linear or branched C C 3 alkyl) group, a -(CH 2 ) 0 - 3 NR'R" group, a -(CI-yo-s- R'-iCHz e-NR'R" group, a -NR'-S(0) 2 (CH 2 )o.
  • substituents selected from a halogen atom, a hydroxyl group, a linear or branched CV C 4 alkyl group, a linear or branched Ci-C 4 hydroxyalkyl group, a - 0-(linear or branched C C 3 alkyl)
  • R 5 represents a moiety of formula
  • (*) represents the point of attachment of R 5 to the carbon atom bonded to R 4 and to the pyrrolotriazine group
  • Z represents a nitrogen atom or a -CH group
  • Rg, Rii, Ri 3, Ri 4 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C1-C4 alkyl group
  • R 10 and R 12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a linear or branched C ⁇ C* hydroxyalkyl group, a - 0-(linear or branched C r C 3 alkyl) group, a -(CH 2 ) 0 -3-C(O)-(CH 2
  • R 5 preferably represents a moiety of formula (11-1 ), (II-5 or (II-7)
  • R 9i R 10 , R11 , Ri 2 , Ri3, Ri4, Ri5 and Z are as defined above.
  • R 5 preferrably represents a moiety of formula (11-1), (II-5) or (II-7)
  • ( * ) represents the point of attachment of R 5 to the carbon atom bonded to R 4 and to the pyrrolotriazine group
  • Z represents a nitrogen atom or a -CH group
  • R9, R11 , i 3, Ri 4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 4 alkyl group
  • R 10 and R 2 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, or a linear or branched C C 4 hydroxyalkyl group.
  • L represents a direct bond or a linker selected from -0-(CH 2 )o-3-, -S- (CH 2 ) 0 -3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a -C(0)-0- group or a -(CH 2 ) 1-4 group.
  • L represents a direct bond or a linker selected from -O-(CH 2 ) 0 _ 3 -, -S- (CH 2 ) 0 . 3- or a -(CH 2 ) 1-4 group.
  • a linker selected from -O-(CH 2 ) 0 _ 3 -, -S- (CH 2 ) 0 . 3- or a -(CH 2 ) 1-4 group.
  • W represents a direct bond or a linker selected from a -0-(CH 2 )o-3- group, a -S-(CH 2 ) 0 . 3 - group, a -(CH 2 )i- 4 - group, a -(CH 2 )o-3-NR a -(CH 2 )o. 3 - group, a -(CH 2 ) 0 . 3 -NR a -C(0)-(CH 2 )o.
  • R a and R b each independently represents hydrogen, a linear or branched CV C alkyl group or a -(CH 2 ) 0 -3-O-(linear or branched C ⁇ C 4 alkyl) group; and wherein (*) represents the point of attachment to R ⁇
  • R° represents a C 3 -C 10 cycloalkyi group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyi, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH 2 group, a -CHF 2 group, a -CF 3 group or a linear or branched C C 4 alkyl group;
  • X represents a nitrogen atom or a -CR 6 group;
  • Ri represents a linear or branched C C 6 alkyl group, a linear or branched C C 6 hydroxyalkyl group, a -(CH 2 ) 0 -3N(R d )R e group, a linear or branched C Ce haloalkyl group, a C 3 -C 10 cycloalkyi group, a C 3 -C 10 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein R d and R e each independently represents hydrogen or a linear or branched C1-C4 alkyl group; and
  • cycloalkyi, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyi group, a -( ⁇ 2 ) 1-3 ⁇ group, a -(CH 2 ) 0- 3-0-(CH 2 )o-3-0-R 7 group, a -(CH 2 )o- 3 -0-(linear or branched C C A alkyl) group, a -(CH 2 ) 0 - 3 -O-(CH 2 ) 2 .
  • NR 7 R 8 group a -(CH 2 ) 0 . 3 NR 7 R 8 group, a -(CH 2 ) 0 . 3 NH-(CH 2 ) 2 .
  • NR 7 R 8 group a -
  • heteroatom selected from O, S and N) group a -C(0)-(CH 2 )o.3-NR 7 [CH(C 1 -C 2 alkyl)] 0 .3-(phenyl) group, a -C(0)-(CH 2 ) 0 .3-NR 7 (CH 2 )o- 3 -(phenyl) group, a -C(O)- (CH 2 )o-3-NR 7 (CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH 2 ) 0 . 3 -NR 7 (CH 2 ) 0 .
