WO2014060431A1 - Pyrrolotriazinone derivatives as pi3k inhibitors - Google Patents

Pyrrolotriazinone derivatives as pi3k inhibitors Download PDF

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WO2014060431A1
WO2014060431A1 PCT/EP2013/071550 EP2013071550W WO2014060431A1 WO 2014060431 A1 WO2014060431 A1 WO 2014060431A1 EP 2013071550 W EP2013071550 W EP 2013071550W WO 2014060431 A1 WO2014060431 A1 WO 2014060431A1
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phenyl
methyl
branched
linear
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French (fr)
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Jordi Gracia Ferrer
Marta Carrascal Riera
Montserrat Erra Sola
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Almirall, S.A.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

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, p1 10b, p1 10d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits.
  • p1 10a PI3Ka or PI3Ka
  • p1 10b PI3Kb or ⁇ 3 ⁇
  • p110g PI3Kg or ⁇ 3 ⁇
  • p1 10d 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 p1 10d 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. Pharmacol 161 , 2010).
  • 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,
  • novel pyrrolotriazinone 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
  • 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
  • n 0, 1 , 2 or 3;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
  • Ri represents a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N,
  • cycloalkyl, cycloalkenyl, aryl, 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 C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -(CH 2 )i -3 CN group, a -(CH 2 ) 0 -3OR 9 group, a -(CH 2 )o-3N R 9 Rio group, a -C(0)-(CH 2 )i-3-CN group, a -C(O)-(CH 2 ) 0 .3-R 9 group, a -C(0)-(CH 2 )o- 3 -N R 9 R 10 group, a - -
  • R 9 group a -S(0)(CH 2 )o- 3 R9 group, a -S(O)(CH 2 ) 0 .3N R 9 R 10 group, a -S(O) 2 (CH 2 ) 0 - 3 R 9 group, a -S(O) 2 (CH 2 ) 0 - 3 N R 9 R 10 group or
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl 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 C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 -3-(C 3 -C4 cycloalkyl) group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o- 3 -S-(CH 2 )o- 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -S- (CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 ) 0 -3-0-(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 -O- (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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 Rio group, a -(CH 2 )o-3-0(CrC 4 alkyl) group, a -(CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH 2 ) 0- 3-(phenyl) group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0-3 - S(O) 2 (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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a
  • R 6 and R 7 each independently represent a hydrogen atom, a -(CH 2 ) 0-3 CN group, a - C(0)-(CH 2 )i. 3 -CN group, a -C(O)-(CH 2 ) 0 - 3 -R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 ) 0 .
  • R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyi) group or a linear or branched Ci- C 4 alkyi group;
  • R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N
  • a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi group, a -(CH 2 ) 1-3 NR a R b 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyi group, a CrC 4 alkoxy group or a C 3 -C 4 cycloalkyl group;
  • R 9 and Ri 0 each independently represent a hydrogen atom, a CrC 4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
  • R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -NH 2 group, a -N H(Ci-C 4 alkyi) group, a - N H-S(0) 2 -(CrC 4 alkyi) group
  • R- 12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 )i-4 group; wherein R
  • 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
  • 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 amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), 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; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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
  • 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.
  • 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; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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
  • C1-C6 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.
  • the 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.
  • the term C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, which is bonded to one or more, preferably 1 , 2 or 3 halogen atoms.
  • said haloakyl group is chosen from -CCI3, -CHF 2 and -CF 3 .
  • Ci-C 4 hydroxyalkyl 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.
  • C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • C3-C10 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 C3-C10 cycloalkyl 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.
  • substituents on a C3-C10 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 -Cio cycloalkenyl embraces partially unsaturated carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms.
  • a C 3 -Ci 0 cycloalkenyl 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 cycloalkenyl group are themselves unsubstituted.
  • C 6 -Ci 4 aryl radical embraces typically a C 6 -C-
  • a said optionally substituted Ce-C-u aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • a C6-C14 aryl radical When a C6-C14 aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a C6-C14 aryl group are typically themselves unsubstituted.
  • the term 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 6- 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 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-C14 carbocyclic ring system, preferably C 5 - do carbocyclic ring system, more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 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 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 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, tetrahydrothiopyrany
  • the bicyclic N-containing heteroaryl group is a C 8 -Ci 0 membered ring system where two rings have been fused and wherein at least in one ring one of the carbon atoms is replaced by N and optionally in which 1 , 2, 3, or 4, preferably 1 , 2, or 3 further carbon atoms of any ring which form the group are replaced by N.
  • Examples include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3- d]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolinyl, indazolyl, purinyl, indolinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1
  • 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.
  • the term halo when used as a prefix has the same meaning.
  • 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.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the 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).
  • 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.
  • the term 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.
  • Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methan
  • 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, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the
  • 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 1 1 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.
  • the term 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 PI3K 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 50 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 5 o) 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. Anal Biochem, 2003; 313: 234-45)
  • X represents N (a nitrogen atom) or CH.
  • X represents N.
  • R a and Rb each independently represent a hydrogen atom, a Ci-C 4 haloalkyl group, a Ci-C 4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group.
  • R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group. More preferably R a and Rb each independently represent a hydrogen atom, a methyl group or an ethyl group.
  • Ri represents a C3-C10 cycloalkyl group, a C 3 - C10 cycloalkenyl group, a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, cycloalkenyl, aryl, 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 C1-
  • Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group;
  • cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a CrC 4 haloalkyl group, a Ci-C 4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -S(CH 2 ) 0 - 3 R 9 group, a -S(O)(CH 2 ) 0-3 R9 group, a -S(0)(CH 2 )o-3N R 9 Rio group, a -S(0) 2 (CH 2 )o-3R9 group, a -S(0) 2 (CH 2 )o-3N R 9 Rio group or
  • Ri represents a phenyl group
  • said phenyl group is directly bonded to the pyrrolotriazinone group.
  • the linker -(R a -C-Rb) n - is not present.
  • R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a Ci-C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a C C 4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group.
  • R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C C 4 alkyl group. More preferably R 2 represents a hydrogen atom.
  • R 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl 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 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C1-C4 alkyl group. More preferably
  • R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a - (CH 2 )o-3-(C3-C 4 cycloalkyl) group, a -(CH 2 )o- 3 -0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 - 3 -S-(CH 2 ) 0 _ 3 -(phenyl) group, a -(CH 2 )o- 3 -S-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3- (phenyl) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3
  • R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a - (CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 - 3 -S- (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3-(phenyl) group, or 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) group; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituenta
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 R 10 group, a -(CH 2 ) 0 - 3 -O(Cr C 4 alkyl) group, a -(CH 2 ) 0 - 3 -(C 3 -C4 cycloalkyl) group, a C 2 -C 4 alkynyl group, a -(CH 2 ) 0 .
  • R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH 2 )o-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C 1 -C4 alkyl group
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a C 2 -C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 )o-3-S(0) 2 (CH 2 )o-3-(phenyl) group, a -(CH 2 )o.3-S(0) 2 (CH 2 )o -3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o
  • R 6 represents a hydrogen atom, a -(CH 2 )o-3CN group, a -C(0)-(CH 2 )i. 3 -CN group, a -C(0)-(CH 2 )o-3-R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 )o- 3 NR'R” group, or a linear or branched C 1 -C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a -(CH 2 ) 0 -3-O(Ci-C 4 alkyl) group or a linear or branched C 1 -C4 alkyl group.
  • R 6 represents a hydrogen atom, a -C(0)-(CH 2 )o-3-(CrC 4 alkyl) group, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C 1 -C4 alkyl group. More preferably R 6 represents a hydrogen atom or a -NH 2 group.
  • R 7 represents a hydrogen atom, a -(CH 2 ) 0 .3CN group, a -C(0)-(CH 2 )i -3 -CN group, a -C(O)-(CH 2 ) 0 - 3 -R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 )o- 3 NR'R” group, or a linear or branched C 1 -C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a -(CH 2 ) 0 - 3 -O(Ci-C 4 alkyl) group or a linear or branched C 1 -C4 alkyl group.
  • R 7 represents a hydrogen atom, a -C(0)-(CH 2 )o-3-(CrC 4 alkyl) group, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C 1 -C4 alkyl group. More preferably R 7 represents a hydrogen atom or a -NH 2 group.
  • R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a
  • 8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched CrC 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-0(Ci-C 4 haloalkyl) group, a -(CH 2 )o- 3-0-(CH 2 )i-3-0(Ci-C4 alkyl) group, a -(CH 2 ) 0 -3-O-(CH 2 )i
  • R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH 2 ) -3 N R a R b 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group.
  • R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group,
  • R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C 4 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, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group.
  • R 8 preferably represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a C 3 -C 7 cycloalkyl group, a -(CH 2 ) o-3NR' R" group, a - (CH2)o-3-C(0)-(CH 2 ) o-3-N R'R"group or a -(CH 2 ) o-3NR'-S(0) 2 R" group, wherein R
  • R 9 represents a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group or a linear or branched C C 4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group.
  • R 9 represents a hydrogen atom or a linear or branched C1-C4 alkyl group.
  • Rn represents a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH 2 group, a -NH(d-C 4 alkyl) group or a -NH-S(0) 2 -(Ci-C 4 alkyl) group group.
  • R 12 represents represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N.
  • Ri 2 represents a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, a pyrrazolyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a
  • L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(0)-N R'- group, a C(0)-0-R"'- group or a - (CH 2 )i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C1-C4 alkyl group.
  • L represents a direct bound or a linker selected from -0-, -S-, a -NH- group or a -(CH 2 )i-4 group.
  • R' and/or R" When R' and/or R" are attached to a nitrogen atom, preferably R' and/or R" do not represent a hydroxyl group or alkoxy group. Where any of the above moieties represent -(CH 2 )o-4-C(0)-(CH 2 )o-4- R' or -C(0)-(CH 2 )o- 3-R', it is preferable that R' does not represent a hydrogen atom if the alkylene spacer moiety is absent.
  • n 0, 1 , or 2;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
  • Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
  • R 9 and R-io each independently represent a hydrogen atom or a C1-C4 alkyl group;
  • R 2 and R 3 each independently represent
  • R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH 2 ) 0 . 3 -(C 3 - C 4 cycloalkyl) group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group, a -(CH 2 )o- 3 -S-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0 -3-O-(CH 2 ) 0 -3-(phenyl) group, or a -(CH 2 ) 0 -3-O-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
  • 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 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 ) 0 - 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 ) 0 -4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o ⁇ -R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group,
  • R 6 and R 7 each independently represent a hydrogen atom, a -N H 2 group, a -N(CH 3 )H group, a -N(CH 3 )2 group, or a linear or branched C1-C4 alkyl group;
  • Rs represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-0(CrC 4 haloalkyl) group, a -(CH 2 )o-3-0-(CH 2 )i-3-0(Ci-C4 alkyl) group, a -(CH 2 ) 0 - 3 -O- (CH 2 ) 1-3 -0(C 1 -C 4 haloalkyl) group, a -(CH 2 ) 0 -3-0-(CH 2 ) o- 3 Ri 2 group,
  • a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH 2 ) 1-3 NR a R b 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group;
  • R 9 and Ri 0 each independently represent a hydrogen atom or a linear or branched Cr C 4 alkyl group
  • Ri 2 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH 2 )i -4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched d- C 4 alkyl group.
  • n represents 0, 1 , or 2;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group
  • Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
  • R 9 and Ri 0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
  • R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a -(CH 2 ) 0 . 3 -(C 3 - C 4 cycloalkyl) group, a -(CH 2 ) 0 -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) group, a -(CH 2 ) 0 - 3 -O-(CH 2 ) 0 - 3 -(phenyl) group, or a -(CH 2 ) 0 - 3 -O-(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH
  • 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 -3-S(0) 2 (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a C C 4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o.
  • R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 - 3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH 2 ) 0 - 3 -(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are
  • R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C1-C4 alkyl group;
  • R 8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 - 3 -O(Ci-C 4 haloalkyl) group, a -(CH 2 )o- 3 -0-(CH 2 )i.3-0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 .
  • a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C 4 alkyl group, a -(CH 2 )i -3 NR a Rb 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 Ci-C 4 hydroxyalkyl group, a Ci-C 4 haloalkyl group, a Ci-C 4 alkoxy group or a C 3 -C 4 cycloalkyl group;
  • R g and Ri 0 each independently represent a hydrogen atom or a linear or branched Cr C 4 alkyl group
  • R 12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
  • L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 ) 1-4 group; wherein R' represents hydrogen or a linear or branched Ci-C alkyl group, and R'" represents a linear or branched C C 4 alkyl group.
  • n is 0 or 1 ;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom or C 1 -C4 alkyl group;
  • Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 ,1 -dioxide group,
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched Ci-C 3 alkyl group, a C 1 -C3 alkoxy group, a -S(Ci-C 4 alkyl) group, a -
  • R 2 and R 3 each independently represent a hydrogen atom or a linear or branched C 1 -C4 alkyl group
  • R 4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group
  • R 5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-S(0) 2 -(CH 2 )o-3-(phenyl) group or a -(CH 2 ) 0 -3-S-(CH 2 )o -3 -(phenyl) group;
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C 1 -C4 alkyl group;
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH 2 )o-4-C(0)-N(H)-(CH 2 )o-4-(morpholinyl) group, a
  • R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, or a linear or branched C 1 -C4 alkyl group;
  • R 8 represents 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 C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a -(CH 2 ) 0 .
  • n 0, 1 , 2 or 3;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
  • Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, or a 5- to 10- membered heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N;
  • cycloalkyl, phenyl, heteroaryl or heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -
  • R 2 and R 3 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C3 alkoxy group, a linear or branched C1-C4 alkyl group, a C1-C3 haloalkyi group, a C 3 -C 4 cycloalkyl group or a -NH 2 group;
  • R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-(C 3 -C4 cycloalkyl) group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-S-(CH 2 )o- 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -S-
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 Rio group, a -(CH 2 )o-3-0(CrC 4 alkyl) group, a -(CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH 2 ) 0- 3-(phenyl) group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0 - 3 - S(O) 2 (CH 2 ) 0 - 3 -Rn group,
  • 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 -3- 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a
  • R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N ,
  • aryl , heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 alkyi group, a C C 4 haloalkyl group, a C1-C4 hydroxyalkyi group, a -(CH 2 )o-3-0(C C 4 alkyi) group, a C 3 -C 7 cycloalkyl group, a -(CH 2 ) o- 3 NR'R" group, a -(CH 2 ) 0 - 3 -C(O)-(CH 2 ) 0 -3-NR'R"group, a -((CH
  • R 9 and Ri 0 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group;
  • R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH 2 group, a -N H(CrC 4 alkyi) group or a - NH-S(0) 2 -(Ci-C 4 alkyi) group;
  • L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 )i -4 group; wherein R' represents hydrogen or a linear or branched CrC 4 alkyi group, and R'" represents a linear or branched d- C 4 alkyi group.
  • R' represents hydrogen or a linear or branched CrC 4 alkyi group
  • R'" represents a linear or branched d- C 4 alkyi group.
  • n 0, 1 , or 2;
  • X represents N or CH;
  • R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
  • Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
  • R 9 and R b each independently represent a hydrogen atom or a C1-C4 alkyl group;
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
  • R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a -(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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(CH 2 )o-3-(phenyl) group, a -(CH 2 )o- 3 -S(0) 2 (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o.4-R" group, a -(CH 2 ) 0 -4-C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group,
  • R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C1-C4 alkyl group;
  • Rs represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH 2 ) o- 3 NR'R" group, a -(CH 2 )o-3-C(0)-(CH 2 ) o-3-NR'R”group or a - (CH 2 ) o- 3 NR'-S(0) 2 R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group or a
  • L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH 2 ) 1-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C C 4 alkyl group;
  • n is O or l ;
  • X represents N or CH ;
  • R a and R b each independently represent a hydrogen atom or C1-C4 alkyl group
  • Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 , 1 -dioxide group,
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a -S(d-C 4 alkyl) group, a -S(0)(C C 4 alkyl) group, or a -S(0) 2 (d-C 4 alkyl) group;
  • R 2 and Rs each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group
  • R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group
  • R 5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-S(0)2-(CH 2 )o-3-(phenyl) group or a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group;
  • phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C 1 -C4 alkyl group;
  • alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH 2 ) 0 -4-C(O)-N(H)-(CH 2 ) 0 -4-(morpholinyl) group, a -(CH 2 ) 0- 4-C(0)-N-[(CH 2 )o -3 -0(Ci-C4 alkyl)] 2 group or a -(CH 2 ) 0- 4-C(O)-(CH 2 ) 0- 4-
  • R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, or a linear or branched C C 4 alkyl group;
  • R 8 represents 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 C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a -(CH 2 ) 0 - 3 -O(Ci-
  • C 4 alkyl) group a -(CH 2 ) 0 - 3 NH 2 group or a -(CH 2 ) 0 . 3 NR'-S(O) 2 (Ci-C 4 alkyl) group, wherein R' represents a hydrogen atom or a linear or branched C-i-C 4 alkyl group; L represents a direct bound or -S-.
  • 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 amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), 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; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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
  • 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
  • the term 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 alkanoyi 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) and tert-butyldimethylsilyl (TBS); and the like.
  • 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 alkanoyi 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 alkanoyi 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 (III), where the group Zi 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.
  • Compounds of Formula (I) can be obtained directly from compounds of Formula (I I I) or in a two steps synthesis, by treatment of (I II) with compounds of Formula (I I) or compounds of Formula (IV) in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as fert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane 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 fert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
  • ⁇ is a 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.
  • synthesis compounds of Formula (V) can be converted to compounds of Formula (I) by reacting with the corresponding boronic acid using standard Suzuki coupling conditions.
  • compounds of general Formula (I) where the group L represents a NH , O or S can be obtained from compounds of Formula (V), by reacting with the corresponding aniline or thiophenol or phenol by using copper or palladium catalysed coupling methods well known in the art.
  • Boronic acids, anilines, thiophenols or phenols 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 suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the compounds of Formula (I II) can also be prepared by treating the compounds of Formula (VI I) with 2-chloro-1 ,1 , 1 -trimethoxyethane in the presence of pyridinium p-toluenesulfonate at a temperature between 50 °C and 150 °C.
  • Compounds of Formula (VI I) can be transformed in amides of Formula (VI) by treatment with carboxylic acids of Formula (IX) in the presence of an activating agent by methods and conditions well described in the literature, for example using T3P®, EDC.HCI or HATU as an activating agent in a solvent such as ,/V-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.HCI or HATU as an activating agent in a solvent such as ,/V-dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
  • amides of Formula (VI) can be obtained from compounds of Formula (VII) by treatment with acid chlorides of Formula (VIII) at room temperature in a suitable solvent such as acetic acid or 1 ,4-dioxane or alternatively in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane.
  • a suitable solvent such as acetic acid or 1 ,4-dioxane
  • a base such as triethylamine in a suitable solvent such as dichloromethane.
  • compounds of Formula (VI) can yield compounds of Formula (III) by treatment with phosphorous oxychloride at temperatures ranging from room
  • compounds of Formula (VI) can yield compounds of Formula (III) by treatment of compounds of Formula (VI) 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 or without a subsequent treatment with a base such as ammonia, pirrolidine, piperidine or potassium carbonate or a nucleophile such us sodium methanethiolate in a solvent such as methanol, ethyl acetate or N,N- dimethylformamide at a temperature between room temperature and 100 °C.
  • a base such as triethylamine
  • Carboxylic acids (XII) can be activated with any activating reagent described in the literature such as thionyl chloride, oxalyl chloride, phosphorous oxychloride, 2-(3H- [1 ,2,3]triazolo[4,5-6]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium
  • a base such as diisopropylethylamine
  • a suitable solvent such as dioxane, dichloromethane, /V,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from 0 °C to reflux to give amides of Formula (X).
  • amides of Formula (X) can be aminated on the nitrogen atom in position 1 by any of the aminating reagents described in the literature, such as O- (mesitylenesulfonyl)hydroxylamine, 0-(p-nitrobenzoyl)-hydroxylamine, 0-(diphenyl- phosphinyl)-hydroxylamine, 0-(2,4-dinitrophenyl)-hydroxylamine, hydroxylamine-O- sulfonic acid using a suitable base such as triethylamine, potassium carbonate, sodium hydride or butyl lithium in an appropriate solvent such as ⁇ /, ⁇ '-dimethylformamide, tetrahydrofurane, 1 ,4-dioxane at temperatures ranging from -78 to 100 °C.
  • 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 dialkyl 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 (XII) can either be commercially available compounds or can be prepared by the synthetic scheme illustrated in Schemes 4.
  • R 5 represents a C 3 -C 7 cycloalkyl group, or a linear or branched Ci-C 4 alkyl group
  • compounds (Xlla) can be prepared, as illustrated in Scheme 4, from bromopyrrol of Formula (XIV) 2 by Suzuki coupling with the corresponding alkyl or cycloalkylboronic acids in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) and appropriate base such as potassium carbonate and in a suitable solvent such as toluene at a temperature ranging from 60°C to 150°C.
  • a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O)
  • appropriate base such as potassium carbonate
  • Compounds of Formula (Xlla) can be obtained by simultaneous cleavage of the sulphone and ester groups of compounds of Formula (XIII) by means of a base such as lithium hydroxide in a suitable solvent or mixture of solvents such as water or tetrahydrofurane at temperatures ranging from room temperature to 220 °C, with or without the use of microwaves irradiation.
  • a base such as lithium hydroxide
  • suitable solvent or mixture of solvents such as water or tetrahydrofurane
  • the cleavage of the sulphone and ester groups of compounds of Formula (XIII) can be done sequentially by treatment of compounds (XII I) with tetrabutylammonium fluoride in an appropriate solvent such as
  • compounds (Xa) can be prepared, as illustrated in Scheme 5, from pyrrols of Formula (XVI). Pyrrols of Formula (XVI) can be reacted with 2,2,2-trichloroacetyl chloride in a suitable solvent such as diethyl ether at a temperature ranging from room temperature to reflux affording ketones of Formula (XV). These intermediate compounds of Formula (XV) can be reacted with the corresponding amines of Formula (XI) with or without solvent in the presence of a base such as triethylamine at a temperature ranging from room te
  • compounds of general Formula (VI) may be prepared by the synthetic route illustrated in Scheme 6.
  • compounds of Formula (VI) can be prepared from compounds of Formula (XVI I) by known amide formation methods such as those described above.
  • Compounds of Formula (XVII) can be prepared by the known coupling methods previously described.
  • Compounds of Formula (XVI II) can be obtained by amination of compounds of Formula (XIX) by the methods already described.
  • compounds of general Formula (1Mb) can also be synthesized from compounds of Formula (Ilia) as shown in Scheme 7 by the general methods described as it follows.
  • the bromine atom of compound of Formula (Ilia) has to be converted first into a iodine atom by treatment of (Ilia) 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
  • R 5 is a alkyl or cycloalkyl group
  • an aromatic or heteroaromatic ring compounds of Formula (III) can be obtained by standard Suzuki or Stille couplings with the corresponding boronic acid 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 cesium carbonate and in a suitable solvent such as toluene or dioxane or N,N- dimethylformamide at temperatures ranging from 60°C to 150°C.
  • a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate with or without an appropriate base such as potassium carbonate or cesium carbonate
  • a suitable solvent such as toluene or dioxane or N,N- dimethylformamide at temperatures ranging from 60°C to 150°C.
  • compound of Formula (Ilia) can be treated with a lithiating agent such as n-BuLi, in a non protic solvent such as hexanes and at a temperature between -78°C and 0°C and subsequently treated with a suitable fluorine source such as /V-fluoro-/V-(phenylsulfonyl)-benzenesulfonamide at a temperature between -78°C and room temperature.
  • a lithiating agent such as n-BuLi
  • a non protic solvent such as hexanes
  • compounds of Formula (1Mb) where R 5 is hydrogen can alternatively be obtained by hydrogenolysis of compounds of Formula (Ilia) using an appropriate catalyst such as 10% palladium on charcoal in a suitable solvent such as an alkyl alcohol under a hydrogen atmosphere at pressures ranging from atmospheric pressure to 60 psi and at temperatures ranging from room
  • compounds of Formula (Ilia) can be converted first into a iodine following the general methods previously described.
  • the iodine intermediate can then react with the corresponding thiophenol in the presence of copper (I) iodide and a base such as potassium carbonate in solvent such as DMF and at temperatures ranging from room temperature to 150°C.
  • compounds of Formula (lllb) can be obtained by reacting with the corresponding alkyne derivative in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(ll) chloride and copper (I) iodide in a suitable solvent such as diethylamine at temperatures ranging from room temperature to 100°C.
  • a palladium catalyst such as bis(triphenylphosphine)palladium(ll) chloride and copper (I) iodide
  • a suitable solvent such as diethylamine
  • compounds of general Formula (I) can also be synthesized from compounds of Formula (la) or (lb) as shown in Scheme 8 by the same general methods previously described.
  • Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Concentration or evaporation refers to evaporation under vacuum using a BGchi rotatory evaporator. Reaction products were purified, when necessary, by flash or reverse phase chromatography in a Biotage SP1 ® or Isolera ® automatic purification systems.
  • 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.
  • the HPLC chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
  • the mobile phases were (B): formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) and (A): formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the gradients are specified in the following table for each method used.
  • the flow rate was 0.8 mL/min for method A and 0.4 mL/min for method B, C and D.
  • the injection volume was 5 microliter.
  • a Waters 2996 diode array was used as a UV detector.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the HPLC.
  • the UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
  • the system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50mm, 1 .7 ⁇ ) 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).
  • a gradient between 0 to 95% of B was used.
  • the run time was 3 or 5 minutes
  • the injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
  • 2,2,2-Trichloroacetyl chloride (5 mL, 45.27 mmol) was dissolved in 30 mL diethyl ether. 3-Methyl-1 H-pyrrole (3.1 g, 38.10 mmol) dissolved in 12 mL diethyl ether was added dropwise over 1 h and the reaction mixture was then heated at 45°C for 2 h. The mixture was diluted in diethyl ether and washed with water and brine. The organics were dried over sodium sulphate, filtered and evaporated. The residue was purified using SP1 Purification System (hexane-dichloromethane, 0% to 30%) to give 1.31 g (15 % yield) of the title compound. Purity 100%.
  • o-Toluidine (730 ⁇ , 6.84 mmol) and triethylamine (960 ⁇ , 6.89 mmol) were added to 2,2,2-trichloro-1 -(3-methyl-1 H-pyrrol-2-yl)ethanone (1.26 g, 5.56 mmol) in a Schlenk vessel and the reaction mixture was submitted to three vacuum-argon cycles. The mixture was heated at 60°C for two days. The solvent was concentrated and the residue was re-dissolved in ethyl acetate. The organic phase was washed with water, sodium bicarbonate 4% and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure.
  • PREPARATION 8 2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 - yl)methyl)-5-bromo-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -/][1,2,4]triazin-4(3H)- one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-bromo-3-(3-
  • Methyl 3-Bromo-1 -(phenylsulfonyl)-1 H-pyrrole-2-carboxylate 2 (25 g, 0.07 mol) was treated with aniline (10 ml_, 0.1 1 mol) and trimethyl aluminium (2 M in toluene, 109 ml_, 0.22 mol) according to the method of Preparation 5a to give 29.80 g (88% yield) of the title compound as a colourless oil.
  • reaction vessel was sealed and the mixture was heated at 80°C overnight.
  • the reaction mixture was partitioned with ethyl acetate and it was washed with water and brine.
  • the organic layer was dried over sodium sulphate, filtered and evaporated to give 780 mg of the title compound used in the following step without further purification.
  • Methanesulfonyl chloride (49 ⁇ , 0.63 mmol) was added and the mixture was stirred for 1 h in the ice bath. The mixture was diluted in dichloromethane and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 195 mg of the title compound pure enough to follow the next step.
  • Triphenylphosphine (2.13 g, 8.12 mmols) was dissolved in 45 mL dichloromehtane. Bromine (420 ⁇ , 8.19 mmol) was added dropwise over 30 min and then triethylamine (4.35 mL, 31.38 mmol) and ethyl 1-(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2- carboxylate dissolved in 2 mL dichloromethane were added. The mixture was stirred at room temperature for 2 h. The solvent was concentrated and the residue was suspended in 1 15 mL toluene.
  • Tetrahydro-2H-thiopyran-4-amine (3.65 g, 31.14 mmol) was added and the reaction was stirred at 100°C for 48 h. The mixture was diluted with ethyl acetate and washed sequentially twice with 1 N hydrochloric acid and brine, dried over sodium sulphate, filtered and evaporated. The residue was purified using Isolera Purification System by reverse phase to give 1.05 g (53% yield) of the title product as a white solid.
  • the crude was cooled at room temperature and saturated sodium bicarbonate solution (750 mL), ethyl acetate (400 mL) and sodium tartrate (0.5M in water, 750 mL) were added.
  • the organics were washed with water and brine, dried over sodium sulphate , filtered and evaporated.
  • the residue was purified using SP1 Purification System (0% to 30%, hexane-ethyl acetate) to give 10.41 g (75% yield) of the desired compound as a white solid. Purity 99%.
  • the semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 720 mg (58% yield) of the final compound as a mixture of boronic acid and boronate. Yield 100%.
  • Triethylamine (55 ⁇ , 0.39 mmol) and palladium on carbon (10 %, 14 mg, 0.03 mmol) were added under nitrogen atmosphere.
  • the reaction was hydrogenated at 30 psi overnight. Under nitrogen conditions was filtered and evaporated.
  • the crude was re-dissolved in dichoromethane and washed with 1 N hydrochloric acid, water and brine. The residue was dried over sodium sulphate, filtered and evaporated to obtain 70 mg (95% yield) of the title compound. Purity 92%.
  • the semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 270 mg (78% yield) of the final compound as a mixture of boronic acid and boronate. Purity 77%.
  • Methyl 3-methyl-1 H-pyrrole-2-carboxylate (10 g, 0.07 mol) was dissolved in 200 mL methanol and a solution of sodium hydroxide (2N, 108 ml_, 0.22 mol) was added. The mixture was heated at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 2-3 with 2N hydrochloric acid. A white precipitate was formed and was filtered and washed with cool water. The solid was dried in the oven to give 6.97 g (77% yield) of the desired compound. Purity 100%.
  • Hex-5-ynoic acid 200 mg, 1 .78 mmol was dissolved in 10 mL dichoromethane.
  • N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (394 mg, 2.05 mmol) and 4- (dimethylamino)pyridine (1 1 mg, 0.09 mmol) were added and the mixture was cooled at 0°C.
  • 1 -lsopropylpiperazine (229 mg, 1 .78 mmol) dissolved in 1 mL dichloromethane was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed with 4% sodium bicarbonate solution.
  • N-(3-bromo-5-hydroxyphenyl)methanesulfonamide (0.87 g, 3.27 mmol, prepared as described at C.Cannizzaro et al. US7417055 B2 20080826) was treated with bis(pinacolato)diboron (1.25 g, 4.90 mmol), potassium acetate (0.96 g, 9.81 mmol) and bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.27 g, 0.33 mmol) according to the method described in Preparation 16. The crude was purified using SP1 Purification System (0%-100%, hexane- ethyl acetate) to give 390 mg (31% yield) to the title compound as a solid.
  • SP1 Purification System 0%-100%, hexane- ethyl acetate
  • indium(lll) chloride (2 mg, 0.02 mmol) was dissolved in 1 ml anhydrous tetrahydrofuran under nitrogen atmosphere. Titanium tetrachloride (5 ⁇ , 0.05 mmol) was added and the mixture was stirred at room temperature for 1 h.
  • 2,4,6-Trimethylboroxin (57 ⁇ , 0.41 mmol), sodium carbonate (2M, 246 ⁇ , 0.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.50 mmol) were added in a Schlenck vessel under argon conditions. The mixture was heated at 150°C for 30 min. The mixture was allowed to cool and was filtered through a plug of Celite, washing several times with dichloromethane. The combinated filtrates were concentrated under reduced pressure. The residue was directly purified by reverse phase using the Isolera Purification System (0% to 5%, dichloromethane-methanol) to give 9 mg (20% yield) as a solid. Purity 98%.