  • each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group, a linear or branched C C 4 hydroxyalkyl group, a -(CH 2 ) 0 - 3 -O-(linear or branched C C 4 alkyl) group, a -C(0)-0-(linear or branched C C 4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH 2 ) 0 .
  • heteroaryl group containing at least one heteroatom selected from O, S and N
  • heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched alkyl group or a -(CH 2 )o- 3 NR f R 9 group
  • R f and R 9 each independently represents hydrogen, a linear or branched C -C 4 alkyl group or a linear or branched C C hydroxyalkyl group
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ! -C 4 alkyl group, a C1-C4 haloalkyi group, a linear or branched Ci-C hydroxyalkyi group, a C 3 -C 4 cycloalkyl group, a C1-C4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group;
  • R 4 represents a hydrogen atom, a linear or branched CrC alkyl group, a CVC 4 haloalkyi group, a linear or branched C C 4 hydroxyalkyi group, a C 3 -C 7 cycloalkyl group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl group), a -(CH 2 ) 0- 3-S-(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N), a - (CH 2 )o-3-0-(CH 2 ) 0 .
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C hydroxyalkyi group or a Ci-C 4 alkoxy group;
  • R 6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched Ci-C alkyl group; a C1-C4 alkoxy group; a Ci-C 4 haloalkyi group; a linear or branched C C 4 hydroxyalkyi group; a C 3 -C 7 cycloalkyl group; a -(CH 2 ) 0 .
  • 3NR 7 R 8 group a -(CH 2 ) 1-3 -0-(linear or branched C C 4 alkyl group); a -(CH 2 ) 0 -3-OC(O)-( linear or branched C C 4 alkyl group); a -(CH 2 ) 0 - 3 -C(O)O-(linear or branched C C 4 alkyl group); a -C(O)-(CH 2 ) 0 . 3 -NR 7 R 8 group; or a -(CH 2 )o. 3 -C(0)OH group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched Ci-C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C r C 4 hydroxyalkyi group, a C 3 -C cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched Ci-C 4 hydroxyalkyi group or a Ci-C 4 alkoxy group;
  • R 5 represents a m
  • R 9 , R 0 , R , R 12 , Ri3, Ri 4 , Ris, Z and L are as defined above.
  • W represents a direct bond or a linker selected from a-0-(CH 2 )o-3- group, a -S- (CH 2 )o-3- group, a -(CH 2 )i. 4 - group, a -(CH 2 )o. 3 -NR a -(CH 2 )o-3- group, a -(CH 2 ) 0 .3-NR a -C(O)-(CH 2 ) 0- 3- group, a -0-(CH 2 ) 2 . 4 -N(*)R a group, a -(CH 2 ) 0 .
  • R a and R b each independently represents hydrogen, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0-3 -O-(linear or branched Ci-C 4 alkyl) group; and wherein (*) represents the point of attachment to R ⁇
  • R c represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH 2 group, a -CHF 2 group, a -CF 3 group or a linear or branched Ci-C 4 alkyl group;
  • X represents a nitrogen atom or a -CR 6 group
  • R- ⁇ represents a linear or branched C Ce alkyl group, a linear or branched C C 6 hydroxyalkyl group, a -(CH 2 ) 0 - 3 N(R d )R e group, a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein R d and R e each independently represents hydrogen or a linear or branched C ⁇ -C 4 alkyl group; and
  • cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched CrC 4 hydroxyalkyi group, a C3-C4 cycloalkyl group, a -(CH 2 )o-3-0-(CH 2 )o-3-0-R7 group, a -(CH 2 ) 0 -3-O-(linear or branched C C 4 alkyl) group, a -(CH 2 ) 0 -3-O-(CH 2 ) 2 .
  • 4 -NR 7 R 8 group a -(CH 2 ) 0 . 3NR 7 R 8 group, a -(CH 2 )o. 3 H-(CH 2 ) 2.
  • 4 NR 7 R8 group a -C(0)-0-(linear or branched d-C 4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH 2 ) 0 .
  • each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group, a linear or branched C C 4 hydroxyalkyi group, a -(CH 2 ) 0- 3-O-(linear or branched d- C alkyl) group, a -C(0)-0-(linear or branched C1-C4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH 2 ) 0 -3-(linear or branched C ⁇ C alkyl) group, a -C(0)-(CH 2 )o.
  • NR f R 9 group 3 NR f R 9 group, a -NR f -S(0) 2 (CH 2 )o- 3 R 9 group, a -(CH 2 ) 0 - 3 - 0-(CH 2 ) 2- 4-NR f R 9 group or a -(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C 3 alkyl group or a -(CH 2 ) 0 .
  • R f and R 9 each independently represents hydrogen, a linear or branched C C 4 alkyl group or a linear or branched C ⁇ C 4 hydroxyalkyi group;
  • R 2 represents a hydrogen atom or a linear or branched C C 4 alkyl group;
  • R 3 represents a hydrogen atom or a linear or branched C 1 -C4 alkyl group
  • R 4 represents a hydrogen atom, a linear or branched Ci-C 4 alkyl group, or a -(CH 2 ) 0 . 3 - (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ⁇ C 4 alkyl group;
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC ⁇ alkyl group, a C C haloalkyi group, or a linear or branched C C 4 hydroxyalkyi group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C alkyl group, a linear or branched C C 3 hydroxyalkyi group, a C 3 -C 7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C T C 4 hydroxyalkyi group or a C,-C 4 alkoxy group;
  • R 5 represents a m
  • Z represents a nitrogen atom or a -CH group
  • R 9i Rn , R 13i R 14 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 4 alkyl group;
  • R 0 and R 12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C1-C4 alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a -0-(linear or branched ( C 3 alkyl) group, a -(CH 2 ) 0 - 3 - C(O)-(CH 2 ) 0 -3-NR'R"group, a -(CH 2 ) 0 .
  • piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched CVC alkyl group or a -(CH 2 ) 0 .
  • R' represents a hydrogen atom or a linear or branched C C 3 alkyl group
  • R" represents a hydrogen atom, a linear or branched C1-C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C1-C4 alkyl group
  • L represents a direct bond or a linker selected from -0-(CH 2 )o-3-, -S-
  • W represents a direct bond or a linker selected from a-0-(CH 2 )o- 3 - group, a -(CH 2 ) 1- - group, a -(CH 2 ) 0 - 3 -NR a -(CH 2 )o-3- group, a -0-(CH 2 ) 2 .
  • R a and R each independently represents hydrogen, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0- 3-O-(linear or branched C C 4 alkyl) group; and wherein (*) represents the point of attachment to R ⁇ R c represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • X represents a -CR 6 group; represents a linear or branched C C 6 alkyl group, a linear or branched C ⁇ Ce hydroxyalkyl group, a -(CH 2 ) 0 - 3 N(R d )R e group, a C 3 -C 7 cycloalkyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, a 1 ,4-azathianyl group, a thiomorpholinyl 1 , 1 -dioxide group, a 2,5-diazabicyclo[2.2.1 ]heptan-2-yl group, a 2,5-diazabicyclo[2.2.1]octan-2-yl group, a pyrroli
  • cycloalkyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1 ,4-azathianyl, thiomorpholinyl 1 , 1 - dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1 ]octan-2-yl, pyrrolidinyl-2-one or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C ⁇ C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group
  • each phenyl, pyridinyl, pyrrolidinyl, piperazinyl or piperidinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C ⁇ C 4 alkyl group, a linear or branched CVC 4 hydroxyalkyl group, a -(CH 2 ) 0 . 3 -O-(linear or branched C C 4 alkyl) group, a -C(0)-0-(linear or branched C C 4 alkyl) group, a -C(0)-OH group, a -C(O)-(CH 2 ) 0 .