Abstract

New pyrrolotriazinone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

Description

PYRROLOTRIAZI NON E DERIVATIVES AS PI3 INHIBITORS
When cells are activated by extracellular stimuli, intracellular signalling cascades involving the regulation of second messengers are initiated that eventually produce a response of the cell to the stimuli. Phosphoinositide 3-Kinases (PI3Ks) 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). The resulting 3-phosphoinositides mediate correct localization and subsequent activation of a number of downstream effector proteins that bind to the lipids via specific lipid binding sequences such as the pleckstrin homology (PH) domain
(Vanhaesebroeck B, 2010, Nat Rev Mol Cell Biol 5:11381-6). The PI3K family is divided into 3 different classes (PI3K class I, class II, and class III), depending on substrate preference and structural features.
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, p1 10b, p1 10d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits. Whereas p1 10a (PI3Ka or PI3Ka) and p1 10b (PI3Kb or ΡΙ3Κβ) isoforms are expressed ubiquitously, p110g (PI3Kg or ΡΙ3Κγ) and especially p1 10d (PI3Kd or PI3K5) have a more restricted expression pattern and seem to play a major role in leukocytes (Kok K, Trends Biochem Science 34:115-127, 2009).
Both, PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli. Pharmacological inhibition or genetic deficiency in active p1 10d 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). In addition, 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. In vivo, 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).
In addition, 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).
In terms of neutrophil function, 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
transendothelial migration (Puri KD, Blood 103, 2004). Furthermore, 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). In addition, TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005).
In contrast to the dominant role of PI3Kd in lymphocyte activation, 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
The above mentioned findings suggest that selective 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, eczema, acne, chronic urticaria, blistering diseases including but not limited to bullous pemphigoid, scleroderma, dermatomyositis, etc.), cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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) as well as in bone marrow and organ transplant rejection; 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 cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)).
There is substantial experimental evidence supporting this view. In rodent models of allergic lung inflammation, genetic or pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition reduces cell influx, mucus production, cytokine production and airway hyperreactivity (Nashed et a. 2007, Eur J Immunol 37:416; Lee et al. 2006, FASEB J 20:455 & Lee KS et al. 2006, J Allergy Clin Immunol 1 18:403; Doukas J, JPET 2009;328:758; Par SJ, ERJ 2010). Moreover, LPS induced lung neutrophil infiltration is blocked by PI3Kd inhibition (Puri KD, Blood 2004;103:3448) and inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor (Doukas J, JPET 2009;328:758). Moreover, PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment associated with oxidative stress and chronic obstructive pulmonary disease (COPD). This notion is based on the findings that tobacco smoke induced inflammation remains responsive to treatment with budesonide, whereas wild type or PI3Kg deficient mice develop resistance to corticosteroid treatment (Marwick JA, JRCCM 179:542-548, 2009).
Similar results were obtained with a PI3Kd selective inhibitor (To Y, AJRCCM 182:897- 904, 2010). In addition, in vitro induction of corticosteroid resistance by oxidative stress is prevented by PI3Kd inhibition (To Y, AJRCCM 2010). In COPD patients, 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).
Furthermore, PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010). In a model of experimental autoimmune
encephalomyelitis, 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). In line with that, genetic deficiency or pharmacological inhibition of PI3Kd diminished joint erosion in a mouse model of inflammatory arthritis (Randis TM, Eur J Immunol 38, 2008).
Concerning metabolic diseases, 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. Pharmacol 161 , 2010).
There is also substantial experimental evidence supporting that genetic of
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. In this aspect, 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).
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, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, scleroderma, dermatomyositis and blistering diseases including but not limited to bullous pemphigoid), cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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) as well as in bone marrow and organ transplant rejection; 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 cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)).
In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of the PI3K pathway or modulation of the PI3 Kinases it is immediately apparent that new compounds that modulate PI3K pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients. Provided herein are novel pyrrolotriazinone 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 dermatitis, contact dermatitis, eczema, acne, chronic urticaria, scleroderma, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis and blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa), cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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) as well as in bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or mielofibrosis); 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 cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)).
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, 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));
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 keratosis.
It has now been found that certain pyrrolotriazinone derivatives are novel and potent PI3K inhibitors and can therefore be used in the treatment or prevention of these diseases.
Thus the present invention is directed to compounds of formula (I), or a
pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof:
Figure imgf000008_0001
Formula (I) wherein, n represents 0, 1 , 2 or 3;
X represents N or CH; Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, aryl, 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 C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)i-3CN group, a -(CH2)0-3OR9 group, a -(CH2)o-3N R9Rio group, a -C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0.3-R9 group, a -C(0)-(CH2)o-3-N R9R10 group, a -S(CH2)0.3R9 group, a -S(0)(CH2)o-3R9 group, a -S(O)(CH2)0.3N R9R10 group, a -S(O)2(CH2)0-3R9 group, a -S(O)2(CH2)0-3N R9R10 group or
a -(CH2)0-3(phenyl)-OR9 group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C1-C4 alkoxy group, a -NH2 group, a -N(CH3)H group or a -N(CH3)2 group;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-(C3-C4 cycloalkyl) group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)0-3-O- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9Rio group, a -(CH2)o-3-0(CrC4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3- S(O)2(CH2)0.3-Rn group, a -(CH2)0-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-SH group, a -(CH2)o-3-S- (CH2)o-3-Ri i group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)0-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)o-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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;
R6 and R7 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a - C(0)-(CH2)i.3-CN group, a -C(O)-(CH2)0-3-R' group, a -C(O)-(CH2)0-3-NR'R", a -(CH2)0. 3NR'R" group, or a linear or branched C1-C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyi) group or a linear or branched Ci- C4 alkyi group; R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N , wherein the aryl , heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 alkyi group, a C C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyi) group, a -(CH2)o-3-0(Ci-C haloalkyi) group, a -(CH2)o-3-0-(CH2)i-3-0(Ci-C4 alkyi) group, a -(CH2)0-3-O- (CH2)i.3-0(Ci-C4 haloalkyi) group, a -(CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3- 0-(CH2)1-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2)0-3NR'R" group, a - (CH2)o-3-C(0)-(CH2)o-3-NR'R"group, a -(CH2)0-3-C(0)0-(CH2) o-3R' group, a - (CH2)o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Rii group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)0-3-Rii group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi group, a -(CH2)1-3NRaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyi group, a CrC4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a CrC4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -NH2 group, a -N H(Ci-C4 alkyi) group, a - N H-S(0)2-(CrC4 alkyi) group, R-12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched d- C4 alkyl group. 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 amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), 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; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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, 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). 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.
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. 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; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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, 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).
As used herein the term C1-C6 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.
When it is mentioned that the 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. As used herein, the term C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, which is bonded to one or more, preferably 1 , 2 or 3 halogen atoms. Preferably, said haloakyl group is chosen from -CCI3, -CHF2 and -CF3.
As used herein, the term Ci-C4 hydroxyalkyl 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.
As used herein, the term C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
As used herein, the term C3-C10 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 C3-C10 cycloalkyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a C3- C10 cycloalkyl radical carries 2 or more substituents, the substituents may be the same or different. Typically the substituents on a C3-C10 cycloalkyl group are themselves unsubstituted. Polycyclic cycloalkyl radicals contains two or more fused cycloalkyl groups, preferably two cycloalkyl groups. Typically, 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. As used herein, the term C3-Cio cycloalkenyl embraces partially unsaturated carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A C3-Ci0 cycloalkenyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a C3-C10 cycloalkenyl radical carries 2 or more substituents, the substituents may be the same or different. Typically, the substituents on a cycloalkenyl group are themselves unsubstituted.
Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl. As used herein, the term C6-Ci4 aryl radical embraces typically a C6-C-|4, more preferably C6-C10 monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. A said optionally substituted Ce-C-u aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a C6-C14 aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a C6-C14 aryl group are typically themselves unsubstituted. As used herein, the term 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 6- 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. When a 5- to 14- membered heteroaryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, 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, 2H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d] pyrimidinyl and the various pyrrolopyridyl radicals.
As used herein, the term 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-C14 carbocyclic ring system, preferably C5- do carbocyclic ring system, more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 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 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 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, tetrahydrothiopyranyl, 1 ,4-azathianyl, oxepanyl, thiephanyl, azepanyl, 1 ,4-dioxepnayl, 1 ,4-oxathiepanyl, 1 ,4-oxaazepanyl, 1 ,4-dithiepanyl, 1 ,4- thiezepanyl, 1 ,4-diazepanyl, tropanyl, (1 S,5R)-3-aza-bicyclo[3.1.0]hexyl, 3,4-dihydro- 2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 2,3-hydrobenzofuranyl, 1 ,2,3,4- tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, isoindolinyl and indolinyl. Where a 5- to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
As used herein, the bicyclic N-containing heteroaryl group is a C8-Ci0 membered ring system where two rings have been fused and wherein at least in one ring one of the carbon atoms is replaced by N and optionally in which 1 , 2, 3, or 4, preferably 1 , 2, or 3 further carbon atoms of any ring which form the group are replaced by N.
Examples include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3- d]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolinyl, indazolyl, purinyl, indolinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1 ,5- a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, azaquinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyrido[3,2- d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrazolo[1 ,5-a]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4- d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-d]pyrimidinyl. As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, moieties, chains and cycles 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. When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
As used herein, the term 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. The term halo when used as a prefix has the same meaning. Also included within the scope of the invention are the isomers, polymorphs, pharmaceutically acceptable salts, N-oxides, isotopes, solvates and prodrugs of the compounds of formula (I). 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).
Isomers
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). Alternatively, the 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. 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 (and chiral precursors thereof) 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.
Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization. In 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.
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.
Moreover, 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
As used herein, 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.
As used herein, the term 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. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids.
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, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. 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. 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.
N-oxides
As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent. Isotopes
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. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1 1 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, for example, those incorporating a radioactive isotope, 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.
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. As used herein, the term 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 %.
Solvates
The compounds of the invention may exist in both unsolvated and solvated forms. The term 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. The term hydrate is employed when said solvent is water. Examples of 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.
Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, 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
Prodrugs of the compounds described herein are also within the scope of the invention. Thus 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).
As used herein, the term PI3Kd inhibitor generally refers to a compound that inhibits the activity of the PI3Kd isoform more effectively than other isoforms of the PI3K family. As used herein, the term 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 (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC50." IC50 determinations can be accomplished using conventional techniques known in the art. In general, an IC50 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 IC50 value.
Accordingly, a PI3Kd inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC5o) with respect to PI3Kd that is at least of less than about 100 μΜ, preferably of less than about 50 μΜ, more preferably of less than about 20 μΜ, even more preferably of less than about 10 μΜ PI3K HTRF assay (as described in Gray et al. Anal Biochem, 2003; 313: 234-45) Typically, in the compound of formula (I), X represents N (a nitrogen atom) or CH. Preferably, X represents N. Typically, in the compound of formula (I), Ra and Rb each independently represent a hydrogen atom, a Ci-C4 haloalkyl group, a Ci-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group.
Preferably, Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group. More preferably Ra and Rb each independently represent a hydrogen atom, a methyl group or an ethyl group.
Typically, n represents 0, 1 or 2, preferably 0 or 1 , more preferably 0. Typically, in the compound of formula (I) Ri represents a C3-C10 cycloalkyl group, a C3- C10 cycloalkenyl group, a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, cycloalkenyl, aryl, 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 C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)i-3CN group, a -(CH2)o- 3OR9 group, a -(CH2)0-3N R9R10 group, a -C(0)-(CH2)i-3-CN group, a -C(0)-(CH2)o-3-R9 group, a -C(0)-(CH2)o-3-NR9R10 group, a -S(CH2)0-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(O)(CH2)0.3NR9R10 group, a -S(O)2(CH2)0-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and Ri0 are as defined above.
Preferably, Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group;
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a CrC4 haloalkyl group, a Ci-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -S(CH2)0-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3N R9Rio group, a -S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3N R9Rio group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and Ri0 each independently represent a hydrogen atom or a C1-C4 alkyl group More preferably, Ri represents a phenyl group, which phenyl group is unsubstituted or substituted by one, two or three substituents selected from a halogen atom or a linear or branched C1-C3 alkyl group.
Preferably, when Ri represents a phenyl group, said phenyl group is directly bonded to the pyrrolotriazinone group. In other words, the linker -(Ra-C-Rb)n- is not present.
Typically, in the compound of formula (I) R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C1-C4 haloalkyl group, a Ci-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C C4 alkoxy group, a -NH2 group, a -N(CH3)H group or a -N(CH3)2 group.
Preferably, R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C C4 alkyl group. More preferably R2 represents a hydrogen atom. Typically, in the compound of formula (I) R3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C1-C4 alkoxy group, a -NH2 group, a -N(CH3)H group or a -N(CH3)2 group. Preferably, R3 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C1-C4 alkyl group. More preferably R3 represents a hydrogen atom.
Typically, in the compound of formula (I), R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a - (CH2)o-3-(C3-C4 cycloalkyl) group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-S-(CH2)0_ 3-(phenyl) group, a -(CH2)o-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)0-3- (phenyl) group, a -(CH2)o-3-0-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group. Preferably, R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a - (CH2)o-3-(C3-C4 cycloalkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)0-3-(phenyl) group, or a -(CH2)0-3- 0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group. More preferably, R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group.
Typically, in the compound of formula (I), R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9R10 group, a -(CH2)0-3-O(Cr C4 alkyl) group, a -(CH2)0-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0.3- (phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a - (CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)0.3-S(0)2(CH2)o.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-SH group, a -(CH2)0-3-S-(CH2)o.3-Ri i group, a -(CH2)0-3-S-(CH2)0.3-(phenyl) group, a -(CH2)0-3-S-(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)0-3-(phenyl) group, a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a Ci-C4 alkoxy group; and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C C4 hydroxyalkyl group, a Ci-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)0- 4-R" group, a -(CH2)o-4-C(0)-(CH2)0-4-R' group; wherein R-n is as defined above;
wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)o-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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. Preferably, R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o.3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; wherein the 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 C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group; and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C C4 alkoxy group, a -(CH2)0-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)0-4-C(O)- (CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci- C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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. Typically, in the compound of formula (I), R6 represents a hydrogen atom, a -(CH2)o-3CN group, a -C(0)-(CH2)i.3-CN group, a -C(0)-(CH2)o-3-R' group, a -C(O)-(CH2)0-3-NR'R", a -(CH2)o-3NR'R" group, or a linear or branched C1-C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group or a linear or branched C1-C4 alkyl group. Preferably, R6 represents a hydrogen atom, a -C(0)-(CH2)o-3-(CrC4 alkyl) group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group. More preferably R6 represents a hydrogen atom or a -NH2 group. Typically, in the compound of formula (I), R7 represents a hydrogen atom, a -(CH2)0.3CN group, a -C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0-3-R' group, a -C(O)-(CH2)0-3-NR'R", a -(CH2)o-3NR'R" group, or a linear or branched C1-C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group or a linear or branched C1-C4 alkyl group.
Preferably, R7 represents a hydrogen atom, a -C(0)-(CH2)o-3-(CrC4 alkyl) group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group. More preferably R7 represents a hydrogen atom or a -NH2 group.
Typically, in the compound of formula (I), R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group 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 C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group, a -(CH2)0-3-O(Ci-C4 haloalkyl) group, a -(CH2)o- 3-0-(CH2)1-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O-(CH2)1-3-O(Ci-C4 haloalkyl) group, a - (CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3-O-(CH2)1_3NR'R" group, a C3-C7 cycloalkyi group, a -(CH2) 0-3NR'R" group, a -(CH2)0_3-C(O)-(CH2) 0-3-NR'R"group, a -(CH2)0-3- C(0)0-(CH2) o-3R' group, a -(CH2) 0-3NR'-S(O)2R" group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)o-3-Rn group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH2)i-3NRaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyi group. Preferably, in the compound of formula (I), 8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched CrC4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-0(Ci-C4 haloalkyl) group, a -(CH2)o- 3-0-(CH2)i-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O-(CH2)i-3-O(Ci-C4 haloalkyl) group, a - (CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3-O-(CH2)i-3NR' R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3N R' R" group, a -(CH2)0-3-C(0)-(CH2) o.3-N R'R"group, a -(CH2)0-3- C(0)0-(CH2) o-3R' group, a -(CH2) o-3N R'-S(0)2R" group, a -(CH2)0.3- S(O)2(CH2)0.3-Rn group, a -(CH2)o-3-SH group, or a -(CH2)o-3-S-(CH2)o-3-Rii group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH2) -3N RaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group.
In one embodiment, in the compound of formula (I), R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C alkyl) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR' R" group, a -(CH2)0-3-C(0)-(CH2) o-3-N R' R"group, a -(CH2) 0-3N R'-S(O)2R" group, a -(CH2)0-3- S(0)2(CH2)o-3-Ri i group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-
(CH2)o-3-Ri i group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C4 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, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group. In one embodiment, R8 preferably represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR' R" group, a - (CH2)o-3-C(0)-(CH2) o-3-N R'R"group or a -(CH2) o-3NR'-S(0)2R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 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, a cyano group, a C1-C4 hydroxy alkyl group, a C1-C4 haloalkyi group, a C1-C4 alkoxy group, a C3-C4 cycloalkyl group or a linear or branched alkyl group.
Typically, in the compound of formula (I), R9 represents a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group or a linear or branched C C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
Preferably, R9 represents a hydrogen atom or a linear or branched C1-C4 alkyl group.
Typically, in the compound of formula (I), Rn represents a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH2 group, a -NH(d-C4 alkyl) group or a -NH-S(0)2-(Ci-C4 alkyl) group group. Typically, in the compound of formula (I), R12 represents represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N. Prefarably, in the compound of formula (I), Ri2 represents a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, a pyrrazolyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a
tetrahydrothiopyranyl group or a morpholinyl group. Typically, in the compound of formula (I), L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(0)-N R'- group, a C(0)-0-R"'- group or a - (CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C1-C4 alkyl group.
Preferably, L represents a direct bound or a linker selected from -0-, -S-, a -NH- group or a -(CH2)i-4 group.
When R' and/or R" are attached to a nitrogen atom, preferably R' and/or R" do not represent a hydroxyl group or alkoxy group. Where any of the above moieties represent -(CH2)o-4-C(0)-(CH2)o-4- R' or -C(0)-(CH2)o- 3-R', it is preferable that R' does not represent a hydrogen atom if the alkylene spacer moiety is absent.
Preferably, in the compound of formula (I) n represents 0, 1 , or 2; X represents N or CH; Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3NR9Rio group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R-io each independently represent a hydrogen atom or a C1-C4 alkyl group; R2 and R3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH2)0.3-(C3- C4 cycloalkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)0-3-S(O)2(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a
C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)0-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)o-4-C(0)-(CH2)o^-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from 0, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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;
R6 and R7 each independently represent a hydrogen atom, a -N H2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group;
Rs represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-0(CrC4 haloalkyl) group, a -(CH2)o-3-0-(CH2)i-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O- (CH2)1-3-0(C1-C4 haloalkyl) group, a -(CH2)0-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3- 0-(CH2)1-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a -
(CH2)o-3-C(0)-(CH2) o-3-NR'R"group, a -(CH2)0-3-C(0)0-(CH2) o-3R' group, a - (CH2) o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Ri i group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)0-3-Rn group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH2)1-3NRaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom or a linear or branched Cr C4 alkyl group;
Ri2 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched d- C4 alkyl group. In a particular preferred embodiment, in the compound of formula (I) n represents 0, 1 , or 2; X represents N or CH;
Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3NR9Rio group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3N R9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and Ri0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a -(CH2)0.3-(C3- C4 cycloalkyl) group, a -(CH2)0-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a
C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)0-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a
C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a C C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o.4-R" group, a -(CH2)0-4-C(O)-(CH2)0-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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;
R6 and R7 each independently represent a hydrogen atom, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group; R8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O(Ci-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2)i.3-0(Ci-C4 alkyl) group, a -(CH2)0.3-O- (CH2)1-3-0(Ci-C4 haloalkyl) group, a -(CH2)0-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3- 0-(CH2)i-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR'R" group, a - (CH2)o-3-C(0)-(CH2) o-3-NR'R"group, a -(CH2)o-3-C(0)0-(CH2) o-3R' group, a - (CH2) o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Rn group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)o-3-Rn group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C4 alkyl group, a -(CH2)i-3NRaRb 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 Ci-C4 hydroxyalkyl group, a Ci-C4 haloalkyl group, a Ci-C4 alkoxy group or a C3-C4 cycloalkyl group;
Rg and Ri0 each independently represent a hydrogen atom or a linear or branched Cr C4 alkyl group; R12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)1-4 group; wherein R' represents hydrogen or a linear or branched Ci-C alkyl group, and R'" represents a linear or branched C C4 alkyl group.
In another particular preferred embodiment, in the compound of formula (I): n is 0 or 1 ;
X represents N or CH; Ra and Rb each independently represent a hydrogen atom or C1-C4 alkyl group;
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 ,1 -dioxide group,
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched Ci-C3 alkyl group, a C1-C3 alkoxy group, a -S(Ci-C4 alkyl) group, a -
S(0)(Ci-C4 alkyl) group, or a -S(0)2(C C4 alkyl) group; R2 and R3 each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2-(CH2)o-3-(phenyl) group or a -(CH2)0-3-S-(CH2)o-3-(phenyl) group;
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C1-C4 alkyl group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH2)o-4-C(0)-N(H)-(CH2)o-4-(morpholinyl) group, a
-(CH2)0-4-C(0)-N-[(CH2)o-3-0(C1-C4 alkyl)]2 group or a -(CH2)0-4-C(0)-(CH2)o-4- (isopropylpiperazinyl) group;
R6 and R7 each independently represent a hydrogen atom, a -NH2 group, or a linear or branched C1-C4 alkyl group;
R8 represents 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a -(CH2)0.3-O(Ci- C4 alkyl) group, a -(CH2)o-3-0(C1-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2) 0-3- (morpholinyl) group, a -(CH2)0-3-O-(CH2)1-3NR'R" group, a -(CH2) 0-3NH2 group, a -(CH2) o-3NH-(CH2)i-3N R'R" group, a -(CH2) o-3NR'-S(0)2(CrC4 alkyl) group, a - (CH2)o-3-C(0)-(CH2)0-3-NH-(CH2)1.3NH2 group, a -(CH.Va-CiO -iCH.J o-ald-^ alkyl) group, a -(CH2)0-3-C(O)OH grup, or a -(CH2) 0-3NR'-S(O)2(phenyl) group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a C1-C4 hydroxyalkyl group, a C C4 haloalkyl group or a C C4 alkoxy group; and wherein R' and R" each independently represent a hydrogen atom or a linear or branched C C4 alkyl group; L represents a direct bound or -S-.
In a particular embodiment, in the compound of formula (I): n represents 0, 1 , 2 or 3; X represents N or CH; Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, or a 5- to 10- membered heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N;
wherein the cycloalkyl, phenyl, heteroaryl or heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -
S(CH2)o-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3NR9Rio group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R 0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
R2 and R3 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C3 alkoxy group, a linear or branched C1-C4 alkyl group, a C1-C3 haloalkyi group, a C3-C4 cycloalkyl group or a -NH2 group; R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)0-3-(phenyl) group, a -(CH2)o-3-0- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9Rio group, a -(CH2)o-3-0(CrC4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-SI-l group, a -(CH2)o-3-S- (CH2)o-3-Rii group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)0-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)o-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -C(0)-(CH2)o-3-(CrC4 alkyi) group, a -N H2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyi group;
R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N ,
wherein the aryl , heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 alkyi group, a C C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a -(CH2)o-3-0(C C4 alkyi) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR'R" group, a -(CH2)0-3-C(O)-(CH2) 0-3-NR'R"group, a -(CH2) 0-3NR'- S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)0-3-SH group, or a - (CH2)o-3-S-(CH2)o-3-Rii group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi 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 C1-C4 hydroxyalkyi group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group;
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH2 group, a -N H(CrC4 alkyi) group or a - NH-S(0)2-(Ci-C4 alkyi) group;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched CrC4 alkyi group, and R'" represents a linear or branched d- C4 alkyi group. In a particular preferred embodiment, in the compound of formula (I)
n represents 0, 1 , or 2; X represents N or CH; Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3NR9Rio group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and Rb each independently represent a hydrogen atom or a C1-C4 alkyl group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group; R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a -(CH2)0.3-(C3- C4 cycloalkyl) group, a -(CH2)0-3-S-(CH2)0-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o.4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and
N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group;
Rs represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR'R" group, a -(CH2)o-3-C(0)-(CH2) o-3-NR'R"group or a - (CH2) o-3NR'-S(0)2R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 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, a cyano group, a C1-C4 hydroxy alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C3-C4 cycloalkyl group or a linear or branched alkyl group. R9 and Rio each independently represent a hydrogen atom or a linear or branched Ci- C4 alkyl group;
L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH2)1-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C C4 alkyl group;
I n another particularly preferred embodiment, in the compound of formula (I) n is O or l ;
X represents N or CH ;
Ra and Rb each independently represent a hydrogen atom or C1-C4 alkyl group;
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 , 1 -dioxide group,
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a -S(d-C4 alkyl) group, a -S(0)(C C4 alkyl) group, or a -S(0)2(d-C4 alkyl) group;
R2 and Rs each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2-(CH2)o-3-(phenyl) group or a -(CH2)o-3-S-(CH2)o-3-(phenyl) group;
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C1-C4 alkyl group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH2)0-4-C(O)-N(H)-(CH2)0-4-(morpholinyl) group, a -(CH2)0-4-C(0)-N-[(CH2)o-3-0(Ci-C4 alkyl)]2 group or a -(CH2)0-4-C(O)-(CH2)0-4-
(isopropylpiperazinyl) group;
R6 and R7 each independently represent a hydrogen atom, a -NH2 group, or a linear or branched C C4 alkyl group;
R8 represents 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a -(CH2)0-3-O(Ci-
C4 alkyl) group, a -(CH2)0-3NH2 group or a -(CH2) 0.3NR'-S(O)2(Ci-C4 alkyl) group, wherein R' represents a hydrogen atom or a linear or branched C-i-C4 alkyl group; L represents a direct bound or -S-.
Particular individual compounds of the invention include:
2-((4-Amino-3-(3-hydroxyphenyl)-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- (o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 -/-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-3- (o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-7 -/-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (first enantiomer); 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- bromo-3-(3-(methylthio)phenyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- /]pyrimidin-1 -yl)methyl)-5-
(trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3 - )-one;
2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 - -pyrazolo[3,4-c ]pynmidin-1 - yl)methyl)pyrrolo[2,1 -f|[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfinyl)phenyl)pyrrolo[2, 1 -f \ ,2,4]triazir (3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)- 1 H-pyrazolo[3,4-c ]pyrimidin-1-yl)methyl)-3- (S-imethylsulfiny pheny pyrrolo^ -flfl ^^^riazin^iSHJ-one;
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)- 1 H-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-/][1 ,2,4]tnazin-4(3/-/)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-< ]pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-/][1 ,2,4]triazin-4(3/-/)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- phenylpyrrolo^.l- lfl ^^^riazin^iSH^one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2,1- ][1 !2!4]triazin-4(3 - )-one;
2-((4-amino-3-(3-fluoro-4-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2,1- ][1 !2!4]triazin-4(3 - )-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylthio)pyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-o^pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2!4]triazin-4(3 -/)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-o pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]tn'azin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 - |[1 ,2,4]triazin-4(3H)-one (second enantiomer);
2-((4-amino-3-(3-chloro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3/-/)-one;
2-((4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-((3-hydroxyphenyl)thio)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyra^
5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one; 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-o0pyrimidin-1-yl)methyl)-5- ethynyl-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one;
2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-methylpyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one; (S)-2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c pyrimidin-1-yl)methyl)-
3- (1 -phenylethyl)pyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1 - yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 - |[1 !2!4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-c^pyrimidin-1- yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 -f|[1 !2!4]triazin-4(3H)-one;
(S)-N-(5-(4-amino-1 -((4-oxo-3-(1 -phenylethyl)-3!4-di ydropyrrolo[2,1 -/][1 !2,4]tnazin-2- yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-3-yl)-2-methoxypyridin-3- yl)methanesulfonamide;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylsulfonyl)pyrrolo[2,1- |[1 ,2,4]triazin-4(3H)-one;
6-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f|[1 ,2,4]triazin-5-yl)-N,N-bis(2-methoxyethyl)hex-
5- ynamide;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- ((3-hydroxyp enyl)thio)-3-phenylpyrrolo[2, 1 - |[1 ,2,4]triazin-4(3 -/)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-a pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylthio)phenyl)pyrrolo[2!1- ][1 !2!4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2, 1 -f\ \ ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1- yl)methyl)-3-phenylpyrrolo[2,1-/][1 !2!4]triazin-4(3/- -one;
2- ((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-
3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-f|[1 ,2,4]triazin-4(3H)-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-hydroxypyndin-3-yl)-4- methoxybenzenesulfonamide;
(R)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-cGpyrimidin-1-yl)ethyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3/-/)-one;
(S)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)ethyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one; 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- (6-(4-isopropylpiperazin-1 -yl)-6-oxohex-1-yn-1 -yl)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin- 4(3H)-one;
6-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1 -yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2 -^[1 ,2,4]triazin-5-yl)-N-(2-morpholinoethyl)hex-5- ynamide;
2-((4,6-diamino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pynmidin-1 -yl)methyl)-
5- methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-5-(3-fluoro-5-hydroxyphenyl)-7H-pyrrolo[2,3-(^pyrimidin-7-yl)methyl)-3- (1 -phenylethyl)pyrrolo[2, 1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-
(S-hydroxybenzy -S-phenylpyrrolo^ - lfl ^^^riazin^CSHJ-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-
((4-hydroxyp enyl)thio)-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3 -/)-one;
N-(3-(4-amino-1-((5-((4-hydroxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- |[1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-3- yl)phenyl)methanesulfonamide;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4- |pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-G0pyrimidin-1 -yl)methyl)-3-(1- phenylethyl)pyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(2-aminopyridin-4-yl)-1 H-pyrazolo[3,4-oGpyrimidin-1-yl)methyl)-5-( hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-cif]pyrimidin-1 -yl)methyl)- 5-((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-rf]pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4- f|pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-3- (2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one;
2- ((4-amino-3-(3,5-dihydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-methyl-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-hydroxy-5-methoxyphenyl)-1 H-pyrazolo[3,4 ]pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3/-/)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- (2,4-dihydroxybenzyl)-5-methylpyrrolo[2,1-f|[1 ,2,4]tnazin-4(3/-/)-one; N-(3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonamide;
2-((4-amino-3-(3-(2-(dimethylamino)ethoxy)-5-hydroxyphenyl)-1 - -pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3-
(2-hydroxy-4-methoxybenzyl)-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
(S)-N-(3-(4-amino-1 -((4-oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]tnazin-2- yl)methyl)-1 H-pyrazolo[3,4-c ]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonarriide;
2-((4-amino-3-(3-hydroxy-5-(2-methoxyethoxy)phenyl)-1 H-pyrazolo[3,4-<^pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2!4]triazin-4(3 -/)-one;
2-((4-amino-3-(3,5-bis(2-morpholinoethoxy)phenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2!4]triazin-4(3 -/)-one;
(S)-2-(1 -(4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-c^pyrimidin-
1 -yl)ethyl)-5-methyl-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 /- -pyrazolo[3,4-c/]pyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)ethyl)-5- methyl-3-phenylpyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-yl)acetarriide;
methyl 3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - |[1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoate;
2- ((4-amino-3-(3-((ethylamino)methyl)-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2!4]triazin-4(3 -/)-one;
3- (4-amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4- /]pyrimidin-3-yl)-5-hydroxybenzoic acid;
3-(4-amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-3-yl)-N-(2-aminoethyl)-5-hydroxybenzamide; 2-((4-amino-3-(3-(aminomethyl)-5-hydroxyphenyl)-1 - -pyrazolo[3,4-c ]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-(((2-aminoethyl)amino)methyl)-5-hydroxyphenyl)-1 -/-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- |[1 ,2,4]triazin-4(3 - )-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-1 /-/-pyrazolo[3,4-c ]pyrimidin-3-yl)pyridin-3-yl)methanesulfonamide; 2-((4-amino-3-(5-(2,2-difluoroethoxy)pyridin-3-yl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-hydroxy-5-(trifluoromethoxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 - -one; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
Examples of the preferred compounds are:
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2!1-f][1 !2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- y methy -S-phenylpyrrolo^ -fJfl ^^ltriazin^iSHJ-one;
2-((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
S-phenyl-S-itrifluoromethy pyrrolo^ -fJfl ^^ltriazin^iSH^one;
(S)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-
5-methyl-3-phenylpyrrolo[2!1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4,6-diamino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)- 5-methyl-3-phenylpyrrolo[2!1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-
1-yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof. In one embodiment, particular individual compounds of the invention include:
2-((4-Amino-3-(3-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- (o-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (o-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (first enantiomer);
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- bromo-3-(3-(methylthio)phenyl)pyrrolo[2!1-f][1 !2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- (trifluoromethy pyrrolop.l -fJfl ^^ltriazin^CSHJ-one;
2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)pyrrolo[2,1 -f][1 !2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -f][1 ,2,4]triazin^(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (S-imethylsulfiny pheny pyrrolop -fJfl ^^ltriazin^iSHJ-one;
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2!1-f][1 !2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-4-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylthio)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one; 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (second enantiomer);
2-((4-amino-3-(3-chloro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-((3-hydroxyphenyl)thio)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-
5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- ethynyl-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2!1-f][1 ,2,4]triazin-4(3H)-one;
2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one; (S)-2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-
3- (1 -phenylethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-N-(5-(4-amino-1 -((4-oxo-3-(1 -phenylethyl)-3!4-dihydropyrrolo[2,1 -f][1 !2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxypyridin-3- yl)methanesulfonamide;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylsulfonyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
6- (2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2 -f][1 ,2,4]triazin-5-yl)-N,N-bis(2-methoxyethyl)hex-
5- ynamide;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- ((3-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one; 2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2- ((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]tnazin-4(3H)-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-hydroxypyridin-3-yl)-4- methoxybenzenesulfonamide;
(R)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)- 5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-
5- methyl-S-phenylpyrrolo^ -^fl ^^ltriazin^iSHVone;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- (6-(4-isopropylpiperazin-1 -yl)-6-oxohex-1-yn-1 -yl)-3-phGnylpyrrolo[2,1-f][1 ,2,4]triazin- 4(3H)-one;
6- (2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2 -f][1 ,2,4]tnazin-5-yl)-N-(2-morpholinoethyl)hex-5- ynamide;
2-((4,6-diamino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
5- met yl-3-phenylpyrrolo[2,1 -f][1 !2,4]triazin-4(3H)-one;
(S)-2-((4-amino-5-(3-fluoro-5-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3- (1 -phenylethyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- (3-hydroxybenzyl)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- ((4-hydroxyp enyl)thio)-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
N-(3-(4-amino-1-((5-((4-hydroxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pynmidin-3- yl)phenyl)methanesulfonamide;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2!1 -f][1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(1- phenylethyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(2-aminopyridin-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)- 5-((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin^(3H)-one; 2-((4-amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
N-(3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonamide; 2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
Examples of the preferred compounds in this embodiment are:
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (first enantiomer);
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (second enantiomer);
2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
2- ((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-
3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)- 5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4,6-diamino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)- 5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
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 amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), 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; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; 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, 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).