  • R 9 group a -(CH 2 ) 0 - 3 -O-(CH 2 ) 2 . 4 -NR f R 9 group or a -(CH 2 ) 0 - 3 -(pyridinyl) group; which pyridinyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C 3 alkyl group or a - (CH 2 )o- 3 NR f R 9 group; and wherein R f and R 9 each independently represents hydrogen, a linear or branched C C 4 alkyl group or a linear or branched C C hydroxyalkyl group;
  • R 2 represents a hydrogen atom
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, or a -(CH 2 ) 0 . 3 - (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups;
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched C ! -C 3 alkyl group
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C 3 alkyl group, a linear or branched C ⁇ Cs hydroxyalkyi group, a C 3 -C 4 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more Ci- C 4 alkoxy groups;
  • R 5 represents a m
  • ( * ) represents the point of attachment of R 5 to the carbon atom bonded to R 4 and to the pyrrolotriazine group
  • Z represents a nitrogen atom
  • R- , ii , Ri 3, Ri 4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 3 alkyl group;
  • R1 0 and R 12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
  • phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C 4 alkyl group, a C C haloalkyl group, a linear or branched C C 4 hydroxyalkyi group, a -0-(linear or branched ( C 3 alkyl) group, a -(CH 2 )o-3-C(0)-(CH 2 ) o.3-NR'R"group, a -(CH 2 ) 0 .
  • L represents a direct bond
  • W represents a direct bond or a linker selected from a -O-(CH 2 ) 0 -3- group, a -S- (CH 2 ) 0- 3- group, a -(CH 2 ) 1-4 - group, a -(CH 2 )o. 3 -NR a -(CH 2 ) 0 .3- group, a -(CH 2 ) 0 - 3 -NR a -C(O)- (CH 2 )o-3- group, a -0-(CH 2 ) 2 . 4 -N(*)R a group, a -(CH 2 ) 0 .3-N(*)-(CH 2 ) 2 .
  • R a and R b each independently represents hydrogen, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0 - 3 -O-(linear or branched Ci-C 4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen
  • R c represents a C 3 -C 10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH 2 group, a -CHF 2 group, a -CF 3 group or a linear or branched C C 4 alkyl group;
  • cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group; a cyano group; a linear or branched Ci-C 4 alkyl group; a C C 4 haloalkyi group; a linear or branched C ⁇ C 4 hydroxyalkyl group; a C3-C4 cycloalkyl group; a -(CH 2 )i- 3 CN group; a -(CH 2 )o-3-0-(linear or branched C C 4 alkyl) group; a -(CH2)o-3-0-(CH 2 )2-4-NR 7 8 group; a -(CH 2 ) 0 -3NR 7 R 8 group; a -(CH 2 )o- 3 NH-(CH 2 ) 2 . 4 NR 7 R 8 group;
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C 4 haloalkyi group, or a linear or branched C C 4 hydroxyalkyl group;
  • R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C cycloalkyl group, a -(CH 2 )o- 3 -S-(CH 2 )o- 3 -(phenyl group), a -(CH 2 )o-3-0-(CH 2 ) 0 - 3 -(phenyl group), or a -(CH 2 )o- 3 -(phenyl group);
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C ⁇ C 4 haloalkyi group, a linear or branched C ⁇ C 4 hydroxyalkyl group or a C C 4 alkoxy group;
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, or a linear or branched C ⁇ C 4 hydroxyalkyl group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C 4 alkyl group, a C C 4 haloalkyi group, a linear or branched C1-C4 hydroxyalkyl group, a C 3 -C 7
  • R 5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
  • R 9 R 0 , Rii Ri2 i3 i4, i5, Z and L are as defined above.
  • W represents a direct bond or a linker selected from a -0-(CH 2 )o-3- group, a -S- (CH 2 )o- 3- group, a -(CH 2 ) M - group, a -(CH 2 )o. 3 -NR a -(CH 2 )o-3- group, a -(CH 2 ) 0-3 -NR a -C(O)- (CH 2 )o- 3 - group, a -0-(CH 2 ) 2 . 4 -N(*)R a group, a -(CH 2 ) 0 - 3 -N(*)-(CH 2 ) 2 .
  • R a and R b each independently represents hydrogen, a linear or branched C C 4 alkyl group or a -(CH 2 ) 0 - 3 -O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R ⁇
  • R c represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH 2 group, a -CHF 2 group, a -CF 3 group or a linear or branched C1-C4 alkyl group;
  • X represents a nitrogen atom or a -CR 6 group; represents a linear or branched Ci-C 6 alkyl group, a linear or branched C ⁇ C e hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 7
  • cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C 1 -C 4 alkyl group, a C C haloalkyi group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -(CH 2 ) 0 - 3 -O-(linear or branched C1-C4 alkyl) group, a -(CH 2 )o- 3-0-(CH 2 ) 2 -4-NR 7 R 8 group, a -(CH 2 )o- 3 NR 7 R 8 group, a -(CH 2 ) 0 - 3 NH-(CH 2 ) 2-4 NR 7 R8 group, a -C(0)-0-(linear or branched C C 4
  • R 8 group a -(CH 2 ) 0-3 -(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a - (CH 2 ) 0 - 3 -(phenyl) group or a -(CH 2 )o- 3 -0-(CH 2 ) 0 .
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C -C 4 alkyl group or a -(CH 2 )o- 3 -0-(CH 2 ) 2 - 4 -NR 7 R 8 group;
  • R 2 represents a hydrogen atom or a linear or branched C1-C4 alkyl group
  • R 3 represents a hydrogen atom or a linear or branched C ! -C 4 alkyl group
  • R 4 represents a hydrogen atom, a linear or branched C ! -C alkyl group, or a -(CH 2 ) 0-3 - (phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C alkyl group;
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CTC 4 alkyl group, a C C haloalkyi group, or a linear or branched C C 4 hydroxyalkyl group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched C C 4 alkyl group, a C 3 -C 7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched CrC alkyl group, a C C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group or a CVC 4 alkoxy group;
  • R 5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
  • Z represents a nitrogen atom or a -CH group
  • R g, Rn , R 13, R 14 and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C C 4 alkyl group;
  • R 10 and R 12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
  • phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched CVC 4 alkyl group, a C C 4 haloalkyl group, or a linear or branched CVC hydroxyalkyl group;
  • L represents a direct bond or a linker selected from -O-(CH 2 ) 0 - 3 -, -S- (CH 2 )o-3- a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH 2 )i- 4 group.
  • W represents a direct bond or a linker selected from a-O-(CH 2 ) 0- 3- group, a -(CH 2 ) 1-4 - group, a -(CH 2 ) 0 - 3 -NR a -(CH 2 )o-3- group, a -0-(CH 2 ) 2 . 4 -N(*)R a group, a -(CH 2 ) 0 - 3 -N(*)- (CH 2 ) 2 -4-N(R a )R b group or a -(CH 2 )o.
  • R a and R b each independently represents hydrogen, a linear or branched CVC 4 alkyl group or a -(CH 2 ) 0 . 3 -0-(linear or branched C ⁇ C 4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R ⁇
  • R c represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • X represents a -CR 6 group
  • Ri represents a linear or branched C C 6 alkyl group, a linear or branched C ⁇ C 6 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a phenyl group, a pyridyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group;
  • tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C,-C 4 alkyl group, a C ⁇ -C 4 haloalkyl group, a linear or branched C C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a - (CH 2 )o- 3 -0-(linear or branched d-C 4 alkyl) group, a -(CH2)o-3-0-(CH 2 )2- 4 -NR 7 R 8 group, a -(CH 2 ) 0 - 3 NR 7 R 8 group, a -(CH 2 )o- 3 NH-(CH 2 ) 2 .
  • NR 7 R8 group a -C(0)-0- (linear or branched C C 4 alkyl) group, a -C(0)-(CH 2 )o-3-NR 7 R8 group, a -C(O)- (CH 2 )o-3-NR 7 -(CH 2 )2- 4 -NR 7 R8 group, a -NR 7 -S(O) 2 (CH 2 ) 0 -3R8 group, a - S(0) 2 (CH 2 )o- 3 R 8 group, a -(CH 2 ) 0 -3-(pyrrolidinyl) group, a -(CH 2 )o- 3 -(phenyl) group or a -(CH 2 )o.3-0-(CH 2 )o-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C 4 alkyl group or
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom, a linear or branched C C alkyl group, or a -(CH 2 ) 0 . 3 - (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups;
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched ( C 3 alkyl group;
  • R 7 and R 8 each independently represent a hydrogen atom, a linear or branched Ci alkyl group, a C 3 -C 4 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C ⁇ -C A alkoxy groups;
  • R 5 represents a moiety of formula (11-1 ), (H-5) or (II-7)
  • R 9 Rn R 3 R and R 15 each independently represent a hydrogen atom, a cyano group, a -NH 2 group, or a linear or branched C 1 -C3 alkyl group;
  • R 10 and R 12 each independently represent a phenyl group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C 3 alkyl group;
  • Particular individual compounds of the invention include:
  • particular individual compounds of the invention include:
  • the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
  • Phosphoinositide 3-Kinases in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders and pain; cardiovascular diseases; viral infection;
  • RA rheumatoid artritis
  • MS multiple sclerosis
  • amyotrophic lateral sclerosis Crohn's disease
  • ulcerative colitis systemic lupus erythematosis
  • autoimmune hemolytic anemia type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK).