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.
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. As used herein, the term therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
As used herein, the term treatment refers to the treatment of a disease or medical condition in a human patient which includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.
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.
Additionally, as will be apparent to those skilled in the art, conventional 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
Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
The term 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 alkanoyi 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) and tert-butyldimethylsilyl (TBS); and the like.
The term 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 alkanoyi 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.
According to one embodiment of the present invention, compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1 , from compounds of Formula (III), where the group Zi 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.
Compounds of Formula (I) can be obtained directly from compounds of Formula (I I I) or in a two steps synthesis, by treatment of (I II) with compounds of Formula (I I) or compounds of Formula (IV) in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as fert-butanol, Λ/,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
When Ζ is a 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.
In the two steps synthesis compounds of Formula (V) can be converted to compounds of Formula (I) by reacting with the corresponding boronic acid using standard Suzuki coupling conditions. Alternatively, compounds of general Formula (I) where the group L represents a NH , O or S, can be obtained from compounds of Formula (V), by reacting with the corresponding aniline or thiophenol or phenol by using copper or palladium catalysed coupling methods well known in the art. Boronic acids, anilines, thiophenols or phenols 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 suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
Figure imgf000056_0001
Formula (V)
Scheme 1 Compounds of general Formula (II I) can be prepared directly from compounds of
Formula (VI I) as illustrated in Scheme 2 by treatment of compounds with Formula (VI I) with the appropriate acid chlorides of Formula (VI II) in a solvent such as acetic acid or, alternatively, in toluene or xylene with the presence of pyridinium p-toluenesulfonate at a temperature ranging from room temperature to 150°C with or without the use of microwaves irradiation.
In the particular case where Ζ is a chlorine atom and R4 is hydrogen, the compounds of Formula (I II) can also be prepared by treating the compounds of Formula (VI I) with 2-chloro-1 ,1 , 1 -trimethoxyethane in the presence of pyridinium p-toluenesulfonate at a temperature between 50 °C and 150 °C.
Alternatively, compounds of Formula (II I) can be obtained in two steps from
compounds of Formula (VI I), isolating the intermediate amides of Formula (VI).
Compounds of Formula (VI I) can be transformed in amides of Formula (VI) by treatment with carboxylic acids of Formula (IX) in the presence of an activating agent by methods and conditions well described in the literature, for example using T3P®, EDC.HCI or HATU as an activating agent in a solvent such as ,/V-dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
Alternatively, amides of Formula (VI) can be obtained from compounds of Formula (VII) by treatment with acid chlorides of Formula (VIII) at room temperature in a suitable solvent such as acetic acid or 1 ,4-dioxane or alternatively in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane.
In a second step, compounds of Formula (VI) can yield compounds of Formula (III) by treatment with phosphorous oxychloride at temperatures ranging from room
temperature to 100 °C, with or without a subsequent treatment with a solution of a base such as ammonia, pyrolidine, piperidine or potassium carbonate in a solvent such as methanol, ethyl acetate or /V,/V-dimethylformamide at a temperature between room temperature and 100 °C. Also with a pyridinium p-toluenesulfonate in toluene or xylene as a solvent at temperature between 80°C and 130°C.
Alternatively, compounds of Formula (VI) can yield compounds of Formula (III) by treatment of compounds of Formula (VI) 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 or without a subsequent treatment with a base such as ammonia, pirrolidine, piperidine or potassium carbonate or a nucleophile such us sodium methanethiolate in a solvent such as methanol, ethyl acetate or N,N- dimethylformamide at a temperature between room temperature and 100 °C.
Figure imgf000058_0001
Formula (VI)
Scheme 2 The acid chlorides of Formula (VIII) and the carboxylic acids of Formula (IX) 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 suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
Compounds of Formula (VII) can be prepared from carboxylic acids of Formula (XII) following the scheme described in Scheme 3.
Carboxylic acids (XII) can be activated with any activating reagent described in the literature such as thionyl chloride, oxalyl chloride, phosphorous oxychloride, 2-(3H- [1 ,2,3]triazolo[4,5-6]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium
hexafluorophosphate(V), 3-((ethylimino)methyleneamino)-A/,/V-dimethylpropan-1 - aminium chloride and treated with amines of Formula (XI) in the presence of a base such as diisopropylethylamine when needed in a suitable solvent such as dioxane, dichloromethane, /V,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from 0 °C to reflux to give amides of Formula (X). Subsequently, amides of Formula (X) can be aminated on the nitrogen atom in position 1 by any of the aminating reagents described in the literature, such as O- (mesitylenesulfonyl)hydroxylamine, 0-(p-nitrobenzoyl)-hydroxylamine, 0-(diphenyl- phosphinyl)-hydroxylamine, 0-(2,4-dinitrophenyl)-hydroxylamine, hydroxylamine-O- sulfonic acid using a suitable base such as triethylamine, potassium carbonate, sodium hydride or butyl lithium in an appropriate solvent such as Λ/,Λ '-dimethylformamide, tetrahydrofurane, 1 ,4-dioxane at temperatures ranging from -78 to 100 °C.
Alternatively, 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 dialkyl ethers and adding a phase transfer catalyst such as Aliquat 336® at temperatures ranging from 0 °C to room temperature.
Figure imgf000059_0001
Compounds (XII) can either be commercially available compounds or can be prepared by the synthetic scheme illustrated in Schemes 4. In the particular case when R5 represents a C3-C7 cycloalkyl group, or a linear or branched Ci-C4 alkyl group, compounds (Xlla) can be prepared, as illustrated in Scheme 4, from bromopyrrol of Formula (XIV)2 by Suzuki coupling with the corresponding alkyl or cycloalkylboronic acids in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) and appropriate base such as potassium carbonate and in a suitable solvent such as toluene at a temperature ranging from 60°C to 150°C. Compounds of Formula (Xlla) can be obtained by simultaneous cleavage of the sulphone and ester groups of compounds of Formula (XIII) by means of a base such as lithium hydroxide in a suitable solvent or mixture of solvents such as water or tetrahydrofurane at temperatures ranging from room temperature to 220 °C, with or without the use of microwaves irradiation. Alternatively, the cleavage of the sulphone and ester groups of compounds of Formula (XIII) can be done sequentially by treatment of compounds (XII I) with tetrabutylammonium fluoride in an appropriate solvent such as
tetrahydrofurane at a temperature from room temperature to reflux and subsequent hyd ester roup by any of the methods well known in the literature.
Figure imgf000060_0001
Formula (XIV) Formula (XIII) Scheme 4
In the particular case when R5 represents hydrogen or C3-C7 cycloalkyi group, or a linear or branched C C4 alkyl group, and R2 independently represents hydrogen or C3- C7 cycloalkyi group, or a linear or branched Ci-C4 alkyl group, compounds (Xa) can be prepared, as illustrated in Scheme 5, from pyrrols of Formula (XVI). Pyrrols of Formula (XVI) can be reacted with 2,2,2-trichloroacetyl chloride in a suitable solvent such as diethyl ether at a temperature ranging from room temperature to reflux affording ketones of Formula (XV). These intermediate compounds of Formula (XV) can be reacted with the corresponding amines of Formula (XI) with or without solvent in the presence of a base such as triethylamine at a temperature ranging from room te
Figure imgf000060_0002
Formula (XVI)
Scheme 5 Alternatively, compounds of general Formula (VI) may be prepared by the synthetic route illustrated in Scheme 6. Thus, compounds of Formula (VI) can be prepared from compounds of Formula (XVI I) by known amide formation methods such as those described above. Compounds of Formula (XVII) can be prepared by the known coupling methods previously described. Compounds of Formula (XVI II) can be obtained by amination of compounds of Formula (XIX) by the methods already described.
Figure imgf000061_0001
Formula (VI)
Scheme 6
In another embodiment of the present invention, compounds of general Formula (1Mb) can also be synthesized from compounds of Formula (Ilia) as shown in Scheme 7 by the general methods described as it follows.
Figure imgf000061_0002
Scheme 7
In the particular case where R5 is a trifluoromethyl group, the bromine atom of compound of Formula (Ilia) has to be converted first into a iodine atom by treatment of (Ilia) 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. Next, treatment of iodine intermediate with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate or any other trifluoromethylating agent using a suitable catalyst such as copper (I) iodide in the presence or not of a chelating agent such as hexamethylphosphoramide and in an appropriate solvent such as Λ/,Λ '-dimethylformamide afforded compounds of Formula (1Mb). In the particular case where R5 is a alkyl or cycloalkyl group, or an aromatic or heteroaromatic ring compounds of Formula (III) can be obtained by standard Suzuki or Stille couplings with the corresponding boronic acid 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 cesium carbonate and in a suitable solvent such as toluene or dioxane or N,N- dimethylformamide at temperatures ranging from 60°C to 150°C.
In the particular case where R5 is a fluorine, compound of Formula (Ilia) can be treated with a lithiating agent such as n-BuLi, in a non protic solvent such as hexanes and at a temperature between -78°C and 0°C and subsequently treated with a suitable fluorine source such as /V-fluoro-/V-(phenylsulfonyl)-benzenesulfonamide at a temperature between -78°C and room temperature.
In the particular case of compounds of Formula (1Mb) where R5 is hydrogen, compounds can alternatively be obtained by hydrogenolysis of compounds of Formula (Ilia) using an appropriate catalyst such as 10% palladium on charcoal in a suitable solvent such as an alkyl alcohol under a hydrogen atmosphere at pressures ranging from atmospheric pressure to 60 psi and at temperatures ranging from room
temperature to 60°C.
In the particular case of compounds of Formula (lllb) where R5 is a thiophenol, compounds of Formula (Ilia) can be converted first into a iodine following the general methods previously described. The iodine intermediate can then react with the corresponding thiophenol in the presence of copper (I) iodide and a base such as potassium carbonate in solvent such as DMF and at temperatures ranging from room temperature to 150°C.
In the particular case of compounds of Formula (lllb) where R5 is a C2-C4 alkynyl group, wherein the alkynyl group is unsubstituted or substituted as described in claim 1 , compounds of Formula (lllb) can be obtained by reacting with the corresponding alkyne derivative in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(ll) chloride and copper (I) iodide in a suitable solvent such as diethylamine at temperatures ranging from room temperature to 100°C.
In another embodiment of the present invention, compounds of general Formula (I) can also be synthesized from compounds of Formula (la) or (lb) as shown in Scheme 8 by the same general methods previously described.
Figure imgf000063_0001
Formula (I)
Z5 =Br Formula (la)
Z5=l Formula (lb)
Scheme 8
EXAMPLES General
The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the following Examples (1 -77) (including Preparation
Examples (Preparations 1-89)) are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.
Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Concentration or evaporation refers to evaporation under vacuum using a BGchi rotatory evaporator. Reaction products were purified, when necessary, by flash or reverse phase chromatography in a Biotage SP1® or Isolera® automatic purification systems.
Purifications in reverse phase were made in a Biotage SP1® automated purification system equipped with a C18 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 conditions "formic acid buffer" refer to the use of 0.1% v/v formic acid in both phases. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized. 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.
The HPLC chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 μΜ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 μΜ) for method D. The mobile phases were (B): formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) and (A): formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the gradients are specified in the following table for each method used.
Figure imgf000064_0001
The flow rate was 0.8 mL/min for method A and 0.4 mL/min for method B, C and D. The injection volume was 5 microliter. A Waters 2996 diode array was used as a UV detector. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the HPLC.
The UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector. The system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50mm, 1 .7 μηι) 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). A gradient between 0 to 95% of B was used. The run time was 3 or 5 minutes The injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
1H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400MHz for the 1H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.
Abbreviations:
DMF /VJv-Dimethylformamide
DMSO Dimethylsulfoxide
CDCI3 Deuterated chloroform
NMR Nuclear magnetic resonance
s Singlet
d Doublet
dd Doublet of doublets
td Triplet of doublets
br Broad
q Quadret
t Triplet
m Multiplet
LRMS Low resolution mass spectrometry
h hour
min minutes
Oxone® Potassium peroxomonosulfate
NMM N-methylmorpholine
DMF /V,/V-dimethylformamide
DCM dichloromethane, methylene chloride
AcOEt ethyl acetate
EDC HCI 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride
THF tetrahydrofurane
DIEA diisopropylethyamine
HOBt 1-Hydroxybenzotriazole hydrate MeOH methanol
DPPONH2 Ρ,Ρ-diphenylphosphinic amide
PPTS pyridinium p-toluenesulphonate
Pd(PPh3)4 Tetrakis(triphenylphosphane) palladium(O)
HMPA hexamethylphosphoramide
Celite' diatomaceous earth
BINAP 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl
T3P' 2,4,6-Tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
HATU 2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uronium
hexafluorophosphate
psi Pounds per square inch
PREPARATION 1
1 -Amino-3-methyl-/V-(o-tolyl)-1 H-pyrrole-2-carboxamide a) 2,2,2-Trichloro-1 -(3-methyl-1 H-pyrrol-2-yl)ethanone
2,2,2-Trichloroacetyl chloride (5 mL, 45.27 mmol) was dissolved in 30 mL diethyl ether. 3-Methyl-1 H-pyrrole (3.1 g, 38.10 mmol) dissolved in 12 mL diethyl ether was added dropwise over 1 h and the reaction mixture was then heated at 45°C for 2 h. The mixture was diluted in diethyl ether and washed with water and brine. The organics were dried over sodium sulphate, filtered and evaporated. The residue was purified using SP1 Purification System (hexane-dichloromethane, 0% to 30%) to give 1.31 g (15 % yield) of the title compound. Purity 100%.
LRMS (m/z): 227 (M+1 )+. b) 3 -Methyl - V-(o-tolyl)-1 H-pyrrole-2-carboxamide
o-Toluidine (730 μΙ, 6.84 mmol) and triethylamine (960 μΙ, 6.89 mmol) were added to 2,2,2-trichloro-1 -(3-methyl-1 H-pyrrol-2-yl)ethanone (1.26 g, 5.56 mmol) in a Schlenk vessel and the reaction mixture was submitted to three vacuum-argon cycles. The mixture was heated at 60°C for two days. The solvent was concentrated and the residue was re-dissolved in ethyl acetate. The organic phase was washed with water, sodium bicarbonate 4% and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The resulting solid was triturated with hexane and ether to give a solid that was collected by filtration, washed with ether and dried in the oven to give 0.621 g of the title compound (52% yield). Purity 98%. LRMS (m/z): 215 (M+1 )+. c) 1 -Amino-3-methyl-A/-(o-tolyl)-1H-pyrrole-2-carboxamide
In a three-necked flask it was placed aqueous solution of sodium hydroxide (28%, 8 ml_, 56 mmol), 4.1 ml_ of a 28% ammonium hydroxide solution (28%, 2.6 ml_, 18.5 mmol), ammonium chloride (0.9 g, 16.82 mmol) and Aliquat 336 (drops). Afterwards, a solution of the title compound of 3-methyl-/V-(o-tolyl)-1 /-/-pyrrole-2-carboxamide (0.604 g, 2.82 mmol) dissolved in 10 mL diethyl ether and 10 mL methyl ierf-butyl ether was added and the mixture was cooled at 0°C affording a suspension. Over this suspension, a 10% aqueous solution of sodium hypochlorite (10%, 18 mL, 20.70 mmol) was added dropwise over 25 min with vigorous stirring. The reaction mixture was stirred at room temperature for 2 h. The reaction crude was diluted with ethyl acetate until no suspended material was observed. The layers were separated and the organic phase was washed with a 25% aqueous solution of sodium thiosulphate, water and brine, dried over sodium sulphate and concentrated under reduce pressure. The residue was purified using the Isolera Purification System (hexane-ethyl acetate 20%) to give 0.28 g (41 % yield) of the title compound as a solid.
LRMS (m/z): 230 (M+1 )+. PREPARATION 2
2-(Chloromethyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1 -f|[1 ,2,4]triazin-4(3W)-one
1-Amino-3-methyl-/V-(o-tolyl)-1 H-pyrrole-2-carboxamide (50 mg, 0.22 mmol) was dissolved in 1 mL glacial acetic acid. 2-Chloroacetyl chloride was added dropwise to a suspension and the mixture was heated at 120 °C for 30 min. The reaction mixture was cooled down and poured into a water-ice mixture. The suspension was extracted with ethyl acetate and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine. It was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified using the Isolera Purification System (hexane-ethyl acetate 0% to 40%) to give 28 mg (45% yield) of the title compound as a white solid.
LRMS (m/z): 288 (M+1 )+.
PREPARATION 3
1 -Amino-W-o-tolyl-1 H-pyrrole-2-carboxamide a) A/-o-Tolyl-1 W-pyrrole-2-carboxamide 1 /-/-Pyrrol 2-carboxylic acid (15 g, 135 mmol) was suspended in a mixture of 1.2 mL DMF and 150 mL dichloromethane. To this suspension, oxalyl chloride (18 mL, 203 mmol) dissolved in 105 mL dichloromethane was added dropwise over 30 minutes. The reaction was stirred two hours and then concentrated under reduced pressure. The residue oil was re-dissolved in 150 mL dichloromethane and o-toluidine (15.9 g, 148 mmol) dissolved in 16 mL dichloromethane (16 mL) was added dropwise in the reaction mixture. The reaction was stirred overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and the organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane-ethyl acetate 0% to 30%) to give 15.45 g (100% yield) of the title compound.
LRMS (m/z): 201 (M+1 )+. b) 1 -Amino-/V-o-tolyl-1 H-pyrrole-2-carboxamide
/V-o-Tolyl-1 /-/-pyrrole-2-carboxamide (100 mg, 0.50 mmol) was treated with aqueous solution of sodium hydroxide (32%, 1 .44 mL, 10 mmol), ammonium hydroxide solution (28%, 0.46 mL, 3.71 mmol), ammonium chloride (0.160 g, 3 mmol) and Aliquat 336 (drops). Afterwards, it was treated with a aqueous solution of sodium hypochlorite (10%, 3.3 mL, 4.42 mmol) according to the method of Preparation 1 c. The solid formed was triturated with diethyl ether and filtered to give 61 mg (57%) of the title compound as an orange solid. Purity 100%.
LRMS (m/z): 216 (M+1 )+.
PREPARATION 4
2-(Chloromethyl)-3-o-tolylpyrrolo[1 ,2-fl[1 ,2,4]triazin-4(3W)-one
1-Amino-/V-o-tolyl-1 H-pyrrole-2-carboxamide (40 mg, 0.19 mmol) was treated with 2- chloroacetyl chloride (74 μΙ, 0.93 mmol) according to the method of Preparation 2 to obtain 37 mg (73% yield) of the title compound. Purity 100%.
LRMS (m/z): 274 (M+1 )+.
PREPARATION 5
1 -Amino-3-bromo-N-(3-(methylthio)phenyl)-1W-pyrrole-2-carboxamide a) 3-Bromo-/V-(3-(methylthio)phenyl)-1 -(phenylsulfonyl)-l H-pyrrole-2- carboxamide In a three-necked round-bottom flask 3-(methylthio)aniline (8 mL, 65.34 mmol) was dissolved in 610 mL of toluene under inert atmosphere. To this solution was added trimethyl aluminium (2 M in toluene, 65.4 mL, 130.8 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution of methyl 3-bromo-1 - (phenylsulfonyl)-1 /- -pyrrole-2-carboxylate2 (15 g, 43.58 mmol) in 150 mL toluene was added and the reaction mixture was heated at 80°C for 3h. Then the mixture was allowed to cool to room temperature and 310 mL of water and 310 mL of 0,5M aqueous solution of disodium tartrate dihydrate were added to hydrolize unreacted trimethyl aluminium. After stirring for a while, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with HCI 1 N, water and brine and then dried over sodium sulphate and concentrated under reduced pressure to give 23.35 g ( 79% purity, 93% yield) of a residue that was used in the following step without further purification.
LRMS (m/z): 451 , 453 (M+1 )+. b) 3-Bromo-W-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide
3-Bromo-A/-(3-(methylthio)phenyl)-1-(phenylsulfonyl)-1 /- -pyrrole-2-carboxamide (23 g, 0.04 mmol) was dissolved in 370 mL methanol. Sodium hydroxide (1 N, 110 mL, 0.1 1 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and a precipitate was formed which was filtered off and washed several times with water. The solid was dried in the vacuum oven to give 13.27 g of the title compound and used in the following step without any further purification.
LRMS (m/z): 311 , 313 (M+1 )+. c) 1 -Amino-3-bromo-W-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide
3-Bromo-A/-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide (12.6 g, 40.68 mmol) according to the experimental procedure of Preparation 1 c gave 11.7 g (85% yield) of final product as a pale yellow solid.
LRMS (m/z): 326, 328 (M+1 )+.
PREPARATION 6
5-Bromo-2-(chloromethyl)-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -/][1 ,2,4]triazin- 4(3H)- one a) 3-Bromo-1 -(2-chloroacetamido)-A/-(3-(methylthio)phenyl)-1 H-pyrrole-2- carboxamide
1- Amino-3-bromo-N-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide (1 g, 3.07 mmol) was suspended in 25 mL acetic. Chloroacetyl chloride (1 .27 ml_, 15.92 mmol) was added dropwise and the mixture was stirred at room temperature for 1 h. The mixture was poured into water and ice and a solid was formed. The solid was filtered and washed with water. Then it was re-dissolved in ethyl acetate and the organic phase was washed with sodium bicarbonate solution, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to give 1.09 g (84% yield) of the desired compound.
LRMS (m/z): 402, 404 (M+1 )+. b) 5-Bromo-2-(chloromethyl)-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 - f][1,2,4]triazin-4(3H)- one
3-Bromo-1 -(2-chloroacetamido)-A/-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide (1 g, 2.48 mmol) was dissolved in 60 mL xylene. A catalytic amount of Pyridinium p- toluenesulfonate and molecular sieves was added and the mixture was stirred at 140°C overnight. The mixture was filtered and the residue was dissolved in ethyl acetate and washed with sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (0 to 30%, hexane-ethyl acetate) to give 0.265 g (28% yield) as colourless oil.
LRMS (m/z): 400, 402 (M+1 )+.
PREPARATION 7
2- ((4-Amino-3-iodo-1W^yrazolo[3,4-oQpyrimidin-1 -yl)methyl)-5-bromo-3-(3- (methylsulfinyl)phenyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 5-Bromo-2-(chloromethyl)-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1-r][1 ,2,4]triazin-4(3H)- one (0.265 g, 0.66 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4-oi]pyrimidin-4-amine (0.207 g, 0.79 mmol) and potassium carbonate (0.183 g, 1 .32 mmol) according to the method of Preparation 14 to give 0.260 g (62 % yield) of the title compound.
LRMS (m/z): 625, 627 (M+1 )+.
PREPARATION 8 2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1
Figure imgf000071_0001
- yl)methyl)-5-bromo-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -/][1,2,4]triazin-4(3H)- one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-bromo-3-(3-
(methylsulfinyl)phenyl)pyrrolo[2,1- ][1 !2!4]triazin-4(3 - )-one (0.220 g, 0.30 mmol) was dissolved in dioxane (10 ml_). (3-Fluoro-5-hydroxyphenyl)boronic acid (0.045 g, 0.30 mmol), 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.026 g, 0.03 mmol) and a solution of cesium carbonate ( 2M, 296 μΙ, 0.59 mmol) were added. The mixture was submitted to three vacuum-argon cycles and was then stirred at 100°C overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine and was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by SP1 Purification System (0-7%, methanol- dichloromethane) to give 0.022 g (12 % yield) of the title compound as a yellow solid.
L MS (m/z): 609, 61 1 (M+1 )+.
PREPARATION 9
1 -Amino-3-bromo-/V-phenyl-1 H-pyrrole-2-carboxamide a) 3-Bromo-/V-phenyl-1 -(phenylsulfonyl)-l W-pyrrole-2-carboxamide
Methyl 3-Bromo-1 -(phenylsulfonyl)-1 H-pyrrole-2-carboxylate2 (25 g, 0.07 mol) was treated with aniline (10 ml_, 0.1 1 mol) and trimethyl aluminium (2 M in toluene, 109 ml_, 0.22 mol) according to the method of Preparation 5a to give 29.80 g (88% yield) of the title compound as a colourless oil.
LRMS (m/z): 405, 407 (M+1 )+. b) 3-Bromo-W-phenyl-1 H-pyrrole-2-carboxamide
3- Bromo-/v-phenyl-1 -(phenylsulfonyl)-1 H-pyrrole-2-carboxamide (29.8 g, 0.06 mol) was treated with sodium hydroxide ( 75 ml_, 0.18 mol) according to the method of
Preparation 5b to give 16.68 g (98% yield) of the title compound as a yellow solid. Purity 95%.
LRMS (m/z): 265, 267 (M+1 )+. c) 1 -Amino-3-bromo-W-phenyl-1H-pyrrole-2-carboxamide
3-Bromo-A/-phenyl-1 H-pyrrole-2-carboxamide (16.8 g, 0.06 mol) was treated aqueous solution of sodium hydroxide (32%, 208 mL, 1 .66 mol), ammonium hydroxide solution (28%, 67 ml_, 0.47 mol), ammonium chloride (20.5 g, 0.3 mol) and Aliquat 336 (2.4 mL, 0.01 mol) Afterwards, it was treated with a aqueous solution of sodium hypochlorite (10%, 420 mL, 0.56 mol) according to the method of Preparation 1 c. The solid formed was triturated with diethyl eher and filtered to give 13.38 g (75%) of the title compound as a yellow solid. Purity 88%.
LRMS (m/z): 280, 282 (M+1 )+.
PREPARATION 10
(5-Bromo-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl acetate a) 2-((3-Bromo-2-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)amino)-2-oxoethyl acetate
1 -Amino-3-bromo-A/-phenyl-1 H-pyrrole-2-carboxamide (1 g, 3.57 mmol) was treated with 2-chloro-2-oxoethyl acetate (2 mL, 18.60 mmol) according to the method of Preparation 6a to give 1 .1 g (81 % yield) of the final product as a grey solid. Purity 97%.
LRMS (m/z): 380, 382 (M+1 )+. b) (5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl acetate
2-((3-Bromo-2-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)amino)-2-oxoethyl acetate (1 .1 g, 2.89 mmol) was treated with a catalytic amount of Pyridinium p-toluenesulfonate and molecular sieves according with the method of Preparation 6b. The residue was purified by flash chromatography (0 to 30%, hexane-ethyl acetate) to give 0.53 g (50% yield) as a colourless oil. Purity 97%.
LRMS (m/z): 362, 364 (M+1 )+.
PREPARATION 1 1
(5-lodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl acetate (5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl acetate (529 mg, 1 .46 mmol) was dissolved in 10 mL anhydrous dioxane in a Schlenk vessel. Sodium iodide (875 mg, 5.84 mmol), Copper(l) iodide (83.4 mg, 0.44 mmol) and trans- /V,/V'-dimethylcyclohexane-1 ,2-diamine (124 mg, 0.88 mmol) were added under argon conditions and the mixture was further submitted to three vacuum-argon cycles. The reaction vessel was sealed and the mixture was heated at 120°C overnight. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered throught celite. The organic phase was washed with 1 N hydrochloric acid, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 620 mg (72% yield) of the title compound. Purity 70%.
LRMS (m/z): 410 (M+1 )+.
PREPARATION 12
(4-Oxo-3^henyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]tri
yl)methyl methanesulfonate a) (4-Oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)methyl acetate
(5-lodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl acetate (620 mg, 1.52 mmol) was dissolved in 10 ml_ dimethylformamide in a Schlenk vessel. Copper(l) iodide (346.2 mg, 1 .82 mmol), hexamethylphosphoramide (1 .32 ml_, 7.58 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (963 μΙ, 7.58 mmol) were added under argon condition and the mixture was further submitted to three vacuum- argon cycles. The reaction vessel was sealed and the mixture was heated at 80°C overnight. The reaction mixture was partitioned with ethyl acetate and it was washed with water and brine. The organic layer was dried over sodium sulphate, filtered and evaporated to give 780 mg of the title compound used in the following step without further purification.
LRMS (m/z): 352 (M+1 )+. b) 2-(Hydroxymethyl)-3^henyl-5-(trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)- one
(4-Oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl acetate (780 mg, 1.1 1 mmol) was dissolved in 2ml_ ethanol. p-Toluenesulfonic acid monohydrate (21.12 mg, 0.11 mmol) was added and the mixture was heated at 80°C for 48 h. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using Isolera Purification System (hexane-ethyl acetate, 0% to 40 %) to give 236 mg (45% yield) of the title compound as a colourless oil.
LRMS (m/z): 310 (M+1 )+. c) (4-Oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)methyl methanesulfonate 2- (Hydroxymethyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[2,1 - |[1 ,2,4]triazin-4(3H)-one (150 mg, 0.26 mmol) was dissolved in 3 ml_ dichloromethane and triethylamine (1 10 μΙ, 0.79 mmol) was added. The reaction mixture was cooled in an ice bath. Methanesulfonyl chloride (49 μΙ, 0.63 mmol) was added and the mixture was stirred for 1 h in the ice bath. The mixture was diluted in dichloromethane and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 195 mg of the title compound pure enough to follow the next step.
LRMS (m/z): 388 (M+1 )+. PREPARATION 13
3- (3-Fluoro-5-methoxyphenyl)-1W-pyrazolo[3,4-d]pyrimidin-4-amine
3-lodo-1 -/-pyrazolo[3,4-c/]pyrimidin-4-amine (100 mg, 0.38 mmol), (3-fluoro-5- methoxyphenyl)boronic acid (195 mg, 1.15 mmol), sodium hydroxide (30.6 mg, 0.77 mmol) and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (15.6 mg, 0.05 mmol) were dissolved in 2 mL dimethylformamide in a Schlenk vessel. The mixture was submitted to three vacuum- argon cycles and was then stirred and heated at 120°C for 48 h. The mixture was filtered through a plug of Celite and the filtrated was purified directly by reverse-phase chromatography using SP1 Purification system to give 80 mg (62% yield) of the title compound as a solid.