  • COPD chronic obstructive pulmonary disease
  • COPD cystic fibrosis
  • CF cystic fibrosis
  • sarcoidosis atopic dermatitis
  • allergic rhinitis contact dermatitis
  • the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
  • PI3Ks Phosphoinositide 3-Kinases
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above, which comprises administering to said subject a therapeutically effective amount of a compound of the invention as described herein.
  • PI3Ks Phosphoinositide 3-Kinases
  • therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic
  • amino-protecting group refers to a protecting group suitable for preventing undesired reactions at amino nitrogen.
  • Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1 ,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert- butyldimethylsilyl (TBS); and the like.
  • TMS trimethylsilyl
  • SEM 2-(trimethylsilyl)
  • hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at a hydroxy group.
  • Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups for example alkanoyl groups, such as acetyl
  • arylmethyl groups such as benzyl (Bn), p-
  • Compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1 , from compounds of Formula (IV).
  • compounds of Formula (IV) can be converted in compounds of Formula (III) by treatment of compounds of Formula (IV) with an appropriate reagent such as phosphorus oxychloride or phosphorus pentachloride or thionyl chloride or mixtures of them at temperatures ranging from room temperature to reflux with or without the presence of an appropriate solvent such as methylene chloride.
  • compounds of Formula (III) can be treated with the corresponding boronic acids or boronic esters in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions, which are widely described in the literature.
  • a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions, which are widely described in the literature.
  • they can be prepared by reaction of compounds of Formula (III) with the corresponding organotin derivatives, in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Stille coupling conditions.
  • W represents a linker selected from -O-(CH 2 ) 0 . 3 -, -S- (CH 2 ) M -, -NR a -(CH 2 ) 0 .
  • compounds of Formula (III) can be treated with the corresponding R ⁇ WH group in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as tert-butanol, /V,/V-dimethylformamide, tetrahydrofurane or acetone at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
  • a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride
  • an appropriate solvent such as tert-butanol, /V,/V-dimethylformamide, tetrahydrofurane or acetone at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
  • compounds of Formula (IV) can be obtained from compounds of Formula (V) where is an -NH 2 group by treatment with compounds of Formula (11-1 ) (II-2) (II-3) (II-4) (II-5) (II-6) as shown in Scheme 2, in the presence of a suitable base such as potassium carbonate or diisopropylethylamine in an appropriate solvent such as tert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation and with or without the use of a suitable catalyst such as caesium fluoride.
  • a suitable base such as potassium carbonate or diisopropylethylamine
  • an appropriate solvent such as tert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane
  • compounds of general Formula (IV) may be prepared from compounds of Formula (V), where the group represents a halogen atom such as chlorine, bromine and iodine or another suitable leaving group such as methanesulfonate or trifluoromethanesulfonate or other groups such as hydroxyl, that can be converted to suitable leaving groups by standard methods described in the literature, such as the Mitsunobu reaction and others, by treatment of compounds of Formula (V) with compounds of Formula (11-7) using the same conditions described above.
  • halogen atom such as chlorine, bromine and iodine
  • another suitable leaving group such as methanesulfonate or trifluoromethanesulfonate or other groups such as hydroxyl
  • halogen atom such as chlorine
  • it can be converted to another more reactive halogen atom such as iodine by treating the compound with the chlorine atom with sodium iodide in acetone at a temperature from room temperature to reflux.
  • Compounds of Formula (II) can either be commercial or prepared by synthetic methods well described in the literature.
  • Scheme 2 compounds of Formula (IV) can be obtained in a two steps synthesis as shown in Scheme 3, by treatment of compounds of Formula (V) with compounds of Formula (VII-1 ) (VII-2) (VII-3) in the presence of a suitable base such as potassium carbonate or diisopropylethylamine in an appropriate solvent such as terf-butanol, N,N- dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation and with or without the use of a suitable catalyst such as caesium fluoride.
  • a suitable base such as potassium carbonate or diisopropylethylamine
  • an appropriate solvent such as terf-butanol, N,N- dimethylformamide or tetrahydrofurane
  • compounds of Formula (IV) can be prepared from compounds of Formula (VI-1 ) (VI-2) (VI-3) where Z 3 represents a halogen atom by reaction with the corresponding boronic acids or boronic esters in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions.
  • a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions.
  • compounds of general Formula (IV) where R 5 represents a moiety of formula (11-1 ), (II-2) or (M-4), wherein L represents a linker selected from -O- (CH 2 )o-3- or -S-(CH 2 )o-3- compounds can be obtained from compounds of Formula (VI- 1 ) (VI-2) (VI-3) by reacting with the corresponding thiols or alcohols of formula HL-R 10 or HL-R 12 by using copper or palladium catalysed coupling methods or any other method well known for those skilled in the art.
  • Boronic acids or esters, thiols and alcohols can be commercial or prepared by standard methods and can be used in a protected form to prevent certain functional groups from undergoing undesired reactions. In these cases, standard methods for the removal of these protecting groups can be used at the most suitable step of the synthesis.
  • compounds of Formula (IV) can be prepared from compounds of Formula (VI-1 ) (VI-2) (VI-3), where Z 3 represents a carboxylic acid, by preparing the corresponding amide or ester by treatment of the carboxylic acid with an activating agent by methods and conditions well described in the literature, for example using T 3 P ® , EDC or HATU as an activating agent in a solvent such as dimethylformamide, tetrahydrofurane, ethyl acetate or dichloromethane at temperatures ranging from room temperature to 80 °C
  • Compounds of Formula (IX) can be transformed in amides of Formula (VIII) by treatment of compounds with Formula (IX) with the appropriate acid chlorides of Formula (X) in a solvent such as acetic acid, toluene, xylene, dioxane or methylene chloride at a temperature ranging from room temperature to 50 °C in the presence or not of a suitable base such as triethylamine or pyridine.
  • a solvent such as acetic acid, toluene, xylene, dioxane or methylene chloride
  • compounds of Formula (IX) can be transformed in amides of Formula (VIII) by treatment with carboxylic acids of Formula (XI) in the presence of an activating agent by methods and conditions well described in the literature, for example using T3P ® , EDC or HATU as an activating agent in a solvent such as dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
  • an activating agent for example using T3P ® , EDC or HATU as an activating agent in a solvent such as dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
  • Compounds of Formula (VIII) where Z 2 is a -NH 2 group or a protected amino group, such as -NHBz(OMe) or -NHBz(OMe) 2 groups can be transformed in compounds of Formula (V) by treatment with acetic acid at a temperature ranging from room temperature to 150 °C or by treatment with pyridinium p-toluenesulfonate in an appropriate solvent such as toluene or xylene at a temperature ranging from room temperature to 150 °C.
  • Deprotection of benzyl groups can be performed at this or at another convenient step of the synthesis by standard methods well described in the literature, such as Pd- catalysed hydrogenolysis or acid-promoted debenzylation with trifluoroacetic acid.
  • Compounds of Formula (VIII) where Z 2 is a -O-alkyl group can be transformed in compounds of Formula (V) by treatment of compounds of Formula (VIII) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with a subsequent treatment with concentrated ammonium hydroxide or a solution of ammonia in an organic solvent such as methanol or dioxane at a temperature ranging from room temperature to 150 °
  • the amination reaction can be carried out in a biphasic system using an aqueous solution of ammonia, sodium hydroxide, ammonium chloride and sodium hypochlorite and a suitable organic solvent such as dialkyi ethers and adding a phase transfer catalyst such as Aliquat 336 ® at temperatures ranging from 0 °C to room temperature.
  • a phase transfer catalyst such as Aliquat 336 ® at temperatures ranging from 0 °C to room temperature.