LRMS (m/z): 260 (M+1 )+.
PREPARATION 14
2-((4-Amino-3-iodo-1W^yrazolo[3,4-(^pyrimidin-1 -yl)rnethyl)-3-phenyl-5- (trifluoromethyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(4-Oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl methanesulfonate (95 mg, 0.18 mmol) was dissolved in 1 .5 mL dimethylformamide. 3- lodo-1 H-pyrazolo[3,4-c ]pyrimidin-4-amine (57.6 mg, 0.22 mmol) and potassium carbonate (50.8 mg, 0.37 mmol) were added and the reaction mixture was heated at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 122 mg (99% yield) of the desired compound.
LRMS (m/z): 553 (M+1 )+. PREPARATION 15
(5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl methanesulfonate a) 5-Bromo-2-(hydroxymethyl)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
(5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2 - ][1 ,2,4]triazin-2-yl)methyl acetate (3.67 g, 10.13 mmol) was treated with p-toluenesulfonic (0.26 g, 1.36 mmol) according to the method of Preparation 12b to give 2.59 g (91 % yield) of the title compound. Purity 98%.
LRMS (m/z): 320, 322 (M+1 f.
b) (5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl methanesulfonate
5-Bromo-2-(hydroxymethyl)-3-phenylpyrrolo[2,1- |[1 ,2,4]triazin-4(3H)-one (2.59 g, 8.09 mmol) was treated with triethylamine (1.69 ml_, 12.13 mmol) and methanesulfonyl chloride (0.75 ml_, 9.70 mmol) according to the method of Preparation 12c to give 3.38 g (81 % yield) as a brown oil.
LRMS (m/z): 398, 400 (M+1 )+.
PREPARATION 16
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-bromo-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3W)-one
(5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl
methanesulfonate (100 mg, 0.25 mmol) was treated with 3-(3-fluoro-5- methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (72 mg, 0.28 mmol) and potassium carbonate (69 mg, 0.50 mmol) according to the method of Preparation 14 to give 139 mg (97%) as a pale brown solid of the title compound. Purity 92%.
LRMS (m/z): 561 (M+1 )+. PREPARATION 17
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(o- tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-(Chloromethyl)-3-(o-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (0.2 g, 0.58 mmol) was dissolved in 4 mL dimethylformamide. 3-lodo-1 - -pyrazolo[3,4-c/]pyrimidin-4-amine (0.18 g, 0.7 mmol) and potassium carbonate (0.16 g, 1.17 mmol) were dissolved. The mixture was stirred at room temperature overnight. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure.
The crude was triturated with diethyl ether to give the title compound (0.26 g, 89%) as a white solid. Purity 100%
LRMS (m/z): 449 (M+1 )\
PREPARATION 18
Ethyl 1 -amino-3-methyl-1H-pyrrole-2-carboxylate
Sodium hydride (60% dispersion in oil, 3.4 g, 0.09 mol) was washed several times with pentane and then in a three-necked round-bottom flask was suspended in 550 mL dimethylformamide. A solution of ethyl 3-methyl-1 H-pyrrole-2-carboxylate (10 g, 0.07 mol) dissolved in 200 mL dimethylformamide was added dropwise over 30 min with stirring, maintaining the reaction temperature at 0°C with an ice bath. The reaction was stirred at 0°C for 30 min and then 0-(diphenylphosphoryl)hydroxylamine (24.40 g, 0.10 mol) was added at 0°C. The reaction was stirred at room temperature overnight.
A solution of sodium thiosulfate saturated (500mL) was added dropwise and then water (500 mL). The mixture was extracted with diethyl ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using Isolera Purification System (0% to 25%, hexane-ethyl acetate) to give 3.01 g to the title. Purity 100%.
LRMS (m/z): 169 (M+1 )+.
PREPARATION 19
2-(Methoxymethyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one a) Ethyl 1 -(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2-carboxylate
Ethyl 1-amino-3-methyl-1 H-pyrrole-2-carboxylate (1 g, 5.95 mmol) was treated with 2- methoxyacetyl chloride (1.64 mL, 1.94 mmol) according to the method of Preparation 6a to give 1 .43 g (99% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 241 (M+1 )+. b) 1 -(2-Methoxyacetamido)-3-methyl-/V-(m-tolyl)-1 W-pyrrole-2-carboxamide
.Ethyl 1 -(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2-carboxylate (1 .43 g, 5.95 mmol) was treated with m-toluidine (0.96 mL, 8.95 mmol) and trimethyl aluminium (2 M in toluene, 8.96 mL, 17.92 mmol) according to the method of Preparation 5a to obtain 1.75 g (94% yield) of the title compound as a red solid. Purity 81 %.
LRMS (m/z): 302 (M+1 )+. c) 2-(Methoxymethyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3W)-one
1- (2-Methoxyacetamido)-3-methyl-A -(m-tolyl)-1 /-/-pyrrole-2-carboxamide (1.70 g, 5.64 mmol) was treated with pyridinium p-toluenesulfonate (0.28 g, 1.1 1 mmol) according to the method of Preparation 6b to obtain 1 .68 g (92%) of the title compound as a oil.
LRMS (m/z): 286 (M+1 )+.
PREPARATION 20
2- (Hydroxymethyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one 2-(Methoxymethyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (1 .56 g, 4.85 mmol) was dissolved in 150 mL dichloromethane and cooled at 0°C with an ice bath. A solution of boron tribromide (1 M, 24.2 mL, 24.2 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The organic was washed with 4% solution of sodium bicarbonate, brine and dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain 1 .75 g of the desired product as a dark oil. Purity 97%.
LRMS (m/z): 272 (M+1 )+.
PREPARATION 21
(5-Methyl-4-oxo-3-(m-tolyl)-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)methyl methanesulfonate
2-(Hydroxymethyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3/-/)-one (1.30 g, 4.83 mmol) was treated with triethylamine (1 .01 mL, 7.25 mmol) and methanesulfonyl chloride (0.45 mL, 5.81 mmol) according to the method described in Preparation 12c to give 2.25 g as a brown oil. The intermediate was used in the following step without further purification. Purity 83%.
LRMS (m/z): 350 (M+1 )+.
PREPARATION 22 2-((4-Amino-3-iodo-1W^yrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-(m- tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
(5-Methyl-4-oxo-3-(m-tolyl)-3,4-dihydropyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl methanesulfonate (1.12 g, 3.22 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (0.93 g, 3.56 mmol) and potassium carbonate (0.89 g, 6.44 mmol) according to the method of Preparation 14 to give 1.21 mg (73 % yield) of the title compound as a light brown solid. Purity 100%.
LRMS (m/z): 515 (M+1 )+.
PREPARATION 23
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W-pyrazolo[3,4-£ ]pyrirnidin-1 - yl)methyl)-5-iodo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3W)-one 2-((4-Amino-3-(3-f luoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1 -yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (120 mg, 0.21 mmol) was treated with sodium iodide (128 mg, 0.86 mmol), copper(l) iodide (12.2 mg, 0.06 mmol) and frans-/V,/V'-dimethylcyclohexane-1 ,2-diamine (18.24 mg, 0.13 mmol) according to the method of Preparation 1 1. The residue was purified using SP1 Purification System (0% to 10% dichloromethane-methanol) to give 50 mg (38 % yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 609 (M+1 )+.
PREPARATION 24
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W-pyrazolo[3,4-d]pyrirnidin-1 - yl)methyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1 -d[1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- iodo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (50 mg, 0.05 mmol) was dissolved in 2ml_ dimethylformamide in a reactor pressure. Phenyl hydrosulfide (13.58 mg, 0.12 mmol), potassium carbonate (17.04 mg, 0.12 mmol) and copper(l) iodide (20.35 mg, 0.11 mmol) were added under argon atmosphere and was then heated at 70°C overnight. The reaction was cooled at room temperature and purified directly by reverse phase using Isolera Purification System to give 33 mg (68% yield) of the title compound. Purity 72%.
LRMS (m/z): 591 (M+1 )+. PREPARATION 25
(5-Methyl-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 - l[1 ,2,4]triazin-2-yl)methyl acetate (5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2 - ][1 ,2,4]triazin-2-yl)methyl acetate (2 g, 4.86 mmol) was dissolved in 80 ml_ anhydrous dimethylformamide. 2,4,6- Trimethylboroxin (5.49 g, 43.74 mmol), sodium carbonate (13.43 g, 97.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.49 mmol) were added under argon conditions. The mixture was heated at 120°C overnight. The mixture was allowed to cool and was filtered through a plug of Celite, washing several times with ethyl acetate. The combined filtrates were washed with water, saturated ammonium chloride solution and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 2.5 g of the title compound that was used in the next step without any further purification.
LRMS (m/z): 298 (M+1 )+.
PREPARATION 26
(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - l[1 ,2,4]triazin-2-yl)methyl methanesulfonate a) (2-(Hydroxymethyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl acetate (2.5 g, 5.63 mmol) was treated with p-toluenesulfonic acid monohydrate (0.11 g, 0.56 mmol) according to the method of Preparation 12b to give 2.34 g. of the title compound that was used in the next step without any further purification.
LRMS (m/z): 256 (M+1 )+. b) (5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl methanesulfonate
(2-(Hydroxymethyl)-5-methyl-3-phenylpyrrolo[2,1-f|[1 ,2,4]triazin-4(3H)-one (2.30 g, 3.78 mmol) was treated with triethylamine (1 .58 ml_, 1 1.35 mmol), methanesulfonyl chloride (703 μΙ, 9.08 mmol) according to the method of Preparation 12c to give 2.18 g to the title compound that was used in the next step without any further purification.
LRMS (m/z): 334 (M+1 )+.
PREPARATION 27 2-((4-Amino-3-iodo-1W^yrazolo[3,4-oQpyrimidin-1 -yl)methyl)-5-rnethyl-3- phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
(5-MethyW-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-^[1 ,2,4]triazin-2-yl)methyl
methanesulfonate (2.18 g, 3.27 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4- c/]pyrimidin-4-amine (0.85 g, 3.27 mmol) and potassium carbonate (0.90 g, 6.54 mmol) according to the method of Preparation 14 to give 1.02 g (63% yield) of the title compound as a soild. Purity 98%.
L MS (m/z): 499 (M+1 )+.
PREPARATION 28
2-((4-Amino-3-((3-methoxyphenyl)thio)-1H^yrazolo[3,4-cnpyrimidin-1 -yl)methyl)- 5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one (60 mg, 0.12 mmol) was treated with 3- methoxybenzenethiol (25.32 mg, 0.18 mmol), potassium carbonate (25 mg, 0.18 mmol) and copper(l) iodide (34.4 mg, 0.18 mmol) according to the method of Preparation 24. The residue was purified by reverse phase using SP1 Purification System to give 25 mg (40 % yield) as a desired product. Purity 100%.
LRMS (m/z): 511 (M+1 )+.
PREPARATION 29
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-bromo-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 -/)-one (500 mg, 0.89 mmol) was treated with a solution of boron tribromide (1 M, 2.67 ml_, 2.67 mmol) according to the method of Preparation 20 to give 668 mg of the title compound. Purity 85%.
LRMS (m/z): 547, 549 (M+1 )+.
PREPARATION 30
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-((trimethylsilyl)eth^^ 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-o0pyrimidin-1-yl)meth bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 -/)-one (50 mg, 0.08 mmol) was dissolved in 1 mL dimethylformamide and 0.15 mL triethylamine in a microwave vessel. Ethynyl(trimethyl)silane (22 μΙ, 0.16 mmol), [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (3.4 mg, 0.05 mmol) , copper(l) iodide (0.74 mg, 0.01 mmol) were added and the reaction mixture was submitted to microwave conditions at 100°C for 2h. The same amount of reactants were added and the reaction was submitted to microwave conditions at 120°C for 2h more. The reaction was not finished but the mixture was filtered throught a plug of celite washing with ethyl acetate. The organic was washed with a solution 1 N of hydrogen chloride, water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase using SP1 Purification System to give 6 mg of the title compound. Purity 80%.
LRMS (m/z): 565 (M+1 )+.
PREPARATION 31
2-(Methoxymethyl)-5-methyl-3-(tetrahydro-2W-thiopyran-4-yl)pyrrolo[2,1 - ][1,2,4]triazin-4(3H)-one a) 1 -(2-Methoxyacetamido)-3-methyl- V-(tetrahydro-2H-thiopyran-4-yl)-1 H-pyrrole- 2-carboxamide
Triphenylphosphine (2.13 g, 8.12 mmols) was dissolved in 45 mL dichloromehtane. Bromine (420 μΙ, 8.19 mmol) was added dropwise over 30 min and then triethylamine (4.35 mL, 31.38 mmol) and ethyl 1-(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2- carboxylate dissolved in 2 mL dichloromethane were added. The mixture was stirred at room temperature for 2 h. The solvent was concentrated and the residue was suspended in 1 15 mL toluene. Tetrahydro-2H-thiopyran-4-amine (3.65 g, 31.14 mmol) was added and the reaction was stirred at 100°C for 48 h. The mixture was diluted with ethyl acetate and washed sequentially twice with 1 N hydrochloric acid and brine, dried over sodium sulphate, filtered and evaporated. The residue was purified using Isolera Purification System by reverse phase to give 1.05 g (53% yield) of the title product as a white solid.
LRMS (m/z): 312 (M+1 )+. b) 2-(Methoxymethyl)-5-methyl-3-(tetrahydro-2W-thiopyran-4-yl)pyrrolo[2,1 - f][1,2,4]triazin-4(3H)-one 1- (2-Methoxyacetamido)-3-methyl-/V-(tetrahydro-2H-th ^
carboxamide (1.03 g, 3.31 mmol) was dissolved in 35 mL toluene in a Dean-Starck vessel. Pyridinium p-toluenesulfonate (0.17 g, 0.66 mmol) was added and the mixture was stirred at 120°C overnight. Further pyridinium p-toluenesulfonate (0.085 g, 0.33 mmol) was added and the mixture was heated at 120°C overnight. The mixture was diluted with ethyl acetate and was washed with 4% sodium bicarbonate solution, 1 N hydrochloric acid and brine. The residue was dried over sodium sulphate, filtered and concentrated to obtain 1.06g (98 % yield) of the title compound that was used in the next step without any further purification.
L MS (m/z): 294 (M+1 )+.
PREPARATION 32
2- (Hydroxymethyl)-5-methyl-3-(tetrahydro-2W-thiopyran-4-yl)pyrrolo[2,1 - f][1 ,2,4]triazin-4(3H)-one
2-(Methoxymethyl)-5-methyl-3-(tetrahydro-2 - -thiopyran-4-yl)pyrrolo[2,1-r][1 ,2,4]triazin- 4(3 - )-one (1.06 g, 3.30 mmol) was treated with a solution of boron tribromide (1 M, 16.47 mL, 16.47 mmol) according to the method of Preparation 20 to give 0.931 g (99% yield) of the title compound as a beige solid.
LRMS (m/z): 280 (M+1 )+.
PREPARATION 33
(5-Methyl-4-oxo-3-(tetrahydro-2W-thiopyran-4-yl)-3,4-dihydropyrrolo[2,1 - f][1 ,2,4]triazin-2-yl)methyl methanesulfonate
2-(Hydroxymethyl)-5-methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1 - ][1 ,2,4]triazin- 4(3H)-one (0.930 g, 3.33 mmol) was treated with triethylamine (696 μΙ, 4.99 mmol) and methanesulfonyl chloride (310 μΙ, 3.99 mmol) according to the method of Preparation 12c to give 1.31 g (99%) of the title compound that was used in the next step without any further purification.
LRMS (m/z): 358 (M+1 )+.
PREPARATION 34
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 W-pyrazolo[3,4-d]pyrirnidin-1 - yl)methyl)-5-methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1 - ][1 ,2,4]triazin- 4(3W)-one (5-Methyl-4 >xo-3-(tetrahydro-2H-thiopy^^
2-yl)methyl methanesulfonate (188 mg, 0.53 mmol) was treated with 3-(3-fluoro-5- methoxyphenyl)-1 - -pyrazolo[3,4-c ]pyrimidin-4-amine (150 mg, 0.58 mmol) and potassium carbonate (145 mg, 1.05 mmol) according to the method of Preparation 14 to give 126 mg (46% yield ) of the title compound as a beige solid.
LRMS (m/z): 521 (M+1 )+.
PREPARATION 35
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W^yrazolo[3,4-dlpyrirnidin-1 - yl)methyl)-3-(1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-methylpyrrolo[2,1 - f][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (60 mg, 0.12 mmol) was dissolved in 3.4 mL methanol and 3.4 mL tetrahydrofuran. Oxone® (215 mg, 0.35 mmol) in 5 mL water was added dropwise and the mixture was stirred at room temperature overnight. The mixture was diluted in ethyl acetate and washed sequentially with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase using SP1 Purification System to obtain 66 mg (99% yield) of the desired product as a oil.
LRMS (m/z): 553 (M+1 )\
PREPARATION 36
2-((4-Amino-3-iodo-1W^yrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-(o- tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-(Chloromethyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (0.317 g, 1.10 mmol) was dissolved in 10 mL dimethylformamide. 3-lodo-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (0.316 g, 1.21 mmol) and potassium carbonate (0.167 g, 1.21 mmol) were added. The mixture was stirred at room temperature for 2 h. The solvent was concentrated and the residue was partitioned between dichloromethane and water. The organic phase was washed sequentially with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure.
The residue was purified by reverse phase chromatography using SP1 Purification System to obtain the title compound (0.508 g, 90%) as a white solid.
LRMS (m/z): 513 (M+1 )+. PREPARATION 37
(SJ-1 -Amino-/V-(1 -phenylethyl)-1 H-pyrrole-2-carboxamide a) (S)-N-C\ -Phenylethyl)-1 W-pyrrole-2-carboxamide
(S)-I -Phenylethanamine (24.7 mL, 0.19 mmol) was dissolved in 496 mL toluene under argon atmosphere. A solution of trimethylaluminum in toluene (2M, 95.9 mL, 0.19 mmol) was added and the reaction was stirred at room temperature for 20 minutes. The mixture was cooled with an ice bath and methyl 1 H-pyrrole-2-carboxylate (8 g, 0.06mmol) in 1 16 mL toluene was added dropwise. Then, the reaction mixture was heated at 80°C overnight.
The crude was cooled at room temperature and saturated sodium bicarbonate solution (750 mL), ethyl acetate (400 mL) and sodium tartrate (0.5M in water, 750 mL) were added. The organics were washed with water and brine, dried over sodium sulphate , filtered and evaporated. The residue was purified using SP1 Purification System (0% to 30%, hexane-ethyl acetate) to give 10.41 g (75% yield) of the desired compound as a white solid. Purity 99%.
LRMS (m/z): 215 (M+1 )+. b) -Amino-W-(1 -phenylethyl)-1 W-pyrrole-2-carboxamide
('S)-A/-(1-Phenylethyl)-1 H-pyrrole-2-carboxamide (1 1.54 g, 0.05 mmol) was treated with sodium hydroxide (28%, 156 mL, 20.21 mmol), ammonium hydroxide solution (28%, 50 mL, 0.4 mmol), ammonium chloride (17.3 g, 0.32 mmol), Aliquat 336 (1.97 mL, 0.01 mmol) and aqueous solution of sodium hypochlorite (10%, 356 mL, 0.48 mmol) according to the method of Preparation P1 c to give 9.81 g (80% yield) of the title compound as a yellow oil. Purity 100%
LRMS (m/z): 230 (M+1 )+.
PREPARATION 38
(S)-(4-Oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl acetate a) (S)-2-Oxo-2-((2-((1 -phenylethyl)carbamoyl)-1H-pyrrol-1 -yl)amino)ethyl acetate
(S)-1 -Amino-/V-(1-phenylethyl)-1 H-pyrrole-2-carboxamide (1.2 g, 5.23 mmol) was treated with 2-chloro-2-oxoethyl acetate (2.93 mL, 27.25 mmol) according to the method of Preparation 6a to give 2.04 g of the title compound that was used in the next step without any further purification.
LRMS (m/z): 330 (M+1 )+. b) (S)-(4-Oxo-3-(1 ^henylethyl)-3,4-dihydropyrrolo[2,1 - ][1,2,4]triazin-2-yl)methyl acetate
(S)-2-Oxo-2-((2-((1-phenylethyl)carbamoyl)-1 H-pyrrol-1 -yl)amino)ethyl acetate (1.72 g, 5.22 mmol) was treated with pyridinium p-toluenesulfonate (0.263 g, 1 .05 mmol) according with the method of Preparation 6b to give 1 .8 g of the title compound that was used in the next step without any further purification. Purity 75%.
LRMS (m/z): 312 (M+1 )+. PREPARATION 39
(S)-(4-Oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl methanesulfonate a) (S)-2-(Hydroxymethyl)-3-(1 -phenylethyl)pyrrolo[2,1 ,2,4]triazin-4(3H)-one (S)-(4-Oxo-3-(1-phenylethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl acetate (1 .60 g, 3.85 mmol) was treated with p-toluenesulfonic acid monohydrate (0.1 1 g, 0.58 mmol) according to the method of Preparation 12b to give 1.45 g ( 100% yield) of the title compound as a oil.
LRMS (m/z): 31 1 (M+1 )+. b) (S)-(4-Oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl methanesulfonate
(S)-2-(Hydroxymethyl)-3-(1-phenylethyl)pyrrolo[2,1-r][1 ,2,4]triazin-4(3H)-one (1.04 g, 3.86 mmol) was treated with triethylamine (0.81 mL, 5.78 mmol) and methanesulfonyl chloride (0.36 mL, 4.63 mmol) according to the method of Preparation 12c to give 1.71 g (yield 99%) of the title compound that was used in the next step without any further purification. Purity 80%.
LRMS (m/z): 347 (M+1 )+. PREPARATION 40
(S)-2-((4-Amino-3-iodo-1 W-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(1 - phenylethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
(S)-(4-Oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)methyl methanesulfonate (772 mg, 1.74 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (500 mg, 1.92 mmol) and potassium carbonate (481 mg, 3.48 mmol) according to the method of Preparation 14 to give 752 mg (82%) of the desired compound as a beige solid. Purity 97%.
LRMS (m/z): 513 (M+1 )+. PREPARATION 41
(3,4-Difluoro-5-hydroxyphenyl)boronic acid
(3,4-difluoro-5-methoxyphenyl)boronic acid (300 mg, 1.60 mmol) was treated with a solution of boron tribromide (1 M, 4.79 mL, 4.79 mmol) according to the method of Preparation 20 to give 281 mg (96% yield) of the title compound as a white solid. Purity 90%.
LRMS (m/z): 173 (M+1 )+. PREPARATION 42
/V-(2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)methanesulfonamide a) 2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine
5-Bromo-2-methoxypyridin-3-amine (1.73 g, 6.82 mmol) was dissolved in 50 mL dioxane. Bis(pinacolato)diboron (4.4 g, 17.33 mmol), potassium acetate (2.5 g, 25.47 mmol) were added and the mixture was submitted to three vacuum-argon cycles. Finally, bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.9 g, 0.16 mmol) was added under argon conditions. The mixture was then heated at 80°C for 2h. The crude was partitioned between ethyl acetate and water and then filtered through a plug of celite. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1 Purification System (0% to 20%, hexane-ethyl acetate) to obtain 1.43g. This solid was triturated with hexane, filtered and dried in the oven to give 0.94 g (55% yield) of the desired product as a solid. Purity 100%.
LRMS (m/z): 251 (M+1 )+. b) W-(2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)methanesulfonamide
2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine (940 mg, 3.76 mol) was dissolved in 20 mL pyridine. The mixture was submitted to three vacuum-argon cycles and was cooled at 0°C with an ice bath. Methanesulfonyl chloride (600 μΙ, 7.75 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 720 mg (58% yield) of the final compound as a mixture of boronic acid and boronate. Yield 100%.
LRMS (m/z): 329 (M+1 )+.
PREPARATION 43
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 W-pyrazolo[3,4-t/lpyrirnidin-1 - yl)methyl)-3 -phenyl -5-(phenylsulfonyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H) -one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1 -yl)methyl)-3- phenyl-5-(phenylthio)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3/-/)-one (50 mg, 0.08mmol) was treated with Oxone® (105 mg, 0.17 mmol) according to the method of Preparation 35. The residue was purified using SP1 Purification System (50% to 100% hexane-ethyl acetate) to give 14 mg (26% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 623 (M+1 )+. PREPARATION 44
/V,yV-Bis(2-methoxyethyl)hex-5-ynamide
Hex-5-ynoic acid (1 .5 g, 13.38 mmol) was dissolved in 125 ml_ dichloromethane. N-(3- Dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride (2.95 g, 15.39 mmol) and 4- (dimethylamino)pyridine (82 mg, 0.01 mmol) were added. The mixture was cooled at 0°C in an ice bath and bis(2-methoxyethyl)amine was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with 1 N hydrochloric acid and brine. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain 2.83 g (89% yield) as a yellow oil of the title compound. Purity 94%.
LRMS (m/z): 228 (M+1 )+
PREPARATION 45
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-((3-methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)- one 2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 ^
iodo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 - )-one (115 mg, 0.13 mmol) was treated with 3-methoxybenzenethiol (28.2 mg, 0.20 mmol), potassium carbonate (27.8 mg, 0.2 mmol) and copper(l) iodide (28 mg, 0.20 mmol) according to the method of Preparation 24. The residue was purified by reverse phase using SP1 Purification System to give 28 mg (33% yield) of the title compound as a yelow solid. Purity 100%
LRMS (m/z): 621 (M+1 )+
PREPARATION 46
(5-Bromo-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)methyl acetate a) 2-((3-Bromo-2-((3-(methylthio)phenyl)carbamoyl)-1W-pyrrol-1 -yl)amino)-2- oxoethyl acetate
1-Amino-3-bromo-A/-(3-(methylthio)phenyl)-1 H-pyrrole-2-carboxamide (10.85 g, 33.26 mmol) was treated with 2-chloro-2-oxoethyl acetate (18.6 mL, 173.02 mmol) according to the method of Preparation 6a. The solid formed was triturated with isopropyl ether to give 11.26 g (77% yield) of the title compound as a beige solid. Purity 96%.
LRMS (m/z): 427, 429 (M+1 )+ b) (5-Bromo-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2,1 - f][1,2,4]triazin-2-yl)methyl acetate
2-((3-Bromo-2-((3-(methylthio)phenyl)carbamoyl)-1 -/-pyrrol-1 -yl)amino)-2-oxoethyl acetate (1 1.26 g, 26.41 mmol) was treated with pyridinium p-toluenesulfonate (1.33 g, 5.29 mmol) according to the method 6b. The residue was crystallized with ethyl ether to give 7.29 g ( 68% yield) of the title compound as a beige solid.
LRMS (m/z): 408, 410 (M+1 )+
PREPARATION 47
2-(Hydroxymethyl)-5-methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1 - ][1,2,4]triazin- 4(3H)-one a) (5-Methyl-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin- 2-yl)methyl acetate)
(5-Bromo-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2, 1 - |[1 ,2,4]triazin-2- yl)methyl acetate (2 g, 4.90 mmol) was treated with 2,4,6-trimethylboroxin (6.15 mL, 44.09 mmol), sodium carbonate (13.55 g, 98.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.57 g, 0.49 mmol) according to the method of Preparation 25. The residue was purified using SP1 Purification System (0% to 20%, hexane-ethyl acetate) to obtain 602 mg (36% yield) of title compound as a oil. Purity 100%.
LRMS (m/z): 344 (M+1 )+ b) 2-(Hydroxymethyl)-5-methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1 - ][1 ,2,4]triazin- 4(3W)-one
(5-Methyl-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f|[1 ,2,4]triazin-2- yl)methyl acetate (600 mg, 1.75 mmol) was treated with p-Toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) accordind to the method of Preparation 12b to give 500 mf (yield 94%) of the title compound. Yield 98%.
LRMS (m/z): 302 (M+1 )+ PREPARATION 48
(5-Methyl-3-(3-(methylthio)phenyl)^-oxo-3,4-dihydropyrrolo[2J -/][1 ,2,4]triazin-2- yl)methyl methanesulfonate
2-(Hydroxymethyl)-5-methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1- |[1 ,2,4]triazin-4(3/-/)- one (1 .09 g, 3.62 mmol) was treated with triethylamine (0.76 ml_, 5.42 mmol) and methanesulfonyl chloride (0.34 mL, 4.34 mmol) according to the method of Preparation 12c to obtain 1 .22 g (89% yield) of the title compound as a beige solid. Purity 88%.
LRMS (m/z): 380 (M+1 )+ PREPARATION 49
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1H^yrazo
yl )methyl ) -5-methyl -3 -(3 -(methy Ith io^
(5-Methyl-3-(3-(methylthio)phenyl)-4-oxo-3,4-dihydropyrrolo[2,1- |[1 ,2,4]triazin-2- yl)methyl methanesulfonate (200 mg, 0.53 mmol) was treated with (5-iodo-4-oxo-3- phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl acetate (150 mg, 0.58 mmol) and potassium carbonate (145 mg, 1.05 mmol) according to the method of Preparation 14. The residue was crystallized with diethyl ether to obtain 152 mg (53% yield) of the title compound. Purity 100%.
LRMS (m/z): 543 (M+1 )+
PREPARATION 50 2- ((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W^yrazolo[3,4-cflpyrirnidin-1 - yl)methyl)-5-methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2,1 -f][1,2,4]triazin-4(3H)- one 2-((4-Amino-3-(3-f luoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5- methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (67 mg, 0.12 mmol) was treated with Oxone® (152 mg, 0.25 mmol) according to the method of Preparation 35 to obtain 73 mg (100% yield) of the title compound as a beige solid. Purity 99%.
LRMS (m/z): 575 (M+1 )+
PREPARATION 51
3- (3-Methoxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-cnpyrimidin-4-amine 3-lodo-1 -/-pyrazolo[3,4- /]pyrimidin-4-amine (100 mg, 0.38 mmol) was treated with (3- methoxy-5-(trifluoromethyl)phenyl)boronic acid (195 mg, 1.15 mmol), sodium hydroxide (30.6 mg, 0.77 mmol) and 1 ,1 '-bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane complex (15.6 mg, 0.05 mmol) according to the method described in Preparation 13. The residue was purified using SP1 Purification System (0% to 100%, hexane-ethyl acetate) to obtain 150 mg (25% yield) of the title compound. Purity 92%.
LRMS (m/z): 310 (M+1 )+
PREPARATION 52
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-bromo-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl
methanesulfonate (200 mg, 0.39 mmol) was treated with 3-(3-methoxy-5- (trifluoromethyl)phenyl)-1 H-pyrazolo[3,4- /]pyrimidin-4-amine (146 mg, 0.43 mmol) and potassium carbonate (107 mg, 0.77 mmol) according to the method of Preparation 14 to give 280 mg (87%) as solid of the title compound.
LRMS (m/z): 611 , 613 (M+1 , M+3)+ PREPARATION 53
2-((4-Amino-3-(3-methoxy-5-(trifluoromethyl)phenyl)-1W-pyrazolo[3,4-(^pyrimidin- 1 -yl)methyl)-3-phenylpyrrolo[2,1 -/][1,2,4]triazin-4(3H)-one 2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 -/)-one (80 mg, 0.13 mmol) was dissolved in 10 mL methanol. Triethylamine (55 μΙ, 0.39 mmol) and palladium on carbon (10 %, 14 mg, 0.03 mmol) were added under nitrogen atmosphere. The reaction was hydrogenated at 30 psi overnight. Under nitrogen conditions was filtered and evaporated. The crude was re-dissolved in dichoromethane and washed with 1 N hydrochloric acid, water and brine. The residue was dried over sodium sulphate, filtered and evaporated to obtain 70 mg (95% yield) of the title compound. Purity 92%.
L MS (m/z): 533 (M+1 )+
PREPARATION 54
2-((4-Ami no-3 -(5-hydroxypy rid i n -3 -yl )-1 H-py raz
((4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2- ((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-((4-methoxyphenyl)thio)-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.11 mmol) was treated with 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol (38 mg, 0.17 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (9.18 mg, 0.01 mmol) and cesium carbonate (2M, 169 μΙ, 0.34 mmol) according to the method of Preparation 8. The residue was purified using reverse phase to give 38 mg (56% yield) of the title compound. Purity 98%.
LRMS (m/z): 590 (M+1 )+. PREPARATION 55
4- Methoxy-N-(2-methoxy-5-(4,4,5,5-tetrarnethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide
2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mol) was dissolved in 10 mL pyridine. The mixture was submitted to three vacuum- argon cycles and was cooled at 0°C with an ice bath. 4-Methoxybenzene-1 -sulfonyl chloride (331 mg, 1.6 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 270 mg (78% yield) of the final compound as a mixture of boronic acid and boronate. Purity 77%.
LRMS (m/z): 421 (M+1 )+. PREPARATION 56
W-(5-(4-Amino-1 -((5-methyl-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 -/][1,2,4]triazin-
2- yl)methyl)-1 H-pyrazolo[3,4-cnpyrimidin-3-yl)-2-methoxypyridin-3-yl)-4- methoxybenzenesulfonamide 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (75 mg, 0.15 mmol) was treated with 4- methoxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (88.57 mg, 0.21 mmol) ), bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane complex (6 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 301 μΙ, 0.30 mmol) according to the method of Preparation 13. The residue was purified by reverse phase to give 30 mg (30% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 665 (M+1 )+. PREPARATION 57
1 -Amino-3-methyl-/V-phenyl-1 H-pyrrole-2-carboxamide a) 3-Methyl-1 H-pyrrole-2-carboxylic acid
Methyl 3-methyl-1 H-pyrrole-2-carboxylate (10 g, 0.07 mol) was dissolved in 200 mL methanol and a solution of sodium hydroxide (2N, 108 ml_, 0.22 mol) was added. The mixture was heated at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 2-3 with 2N hydrochloric acid. A white precipitate was formed and was filtered and washed with cool water. The solid was dried in the oven to give 6.97 g (77% yield) of the desired compound. Purity 100%.
LRMS (m/z): 126 (M+1 )+. b) 3-Methyl-/V-phenyl-1 W-pyrrole-2-carboxamide
3- Methyl-1 H-pyrrole-2-carboxylic acid (6.97 g, 0.06 mol) was dissolved in 150 mL dichloromethane and 1 mL dimethylformamide. Oxalyl chloride (7.26 mL, 0.08 mol) dissolved in 50 mL dichloromethane was added dropwise over 60 min and the mixture was stirred at room temperature for 2h. The mixture was concentrated to dryness and was re-dissolved in 150 mL dichloromethane. A solution of aniline (5.71 g, 0.06 mol) and /V,A/-diisopropylethylamine (14.5 ml_, 0.08 mol) dissolved in 50 mL dichloromethane was added dropwise and the reaction was stirred at room temperature for 2h.
The mixture was washed with sequentially twice with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using the Isolera Purification System (0% to 40%, hexane-ethyl acetate) to give 6.66 g (60% yield) of the title compound as a brown solid.
LRMS (m/z): 201 (M+1 )+. c) 1 -Amino-3-methyl-A/-phenyl-1H-pyrrole-2-carboxamide
In a three-necked flask it was placed aqueous solution of sodium hydroxide (32%, 95 mL, 665mmol), ammonium hydroxide solution (8M, 31 ml_, 250 mmol), ammonium chloride (10.7 g, 200 mmol) and Aliquat 336 (1 .34 g, 3.3 mmol). Afterwards, a solution of 3-methyl-N-phenyl-1 H-pyrrole-2-carboxamide (6.6 g, 33.2 mmol) dissolved in 140 mL of diethyl ether and 70 mL of methyl ferf-butyl ether was added and the mixture was cooled at 0°C affording a suspension. Over this suspension, a 10% aqueous solution of sodium hypochlorite (10%, 224 mL, 300 mmol) was added dropwise over 60 min with vigorous stirring more. The reaction mixture was stirred at room temperature overnight. The reaction crude was diluted with ethyl acetate until no suspended material was observed. The layers were separated and the organic phase was washed with water and brine, dried over sodium sulphate and concentrated under reduce pressure to give 7.54 g (90% yield) of the title compound that was used in the next step without any further purification.
LRMS (m/z): 216 (M+1 )+.
PREPARATION 58
( ?)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f [\ ,2,4]triazin-2-yl)ethyl acetate a) ( ?)-1 -((3-methyl-2-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)amino)-1 -oxopropan-2-yl acetate
1-Amino-3-methyl-N-phenyl-1 H-pyrrole-2-carboxamide (800 mg, 3.72 mmol) was dissolved in 14 mL ethyl acetate and (R)-2-acetoxypropanoic acid (407 μΙ, 3.72 mmol) was added. The mixture was cooled in an ice bath and /V,A/-Diisopropylethylamine (2.14 mL, 12.26 mmol) was added dropwise. After 15 min stirring, maintaining the reaction temperature at 0°C, T3P® (50% in ethyl acetate, 3.10 mL, 5.20 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 570 mg (46% yield) of the desired product. Purity 70%.
LRMS (m/z): 330 (M+1 )+. b) ( ?)-1 -(5-methyl-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 - ][1,2,4]triazin-2-yl)ethyl acetate
(f?)-1 -((3-methyl-2-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)amino)-1-oxopropan-2-yl acetate (570 m g, 1 .16 mmol) was treated with pyridinium p-toluenesulfonate (59 mg, 0.23 mmol) according with the method of Preparation 6b to give 430 mg of the title compound that was used in the next step without any further purification. Purity 50%.
LRMS (m/z): 312 (M+1 )+.
PREPARATION 59
( ?)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f {\ ,2,4]triazin-2-yl)ethyl methanesulfonate a) ( ?)-2-(1 -Hydroxyethyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(R)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f|[1 ,2,4]triazin-2-yl)ethyl acetate (430 mg, 0.69 mmol) was treated with p-toluenesulfonic (13 mg, 0.07 mmol) according to the method of Preparation 12b to give 350 mg of the title compound. Purity 69%.
LRMS (m/z): 270 (M+1 )+. b) (R)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1,2,4]triazin-2-yl)ethyl methanesulfonate
(R)-2-(1 -Hydroxyethyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 - )-one
(350 mg, 0.90 mmol) was treated with triethylamine (375 μΙ, 2.69 mmol) and methanesulfonyl chloride (167 μΙ, 2.15 mmol) according to the method of Preparation 12c to give 424 mg as a brown oil. Purity 51%.
LRMS (m/z): 348 (M+1 )+.
PREPARATION 60
(S)-2-(1 -(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
(R)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl methanesulfonate (424 mg, 0.62 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (195 mg, 0.75 mmol) and potassium carbonate (172 mg, 1.24 mmol) according to the method of Preparation 14 to give 230 mg (59% yield) of the desired compound and its enantiomer (9/1 mixture). This mixture was separated on a CHIRALPAK® AD preparative column using 80/20/0.2 heptane/ethanol/DEA mobile phase at room temperature at 15ML/min in a run time of 22min. The desired enantiomer was isolated with >98% e.e.
LRMS (m/z): 513 (M+1 )+.
PREPARATION 61
(S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl acetate a) (S)-1 -((3-Methyl-2-(phenylcarbamoyl)-1W-pyrrol-1 -yl)amino)-1 -oxopropan-2-yl acetate
1-Amino-3-methyl-N-phenyl-1 H-pyrrole-2-carboxamide (300 mg, 1 .39 mmol) was treated with (S)-2-acetoxypropanoic acid (184 mg, 1.39 mmol), N,N- diisopropylethylamine (801 μΙ, 4.60 mmol) and propylphosphonic anhydride solution (50% in ethyl acetate, 1 .16 ml_, 1.95 mmol) according to the method of Preparation 58a to give 330 mg (72 % yield) of the title compound. Purity 76%.
LRMS (m/z): 330 (M+1 )+. b) (S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)ethyl acetate
(S)-1 -((3-Methyl-2-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)amino)-1 -oxopropan-2-yl acetate (330 mg, 0.76 mmol) was treated with pyridinium p-toluenesulfonate (38 mg, 0.15 mmol) according with the method of Preparation 6b to give 323 mg of the title compound that was used in the next step without any further purification. Purity 48%.
LRMS (m/z): 312 (M+1 )+. PREPARATION 62
(S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f|[1 ,2,4]triazin-2-yl)ethyl methanesulfonate a) (S)-2-(1 -Hydroxyethyl)-5-methyl-3-phenylpyrrolo[2,1 -f|[1 ,2,4]triazin-4(3W)-one (S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl acetate (323 mg, 0.41 mmol) was treated with p-toluenesulfonic (8 mg, 0.04 mmol) according to the method of Preparation 12b to give 230 mg of the title compound. Purity 77%. LRMS (m/z): 270 (M+1 )+. b) (S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl methanesulfonate
(S)-2-(1 -Hydroxyethyl)-5-methyl-3-phenylpyrrolo[2 - ][1 ,2,4]triazin-4(3H)-one
(230 mg, 0.66 mmol) was treated with triethylamine (275 μΙ, 1 .97 mmol) and methanesulfonyl chloride (122 μΙ, 1.58 mmol) according to the method of Preparation 12c to give 267 mg of the title compound. Purity 66%.
LRMS (m/z): 348 (M+1 )+.
PREPARATION 63
(/?)-2-(1 -(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one (S)-1 -(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f|[1 ,2,4]triazin-2-yl)ethyl methanesulfonate (267 mg, 0.51 mmol) was treated with 3-iodo-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (159 mg, 0.61 mmol) and potassium carbonate (140 mg, 1 .01 mmol) according to the method of Preparation 14 to give 315 mg (100% yield) of the desired compound and its enantiomer (9/1 mixture). This mixture was separated according to the method described in Preparation 60. The desired enantiomer was isolated with >98% e.e.
LRMS (m/z): 513 (M+1 )+.
PREPARATION 64
1 -(4-lsopropylpiperazin-1 -yl)hex-5-yn-1 -one
Hex-5-ynoic acid (200 mg, 1 .78 mmol) was dissolved in 10 mL dichoromethane. N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (394 mg, 2.05 mmol) and 4- (dimethylamino)pyridine (1 1 mg, 0.09 mmol) were added and the mixture was cooled at 0°C. 1 -lsopropylpiperazine (229 mg, 1 .78 mmol) dissolved in 1 mL dichloromethane was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed with 4% sodium bicarbonate solution. The organic was acidified with 0.5N hydrochloric acid and the aqueous phase was neutralized with 2 N sodium hydroxide. The product was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 152 mg (38 % yield) of the title compound. Purity 90%.
LRMS (m/z): 223 (M+1 )+. PREPARATION 65
W-(2-Morpholinoethyl)hex-5-ynamide Hex-5-ynoic acid (200 mg, 1.78 mmol) was treated with 2-morpholinoethanamine (232 mg, 1.78 mmol), /V-(3-dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride (394 mg, 2.05 mmol) and 4-(dimethylamino)pyridine (1 1 mg, 0.09 mmol) according to the method described in Preparation 64 to obtain 136 mg (32 % yield) of the title compound. Purity 30%.
LRMS (m/z): 225 (M+1 )+.
PREPARATION 66
3-Bromo-1W-pyrazolo[3,4-cf]pyrimidine-4,6-diamine In a pressure reactor 6-amino-3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-ol (1 .1 g, 4.42 mmol) was suspended in ammonia (0.5 M in dioxane, 105 ml_, 52.5 mmol) and was then heated at 80°C for 90 h. The mixture was evaporated to dryness to obtain 1.54 g of the title compound. Purity 100%.
LRMS (m/z): 229, 231 (M+1 )+.
PREPARATION 67
3-(3-Fluoro-5-methoxyphenyl)-1W-pyrazolo[3,4-oflpyrimidine-4,6-diaiTiine
3-Bromo-1 H-pyrazolo[3,4-<^pyrimidine-4,6-diamine (750 mg, 2.15 mmol) was treated with (3-fluoro-5-methoxyphenyl)boronic acid (730 mg, 4.30 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (88 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 6.5 ml_, 6.50 mmol) according to the method of Preparation 13. The residue was purifed by reverse phase to give 95 mg (17% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 275 (M+1 )+.
PREPARATION 68
5-Bromo-2-((4,6-diamino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-/]pyrimidin-1 -yl)methyl)-3-phenylpyrrolo[2,1 - ][1,2,4]triazin-4(3H)-one
(5-Bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl
methanesulfonate (84 mg, 0.16 mmol) was treated with 3-(3-fluoro-5-methoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (30 mg, 0.1 1 mmol) and potassium carbonate (45 mg, 1.98 mmol) according to the method of Preparation 14 to give 1 12 mg of the desired compound. Purity 78%.
LRMS (m/z): 577 (M+1 )+.
PREPARATION 69
2-((4,6-Diamino-3-(3-fluoro-5-methoxyphenyl)-1 H^yrazolo[3,4- /lpyrirnidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 5-Bromo-2-((4,6-diamino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- /]pyrimidin-1 - yl)methyl)-3-phenylpyrrolo[2,1-r][1 ,2,4]triazin-4(3/-/)-one (118 mg, 0.2 mmol) was treated with 2,4,6-trimethylboroxin (257 μΙ, 1.84 mmol), potassium carbonate (566 mg, 4.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) according to the method described in Preparation 25. The residue was purified using SP1 Purification System (hexane-ethyl acetate, 0% to 100%) to obtain 88 mg (80% yield) of the title compound as a oil. Purity 95%.
LRMS (m/z): 512 (M+1 )+.
PREPARATION 70
(S)-2-((4-Amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-(1 - phenylethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
(S)-(4-Oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl methanesulfonate (295 mg, 0.67 mmol) was dissolved in 5 ml_ dimethylformamide. 5- Bromo-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (156 mg, 0.73 mmol) and potassium carbonate (184 mg, 1.33 mmol) were added. The mixture was stirred at room temperature overnight. The crude was poured over water and the precipitate was filtered and washed with water to give the title compound (239 mg, 55%) as a white solid. Purity 70%
PREPARATION 71
2-(3-Methoxybenzyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
1-(Bromomethyl)-3-methoxybenzene (1 g, 4.97 mmol) was treated with bis(pinacolato)diboron (1 .3 g, 5 mmol), potassium carbonate (2 g, 14.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.26 mmol) according to the method described in Preparation 42 to obtain 1 .35 g of the title compound that was used in the next step without any further purification.
LRMS (m/z): 249 (M+1 )+. PREPARATION 72
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W^yrazolo[3,4-cnpyrimidin-1 - yl)methyl)-5-(3-methoxybenzyl)-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1-yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (54 mg, 0.10 mmol) was dissolved in 1 ml. dioxane and 0.2 mL water. 2-(3-Methoxybenzyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (44 mg, 0.05 mmol), cesium carbonate (34 mg, 0.10 mmol) and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (2.9 mg, 0.01 mmol) were added under argon atmosphere. The reaction mixture was heated at 110°C overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was dried, filtered and concentrated. The crude was purified by reverse phase to give 30 mg (5 % yield) of the title compound. Purity 54%.
LRMS (m/z): 603 (M+1 )+. PREPARATION 73
(5-((4-Methoxyphenyl)thio)-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin- 2-yl)methyl acetate
(5-lodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl acetate (2.82 g, 5.51 mmol) was treated with 4-methoxybenzenethiol (1 .02 mL, 8.27 mmol), potassium carbonate (1 .14 g, 8.27 mmol) and copper(l) iodide (1.58 g, 8.27 mmol) according to the method described in Preparation 24. The residue was purifed using SP1 Purification System (0% to 30%, hexane-ethyl acetate) to give 1 .7 g (58 % yield) of the title compound. Purity 100%.
LRMS (m/z): 422 (M+1 )+.
PREPARATION 74
(5-((4-Methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin- 2-yl)methyl methanesulfonate a) 2-(Hydroxymethyl)-5-((4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1 - ][1,2,4]triazin-4(3H)-one (5-((4-Methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2 - ][1 ,2,4]triazin-2^ yl)methyl acetate (1 g, 2.37 mmol) was treated with p-toluenesulfonic (0.05 g, 0.24 mmol) according to the method of Preparation 12b to give 850 mg (94 % yield) of the title compound. Purity 100%.
LRMS (m/z): 270 (M+1 )+. b) (5-((4-Methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - f][1,2,4]triazin-2-yl)methyl methanesulfonate
2-(hydroxymethyl)-5-((4-methoxyphenyl)thio)-3-phenylpyrrolo[2: 1 - |[1 ,2,4]triazin-4(3H)- one (850 mg, 2.24 mmol) was treated with triethylamine (936 μΙ, 6.72 mmol) and methanesulfonyl chloride (416 μΙ, 5.38 mmol) according to the method of Preparation 12c to give 800 mg (78 % yield) of the title compound. Purity 96%.
LRMS (m/z): 458 (M+1 )+. PREPARATION 75
2-((4-Amino-3-iodo-1W^yrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5-((4- methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3W)-one
(5-((4-Methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f|[1 ,2,4]triazin-2- yl)methyl methanesulfonate (600 mg, 1.31 mmol) was treated with 3-iodo-1 H- pyrazolo[3,4-d]pyrimidin-4-amine (411 mg, 1.57 mmol) and potassium carbonate (362 mg, 2.62 mmol) according to the method described in Preparation 14 to give 850 mg (99 % yield) of the title compound. Purity 95%.
LRMS (m/z): 623 (M+1 )+.
PREPARATION 76
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-((4-methoxyphenyl)thio)-3^henylpyrrolo[2 - l[1 ,2,4]triazin-4(3H)- one
2- ((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-((4-methoxyphenyl)thio)-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.11 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (27 mg, 0.17 mmol), (bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (5 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 225 μΙ, 5.62 mmol) according to the method of Preparation 13. The residue was purifed by reverse phase to give 20 mg (29% yield) of the title compound as a white solid. Purity 58%. LRMS (m/z): 607 (M+1 )+.
PREPARATION 77
/V-(3-(4-Amino-1 -((5-((4-methoxyphenyl)thio)-4-oxo-3 -phenyl -3,4- dihydropyrrolo[2,1 -/][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-cnpyrirnidin-3- yl)phenyl)methanesulfonamide
2- ((4-Amino-3-iodo-1 H-pyrazolo[3,4-Q^pyrimidin-1 -yl)methyl)-5-((4-meth
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (70 mg, 0.11 mmol) was treated with N- (3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (50 mg,
0.17 mmol), (bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (5 mg, 0.01 mmol) and a solution of sodium hydroxide (1 M, 225 μΙ, 0.22 mmol) according to the method of Preparation 13. The residue was purifed by reverse phase to give 17 mg (23% yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 666 (M+1 )+.
PREPARATION 78
5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol 5-Bromopyridin-3-ol (3.70 g, 21.26 mmol) was treated with bis(pinacolato)diboron (10.80 g, 42.53 mmol), potassium acetate (6.26 g, 63.79 mmol) and bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 .74 g, 2.13 mmol), 1 ,1 -bis(diphenylphosphino)ferrocene (1.18 g, 2.13 mmol) according to the method described in Preparation 42a to give 2.5 g (53 % yield) of the title compound as a mixture of boronate and boronic acid. Purity 100%.
LRMS (m/z): 222 (M+1 )+.
PREPARACION 79
2-((4-Amino-3-(2-aminopyridin-4-yl)-1H-pyrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5- ((4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2- ((4-Amino-3-iodo-1 - -pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5-((4-methoxyphenyl)thio)-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.11 mmol) was treated with 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine (37 mg, 0.17 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (9.18 mg, 0.01 mmol) and sodium carbonate (36 mg, 0.34 mmol) according to the method of Preparation 8. The residue was purified using reverse phase to give 42 mg (63% yield) of the title compound. Purity 98%.
LRMS (m/z): 589 (M+1 )+. PREPARATION 80
2- ((4-Amino-3-(2-aminobenzo[cnoxazol-5-yl)-1 H^yrazoto
yl)methyl)-5-((4-methoxyphenyl)thio)-3^henylpyrrolo[2,1 - l[1 ,2,4]triazin-4(3H)- one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-((4-methoxyphenyl)thio)-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (70 mg, 0.11 mmol) was treated with 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (30 mg, 0.17 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (9.18 mg, 0.01 mmol) and cesium carbonate (169 mg, 0.34 mmol) according to the method of Preparation 8. The residue was purified using reverse phase to give 38 mg (50% yield) of the title compound. Purity 88%.
LRMS (m/z): 629 (M+1 )+.
PREPARATION 81
2-((4-Amino-3-(1H^yrazol-4-yl)-1H^yrazolo[3,4-<^
methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -f|[1 ,2,4]triazin-4(3W)-one
2- ((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-((4-methoxyphenyl)thio)-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.11 mmol) was treated with 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (19 mg, 0.17 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (9.18 mg, 0.01 mmol) and cesium carbonate (169 mg, 0.34 mmol) according to the method of Preparation 8. The residue was purified using reverse phase to give 23 mg (36% yield) of the title compound. Purity 98%.
LRMS (m/z): 563 (M+1 )+.
PREPARATION 82
1 -Amino-W-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrrole-2-carboxamide a) 3-Methyl-1 H-pyrrole-2-carboxylic acid 10.0 g (65.3 mmol) of ethyl 3-methyl-1 H-pyrrole-2-carboxylate (purchased from Astatech®, cat. no. 59362) was dissolved in 200 ml of ethanol. 150 ml of a 2 M solution of sodium hydroxide were added and the resulting solution was stirred at room temperature overnight. The organics were removed under reduced pressure and the resulting aqueous solution was neutralized with a 5 M solution of hydrochloric acid. A white solid precipitated, which was filtered, washed with water and dried in the oven. 6.80 g (83% yield) of the title compound were obtained.
LRMS (m/z): 126 (M+1 )+. b) V-(2,4-Dimethoxybenzyl)-3-methyl-1 H-pyrrole-2-carboxamide
6.13 g (49.4 mmol) of 3-methyl-1 H-pyrrole-2-carboxylic acid were dissolved in 150 ml of DCM and 1 ml of DMF was added. To this solution was added a solution of 4.72 ml (54.3 mmol) oxalyl chloride in 50 ml DCM during 1 hour. The solution was stirred for 2 hours and then the volatiles were removed under reduced pressure. The residue was re-dissolved in 135 ml of DCM and cooled in an ice bath. To this solution, 9.5 ml (54.5 mmol) of DIEA and 8.50 ml (56.6 mmol) of (2,4-dimethoxyphenyl)methanamine, dissolved in 40 ml of DCM, were added dropwise, and the reaction was stirred at room temperature overnight. The organics were removed in vacuo and the residue was partitioned between water and AcOEt, the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (0% to 50% hexane/AcOEt) to obtain 9.13 g (67% yield) of the title compound.
LRMS (m/z): 275 (M+1 )+. c) 1 -Amino-W-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrrole-2-carboxarnide
91 ml (0.64 mol) of an 8 M aqueous solution of sodium hydroxide and 40 ml (0.32 mol) of concentrated ammonia were mixed in a three-necked flask. The solution was stirred with a mechanical stirrer in an ice bath, 10.2 g (0.19 mol) of ammonium chloride and 4 g of Aliquat® 336 and a solution of 8.71 g (31.8 mmol) of A/-(2,4-dimethoxybenzyl)-3- methyl-1 H-pyrrole-2-carboxamide suspended in a mixture of 240 ml diethylether and 120 ml of DMTBE were added. To this suspension, 337 ml (0.45 mol) of a 10% aqueous solution of sodium hypochlorite were added dropwise (during 2 hours) with vigorous stirring, keeping the temperature at 0-5 °C. Subsequently, the reaction mixture was stirred at room temperature during 1 hour and then, additional 100 ml of sodium hypochlorite solution were added. The reaction was left at room temperature overnight. The reaction mixture was then diluted with diethylether and the two layers were separated. The aqueous layer was extracted twice with ether and the combined organic solutions were washed with water and brine, dried over magnesium sulphate, filtered and concentrated under vacuum to give a residue that was purified by flash chromatography (0% to 60% hexane/AcOEt) to obtain 4.5 g (49% yield) of the title compound as a pale orange solid.
LRMS (m/z): 290 (M+1 )+.
PREPARATION 83
2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -f][1,2,4]triazin- 4(3H)-one a) 1 -(2-Chloroacetamido)-W-(2,4-dimethoxybenzyl)-3-methyl-1 W-pyrrole-2- carboxamide
4.51 g (15.6 mmol) of 1 -amino-/V-(2,4-dimethoxybenzyl)-3-methyl-1 H-pyrrole-2- carboxamide were dissolved in 70 ml of glacial acetic acid and cooled in an ice bath. 1.36 ml (17.1 mmol) of 2-chloroacetyl chloride was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. Most of the solvent was removed under reduced pressure and the residue was treated with hexane until a solid precipitated. The product was collected by filtration, washed with cyclohexane and was dried in a stream of air. 5.24 g (92% yield) of the title compound were obtained as a pale brown solid.
LRMS (m/z): 366 (M+1 )+. b) 2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin- 4(3H)-one
5.24 g (14.3 mmol) of 1 -(2-chloroacetamido)-A/-(2,4-dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide were suspended in 500 ml of xylene and 3.65 g (14.5 mmol) of PPTS were added. The mixture was stirred at 140 °C for 2 hours and then the solvent was removed. The residue was partitioned between water and AcOEt, the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 4.98 g (100% yield) of the title compound.
LRMS (m/z): 348 (M+1 )+.
PREPARATION 84
2-((4-Amino-3-iodo-1W^yrazolo[3,4-<^pyrimidin-1 -yl)methyl)-3-(2,4- dimethoxybenzyl)-5-methylpyrrolo[2,1 -f [\ ,2,4]triazin-4(3H)-one To a solution of 4.98 g (14.32 mmol) of 2-(chloromethyl)-3-(2,4-dimethoxybenzyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one in DMF (180 ml) were added 4.12 g (15.8 mmol) of 3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-4-amine (purchased from Ark Pharm®, cat. no. AK-32203) and 2.25 g (16.3 mmol) of potassium carbonate. The mixture was stirred at room temperature overnight and most of the solvent was evaporated under reduced pressure. The resulting solution was partitioned between water and AcOEt and the solid that formed was filtered, washed with water and dried in the oven to give 3.80 g of a pale orange solid. The aqueous layer extracted with AcOEt and DCM. The combined organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain an additional 3.34 g of the title compound. The product obtained by filtration was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 1.25 g of the title compound as a pale orange solid. Overall yield: 56%.
LRMS (m/z): 573 (M+1 )+.
PREPARATION 85
2-((4-Amino-3-(3,5-dimethoxyphenyl)-1 H^yrazo
methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one 2-((4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (600 mg, 1.2 mmol) was treated with 2-(3,5- dimethoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (477 mg, 1 .81 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (98 mg, 0.1 mmol) and a solution of cesium carbonate (2M, 1.81 ml, 3.61 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 530 mg (69% yield) of the title compound as a solid. Purity 80%.
LRMS (m/z): 509 (M+1 )+.
PREPARATION 86
N-(3-Hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide
N-(3-bromo-5-hydroxyphenyl)methanesulfonamide (0.87 g, 3.27 mmol, prepared as described at C.Cannizzaro et al. US7417055 B2 20080826) was treated with bis(pinacolato)diboron (1.25 g, 4.90 mmol), potassium acetate (0.96 g, 9.81 mmol) and bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.27 g, 0.33 mmol) according to the method described in Preparation 16. The crude was purified using SP1 Purification System (0%-100%, hexane- ethyl acetate) to give 390 mg (31% yield) to the title compound as a solid.
LRMS (m/z): 312 (M-1 )" PREPARATION 87
3-(2-Methoxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol a) 5-Bromobenzene-1 ,3-diol
1-Bromo-3,5-dimethoxybenzene (5 g, 23 mmol) was treated with a solution of boron tribromide (1 M, 1 15 ml, 1 15 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 4.35 g (98% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 190 (M+1 )+. b) 3-Bromo-5-(2-methoxyethoxy)phenol
5-Bromobenzene-1 ,3-diol 1.2 g (6.3 mmol), 1-chloro-2-methoxyethane (0.64 ml, 6.9 mmol) and potassium carbonate (1 .84 g, 138 mmol) in acetone (60 ml) were heated at 100°C over 10 days. The crude is then filtered, washed with AcOEt and the mother liquor was concentrated in vaccuo. The crude was purified by reverse phase to give 413 mg (26% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 248 (M+1 )+. c) 3-(2-Methoxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol
3-bromo-5-(2-methoxyethoxy)phenol (360 mg, 1.46 mmol) was treated with bis(pinacolato)diboron (734 mg, 2.89 mmol), potassium acetate (429 mg, 4.37 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 19 mg, 0.02 mmol) and 1 ,1 '- bis(diphenylphosphino)ferrocene (81 mg, 0.15 mmol) according to the method described in Preparation 16. The crude was purified by reverse phase to give 266 mg (62% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 295 (M+1 )+. PREPARATION 88
Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate
Methyl 3-bromo-5-hydroxybenzoate (1 g, 4.33 mmol) was treated with bis(pinacolato)diboron (2.19 g, 8.66 mmol), potassium acetate (1 .25 g, 13 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (176 mg, 0.22 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene (120 mg, 0.22 mmol) according to the method described in Preparation 16. The crude was purified by reverse phase to give 783 mg (65% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 279 (M+1 )+. PREPARATION 89
3-(4-Amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzaldehyde a) 3-Bromo-5-hydroxybenzoic acid
Borane-methyl sulfide complex (5.53 ml, 1 1 mmol) was slowly added to a mixture of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) and trimethyl borate (2.1 ml, 18 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature overnight. Methanol (25 ml) was then added and the solvents removed. Dichloromethane (60 ml) and then pyridinium chlorochromate (3.77 g, 17 mmol) were added to the crude and the mixture was stirred at room temperature for an hour. The crude was filtered and the mother liquor concentrated in vaccuo. The residue was purified by reverse phase to give 1.85 g (51 % yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 200 (M-1 )". b) 3-Hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzaldehyde 3-Bromo-5-hydroxybenzoic acid (950 mg, 4.73 mmol) was treated with bis(pinacolato)diboron (2.40 g, 9.45 mmol), potassium acetate (1.39 g, 14 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (386 mg, 0.47 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene (262 mg, 0.47 mmol) according to the method described in Preparation 16. The crude was purified using SP1 Purification System (0%-20%, hexane- ethyl acetate) to give 1.05 g (87% yield) to the title compound as a solid. Purity 97%.
LRMS (m/z): 249 (M+1 )+ c) 3-(4-Amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - f][1,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxybenzaldehyde 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (400 mg, 0.74 mmol) was treated with 3- hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzaldehyde (274 mg, 1.1 1 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (60 mg, 0.07 mmol) and a solution of cesium carbonate (2M, 738 μΙ, 1.48 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 305 mg (72% yield) of the title compound as a solid. Purity 94%.
LRMS (m/z): 493 (M+1 )+.
EXAMPLE 1
2-((4-Amino-3-(3-hydroxyphenyl)-1W-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-(o- tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one was treated with (3-hydroxyphenyl)boronic acid according to the method described in Example 2. The residue was purified by reverse phase using SP1 Purification System to obtain 189 mg (40% yield) of the title compound. Purity 100%.
LRMS (m/z): 479 (M+1 )+
EXAMPLE 2
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-cf]pyrirnidin-1 - yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 - -pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-(o- tolyl)pyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (0.508 g, 0.99 mmol) was dissolved in 25 ml dioxane. (3-Fluoro-5-hydroxyphenyl)boronic acid (0.232 g, 1 .49 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.081 g, 0.10 mmol) and a solution of sodium carbonate (2M, 1.50 mL, 3 mmol) were added. The mixture was submitted to three vacuum-argon cycles and was then stirred at 100°C overnight. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 7%, methanol- dichloromethane). The solid obtained was dried in the vacuum oven to afford 0.344 g (71% yield) of the final compound. LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.85 (s, 3 H), 2.40 (s, 3 H), 5.20 (dd, J=75.22, 15.83 Hz, 2 H), 6.46 (d, J=2.34 Hz, 1 H), 6.66 (none, 2 H), 6.77 - 6.82 (m, J=8.60 Hz, 1 H), 6.86 (s, 1 H), 7.06 - 7.16 (m, 3 H), 7.22 - 7.26 (m, 1 H), 7.57 (d, J=2.74 Hz, 1 H), 7.99 (s, 1 H), 10.19 (s, 1 H).
EXAMPLE 3
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(o-tolyl)pyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-3-(o-tolyl)pyrrolo[2, 1 - f [\ ,2,4]triazin-4(3H)-one (298 mg, 0.6 mmol) was treated with (3-fluoro-5- hydroxyphenyl)boronic acid (1 15 mg, 0.74 mmol), sodium carbonate (99 mg, 0.93 mmol), palladium(ll) acetate (35 mg, 0.16 mmol) and triphenylphosphine (80 mg, 0.31 mmol) according to the method described in Example 19. The residue was purified by reverse phase using SP1 Purification System to obtain 103 mg (35% yield) of the title compound. Purity 100%.