  • Compounds of general Formula (XII) can either be commercial or can be prepared by known synthetic routes described elsewhere in the literature and will be apparent to those versed in the art.
  • compounds of Formula (lb) can be prepared, as illustrated in Scheme 6, from compounds of Formula (lc) by Suzuki or Stille coupling with the corresponding boronic acids or organotin compound in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate with or without an appropriate base such as potassium carbonate or caesium carbonate and in a suitable solvent such as toluene or dioxane or /V,/V-dimethylformamide at temperatures ranging from 60°C to 150°C.
  • a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate
  • an appropriate base such as potassium carbonate or caesium carbonate
  • a suitable solvent such as toluene or dioxane or /V,/V-dimethylformamide at temperatures ranging from 60°C to 150°C.
  • the bromine atom of compound of Formula (lc) can be converted first into a iodine atom by treatment of (lc) with sodium iodide in the presence of a catalysts such as copper (I) iodide and a chelating amine such as frans-1 ,2-bis(methylamino)cyclohexane in an appropriate solvent such as 1 ,4-dioxane at a temperature ranging from 60°C to reflux.
  • a catalysts such as copper (I) iodide and a chelating amine such as frans-1 ,2-bis(methylamino)cyclohexane
  • an appropriate solvent such as 1 ,4-dioxane
  • the bromine atom of compound of Formula (lc) can be converted first into a iodine with the methods previously described or treated directly with dicyanozinc in the presence of a palladium catalyst such as tetrakis(triphenylphoshane) palladium (0) in an appropriate solvent such as ⁇ , ⁇ '- dimethylformamide at a temperature ranging from 60°C to 150°C or by using copper cyanide in a solvent such pyridine at temperatures ranging from 60°C to 150°C.
  • a palladium catalyst such as tetrakis(triphenylphoshane) palladium (0)
  • an appropriate solvent such as ⁇ , ⁇ '- dimethylformamide
  • solvent such as a solvent such pyridine
  • Concentration or evaporation refers to evaporation under vacuum using a BCichi rotatory evaporator.
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 prn) with the solvent system indicated. Purifications in reverse phase were made in a Biotage SP1 ® automated purification system equipped with a C 18 column and using a gradient of water-acetonitrile/MeOH (1 : 1) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 : 1 ) in 40 column volumes. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or lyophilized.
  • Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep C 18 (19 x 300 mm, 7 pm) column or an XBridge Prep C 18 (19 x 100 mm, 5 pm) column.
  • the mobile phase was formic acid (0.4 ml_), ammonia (0.1 ml_), methanol (500 ml_) and acetonitrile (500 ml_) (B) and formic acid (0.5 ml_), ammonia (0.125 ml.) and water (1000 ml_) (A), the specific gradients used are specified in each particular case.
  • the flow rate was 20 mL/min.
  • the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A) and a gradient between 0 to 95% of B was used.
  • HPLC Waters Symmetry (2.1x50mm, 3.5 Dm);
  • UPLC ACQUITY UPLC BEH C-18 (2.1x50mm, 1.7 Dm)
  • the resulting solution was stirred at room temperature for 2 h and the volatiles were removed under reduced pressure.
  • the residue was suspended in 250 ml of concentrated aqueous ammonia and the resulting suspension was stirred at 100 °C in a sealed reactor overnight. Once the mixture reached room temperature, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and AcOEt. The organic layers were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure.
  • the title compound was prepared following the experimental procedure described in Preparation 6b1 , from 2.53 g (16.41 mmol) of methyl 1-amino-3-methyl-1H-pyrrole-2- carboxylate.
  • the crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to yield 4.98 g (93% yield) of the title compound as a white solid.
  • the product was then extracted twice methylene chloride, and the combined organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated.
  • the crude product was purified by flash chromatography (40% to 100% hexane/AcOEt) to obtain 210 mg (43% yield) of the title product as a pale yellow solid.
  • the crude product was purified by reverse phase chromatography (C- 18 silica from Waters ® , water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 135 mg (61 % yield) of the title product as a white solid.
  • the crude product was purified by reverse phase chromatography (C-18 silica from Waters ® , water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 89 mg (32% yield) of the title product as a white solid.
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