LRMS (m/z): 483 (M+1 )+.
1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.13 (s, 3 H), 5.23 (q, J=16.28 Hz, 2 H), 6.51 (d, J=2.34 Hz, 1 H), 6.68 (d, J=9.77 Hz, 1 H), 6.89 - 6.95 (m, 2
H), 7.03 - 7.09 (m, 2 H), 7.12 - 7.18 (m, 1 H), 7.21 - 7.24 (m, 2 H), 7.28 - 7.32 (m, J=2.34 Hz, 1 H), 8.21 (s, 1 H).
EXAMPLE 4
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one (first enantiomer)
The racemic mixture of 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- c/]pyrimidin-1 -yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one was separated on a CHIRALPAK® IA preparative column using 85/15/0.2 heptane/I PA DEA mobile phase at room temperature at 20 mL/min in a run time of 45min. The first enantiomer was isolated with 100% e.e.
LRMS (m/z): 497 (M+1 )+.
EXAMPLE 5 2 -((4-Ami no -3 -(3 -f I u o ro -5 -hyd roxy p he nyl ) -1 H
yl)methyl)-5-bromo-3-(3-(methylthio)phenyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3W)-one
In a two-necked round-bottom flask indium(lll) chloride (2 mg, 0.02 mmol) was dissolved in 1 ml anhydrous tetrahydrofuran under nitrogen atmosphere. Titanium tetrachloride (5 μΙ, 0.05 mmol) was added and the mixture was stirred at room temperature for 1 h. 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 /-/-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-bromo-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1-f|[1 ,2,4]triazin- 4(3H)-one (22 mg, 0.04 mmol) dissolved in 1 ml anhydrous tetrahydrofuran was added and the mixture was stirred at room temperature for 2h. Then, more indium(lll) chloride (8 mg, 0.08 mmol) dissolved in 4 ml anhydrous tetrahydrofuran was added to the reaction followed by titanium tetrachloride (20 μΙ, 0.2 mmol) and the reaction was stirred at room temperature overnight.
The solvent was concentrated and the residue was purified by flash cromatography (0% to 100% hexane-ethyl aetate) to obtain 9 mg (42% yield) of the desired compound. Purity 99%.
LRMS (m/z): 593 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.33 (s, 3 H), 5.32 (dd, J=48.07, 15.63 Hz, 2 H), 6.66 (d, J=10.94 Hz, 1 H), 6.80 (d, J=2.74 Hz, 1 H), 6.87 (dd, J=14.07, 1.95 Hz, 3 H), 6.97 (dd, J=7.82, 2.34 Hz, 2 H), 7.15 (t, J=8.01 Hz, 1
H), 7.78 (d, J=3.13 Hz, 1 H), 7.98 (s, 1 H), 10.36 (br. s., 1 H).
EXAMPLE 6
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1H^yrazolo[3,4-c(]pyrirnidin-1 - yl)methyl)-5-(trifluoromethyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(4-Oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl methanesulfonate (195 mg, 0.25 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1 H- pyrazolo[3,4-d]pyrimidin-4-amine (81.5 mg, 0.25 mmol) were treated with potassium carbonate (70 mg, 0.50 mmol) according to the method of Preparation 14. The resulting residue was purified by reverse phase chromatography to obtain 80 mg (49 % yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 551 (M+1 )+.
1H NMR (400 MHz, CHLOROFORM-d) d ppm 3.87 (s, 3 H), 5.35 (s, 2 H), 5.56 (s, 2 H), 6.71 - 6.77 (m, 1 H), 6.80 (d, J=2.74 Hz, 1 H), 6.94 - 7.02 (m, 2 H), 7.14
- 7.20 (m, 2 H), 7.29 (d, J=2.74 Hz, 1 H), 7.32 - 7.42 (m, 3 H), 8.22 (s, 1 H). EXAMPLE 7
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1W^yrazolo[3,4- lpyrirnidin-1 - yl)methyl)pyrrolo[2,1 -f {\ ,2,4]triazin-4(3H)-one This compound was obtained as a subproduct of Preparation 72. The residue was purified by reverse phase using SP1 Purification System to give 18 mg of the title compound. Purity 99%
L MS (m/z): 483 (M+1 )+.
1H NMR (400 MHz, CHLOROFORM-d) d ppm 3.84 - 3.91 (m, 3 H), 5.32 (s, 2 H), 5.51 (s, 2 H), 6.53 (d, J=3.13 Hz, 1 H), 6.73 (d, J=10.55 Hz, 1 H), 6.93 - 7.02
(m, 2 H), 7.07 (d, J=4.30 Hz, 1 H), 7.14 (d, J=7.03 Hz, 2 H), 7.28 - 7.40 (m, 4 H), 8.22 (s, 1 H).
EXAMPLE 8
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl )methyl ) -5-methyl -3 -(3 -(methyl
one
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- bromo-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 - |[1 ,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was dissolved in 4 ml anhydrous 1 ,2-dichloroethane. 2,4,6-Trimethylboroxin (57 μΙ, 0.41 mmol), sodium carbonate (2M, 246 μΙ, 0.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.50 mmol) were added in a Schlenck vessel under argon conditions. The mixture was heated at 150°C for 30 min. The mixture was allowed to cool and was filtered through a plug of Celite, washing several times with dichloromethane. The combinated filtrates were concentrated under reduced pressure. The residue was directly purified by reverse phase using the Isolera Purification System (0% to 5%, dichloromethane-methanol) to give 9 mg (20% yield) as a solid. Purity 98%.
LRMS (m/z): 545 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 2.69 (s, 3 H), 5.28 - 5.34 (m, 2 H), 6.48 (d, J=2.74 Hz, 1 H), 6.62 - 6.69 (m, 1 H), 6.82 - 6.89 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.30 - 7.44 (m, 3 H), 7.62 (s, 1 H), 7.93 (s, 1 H), 10.21 (s, 1 H).
EXAMPLE 9 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-cr]pyrirnidin-1 - yl)methyl)-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
The title compound was obtained as a subproduct (1 1 mg) of the method of Example 8 as a white solid. Purity 96%.
LRMS (m/z): 531 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.65 (s, 3 H), 5.36 (d, J=9.38 Hz, 2 H), 6.63 - 6.70 (m, 2 H), 6.83 - 6.90 (m, 1 H), 7.02 (s, 1 H), 7.21 - 7.28 (m, 2 H), 7.34 - 7.50 (m, 4 H), 7.77 (s, 1 H), 7.94 (s, 1 H), 8.37 (s, 1 H).
EXAMPLE 10
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-3-phenyl-5-
(trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (40 mg, 0,07 mmol) was treated wtih (3-fluoro-4-hydroxyphenyl)boronic acid (31 ,5 mg, 0.20 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (2.75 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 135 μΙ, 0.13 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1 Purification System to give 29 mg (80% yield) of the title compound. Purity 98%.
LRMS (m/z): 537 (M+1 V\
1H NMR (400 MHz, CHLOROFORM-d) d ppm 5.35 (s, 2 H), 5.54 (s, 2 H), 6.80 (d, J=2.74 Hz, 1 H), 7.12 - 7.21 (m, 3 H), 7.26 (s, 1 H), 7.29 (d, J=2.74 Hz, 1 H),
7.32 - 7.39 (m, 3 H), 7.43 (dd, J=10.94, 1.95 Hz, 1 H), 8.21 (s, 1 H).
EXAMPLE 1 1
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1-yl)methyl)-5- (trifluoromethyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one (62 mg, 0.09 mmol) was dissolved in 2ml dichloromethane in a Schlenk vessel and the mixture was cooled in an ice bath. A solution of boron tribromide solution (1 M in dichloromethane, 270 μΙ, 0.27 mmol) dissolved in 0.5 ml dichloromethane was added dropwise and stirred for 2h. Further boron tribromide solution (1 M in dichloromethane, 270 μΙ, 0.27 mmol) dissolved in 0.5 ml dichloromethane was added dropwise and stirred overnight.
The mixture was diluted with more dichloromethane and then washed sequentially with water and brine. The organics were dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase chromatography using SP1 Purification System to give 10 mg (21% yield) of the title compound. Purity 98%.
LRMS (m/z): 537 (M+1 )+.
1H NMR (400 MHz, METHANOL-d4) d ppm 5.27 (s, 2 H), 6.52 - 6.59 (m, J=10.94 Hz, 1 H), 6.74 - 6.85 (m, 3 H), 7.14 (d, J=7.03 Hz, 2 H), 7.20 - 7.31 (m,
3 H), 7.42 (d, J=2.74 Hz, 1 H), 7.97 (s, 1 H).
EXAMPLE 12
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-rf]pyrirnidin-1 - yl)methyl)-3-phenylpyrrolo[2,1 -/][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (23 mg, 0.04 mmol) was dissolved in 5 ml methanol. Under nitrogen conditions palladium on carbon (9 mg, 0.01 mmol) and triethylamine (18 μΙ, 0.13 mmol) were added. The mixture was submitted to two nitrogen-hydrogen cycles and was hydrogenated at 4 psi for 1 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (1 % to 100%, hexane-ethyl acetate) and then re-purified by reverse phase using the SP1 Purification System to give 4 mg (22% yield) of the title compound as a white solid. Purity 99.5%.
LRMS (m/z): 467 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 5.31 (s, 3 H) 6.58 - 6.70 (m, 2 H) 6.78 - 6.89 (m, 2 H) 6.99 (s, 1 H) 7.09 - 7.27 (m, 5 H) 7.71 (s, 1 H) 7.99 (s, 1 H) 10.26 (s, 1 H).
EXAMPLE 13
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c/]pyrirmidin-1 -yl)methyl)-5-methyl-3-(m-tolyl)-2,3- dihydropyrrolo[2,1-/][1 ,2,4]triazin-4(1 H)-one (150 mg, 0.29 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (137 mg, 0.88 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (13 mg, 0.02 mmol) and a solution of sodium hydroxide ( 1 M, 878 μΙ, 0.88 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1 Purification System to give 42 mg (30% yield) of the title compound as a white solid. Purity 99.7%.
LRMS (m/z): 497 (M+1 )+.
1H NM (400 MHz, DMSO-d6) d ppm 2.04 (s, 3 H), 2.39 (s, 3 H), 5.29 (dd, j=74.64, 15.63 Hz, 2 H), 6.46 (d, J=2.74 Hz, 1 H), 6.61 (s, 1 H), 6.62 - 6.70 (m, 1 H), 6.79 - 6.85 (m, 1 H), 6.86 - 6.91 (m, 2 H), 6.96 - 7.03 (m, 1 H), 7.10 (t, J=7.82 Hz, 1 H), 7.58 (d, J=2.74 Hz, 1 H), 7.97 (s, 1 H), 10.20 (s, 1 H).
EXAMPLE 14
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)-1 H^yrazolo[3,4-<_f]pyrirnidin-1 - yl)methyl)-5-methyl-3-(m-tolyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3-(m-tolyl)-2,3- dihydropyrrolo[2,1-/][1 ,2,4]triazin-4(1 H)-one (150 mg, 0.29 mmol) was treated with (3- fluoro-4-hydroxyphenyl)boronic acid (137 mg, 0.88 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (13 mg, 0.02 mmol) and a solution of sodium hydroxide ( 1 M, 878 μΙ, 0.88 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1 Purification System to give 96 mg (66% yield) of the title compound as a white solid. Purity 98.7%.
LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.03 (s, 3 H), 2.38 (s, 3 H), 5.26 (dd,
J=75.81 , 15.63 Hz, 2 H), 6.45 (d, J=2.74 Hz, 1 H), 6.62 (s, 1 H), 6.88 (d, J=7.82 Hz, 1 H), 7.00 (d, J=7.82 Hz, 1 H), 7.05 - 7.14 (m, 2 H), 7.25 (d, J=8.60 Hz, 1 H), 7.33 (dd, J=11.92, 2.15 Hz, 1 H), 7.57 (d, J=2.74 Hz, 1 H), 7.95 (s, 1 H), 10.22 (s, 1 H).
EXAMPLE 15
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1 -fl[1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-(3-f luoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-3- phenyl-5-(phenylthio)pyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one (33 mg, 0.04 mmol) was treated with a solution of boron tribromide solution (1 M in dichloromethane, 120 μΙ, 0.12 mmol) according to the experimental procedure described in Example 11 to give 7 mg (30% yield) of the title compound as a white solid. Purity 96%.
LRMS (m/z): 577 (M+1 )+.
1H NMR (400 MHz, METHANOL-d4) d ppm 4.51 (s, 2 H), 5.50 (s, 1 H), 5.83 (s,
1 H), 6.06 (s, 1 H), 6.09 - 6.15 (m, 1 H), 6.38 (s, 2 H), 6.52 (s, 8 H), 6.61 (s, 1
H), 7.24 (s, 1 H).
EXAMPLE 16
2-((4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-<^pyrimidin-
1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1,2,4]triazin-4(3H)-one
2- ((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one (76 mg, 0.15 mmol) was treated with (3- hydroxy-5-(trifluoromethyl)phenyl)boronic acid (94.2 mg, 0.46 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6.23 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 305 μΙ, 0.31 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using Isolera Purification System to give 25 mg (34% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 533 (M+1 )+.
1H NMR (600 MHz, DMSO-d6) δ ppm 5.25 (s, 3 H), 6.41 (d, J=2.35 Hz, 1 H), 7.09 (d, J=7.04 Hz, 2 H), 7.12 - 7.22 (m, 3 H), 7.26 (d, J=5.28 Hz, 2 H), 7.51 (d, J=2.35 Hz, 1 H), 7.99 (s, 1 H), 10.37 (s, 1 H).
EXAMPLE 17
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 /-/-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one (80 mg, 0.16 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (75 mg, 0.48 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (7 mg, 0.01 mmol) and a solution of sodium hydroxide (1 M, 320 μΙ, 0.32 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using Isolera Purification System to give 58 mg (74% yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 483 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 5.27 (s, 2 H), 6.45 (d, J=2.34 Hz, 1 H), 6.63 - 6.69 (m, 1 H), 6.82 (d, J=8.21 Hz, 1 H), 6.86 - 6.88 (m, 1
H), 7.09 (d, J=6.64 Hz, 2 H), 7.13 - 7.22 (m, 3 H), 7.56 (d, J=2.74 Hz, 1 H), 7.98 (s, 1 H), 10.20 (s, 1 H).
EXAMPLE 18
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one (second enantiomer)
The racemic mixture of 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one was separated on a CHIRALPAK® IA preparative column using 85/15/0.2 heptane/IPA DEA mobile phase at room temperature at 20 mL/min in a run time of 45min. The second enantiomer was isolated with 98% e.e.
LRMS (m/z): 497 (M+1 )+.
EXAMPLE 19
2-((4-Amino-3-(3-chloro-5-hydroxyphenyl)-1W-pyrazolo[3,4-t/lpyrirnidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one (70 mg, 0.14 mmol) was dissolved in 2 ml anhydrous dioxane in a reactor pressure. (3-Chloro-5-hydroxyphenyl)boronic acid (36.32 mg, 0.21 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 1.5 mg, 0.01 mmol) and sodium carbonate (44.6 mg, 0.42 mmol) were added under argon atmosphere. The reaction was stirred at 100°C overnight. Further (3-chloro-5-hydroxyphenyl)boronic acid (36.32 mg, 0.21 mmol) and bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 1.5 mg, 0.01 mmol) were added and heated at 100°C overnight. The residue was allowed to cool and was filtered through a plug of celite. The filtered was evaporated and purified by reverse phase using a SP1 Purification System to give 40 mg (57% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 499, 501 (M+1 )+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3 H), 5.24 (s, 2 H), 6.43 (d, J=2.34 Hz, 1 H), 6.87 (s, 1 H), 6.95 (s, 1 H), 7.02 (s, 1 H), 7.05 - 7.10 (m, J=6.64 Hz, 2 H), 7.10 - 7.22 (m, 3 H), 7.54 (d, J=2.34 Hz, 1 H), 7.97 (s, 1 H), 10.18 (s, 1 H).
EXAMPLE 20
2-((4-Amino-3-(2-aminobenzo[rf]oxazol-5-yl)-1H^yrazolo[3,4-cflpyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pynmidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.14 mmol) was treated with (2- aminobenzo[d]oxazol-5-yl)boronic acid (37.5 mg, 0.21 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 1.5 mg, 0.01 mmol) and sodium carbonate (44.6 mg, 0.42 mmol) according to the method of Example 19 to give 30 mg (40% yield) to the desired product as a solid. Purity 90%.
LRMS (m/z): 505 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 5.26 (s, 2 H), 6.45 (s, 1 H), 7.06 - 7.26 (m, 7 H), 7.36 (s, 1 H), 7.45 (s, 1 H), 7.47 (s, 1 H), 7.51 - 7.62 (m, 3 H), 7.98 (s, 1 H).
EXAMPLE 21
2-((4-Amino-3-((3-hydroxyphenyl)thio)-1 H-pyrazolo[3,4-cdpyrimidin-1 -yl)methyl)- 5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-((3-methoxyphenyl)thio)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f|[1 ,2,4]triazin-4(3H)-one (25 mg, 0.05 mmol) was treated with a solution of boron tribromide (1 M in dichloromethane, 147 μΙ, 0.15 mmol) according to the experimental procedure described in Example 11 to give 14 mg (57% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 5.22 (s, 2 H), 6.44 (d, J=2.34 Hz, 1 H), 6.59 (s, 1 H), 6.64 (d, J=7.82 Hz, 1 H), 6.70 (d, J=8.21 Hz, 1 H), 7.09 - 7.22 (m, 3 H), 7.24 - 7.33 (m, 3 H), 7.51 (d, J=2.34 Hz, 1 H), 8.01 (s, 1 H), 9.72 (s, 1 H).
EXAMPLE 22 2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1H^yrazolo[3,4-cnpyrirnidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-a0pyrimidin-1 -yl)meth^
phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (70 mg, 0.14 mmol) was treated with (3,4- difluoro-5-hydroxyphenyl)boronic acid (36.6 mg, 0.21 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 1.5 mg, 0.01 mmol) and sodium carbonate (44.6 mg, 0.42 mmol) according to the method of Example 19 to give 29 mg (40% yield) of the title compound as a yellow solid. Purity 95%.
L MS (m/z): 501 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 5.25 (s, 2 H), 6.45 (d, J=2.34 Hz, 1 H), 6.87 - 6.95 (m, 1 H), 6.99 (d, J=7.03 Hz, 1 H), 7.08 (s, 1 H), 7.10 (s, 1 H), 7.13 - 7.24 (m, 3 H), 7.56 (d, J=2.74 Hz, 1 H), 7.97 (s, 1 H), 8.43 (s, 1 H).
EXAMPLE 23
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-cf]pyrirnidin-1 - yl)methyl)-5-ethynyl-3-phenylpyrrolo[2,1 - l[1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 /-/-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-3- phenyl-5-((trimethylsilyl)ethynyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3/-/)-one (6 mg, 0.01 mmol) was dissolved in 0.25 mL dimethylformamide. A solution of tetrabutylammonium fluoride (10 μΙ, 0.01 mmol) was added and the reaction was stirred at room temperature for 10 min and then cooled to 0°C with an ice bath. Water (1.5 mL) was added at 0°C and the reaction was kept at this temperature for 30 min. The solid formed was filtered off and purified by reverse fase using SP1 Purification System to give 11 mg (100% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 493 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 4.15 (s, 1 H), 5.26 (s, 2 H), 6.64 (d,
J=1 1.33 Hz, 1 H), 6.71 - 6.91 (m, 3 H), 7.05 - 7.27 (m, 5 H), 7.66 (d, J=2.74 Hz,
1 H), 7.98 (s, 1 H), 10.17 (s, 1 H).
EXAMPLE 24 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1
Figure imgf000119_0001
- yl)methyl)-5-methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1 -/][1,2,4]triazin-
4(3H)-one 2-((4-Amino-3-(3-f luoro-5-methoxyphenyl)-1 - -pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (80 mg, 0.15 mmol) was treated with a solution of boron tribromide (1 M, 770 μΙ, 0.77 mmol) according to the method of Preparation 20 to give 18 mg (24% yield) of the title compound as a beige solid. Purity 95%.
L MS (m/z): 507 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1 .39 - 1.52 (m, J=12.1 1 Hz, 2 H), 2.08 (t, J=12.70 Hz, 2 H), 2.39 (s, 3 H), 2.57 - 2.70 (m, 4 H), 3.69 - 3.83 (m, 1 H), 5.67 (s, 2 H), 6.39 (d, J=1.56 Hz, 1 H), 6.66 (d, J=10.16 Hz, 1 H), 6.77 - 6.87 (m, 2 H), 7.47 (s, 1 H), 8.40 (s, 1 H), 10.18 (s, 1 H).
EXAMPLE 25
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(1 ,1 -dioxidotetrahydro-2W-thiopyran-4-yl)-5-methylpyrrolo[2,1 - ][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1-yl)methyl)-3- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-methylpyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one (63 mg, 0.11 mmol) was treated with a solution of boron tribromide (1 M, 576 μΙ, 0.58 mmol) according to the method of Preparation 20 to give 4 mg (6% yield) as a desired compound. Purity 90%.
LRMS (m/z): 539 (M+1 )+.
1H NMR (600 MHz, DMSO-d6) d ppm 1 .77 (t, J=12.51 Hz, 2 H), 2.80 (t, 2 H), 3.00 - 3.11 (m, 4 H), 4.35 (t, 1 H), 5.74 (s, 2 H), 6.34 (d, J=3.13 Hz, 1 H), 6.64 (d, J=11 .26 Hz, 1 H), 6.79 - 6.85 (m, 2 H), 7.37 (d, J=3.13 Hz, 1 H), 8.34 (s, 1 H), 10.17 (s, 1 H).
EXAMPLE 26
(S)-2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 -f\[\ ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c/]pyrirmidin-1 -yl)methyl)-3-((R)-1 - phenylethyl)pyrrolo[1 ,2-£>]pyridazin-4(3/-/)-one (100 mg, 0.20 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (91 mg, 0.58 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 390 μΙ, 0.39 mmol) according to the method of Preparation 7 to give 70 mg (72% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 496 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.68 (s, 3 H), 5.50 - 5.70 (m, 2 H), 5.91 (d, J=16.80 Hz, 1 H), 6.56 - 6.61 (m, 1 H), 6.65 (d, J=10.55 Hz, 1 H), 6.73 (d, J=8.60 Hz, 1 H), 6.81 (s, 2 H), 6.87 - 6.95 (m, 2 H), 7.09 (s, 3 H), 7.65 (s, 1 H), 8.23 (s, 1 H), 10.20 (s, 1 H).
EXAMPLE 27
(S)-2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- /lpyrirnidin-1 - yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 /-/-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-3-((R)-1 - phenylethyl)pyrrolo[1 ,2-Jb]pyridazin-4(3/-/)-one (100 mg, 0.20 mmol) was treated with (3,4-difluoro-5-hydroxyphenyl)boronic acid (68 mg, 0.39 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 390 μΙ, 0.39 mmol) according to the method of Preparation 13 to give 73 mg (73% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 515 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.73 (d, J=7.03 Hz, 3 H), 3.04 - 3.10 (m, 3 H), 3.95 - 4.01 (m, 3 H), 5.56 (d, 1 H) 5.69 (d, 1 H), 5.95 (d, J=16.02 Hz, 1 H),
6.58 (dd, J=4.10, 2.54 Hz, 1 H), 6.83 (dd, J=4.30, 1 .56 Hz, 1 H), 6.89 (s, 2 H), 7.04 - 7.14 (m, J=3.13 Hz, 3 H), 7.64 (s, 1 H), 7.75 (d, J=2.34 Hz, 1 H), 8.09 (d, J=1.95 Hz, 1 H), 8.21 - 8.25 (m, 1 H), 9.45 (s, 1 H). EXAMPLE 28
(S)-2-((4-Amino-3-(3-hydroxy-5-(trifluorom
cGpyrimidin-1 -yl)methyl)-3-(1 ^heny^
2-((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-3-((R)-1 - phenylethyl)pyrrolo[1 ,2-£>]pyridazin-4(3/- )-one (100 mg, 0.20 mmol) was treated with (3- hydroxy-5-(trifluoromethyl)phenyl)boronic acid (80.3 mg, 0.39 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (15 mg, 0.02 mmol) and potassium carbonate (62 mg, 0.59 mmol) according to the method of Example 19. The residue was purified by reverse phase using SP1 Purification System to give 55 mg (52% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 547 (M+1 )+.
H NMR (400 MHz, CHLOROFORM-d) d ppm 1.88 (d, J=6.25 Hz, 3 H), 5.24 -
5.42 (m, 1 H), 5.54 (s, 2 H), 5.70 (d, J=15.63 Hz, 1 H), 6.08 (q, 1 H), 6.45 (s, 1 H), 6.96 (d, J=2.74 Hz, 1 H), 7.00 - 7.08 (m, 2 H), 7.09 - 7.13 (m, J=7.03 Hz, 2 H), 7.22 (s, 1 H), 7.26 (s, 1 H), 7.34 (s, 1 H), 8.36 (s, 1 H). EXAMPLE 29
(S)-yV-(5-(4-Amino-1 -((4-oxo-3-(1 -phenylethyl)-3,4-dihydropyrrolo[2,1 -
/][1,2,4]triazin-2-yl)methyl)-1W^yrazolo[3,4-c/lpyrimidin-3-yl)-2-methoxypyri yl)methanesulfonamide 2-((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-3-((R)-1 - phenylethyl)pyrrolo[1 ,2-J ]pyridazin-4(3/-/)-one (100 mg, 0.2 mmol) was treated with N- (2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)methanesulfonamide (128 mg, 0.39 mmol), bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane complex (8 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 390 μΙ, 0.39 mmol) according to the method of Preparation 13 to give 106 mg (92% yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 587 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.67 (d, J=6.25 Hz, 3 H), 5.45 - 5.70 (m, 2 H), 5.89 (d, J=15.24 Hz, 1 H), 6.53 - 6.60 (m, 1 H), 6.81 (d, J=3.13 Hz, 2 H), 6.83 - 6.91 (m, 3 H), 6.93 (d, J=7.03 Hz, 1 H), 7.07 (s, 3 H), 7.63 (s, 1 H), 8.20
(s, 1 H), 8.30 (s, 1 H), 10.67 (s, 1 H).
EXAMPLE 30
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-(phenylsulfonyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylsulfonyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3/- )-one (14 mg, 0.02 mmol) was treated with was treated with a solution of boron tribromide (1 M, 68 μΙ, 0.07 mmol) according to the method Preparation 20. The residue was triturated with isopropyl ether, filtered and dried in the oven to give 9 mg (66% yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 609 (M+1 )+.
1H NMR (400 MHz, METHANOL-d4) d ppm 5.26 (s, 2 H), 6.56 - 6.63 (m, 1 H), 6.76 - 6.82 (m, 1 H), 6.76 - 6.81 (m, 1 H), 6.82 - 6.85 (m, 1 H), 6.82 - 6.84 (m, 1
H), 7.09 (d, 1 H), 7.1 1 (d, J=1 .95 Hz, 1 H), 7.23 - 7.31 (m, 3 H), 7.39 - 7.45 (m, J=7.62, 7.62 Hz, 1 H), 7.48 (d, J=3.13 Hz, 1 H), 7.49 - 7.54 (m, J=7.42, 7.42 Hz, 1 H), 7.95 - 7.98 (m, 1 H), 7.99 (s, 2 H). EXAMPLE 31
6-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1W-pyrazolo[3,4-(^pyrimidin-1 - yl)methyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-5-yl)-W,W-bis(2- methoxyethyl)hex-5-ynamide 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- bromo-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (50 mg, 0.09), A/,/V-bis(2- methoxyethyl)hex-5-ynamide (48.7 mg, 0.23 mmol), diethylamine (2.55 ml_) and copper(l) iodide (1 .74 mg, 0.01 mmol) were added in a reactor pressure. The mixture was submitted to three vacuum-argon cycles and was heated at 60°C for 4h. The solvent was evaporated and re-dissolved in ethyl acetate then washed with a solution of ammonium acetate and brine. The organic layer was dried over sodium sulphate, filtered and dried over reduced pressure to obtain a residue that was purified using SP1 Purification System (0% to 1 % dichlormethane-methanol) to give 13 mg (20% yield) of the title compound as a solid. Purity 93%.
LRMS (m/z): 695 (M+1 )+.
1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.91 (d, J=6.64 Hz, 2 H), 2.50 (t, J=6.45 Hz, 2 H), 2.62 (t, J=7.62 Hz, 2 H), 3.19 (s, 3 H), 3.28 (s, 3 H), 3.41 (t, J=5.47 Hz, 2 H), 3.44 - 3.59 (m, 6 H), 5.31 (s, 2 H), 5.64 (s, 2 H), 6.53 (d, J=2.34 Hz, 1 H), 6.69 (d, J=10.16 Hz, 1 H), 6.88 (d, 1 H), 6.91 (s, 1 H), 7.04 (d, J=5.08 Hz, 2 H), 7.20 (d, J=2.74 Hz, 1 H), 7.21 - 7.25 (m, 2 H), 7.26 (s, 1 H),
8.16 (s, 1 H).
EXAMPLE 32
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-((3-hydroxyphenyl)thio)-3^henylpyrrolo[2J -f][1,2,4]triazin-4(3H)-one 2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- ((3-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (28 mg, 0.05 mmol) was treated with a solution of boron tribromide (1 M, 271 μΙ, 0.27 mmol) according to the method of Preparation 20. The residue was purified by reverse phase to give 20 mg (75% yield) of the title compound as a white solid. Purity 96%.
LRMS (m/z): 593 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 5.26 (s, 2 H), 6.41 (d, J=2.74 Hz, 1 H), 6.58 - 6.68 (m, 3 H), 6.70 (d, J=7.82 Hz, 1 H), 6.81 (d, J=8.60 Hz, 1 H), 6.85 (s, 1 H), 7.04 - 7.27 (m, 6 H), 7.71 (d, J=2.74 Hz, 1 H), 7.99 (s, 1 H), 8.40 (s, 1 H), 9.63 (s, 1 H).
EXAMPLE 33
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-rf]pyrirnidin-1 - yl)methyl)-5-methyl-3-(3-(methylthio)phenyl)pyrrolo[2 - l[1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 - -pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (80 mg, 0.15 mmol) was treated with a solution of boron tribromide (1 M, 737μΙ, 0.74 mmol) according to the method of Preparation 20. The residue was purified using SP1 Purification System (0% to 100%, hexane-ethyl acetate) to obtain 31 mg (40% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 529 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 2.45 (s, 3 H), 5.38 (dd, J=50.80, 15.63 Hz, 2 H), 6.53 (d, J=2.34 Hz, 1 H), 6.69 - 6.76 (m, 1 H), 6.84 (s, 1 H), 6.88 - 7.05 (m, 4 H), 7.19 (dd, J=7.82 Hz, 1 H), 7.66 (d, J=2.74 Hz, 1 H),
8.04 (s, 1 H), 10.31 (s, 1 H).
EXAMPLE 34
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2,1 - ][1,2,4]triazin-4(3H)- one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2,1 - |[1 ,2,4]triazin-4(3 - )-one (70 mg, 0.12 mmol) was treated with a solution of boron tribromide (1 M, 610 μΙ, 0.61 mmol) according to the method of Preparation 20. The residue was purified by reverse phase to give 21 mg (31 % yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 561 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 3.19 (s, 3 H), 5.33 (dd, J=71.90, 15.63 Hz, 3 H), 6.49 (d, J=2.34 Hz, 1 H), 6.66 (d, J=10.55 Hz, 1 H),
6.83 - 6.89 (m, 2 H), 7.28 - 7.33 (m, 1 H), 7.35 - 7.42 (m, 1 H), 7.64 (d, J=2.74 Hz, 1 H), 7.68 (d, J=7.82 Hz, 1 H), 7.86 (s, 1 H), 7.95 (s, 1 H), 10.19 (s, 1 H).
EXAMPLE 35
2-((4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-<^pyrimidin-
1 - yl)methyl)-3-phenylpyrrolo[2,1 -/][1,2,4]triazin-4(3H)-one
2- ((4-Amino-3-(3-methoxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-3-phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with a solution of boron tribromide (1 M, 389 μΙ, 0.39 mmol) according to the method of Preparation 20. The residue was purified by reverse phase to give 27 mg (37% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 519 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 5.30 (s, 2 H), 6.61 (dd, 1 H), 6.97 (d, J=2.74 Hz, 1 H), 7.10 (s, 1 H), 7.13 - 7.34 (m, 7 H), 7.67 (s, 1 H), 8.01 (s, 1 H),
10.40 (s, 1 H).
EXAMPLE 36
2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 - -pyrazolo[3,4- ]pyrimidin-1 -yl)methyl)-3-phenyl-5- (trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (38 mg, 0.07 mmol) was treated with (3,4-difluoro-5-hydroxyphenyl)boronic acid (20.3 mg, 0.12 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (3 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 138 μΙ, 0.14 mmol) according to the method of Preparation 13 to give 27 mg (79% yield) of the title compound as a solid. Purity 96%.
LRMS (m/z): 555 (M+1 )+. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 5.34 (s, 2 H), 5.59 (s, 2 H), 6.79 (d, J=2.74 Hz, 1 H), 7.00 - 7.1 1 (m, 2 H), 7.17 (s, 1 H), 7.18 (s, 1 H), 7.30 - 7.41 (m, J=6.90, 6.90, 6.90 Hz, 3 H), 7.49 - 7.55 (m, 1 H), 8.23 (s, 1 H). EXAMPLE 37
W-(5-(4-Amino-1 -((5-methyl-4-oxo-3^henyl-3,4-dihydropyrrolo[2,1 - ][1,2,4]triazin-
2-yl)methyl)-1 H-pyrazolo[3,4- ]pyrimidin-3-yl)-2-hydroxypyridin-3-yl)-4- methoxybenzenesulfonamide /V-(5-(4-Amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -^[1 ,2,4]triazin-2^ yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxypyridin-3-yl)-4- methoxybenzenesulfonamide was treated with a solution of boron tribromide (1 M, 41.4 μΙ, 0.04 mmol) according to the method of Preparation 20 to give 15 mg (61 % yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 651 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.40 (s, 3 H), 3.77 (s, 3 H), 5.24 (s, 2 H), 6.47 (d, J=2.34 Hz, 1 H), 6.97 (d, J=8.99 Hz, 2 H), 7.06 (s, 1 H), 7.07 (s, 1 H), 7.10 - 7.21 (m, J=8.21 , 8.21 Hz, 3 H), 7.22 - 7.29 (m, 1 H), 7.53 (s, 1 H), 7.59 (d, J=2.74 Hz, 1 H), 7.76 (d, J=8.60 Hz, 2 H), 7.95 (s, 1 H), 9.51 (s, 1 H), 12.07 (s, 1 H).
EXAMPLE 38
( ?)-2-(1 -(4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1W-pyrazolo[3,4-oQpyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(f?)-2-(1 -(4-Amino-3-iodo-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one (80 mg, 0.16 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (73 mg, 0.47 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6.3 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 312 μΙ, 0.31 mmol) according to the method of Preparation 13. The residue was purifed by reverse phase to give 12 mg (15% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, METHANOL-d4) d ppm 1.70 (d, J=6.64 Hz, 3 H), 2.37 (s, 3 H), 5.87 (q, J=6.64 Hz, 1 H), 6.18 (d, J=7.82 Hz, 1 H), 6.38 (d, J=2.34 Hz, 1 H),
6.56 (d, J=10.55 Hz, 1 H), 6.68 - 6.78 (m, 2 H), 6.81 (s, 1 H), 7.01 (dd, J=6.64 Hz, 1 H), 7.32 - 7.38 (m, 2 H), 7.42 (d, J=2.74 Hz, 1 H), 7.82 (s, 1 H). EXAMPLE 39
(S)-2-(1 -(4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H^yrazolo[3,4-cnpyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(S)-2-(1 -(4-Amino-3-iodo-1 /- -pyrazolo[3,4-c/]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (80 mg, 0.16 mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (73 mg, 0.47 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6.3 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 312 μΙ, 0.31 mmol) according to the method of Preparation 13. The residue was purifed by reverse phase to give 41 mg (53% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, METHANOL-d4) d ppm 1 .71 (d, J=7.03 Hz, 3 H), 2.38 (s, 3 H), 5.86 (q, J=6.64 Hz, 1 H), 6.18 (d, J=7.82 Hz, 1 H), 6.38 (d, J=2.74 Hz, 1 H),
6.54 - 6.59 (m, 1 H) 6.69 - 6.73 (m, 1 H) 6.73 - 6.78 (m, 1 H) 6.81 (d, 1.95 Hz, 1 H) 6.97 - 7.05 (m, 1 H) 7.33 - 7.37 (m, 2 H) 7.43 (d, J=2.74 Hz, 1 H) 7.82 (s, 1 H) EXAMPLE 40
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-(6-(4-isopropylpiperazin-1 -yl)-6-oxohex-1 -yn-1 -yl)-3- phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one A mixture of 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 - yl)methyl)-5-bromo-3-phenylpyrrolo[2,1- ][1 !2!4]triazin-4(3 - )-one (50 mg, 0.09 mmol), 1-(4-isopropylpiperazin-1-yl)hex-5-yn-1-one (49 mg, 0.23 mmol), bis(triphenylphosphine)palladium(ll) dichloride (6.4 mg, 0.01 mmol), copper(l) iodide (2 mg, 0.01 mmol) in diethylamine (2.55 mL, 24.66 mmol) was degassed with nitrogen. The reaction mixture was stirred at 60°C for 4h and then at room temperature overnight. The mixture was evaporated under reduced pressure and the residue was partitioned between ammonium acetate solution and ethyl acetate. The organic layer was separated and washed twice with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified by reverse phase to give 14 mg (23 % yield) of the desired compound as a solid. Purity 100%.
LRMS (m/z): 689 (M+1 )+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.87 (d, J=6.25 Hz, 6 H), 1 .59 - 1.71 (m, 2 H), 2.10 (d, J=4.69 Hz, 2 H), 2.25 (d, J=4.69 Hz, 2 H), 2.39 (t, J=6.84 Hz, 2 H), 6.63 (s, 1 H), 6.66 (d, J=2.74 Hz, 1 H), 6.81 (d, J=8.60 Hz, 1 H), 6.85 (s, 1 H), 7.09 - 7.24 (m, 5 H), 7.63 (d, J=2.74 Hz, 1 H), 7.98 (s, 1 H), 8.17 (s, 1 H).
EXAMPLE 41
6-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1W^yrazolo[3,4-(^pyrimidin-1 - yl)methyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-5-yl)-A/-(2- morpholinoethyl)hex-5-ynamide
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 /-/-pyrazolo[3,4-< ]pyrimidin-1-yl)m bromo-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3/-/)-one (50 mg, 0.09 mmol) was treated with A/-(2-morpholinoethyl)hex-5-ynamide (57 mg, 0.23 mmol), bis(triphenylphosphine)palladium(ll) dichloride (6.4 mg, 0.01 mmol), copper(l) iodide (2 mg, 0.01 mmol) in diethylamine (2.55 ml_, 24.66 mmol) according to the method described in Example 40 to give 18 mg (27 % yield) of the title compound as a solid. Purity 97%.
LRMS (m/z): 692 (M+1 )+.
1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.87 (q, 2 H), 2.36 - 2.53 (m, 10 H), 3.26 (q, J=6.12 Hz, 2 H), 3.58 - 3.68 (m, 4 H), 5.34 (s, 2 H), 5.59 - 5.75 (m,
J=1.95 Hz, 2 H), 6.59 (d, J=2.74 Hz, 1 H), 6.65 - 6.72 (m, 1 H), 6.82 (d, J=7.82 Hz, 1 H), 6.90 (s, 1 H), 6.99 (s, 1 H), 7.01 (d, J=1.56 Hz, 1 H), 7.13 - 7.18 (m, J=5.67, 5.67 Hz, 1 H), 7.19 - 7.25 (m, 3 H), 7.30 (d, J=2.74 Hz, 1 H), 8.12 (s, 1 H).
EXAMPLE 42
2-((4,6-Diamino-3-(3-fluoro-5-hydroxyphenyl)-1 W-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 2-((4,6-Diamino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)- 5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3/-/)-one was treated with a solution of boron tribromide (1 M, 815 μΙ, 0.82 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 13 mg (17% yield) of the title compound as a white solid. Purity 100%.
LRMS (m/z): 498 (M+1 )+. 1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 4.98 (s, 2 H), 6.08 (s, 2 H), 6.43 (d, J=2.74 Hz, 1 H), 6.59 - 6.65 (m, 1 H), 6.77 (d, J=8.60 Hz, 1 H), 6.84 (s, 1 H), 7.12 - 7.16 (m, 2 H), 7.23 - 7.30 (m, 3 H), 7.53 (d, J=2.74 Hz, 1 H). EXAMPLE 43
(S)-2-((4-Amino-5-(3-fluoro-5-hydroxyphenyl)-7W^yrrolo[2,3-cnpyrimidin-7- yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
(S)-2-((4-Amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-(1 - phenylethyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-4(3H)-one (80 mg, 0.12 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (38 mg, 0.24 mmol),
bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (5 mg, 0.01 mmol) and a solution of sodium hydroxide ( 1 M, 245 μΙ, 0.25 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1 Purification System (0% to 100%, hexane-ethyl acetate) to give 10 mg (17% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 496 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.68 (d, J=6.25 Hz, 3 H), 5.48 (s, 1 H), 5.64 (d, J=16.02 Hz, 2 H), 6.49 - 6.56 (m, J=2.74 Hz, 2 H), 6.68 (t, J=5.28 Hz, 2 H), 6.79 (d, J=3.13 Hz, 1 H), 7.04 - 7.23 (m, 5 H), 7.42 (s, 1 H), 7.55 (s, 1 H),
8.12 (s, 1 H).
EXAMPLE 44
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-(3-hydroxybenzyl)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-methoxyphenyl)-1 H-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5- (3-methoxybenzyl)-3-phenylpyrrolo[2,1- |[1 ,2,4]triazin-4(3/-/)-one (30 mg, 0.04 mmol) was treated with a solution of boron tribromide (1 M, 224 μΙ, 0.22 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 8 mg (37% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 575 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 4.07 (s, 2 H), 5.26 (s, 2 H), 6.41 (d, J=2.74 Hz, 1 H), 6.51 (dd, J=8.21 , 1 .95 Hz, 1 H), 6.58 - 6.68 (m, 3 H), 6.79 (d, 1 H), 6.85 (s, 1 H), 6.95 - 7.06 (m, 2 H), 7.07 - 7.26 (m, 5 H), 7.56 (d, J=2.34 Hz, 1
H), 7.97 (s, 1 H), 9.19 (s, 1 H). EXAMPLE 45
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H^yrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-((4-hydroxyphenyl)thio)-3^henylpyrrolo[2,1 -/][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)m
((4-methoxyphenyl)thio)-3-phenylpyrrolo[2!1- ][1 !2!4]triazin-4(3H)-one (20 mg, 0.02 mmol) was treated with a solution of boron tribromide (1 M, 58 μΙ, 0.06 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 4 mg (35% yield) of the title compound as a white solid. Purity 98%.
L MS (m/z): 593 (M+1 )+.
EXAMPLE 46
/V-(3-(4-Amino-1 -((5-((4-hydroxyphenyl)thio)-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1 -/][1,2,4]triazin-2-yl)methyl)-1H^yrazolo[3,4-cnpyrimidin-3- yl)phenyl)methanesulfonamide
/V-(3-(4-Amino-1 -((5-((4-methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2, 1 - f [\ ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-3- yl)phenyl)methanesulfonamide (17 mg, 0.03 mmol) was treated with a solution of boron tribromide (1 M, 77 μΙ, 0.08 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 5 mg (30% yield) of the title compound as a white solid. Purity 95%.
LRMS (m/z): 652 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 3.03 (s, 3 H), 5.26 (s, 2 H), 5.94 (d,
J=2.34 Hz, 1 H), 6.80 (d, J=8.99 Hz, 2 H), 7.08 - 7.24 (m, 6 H), 7.27 - 7.37 (m, 4
H), 7.42 (s, 1 H), 7.48 (t, J=7.82 Hz, 1 H), 7.57 (d, J=2.74 Hz, 1 H), 7.98 (s, 1
H), 9.79 (s, 1 H), 9.82 - 9.96 (m, 1 H). EXAMPLE 47
2-((4-Amino-3-(5-hydroxypyridin-3-yl)-1H^yrazolo[3,4-^
methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one (50 mg, 0.10 mmol) was treated with 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol (33 mg, 0.15 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 0.01 mmol) and cesium carbonate (150 mg, 0.30 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (0% to 100%, hexane-ethyl acetate and then 0% to 8% ethyl acetate-methanol) to give 11 mg (25% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 466 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H), 5.28 (s, 2 H), 6.45 (d, J=2.34 Hz, 1 H), 7.08 - 7.24 (m, 5 H), 7.33 - 7.36 (m, 1 H), 7.55 (d, J=2.34 Hz, 1 H), 8.00 (s, 1 H), 8.23 (dd, 15.83, 2.15 Hz, 2 H), 10.17 (dd, 1 H). EXAMPLE 48
(S)-2-((4-Amino-3-(5-hydroxypyridin-3-y/)-1 H-pyrazolo[3,4-<^pyrimidin-1 - yl)methyl)-3-(1 -phenylethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3W)-one
(S)-2-((4-Amino-3-iodo-1 /- -pyrazolo[3,4- /]pynmidin-1 -yl)methyl)-3-(1- phenylethyl)pyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one (62 mg, 0.12 mmol) was treated with 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol (40 mg, 0.18 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (10 mg, 0.01 mmol) and cesium carbonate (182 mg, 0.36 mmol) according to the method of Preparation 8 to give 25 mg (44% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 480 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 1.71 (d, J=6.64 Hz, 3 H), 5.53 - 5.70 (m, J=2.34 Hz, 2 H), 5.94 (d, J=16.02 Hz, 1 H), 6.58 (dd, J=4.30, 2.34 Hz, 2 H), 6.83 (dd, J=4.10, 1.76 Hz, 1 H), 6.88 - 6.94 (m, 2 H), 7.04 - 7.11 (m, 3 H), 7.24 - 7.30 (m, 1 H), 7.65 (s, 1 H), 8.19 (dd, 7=11.72, 2.34 Hz, 2 H), 8.24 (s, 1 H),
10.20 (s, 1 H).
EXAMPLE 49
2-((4-Amino-3-(2-aminopyridin-4-yl)-1H^yrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5- ((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1 -f [\ ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(2-aminopyridin-4-yl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5-((4- methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (42 mg, 0.07 mmol) was treated with a solution of boron tribromide (1 M, 214 μΙ, 0.21 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 23 mg (55% yield) of the title compound as a solid. Purity 98%.
LRMS (m/z): 575 (M+1 )+. 1H NMR (400 MHz, DMSO-d6) d ppm 4.31 (s, 2 H), 5.26 (s, 2 H), 5.94 (d, J=1.56 Hz, 1 H), 6.15 (s, 2 H), 6.67 (s, 2 H), 6.80 (d, J=8.21 Hz, 2 H), 7.04 - 7.24 (m, 4 H,) 7.31 (d, J=8.60 Hz, 2 H), 7.58 (s, 1 H), 7.98 (s, 1 H), 8.01 (d, J=5.08 Hz, 1 H), 8.20 (s, 1 H), 9.83 (s, 1 H).
EXAMPLE 50
2-((4-Amino-3-(2-aminobenzo[cnoxazol-5-yl)-1W^yrazolo[3,4-cnpyrimidin-1 - yl)methyl)-5-((4-hydroxyphenyl)thio)-3^henylpyrrolo[2,1 -/][1,2,4]triazin-4(3H)-one 2-((4-Amino-3-(2-aminobenzo[c/]oxazol-5-yl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)- 5-((4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one (38 mg, 0.06 mmol) was treated with a solution of boron tribromide (1 M, 181 μΙ, 0.18 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 23 mg (58% yield) of the title compound as a solid. Purity 94%.
LRMS (m/z): 615 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 5.25 (s, 2 H), 5.95 (s, 1 H), 6.81 (d, J=8.21 Hz, 2 H), 7.04 - 7.26 (m, 6 H), 7.32 (d, J=8.21 Hz, 2 H), 7.36 (s, 1 H), 7.45 (d, J=8.21 Hz, 1 H), 7.51 - 7.63 (m, 3 H), 7.98 (s, 1 H), 9.85 (s, 1 H). EXAMPLE 51
2-((4-Amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-^
hydroxyphenyl)thio)-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5-((4- methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (23 mg, 0.04 mmol) was treated with a solution of boron tribromide (1 M, 123 μΙ, 0.12 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 17 mg (73% yield) of the title compound as a solid. Purity 95%.
LRMS (m/z): 549 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 5.25 (s, 2 H), 5.95 (s, 1 H), 6.81 (d,
J=8.21 Hz, 2 H), 7.04 - 7.26 (m, 6 H), 7.32 (d, J=8.21 Hz, 2 H), 7.36 (s, 1 H) ,7.45 (d, J=8.21 Hz, 1 H), 7.51 - 7.63 (m, 3 H), 7.98 (s, 1 H), 9.85 (s, 1 H).
EXAMPLE 52
2-((4-Amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-c(]pyrimidin-1 -yl)methyl)-5- ((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1 - ][1 ,2,4]triazin-4(3H)-one 2-((4-Amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)meth methoxyphenyl)thio)-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one (38 mg, 0.06 mmol) was treated with a solution of boron tribromide (1 M, 193 μΙ, 0.19 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 25 mg (66% yield) of the title compound as a solid. Purity 98%.
LRMS (m/z): 576 (M+1 )+.
1 H NMR (400 MHz, DMSO-ds) d ppm 5.26 (s, 2 H) 5.94 (d, J=2.74 Hz, 1 H) 6.79 (d, J=8.60 Hz, 2 H) 7.09 - 7.24 (m, 5 H) 7.30 (d, J=8.60 Hz, 2 H) 7.33 (d, J=1.95 Hz, 1 H) 7.56 (d, J=2.74 Hz, 1 H) 7.99 (s, 1 H) 8.19 (d, J=2.34 Hz, 1 H) 8.23 (s, 1 H) 9.68 - 9.93 (m, 1 H).
EXAMPLE 53
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4- ]pyrimidin-1 -yl)methyl)-3-(2,4-dimethoxybenzyl)- 5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (500 mg, 0.87mmol) was treated with (3- fluoro-5-hydroxyphenyl)boronic acid (204 mg, 1 .31 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (71 mg, 0.09 mmol) and a solution of cesium carbonate (2M, 1 .3 ml, 2.62 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 522 mg (93% yield) of the title compound as a solid. Purity 97%.
LRMS (m/z): 558 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.37 (s, 3 H) 3.57 (s, 3 H) 3.62 (s, 3 H) 4.95 (s, 2 H) 5.60 (s, 2 H) 5.94 - 6.12 (m, 2 H) 6.18 (d, J=1.95 Hz, 1 H) 6.42 (d,
J=2.74 Hz, 1 H) 6.58 - 6.69 (m, 2 H) 6.76 (s, 1 H) 7.52 (d, J=2.74 Hz, 1 H) 8.18 (s, 1 H) 10.05 - 10.31 (m, 1 H)
EXAMPLE 54
2-((4-Amino-3-(3,5-dihydroxyphenyl)-1 H-pyrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3,5-dimethoxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (530 mg, 0.83 mmol) was treated with a solution of boron tribromide (1 M, 4.17 ml, 4.17 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 242 mg (56% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 481 (M+1 )+.
1H NMR (400 MHz, DMSO-d6j d ppm 2.37 (s, 3 H) 5.23 (s, 2 H) 6.27 (s, 1 H) 6.45 (s, 3 H) 6.97 - 7.08 (m, J=6.25 Hz, 2 H) 7.07 - 7.22 (m, J=7.03 Hz, 3 H)
7.54 (s, 1 H) 7.94 (s, 1 H) 9.57 (s, 2 H)
EXAMPLE 55
2-((4-Amino-3-(3-hydroxy-5-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
2-((4-Amino-3-(3,5-dimethoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (530 mg, 0.83 mmol) was treated with a solution of boron tribromide (1 M, 4.17 ml, 4.17 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 13 mg (3% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 495 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H) 3.76 (s, 3 H) 5.26 (s, 2 H) 6.40 - 6.48 (m, 2 H) 6.55 (s, 1 H) 6.63 (s, 1 H) 7.09 (d, J=7.03 Hz, 2 H) 7.12 - 7.24 (m, 3 H) 7.55 (d, J=2.74 Hz, 1 H) 7.98 (s, 1 H) 9.84 (s, 1 H)
EXAMPLE 56
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3-(2,4-dihydroxybenzyl)-5-methylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one 2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (61 mg, 0.09 mmol) was treated with a solution of boron tribromide (1 M, 282μΙ, 0.28 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 15 mg (25% yield) of the title compound as a solid. Purity 90%. LRMS (m/z): 529 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H) 5.03 (s, 2 H) 5.66 (s, 2 H) 6.01 (d, 8.21 Hz, 1 H) 6.21 (s, 1 H) 6.36 (s, 1 H) 6.46 (d, J=7.82 Hz, 1 H) 6.60 - 6.71 (m, 1 H) 6.80 (d, J=8.99 Hz, 1 H) 6.88 (s, 1 H) 7.37 (s, 1 H) 8.21 (s, 1 H) 8.42 (s, 1 H) 9.19 (s, 1 H) 9.64 (s, 1 H) EXAMPLE 57
N-(3-(4-Amino-1 -((5-methyl-4-oxo-3^henyl-3,4-dihydropyrrolo[2 -f][1,2,4]triazin
2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pynmidin-1 -yl)methyl)-5-rriethyl-3- phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3 - )-one (100 mg, 0.2mmol) was treated with N-(3- hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94 mg, 0.3 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (16mg, 0.02 mmol) and a solution of cesium carbonate (2M, 200μΙ, 0.4 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 65 mg (58% yield) of the title compound as a solid. Purity 100%.
L MS (m/z): 558 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.35 (s, 3 H) 2.92 - 3.05 (m, 3 H) 5.23 (s, 2 H) 6.41 (d, J=2.34 Hz, 1 H) 6.70 (s, 1 H) 6.74 (s, 1 H) 6.84 (s, 1 H) 7.03 (s, 1
H) 7.05 (s, 1 H) 7.07 - 7.18 (m, 3 H) 7.48 - 7.56 (m, 1 H) 7.94 (s, 1 H) 9.89 (s, 2 H)
EXAMPLE 58
2-((4-Amino-3-(3-(2-(dimethylamino)ethoxy)-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3^henylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
A mixture of 2-chloro-N,N-dimethylethanamine (31 mg, 0.22 mmol) and K2C03 (59 mg, 0.43mmol) in acetone (3 ml) was stirred at room temperature in a pressure reactor for 15 min. Then 2-((4-amino-3-(3,5-dihydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (100 mg, 0.19 mmol) was added and the reaction mixture was heated at 65°C for 4 days. Then ethyl acetate was added ad the organic phase was washed with water and brine, was dried over magnesium sulphate and the solvent removed in vaccuo.The residue was purified by reverse phase to give 8 mg (7% yield) of the title compound as a solid. Purity 97%. LRMS (m/z): 552 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 8.28 - 8.24 (m, 1 H), 7.98 (s, 1 H), 7.55 (d, J = 2.7 Hz, 1 H), 7.18 (ddd, J = 8.5, 7.9, 6.1 Hz, 3H), 7.1 1 - 7.04 (m, 2H), 6.64 - 6.61 (m, 1 H), 6.58 - 6.53 (m, 1 H), 6.45 (dd, J = 2.7, 0.6 Hz, 1 H), 6.42 (dd, J = 2.2 Hz, 1 H), 5.25 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.39 (s, 3H), 2.22 - 2.19 (m, 6H). EXAMPLE 59
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-3 -(2 -hydroxy -4-methoxybenzyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin- 4(3H)-one
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (61 mg, 0.09 mmol) was treated with a solution of boron tribromide (1 M, 282 μΙ, 0.28 mmol) according to the method of Preparation 20. The crude was purified by reverse phase to give 12 mg (25% yield) of the title compound as a solid. Purity 98%.
L MS (m/z): 543 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.36 (s, 3 H) 3.56 (s, 3 H) 5.00 (s, 2 H) 5.62 (s, 2 H) 6.02 (d, J=8.60 Hz, 1 H) 6.20 (d, 1 H) 6.31 - 6.37 (m, 2 H) 6.59 - 6.66 (m, 1 H) 6.71 (d, J=9.38 Hz, 1 H) 6.81 (s, 1 H) 7.40 (d, J=2.34 Hz, 1 H) 8.17 (s, 1 H) 8.37 (s, 1 H)
EXAMPLE 60
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrirnidin-1 - yl)methyl)-3 -(2 -hydroxy -4-methoxybenzyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin- 4(3H)-one
(S)-2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(1-phenylethyl) pyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (40 mg, 0.08 mmol) was treated with N-(3- hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (37 mg, 0.12 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 1 17 μΙ, 0.23 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (hexane-AcOEt, 0% to 100%) to give 40 mg (88% yield) of the title compound as a solid. Purity 99%.
LRMS (m/z): 572 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 9.86 (s, 1 H), 9.81 (s, 1 H), 8.21 (s, 1 H), 7.65 (s, 1 H), 7.17 - 7.01 (m, J = 2.9 Hz, 4H), 6.89 (s, 2H), 6.87 - 6.84 (m, 1 H), 6.83 - 6.80 (m, 1 H), 6.78 (dd, J = 2.1 Hz, 1 H), 6.74 - 6.68 (m, 1 H), 6.58 (dd, J = 4.3, 2.7 Hz, 1 H), 5.92 (d, J = 15.6 Hz, 1 H), 5.73 - 5.33 (m, 3H), 3.02 (s, 3H), 1.70 (d, J = 6.7 Hz, 3H). EXAMPLE 61
2-((4-Amino-3-(3-hydroxy-5-(2-methoxyethoxy)ph
d]pyrimidin-1 -yl)methyl)-5-methyl-3^henylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-on 2-((4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(2,4-dimethoxybenzyl)- 5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (80 mg, 0.16 mmol) was treated with 3- (2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.24 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (13 mg, 0.02 mmol) and a solution of cesium carbonate (2M, 241 μΙ, 0.48 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (hexane-AcOEt, 0% to 100%) to give 30 mg (34% yield) of the title compound. Purity 99%.
LRMS (m/z): 539 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 9.73 (s, 1 H), 7.98 (s, 1 H), 7.55 (d, J = 2.6 Hz, 1 H), 7.25 - 7.1 1 (m, J = 14.5, 7.3 Hz, 3H), 7.1 1 - 7.03 (m, J = 7.0 Hz, 2H),
6.63 (s, 1 H), 6.56 (s, 1 H), 6.49 - 6.35 (m, 2H), 5.25 (s, 2H), 4.09 (t, 2H), 3.65 (t, 2H), 3.30 (s, 3H), 2.39 (s, 3H).
EXAMPLE 62
2-((4-Amino-3-(3,5-bis(2-morpholinoethoxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
A mixture of 4-(2-chloroethyl)morpholine HCI (53 mg, 0.28 mmol) and K2C03 (79 mg, 0.57mmol) in acetone (4 ml) was stirred at room temperature in a pressure reactor for 15 min. Then 2-((4-amino-3-(3,5-dihydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (125 mg, 0.26 mmol) was added and the reaction mixture was heated at 80°C overnight. Then ethyl acetate was added and the organic phase was washed with water and brine, dried over magnesium sulphate and the solvent removed in vaccuo.The residue was purified by reverse phase to give 50 mg (25% yield) of the title compound as a solid. Purity 93%.
LRMS (m/z): 707 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 8.25 (s, 1 H), 8.00 (s, 1 H), 7.53 (d, J = 2.5 Hz, 1 H), 7.35 - 6.96 (m, 4H), 6.71 (d, J = 2.0 Hz, 2H), 6.63 (s, 1 H), 6.44 (s, 1 H), 5.25 (s, 2H), 4.13 (t, J = 5.4 Hz, 4H), 3.49 - 2.98 (m, J = 23.9 Hz, 8H), 4.70 - 1.57 (m, 42H), 2.67 (t, 4H), 2.48 - 2.42 (m, 8H), 2.38 (s, 3H). EXAMPLE 63
(S)-2-(1 -(4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)ethyl)-5-methyl-3^henylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one (S)-2-(1 -(4-Amino-3-iodo-1 /- -pyrazolo[3,4-c/]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (36 mg, 0.07 mmol) was treated with 3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (22 mg, 0.1 1 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 105 μΙ, 0.21 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (hexane-AcOEt, 0% to 100%) to give 1 1 mg (28% yield) of the title compound. Purity 98%.
LRMS (m/z): 547 (M+1 )+.
1H NMR (400 MHz, DMSO-ds) d ppm 10.36 (s, 1 H), 7.91 (s, 1 H), 7.65 (s, 1 H),
7.58 (d, J = 7.3 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.26 (s, 2H), 7.11 (s, 1 H), 7.07 (d, J = 7.5 Hz, 1 H), 6.76 (dd, J = 7.6 Hz, 1 H), 6.48 (s, 1 H), 6.18 (d, J = 7.3 Hz, 1 H), 5.89 (d, J = 6.8 Hz, 1 H), 4.02 (q, 1 H), 2.38 (s, 3H), 1.67 (d, J = 6.1 Hz, 3H). EXAMPLE 64
(S)-2-(1 -(4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
(S)-2-(1 -(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (36 mg, 0.07 mmol) was treated with (3,4- difluoro-5-hydroxyphenyl)boronic acid (18 mg, 0.1 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 105 μΙ, 0.21 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (hexane-AcOEt, 0% to 100%, AcOEt-MeOH 0-7%) to give 17 mg (46% yield) of the title compound. Purity 97%.
LRMS (m/z): 515 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 10.63 (s, 1 H), 7.88 (s, 1 H), 7.65 (d, J = 2.6 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.37 (dd, J = 7.2 Hz, 1 H), 7.1 1 - 6.88 (m,
J = 23.5, 7.1 Hz, 3H), 6.75 (dd, J = 7.6 Hz, 1 H), 6.49 (d, J = 2.5 Hz, 1 H), 6.19 (d, J = 7.6 Hz, 1 H), 5.87 (q, J = 6.7 Hz, 1 H), 2.39 (s, 3H), 1.65 (d, J = 6.6 Hz, 3H).
EXAMPLE 65
(S)-2-(1 -(4-Amino-3-(5-hydroxypyridin-3-yl)-1 W-pyrazolo[3,4-d]pyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
(S)-2-(1 -(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)ethyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (36 mg, 0.07 mmol) was treated with 5- (4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol (23 mg, 0.1 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 105 μΙ, 0.21 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 13 mg (38% yield) of the title compound as a solid. Purity 97%.
LRMS (m/z): 480 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 10.5 (s, 1 H), 8.59 (s, 1 H), 8.38 - 8.23 (m, 1 H), 7.97 (s, 1 H), 7.72 (d, J = 2.6 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.45 (dd, J = 7.8 Hz, 1 H), 7.40 (s, 1 H), 7.12 (dd, J = 7.5 Hz, 1 H), 6.83 (dd, J = 7.6 Hz, 1 H), 6.55 (d, J = 2.6 Hz, 1 H), 6.25 (d, J = 8.5 Hz, 1 H), 5.95 (q, J = 6.6 Hz, 1 H), 2.45 (s, 3H), 1 .74 (d, J = 6.6 Hz, 3H).
EXAMPLE 66
N-(5-(4-Amino-1 -((5-methyl-4-oxo-3 -phenyl -3, 4-dihydropyrrolo[2, 1 -f][1,2,4]tri azin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-yl)acetamide
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (200 mg, 0.37 mmol) was treated with N- (5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetamide (136 mg, 0.55 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (30mg, 0.04 mmol) and a solution of cesium carbonate (2M, 369 μΙ, 0.74 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 160 mg (80% yield) of the title compound as a solid. Purity 97%.
LRMS (m/z): 507 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.11 (s, 3 H) 2.38 (s, 3 H) 5.30 (s, 2 H) 6.44 (d, J=2.74 Hz, 1 H) 7.08 - 7.24 (m, 5 H) 7.55 (d, J=2.74 Hz, 1 H) 7.55 (d, J=2.74 Hz, 1 H) 8.01 (s, 1 H) 8.26 (dd, J=2.15 Hz, 1 H) 8.45 (d, J=1.95 Hz, 1 H) 8.80 (d, J=2.34 Hz, 1 H) 10.34 (s, 1 H).
EXAMPLE 67
Methyl 3-(4-amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - f][1,2,4]triazin-2-yl)methyl)-1 H^yrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoate
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (245 mg, 0.45 mmol) was treated with methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (188 mg, 0.68 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (37 mg, 0.05 mmol) and a solution of cesium carbonate (2M, 452 μΙ, 0.90 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (hexane-AcOEt, 0% to 100%, AcOEt-MeOH 0-10%) to give 239 mg (79% yield) of the title compound as a solid. Purity 100%.
LRMS (m/z): 523 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.39 (s, 3 H) 3.86 (s, 3 H) 5.27 (s, 2 H) 6.44 (d, J=2.34 Hz, 1 H) 7.08 - 7.1 1 (m, 1 H) 7.12 (d, J=1.95 Hz, 1 H) 7.15 - 7.25 (m, 3 H) 7.27 (d, J=1.56 Hz, 1 H) 7.41 (d, J=1.56 Hz, 1 H) 7.54 (d, J=2.34 Hz, 1 H) 7.61 (s, 1 H) 8.01 (s, 1 H) 10.13 (s, 1 H)
EXAMPLE 68
2- ((4-Amino-3-(3-((ethylamino)methyl)-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
3- (4-Amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzaldehyde (100 mg, 0.2 mmol), ethanamine (107 μΙ, 0.21 mmol) and AcOH (104 μΙ) in methanol (6ml) were stirred at room temperature for 30 min. Then sodium cyanoborohydride (6 mg, 0.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The residue was concentrated in vaccuo and purified by reverse phase to give 30 mg (26% yield) of the title compound as a white solid. Purity 94%.
LRMS (m/z): 522 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 9.63 (s, 1 H), 8.28 (s, 1 H), 7.96 (s, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.20 - 7.04 (m, 5H), 7.01 (s, 1 H), 6.89 (s, 1 H), 6.85 (s, 1 H), 6.43 (d, J = 2.6 Hz, 1 H), 5.24 (s, 2H), 3.74 (s, 2H), 2.59 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H).
EXAMPLE 69
3-(4-Amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoic acid
Methyl 3-(4-amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2, 1 -fj[1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoate (30 mg, 0.06 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (1 ml) was treated with lithium hydroxide monohydrate (24 mg, 0.57 mmol) in water (0.5 ml) and stirred at 60°C overnight. The solvents were removed and more water (5 ml) was added. The solution was acidified with HCI 2N to pH 4-5. The white solid was filtrated and purified by reverse phase to give 17 mg (53% yield) of the title compound as a white solid. Purity 94%.
LRMS (m/z): 509 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.37 (s, 3 H) 5.25 (s, 2 H) 6.42 (s, 1 H) 7.08 (s, 1 H) 7.10 (s, 1 H) 7.13 - 7.25 (m, 4 H) 7.38 (s, 1 H) 7.52 (s, 1 H) 7.59 (s, 1 H) 7.98 (s, 1 H) 10.02 (s, 1 H)
EXAMPLE 70
3-(4-Amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-aminoethyl)-5- hydroxybenzamide
A mixture of 3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoic acid (60 mg, 0.09 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26.13 mg, 0.14 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.14 mmol) and ethilenediamine (9 μΙ, 0.14 mmol) in dimethylformamide (1 .5 ml) was heated at 50°C overnight. The crude was purified by reverse phase to give 15 mg (30% yield) of the title compound as a white solid. Purity 98%.
LRMS (m/z): 551 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.37 (s, 3 H) 2.81 (t, 1 H) 5.26 (s, 2 H) 6.43 (d, J=2.34 Hz, 1 H) 7.08 (d, J=6.64 Hz, 2 H) 7.1 1 - 7.24 (m, 3 H) 7.36 (s, 1
H) 7.47 - 7.56 (m, 2 H) 7.98 (s, 1 H) 8.32 (s, 1 H) 8.59 (s, 1 H) EXAMPLE 71
2- ((4-Amino-3-(3-(aminomethyl)-5-hydroxyph^
yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
3- (4-Amino-1-((5-methyW-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-1l[1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzaldehyde (100 mg, 0.2 mmol), hydroxylamine 50wt% in water (12 μΙ, 0.2 mmol) and Zn (53 mg, 0.81 mmol) in a mixture of methanol (3ml) and acetic acid (2 ml) were stirred at room temperature for 3 days. An additional quantity of Zn (100 mg) was then added and the reaction mixture was heated at 60°C for 2 days. Then the crude was filtered and washed with methanol. The mother liquor concentrated in vaccuo and the residue was purified by reverse phase to give 1 mg (17% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 494 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 8.32 (s, 1 H), 7.95 (s, 1 H), 7.54 (d, J = 2.6
Hz, 1 H), 7.20 - 7.01 (m, 5H), 6.90 (s, 1 H), 6.86 (s, 1 H), 6.43 (d, J = 2.7 Hz, 1 H), 5.25 (s, 2H), 3.80 (s, 2H), 2.34 (d, J = 23.1 Hz, 3H).
EXAMPLE 72
2-((4-Amino-3-(3-(((2-aminoethyl)amino)methyl)-5-hydroxyphenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 - f][1,2,4]triazin-4(3H)-one
3-(4-Amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzaldehyde (94 mg, 0.19 mmol), ethane-1 ,2-diamine (13 μΙ, 0.2 mmol) and AcOH (98 μΙ) in methanol (6ml) were stirred at room temperature for 1 hour. Then sodium cyanoborohydride (6 mg, 0.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The residue was concentrated in vaccuo and purified by reverse phase to give 33 mg (32% yield) of the title compound as a white solid. Purity 99%.
LRMS (m/z): 537 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 8.32 (s, 2H), 7.96 (s, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.22 - 7.10 (m, J = 13.6, 7.0 Hz, 3H), 7.09 - 7.04 (m, 2H), 6.99 (s, 1 H), 6.89 (s, 1 H), 6.87 (s, 1 H), 6.43 (d, J = 2.2 Hz, 1 H), 5.24 (s, 2H), 3.68 (s, 2H), 2.81 (t, J = 5.7 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.37 (s, 3H). EXAMPLE 73
2-((4-Amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (700 mg, 1.4 mmol) was treated with 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (409 mg, 2.1 1 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1 15 mg, 0.14 mmol) and a solution of cesium carbonate (2M, 2.1 1 ml, 4.22 mmol) according to the method of Preparation 8. The residue was purified using SP1 Purification System (AcOEt, AcOEt-MeOH 0-10%) to give 615 mg (40% yield) of the title compound as a solid. Purity 99%.
L MS (m/z): 563 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 13.19 (s, 1 H), 8.11 (s, 1 H), 7.94 (s, 1 H),
7.78 (s, 1 H), 7.51 (d, J = 2.6 Hz, 1 H), 7.30 - 7.05 (m, J = 16.5, 12.2, 5.1 , 3.1 Hz, 5H), 6.42 (dd, J = 2.7, 0.6 Hz, 1 H), 5.19 (s, 2H), 2.37 (s, 3H).
EXAMPLE 74
N-(5-(4-amino-1 -((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin- 2-yl)methyl)-1 H^yrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-yl)methanesulfonarnide
2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (60 mg, 0.12 mmol) was treated with N-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (51 mg, 0.18 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (10 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 120 μΙ, 0.24 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 40 mg (50% yield) of the title compound as a solid. Purity 96%.
LRMS (m/z): 543 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) d ppm 2.36 (s, 3 H) 2.95 (s, 3 H) 5.27 (s, 2 H) 6.42 (d, J=2.74 Hz, 1 H) 7.07 - 7.25 (m, 5 H) 7.52 (d, J=2.34 Hz, 1 H) 7.66 (s, 1 H) 8.00 (s, 1 H) 8.31 (s, 1 H) 8.33 (d, J=2.34 Hz, 1 H)
EXAMPLE 75 2-((4-Amino-3-(5-(2,2-difluoroethoxy)pyridin-3-yl)-1 H^yrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
(2-((4-Amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)-one (39 mg, 0.08 mmol) was treated with potassium carbonate (23 mg, 0.17 mmol) and 1 ,1 -difluoro-2-iodoethane (19 mg, 0.1 mmol) in dimethylformamide (6 ml) and heated under microwave irradiation at 120°C over 2 hours. The crude was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulphate and concentrated in vaccuo. The resulting residue was purified by reverse phase to give 10 mg (22% yield) of the title compound as a solid. Purity 96%.
L MS (m/z): 530 (M+1 )+.
1 H NMR (400 MHz, dmso) δ 8.42 (d, J = 2.8 Hz, 1 H), 8.41 (d, J = 1.6 Hz, 1 H), 8.00 (s, 1 H), 7.58 (dd, J = 2.8, 1.7 Hz, 1 H), 7.51 (d, J = 2.7 Hz, 1 H), 7.26 - 7.04 (m, 5H), 6.61 - 6.24 (m, 2H), 5.27 (s, 2H), 4.49 (td, J = 14.8, 3.4 Hz, 3H), 2.36
(s, 3H).
EXAMPLE 76
2-((4-Amino-3-(1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3^henylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one
(2-((4-Amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) was treated with cesium carbonate (1 14 mg, 0.35 mmol) and 2-chloro-N,N-dimethylethanamine HCI (25 mg, 0.17 mmol) in dimethylformamide (6 ml) and heated at 75°C over 6 hours. The crude was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulphate and concentrated in vaccuo. The resulting oil was crystallized with diethyl ether to give 62 mg (73% yield) of the title compound as a solid. Purity 95%. LRMS (m/z): 510 (M+1 )+.
1 H NMR (400 MHz, dmso) δ 8.1 1 (d, J = 0.6 Hz, 1 H), 7.94 (s, 1 H), 7.71 (d, J = 0.7 Hz, 1 H), 7.51 (d, J = 2.6 Hz, 1 H), 7.24 - 6.97 (m, 5H), 6.42 (dd, J = 2.7, 0.6 Hz, 1 H), 5.19 (s, 2H), 4.24 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 8.2, 4.6 Hz, 2H), 2.37 (s, 3H), 2.17 (s, J = 7.6 Hz, 6H). EXAMPLE 77
2-((4-amino-3-(3-hydroxy-5-(trifluoromethoxy)phenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3^henylpyrrolo[2,1 -f][1,2,4]triazin-4(3H)-one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-f][1 ,2,4]triazin-4(3H)-one (60 mg, 0.12 mmol) was treated with 3- hydroxy-5-(trifluoromethoxy)phenylboronic acid (40 mg, 0.18 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (10 mg, 0.01 mmol) and a solution of cesium carbonate (2M, 182 μΙ, 0.36 mmol) according to the method of Preparation 8. The residue was purified by reverse phase to give 37 mg (54% yield) of the title compound as a solid. Purity 96%.
LRMS (m/z): 549 (M+1 )+.
1 H NMR (400 MHz, dmso) δ 10.32 (s, 1 H), 7.99 (s, 1 H), 7.52 (d, J = 2.7 Hz, 1 H), 7.23 - 7.06 (m, 5H), 7.03 (dd, J = 2.1 , 1.4 Hz, 1 H), 6.97 - 6.84 (m, 1 H), 6.78 (dd, J = 2.1 , 1.1 Hz, 1 H), 6.42 (dd, J = 2.7, 0.6 Hz, 1 H), 5.74 (s, 1 H), 5.25
(s, 2H), 2.37 (s, 3H).
REFERENCES
1. - Tehrani, A. K.; Borremans D.; De Kimpe N. Tetrahedron 1999, 55, 4133-4152
2. - Ohta, T.; Fukuda, T.; Ishibashi, F., Iwao, M. J. Org. Chem. 2009, 74, 8143-8153
3. - Leroy, J.; Porthiel, E.; Bondon, A. Tetrahedron 2002, 58, 6713-6722
PHARMACOLOGICAL ACTIVITY
PI3K α, β, δ and γ Enzymatic Inhibition Assays Compounds were screened for their ability to inhibit PI3Ka (PI3Ka), ΡΙ3Κβ (PI3Kb), PI3K5 (PI3Kd) and ΡΙ3Κγ (PI3Kg) using a cell-free based PI3K HTRF™ assay
(Millipore, ref. #33-017).
PI-3 Kinase HTRF kit (ref. #33-037) and the different PI3K recombinant isoforms (ref. #14-602, ref. #14-603, ref.#14-604, ref.#15-558 for Alpha, Beta, Delta and Gamma respectively) were purchased at Millipore (expressed in insect cells). ATP was purchased at Sigma Aldrich (ref. #A7699). The compounds were pre-incubated with the enzyme for 30 min before starting of the catalytic reaction. [PIP2] was used at its Km. [ATP] was used at 15 μΜ for all isoforms for technical reasons (Km values varied between 10 and 20 μΜ depending on the isoform). Time of assay and [Enzyme] were optimized to work in the linear range. Stop and Detection mixtures were used as specified in the Millipore PI-3 Kinase kit.
• Final Assay conditions
Figure imgf000145_0001
Reaction time and enzyme concentration in the assay will depend of each batch.
All experiments were analysed using Activity Base software from IDBS and the four- parameter log equation.
The results are shown in Table 1.
Example IC50 PI3Kd HTRF (nM)
1 1
2 2
3 5
5 5
15 5
19 3
20 8
21 65
23 4
24 4
25 30
27 4
28 6 Example ICso PI3Kd HTRF (nM)
31 12
32 4
33 10
37 40
40 7
41 15
43 9
44 2
46 141
48 3
50 160
56 6
58 19
59 20
60 5
63 1
68 38
69 66
70 10
73 18
74 17
76 399
It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of Phosphoinositide 3-kinase delta (PI3kd). Preferred compounds of the invention possess an IC50 value for the inhibition of PI3Kd (determined as defined above) of less than 10 μΜ (10,000 nM), preferably less than 1 μΜ (1 ,000 nM), even more preferably of less than 0.2 μΜ (200 nM), most preferably less than 0.05 μΜ (50 nM)
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. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
Combinations
The pyrrolotriazinone derivatives defined herein may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of PI3Ks.
The combinations of the invention can optionally comprise 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; function disorders and neurological disorders; cardiovascular diseases; viral infection;
metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors. Particularly, the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of 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, 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)); 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). Preferably, the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases 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, 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 keratosis.
In particular, the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases 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, type I diabetes, 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 keratosis
The combinations of the invention comprise (i) a compound of the invention as defined above; and (ii) another compound selected from the group consisting of an Adenoside A2A agonist, an agent for treating cardiovascular disorders, an agent for treating diabetes, and an agent for treating liver disease, an anti-allergic agent, an anticholinergic agent, an anti-inflammatory agent, an anti-infective agent, a p2-adrenergic agonist, a Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitor, a chemotherapeutic agent, a corticosteroid, an ΙΚΚβ/ΙΚΒΚΒ (IkB kinase beta or IKK2) inhibitor, an immunosuppressant, a Janus kinase (JAK) inhibitor, a topically acting p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitor, a Phosphosdiesterase (PDE) IV inhibitor, and a Spleen tyrosine kinase (Syk) inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body.
In a particular embodiment, the combinations of the invention can optionally comprise one or more additional active substances selected from a) Dyhydrofolate reductase inhibitors, such as Methotrexate or CH- 1504;
b) Dihydroorotate dehydrogenase (DHODH) inhibitors such as
leflunomide, teriflunomide, or the compounds described in the International Patent Application Nos. WO2008/077639 and
WO2009/021696;
c) Immunomodulators such as Glatiramer acetate (Copaxone),
Laquinimod or Imiquimod;
d) Inhibitors of DNA synthesis and repair, such as Mitoxantrone or Cladribine;
e) Immunosuppressants, such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP);
f) Anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri) ; g) Alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003;
h) Corticoids and glucocorticoids such as prednisone or
methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide or beta-metasone;
i) Fumaric acid esters, such as BG-12;
j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies such as Infliximab, Adalimumab or Certolizumab pegol; k) Soluble Tumor necrosis factor-alpha (TNF-alpha) Antagonists such as Ethanercept;
I) Anti-CD20 (lymphocyte protein) monoclonal antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015;
m) Anti-CD52 (lymphocyte protein) monoclonal antibodies such as alemtuzumab;
n) Anti-CD25 (lymphocyte protein) such as daclizumab;
o) Anti-CD88 (lymphocyte protein), such as eculizumab or
pexilizumab;
p) Anti-lnterleukin 6 Receptor (IL-6R), such as tocilizumab;
q) Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-
23R), such as ustekinumab;
r) Calcineurin inhibitors such as cyclosporine A or tacrolimus;
s) Inosine-monophosphate dehydrogenase (I MPDH) inhibitors, such as mycophenolate mophetyl, ribavirin, mizoribine or mycophenolic acid; t) Cannabinoid receptor agonists such as Sativex;
u) Chemokine CCR1 antagonists such as MLN-3897 or PS-031291 ; v) Chemokine CCR2 antagonists such as INCB-8696;
w) Necrosis factor-kappaB (NF-kappaB or NFKB) Activation Inhibitors such as Sulfasalazine, Iguratimod or MLN-0415;
x) Adenosine A2A agonists, such as ATL-313, ATL-146e, CGS-21680,
Regadenoson or UK-432,097;
y) Sphingosine-1 (S1 P) phosphate receptor agonists such as
fingolimod, BAF-312, or ACT128800;
z) Sphingosine-1 (S1 P) liase inhibitors such as LX2931 ;
aa) Spleen tyrosine kinase (Syk) inhibitors, such as R-1 12;
bb) Protein Kinase Inhibitors (PKC) inhibitors, such as NVP-AEB071 ; cc) Anti-cholinergic agents such as tiotropium or aclidinium;
dd) Beta adrenergic agonists such as formoterol, indacaterol or
LAS100977 (abediterol);
ee) MABA (molecules with dual activity: beta-adrenergic agonists and muscarinic receptor antagonists)
ff) Histamine 1 (H1 ) receptor antagonists, such as azelastine or
ebastine;
gg) Cysteinyl leukotriene (CysLT) receptor antagonists, such as
montelukast;
hh) Mast cell stabilizers, such as nedocromil or chromoglycate;
ii) 5-lipoxygenase-activating protein (FLAP) inhibitors, such as MK886 or BAY X 1005;
jj) 5-lipoxygenase (5-LO) inhibitors, such as WY-50295T;
kk) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ACT-129968, QAV-680;
II) Vitamin D derivatives like calcipotriol (Daivonex) ;
mm) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors such as aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 or valdecoxib;
nn) Anti-allergic agents;
oo) Anti-viral agents;
pp) Phosphodiestearase (PDE) III inhibitors; Phosphosdiesterase (PDE) IV inhibitors such as roflumilast or GRC-4039;
Dual Phosphodiestearase (PDE) lll/IV inhibitors;
Xanthine derivatives, such as theophylline or theobromine;
p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797;
Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, such as ARRY-142886 or ARRY-438162;
Janus kinase (JAK) inhibitors, such as tofacitinib (previously known as tasocitinib or CP-690,550) from Pfizer and INCB-18424, from Incyte;
Interferons comprising Interferon beta 1 a such as Avonex from
Biogen Idee, CinnoVex from CinnaGen and Rebif from EMD
Serono, and Interferon beta 1 b such as Betaferon from Schering and Betaseron from Berlex;
Interferon alpha such as Sumiferon MP;
Epidermal Growth Factor Receptor (EGFR) inhibitors such as erlotinib, Trastuzumab, Herceptin, Avastin, Platins (cisplatin, carboplatin) or Temazolamide;
Antineoplastic agents such as Docetaxel, Estramustine, Anthracyc lines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda), 5 fluorouracil (5 FU), Gemcitabine (Gemzar) or Vinorelbine (Navelbine);
Specific examples of suitable corticoids and glucocorticoids that can be combined with the PI3K inhibitors of the present invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate,
methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone,
methylprednisolone suleptanate, mometasone furcate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541 , deprodone propionate, fluticasone propionate, fluticasone furcate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate.
Specific examples of suitable Syk kinase inhibitors that can be combined with the PI3K inhibitors of the present invention are fosfamatinib (from Rigel), R-348 (from Rigel), R- 343 (from Rigel), R-112 (from Rigel), piceatannol, 2-(2-Aminoethylamino)-4-[3- (trifluoromethyl)phenylamino] pyrimidine-5-carboxamide, R-091 (from Rigel), 6-[5- Fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro- 2H-pyrido[3,2-b][1 ,4]oxazin-3-one benzenesulfonate (R-406 from Rigel), 1 -(2,4,6- Trihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1 -one, N-[4-[6-(Cyclobutylamino)-9H- purin-2-ylamino]phenyl]-N-methylacetamide (QAB-205 from Novartis), 2-[7-(3,4- Dimethoxyphenyl)imidazo[1 ,2-c]pyrimidin-5-ylamino]pyridine-3-carboxamide dihydrochloride (BAY-61 -3606 from Bayer) and AVE-0950 (from Sanofi-Aventis).
Specific examples of suitable M3 antagonists (anticholinergics) that can be combined with the PI3K inhibitors of the present invention are tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, darotropium bromide, CI-923, NPC-14695, BEA-2108, 3-[2- Hydroxy-2,2-bis(2-thienyl)acetoxy]-1 -(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, more preferably aclidinium bromide), 1-(2- Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, 2-oxo- 1 ,2,3,4-tetrahydroquinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo[3.2.1 ]oct-3- yl ester salts (DAU-5884), 3-(4-Benzylpiperazin-1 -yl)-1 -cyclobutyl-1 -hydroxy-1 - phenylpropan-2-one (NPC-14695), N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]- 2(R)-[3,3-difluoro-1 (R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J-104135), 2(R)- Cyclopentyl-2-hydroxy-N-[1 -[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide (J- 106366), 2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2- phenylacetamide (J-104129), 1 -[4-(2-Aminoethyl)piperidin-1 -yl]-2(R)-[3,3- difluorocyclopent-1 (R)-yl]-2-hydroxy-2-phenylethan-1 -one (Banyu-280634), N-[N-[2-[N- [1 -(Cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3- triphenylpropionamide (Banyu CPTP), 2(R)-Cyclopentyl-2-hydroxy-2-phenylacetic acid 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), 3(R)-[4,4-Bis(4- fluorophenyl)-2-oxoimidazolidin-1 -yl]-1 -methyl-1-[2-oxo-2-(3-thienyl)ethyl]pyrrolidinium iodide, N-[1 -(3-Hydroxybenzyl)-1 -methylpiperidinium-3(S)-yl]-N-[N-[4- (isopropoxycarbonyl)phenyl]carbamoyl]-L-tyrosinamide trifluoroacetate, UCB-101333, Merck's OrM3, 7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9- azoniatricyclo[3.3.1.0(2,4)]nonane salts, 3(R)-[4,4-Bis(4-fluorophenyl)-2- oxoimidazolidin-1 -yl]-1 -methyl-1-(2-phenylethyl)pyrrolidinium iodide, trans-4-[2- [Hydroxy-2,2-(dithien-2-yl)acetoxy]-1 -methyl-1-(2-phenoxyethyl)piperidinium bromide from Novartis (412682), 7-(2,2-diphenylpropionyloxy)-7,9,9-trimethyl-3-oxa-9- azoniatricyclo[3.3.1.0*2,4*]nonane salts, 7-hydroxy-7,9,9-trimethyl-3-oxa-9- azoniatricyclo[3.3.1.0*2,4*]nonane 9-methyl-9H-fluorene-9-carboxylic acid ester salts, all of them optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally in the form of their
pharmacologically-compatible acid addition salts. Among the salts chlorides, bromides, iodides and methanesulphonates are preferred.
Specific examples of suitable beta adrenergic agonists (p2-agonists) that can be combined with the PI3K inhibitors of the present invention are are terbutaline sulphate, eformoterol fumarate, formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, dopexamine, metaprotenerol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, salmefamol, salmeterol xinafoate, carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol hydrochloride; Levosalbutamol hydrochloride; (-)- Salbutamol hydrochloride, formoterol, (R,R)-Formoterol tartrate; Arformoterol tartrate, sulfonterol, Bedoradrine sulphate, Indacaterol, Trantinterol hydrochloride, Milveterol hydrochloride, Olodaterol, fenoterol hydrobromide, rimoterol hydrobromide, riproterol hydrochloride, Vilanterol broxaterol, pirbuterol hydrochloride, bitolterol mesylate, clenbuterol hydrochloride, AZD-3199, GSK-159802; GSK-597901 , GSK-678007, GSK- 961081 ; 4-[2-[3-(1 H-Benzimidazol-1-yl)-1 ,1-dimethylpropylamino]-1 -hydroxyethyl]-2-(4- methoxybenzylamino)phenol, 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4- N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo- 4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-domethoxyphenyl)-2-methyl-2-propylamino]ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyhenyl)-2-methyl-2- propylamino]ethanol, KUL-1248, HOKU-81 , SM-1 10444, RP-58802B, LAS100977 (abediterol) and compounds described in PCT patent applications Nos. WO
2007/124898, WO 2006/122788A1 , WO 2008/046598, WO 2008095720, WO
2009/068177 and WO 2010/072354.
Specific examples of suitable anti-allergic agents that can be combined with the PI3K inhibitors of the present invention are anti-histamines (e.g. Methapyrilene, Mequitazine, Azelastine hydrochloride, Acrivastine, Emedastine difumarate, Emedastine fumarate, Loratadine, Cyproheptadine hydrochloride, Diphenhydramine hydrochloride, Doxepin hydrochloride, Promethazine hydrochloride, Levocabastine hydrochloride,
Desloratadine, Cinnarizine, Setastine hydrochloride, Mizolastine, Ebastine, Cetirizine hydrochloride, Epinastine hydrochloride, Olopatadine hydrochloride, Bepotastine besilate,Triprolidine hydrochloride, Rupatadine fumarate, Fexofenadine hydrochloride, Levocetirizine dihydrochloride, Ketotifen, Azatadine maleate, Dimethindene maleate, Clemastine fumarate, Alcaftadine, Bilastine, Vapitadine hydrochloride, AZD-1744, GSK-1004723D, GSK-835726 or SUN-1334H.
Specific examples of suitable Phosphosdiesterase IV (PDE IV) inhibitors that can be combined with the PI3K inhibitors of the present invention are benafentrine dimaleate, etazolate, denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R)-(+)-4- [2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5- Dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2-oxoacetamide
(GSK-842470), 9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N- (3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide (D-4418), 3-[3- (Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride (V-1 1294A), 6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)- 8-methylquinoline-3-carboxamide hydrochloride (GSK-256066), 4-[6,7-Diethoxy-2,3- bis(hydroxymethyl)naphthalen-1-yl]-1 -(2-methoxyethyl)pyridin-2(1 H)-one (T-440), (-)- trans-2-[3'-[3-(N-Cyclopropylcarbamoyl)-4-oxo-1 ,4-dihydro-1 ,8-naphthyridin-1 -yl]-3- fluorobiphenyl-4-yl]cyclopropanecarboxylic acid, MK-0873, CDC-801 , UK-500001 , BLX-914, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluroromethoxyphenyl)cyclohexan1-one, cis [4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol, 5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]- 3(S)-(3-methylbenzyl)piperidin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and the compounds claimed in the PCT patent applications number WO 03/097613, WO 2004/058729, WO 2005/049581 , WO 2005/123693, WO 2005/123692, and WO 2010/069504.
Specific examples of suitable immunosupressants that can be combined with the PI3K inhibitors of the present invention are picremolimus, tacrolimus, cyclosporine A, leflunomide, teriflunomide, vidofludimus, laquinimod, methotrexate, 5-fluorouracil (5- FU), anti-TNF agents and compounds described in PCT patent applications Nos. WO 2008/077639, WO 2009/021696, WO 2009/153043, and WO2010083975 (in particular amino(iso)nicotinic acid derivatives selected from the group consisting of 2-(3'-ethoxy- 3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid, 2-(3,5-difluoro-3'- methoxybiphenyl-4-ylamino)nicotinic acid and 2-(3,5-difluoro-2-methylbiphenyl-4- ylamino)nicotinic acid; and azabiphenylaminobenzoic acid derivatives selected from the group consisting of 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid, 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid and 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid)
Specific examples of suitable anti-infectives that can be combined with the PI3K inhibitors of the present invention are aclarubicin, actinomycin D, amrubicin, annamycin, adhamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, mupiricin, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, retapamulin, stimalamer, streptozocin, valrubicin, zinostatin, amphotericin B, bifonazole, caspofungin, clotrimazole, echinocandin B, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terbinafine, tioconazole, voriconazole and combinations thereof.
Particularly preferred combination products according to the invention comprise a compound of formula (I) and a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, betamethasone valerate, clobetasol propionate, tiotropium salts, glycopyrronium salts, 3-[2-Hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1 - azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, preferably aclidinium bromide), 1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1- azoniabicyclo[2.2.2]octane salts, formoterol, salmeterol, indacaterol, carmoterol, LAS 100977 (abediterol), compounds described in PCT patent applications Nos. WO 2008/077639, WO 2009/021696, WO 2009/153043, and WO 2010/083975 (in particular amino(iso)nicotinic acid derivatives selected from the group consisting of 2- (3'-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid, 2-(3,5-difluoro-3'- methoxybiphenyl-4-ylamino)nicotinic acid and 2-(3,5-difluoro-2-methylbiphenyl-4- ylamino)nicotinic acid; and azabiphenylaminobenzoic acid derivatives selected from the group consisting of 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid, 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid and 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid), methapyrilene, cetirizine, loratadine, ebastine, desloratadine, fexofenadine, azelastine, levocabastine, olopatadine, Montelukast, picremolimus, tacrolimus, mupiricin, retapamulin, clotrimazole, ketoconazole and terbinafine.
The compounds of formula (I) and the combinations of the invention may be used in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors, wherein the use of a PI3K inhibitor is expected to have a beneficial effect, for example 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis.
The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time. Preferably, at least two, and more preferably all actives would be administered as an admixture.
The invention is also directed to a combination product of the compounds of the invention together with one or more other therapeutic agents for use in the 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 selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders;
cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); 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 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis.
The invention also encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases. 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 selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection;
metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or
mielofibrosis); 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 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis.
The active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc). The active compounds in the combination, i.e. the pyrrolotriazinone derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
One execution of the present invention consists of a kit of parts comprising a imidazopyridine derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders;
cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); 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 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis.
Another execution of the present invention consists of a package comprising a imidazopyridine derivative of the invention and another active compound useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); 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 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis.
Pharmaceutical Compositions
Pharmaceutical compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or prodrugs thereof, with other chemical components, such as
physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. The invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of
Phosphoinositide 3-Kinases (PI3Ks), such as the ones previously described.
The invention is also directed to pharmaceutical compositions of the invention for use in the 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 selected from respiratory diseases; allergic diseases;
inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); 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 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 keratosis.
In particular the pathological condition or disease is 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, 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 keratosis. The invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.
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 selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection;
metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or
mielofibrosis); 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 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 keratosis; more in particular the pathological condition or disease is 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, 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 keratosis; comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.
Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001. The pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001. i) Oral Administration
The compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, electuary or paste.
Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste- masking agents.
Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule. Where the composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. ii) Oral mucosal administration
The compounds of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug
administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others) iii) Inhaled administration
The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using
electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 , 1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 0.001 -50 mg, more preferably 0.01 -5 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients.
Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
For inhalers of the first type, single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler. Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients.
Other drawbacks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection against moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indenture, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported (e. g. Nielsen et al, 1997).
Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (Ex. EP0069715) or disks (Ex. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (Ex. EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (Ex. WO
92/00771 ), all having cavities which have to be filled with powder from the container. Other multi dose devices have measuring slides (Ex. US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (Ex. EP 0505321 , WO 92/04068 and WO 92/04928), or measuring slides such as the Genuair® (formerly known as Novolizer SD2FL), which is described the following patent applications Nos: WO97/000703, WO03/000325 and WO2006/008027.
Reproducible dose measuring is one of the major concerns for multi dose inhaler devices.
The powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
For reloaded single dose and multiple unit dose inhalers, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge. Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi- dose devices, powder adhesion onto the inner walls of the air conduits and the de- agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even more strict. Apart from applications through dry powder inhalers the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of so- called atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable particles results. The advantage of these atomisers is that the use of propellant gases can be completely dispensed with. Such atomiser is the Respimat® which is described, for example, in PCT Patent Applications Nos. W0 91/14468 and WO 97/12687, reference here is being made to the contents thereof.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient (s) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1 ,1 , 1 , 2-tetrafluoroethane, 1 ,1 , 1 ,2, 3,3, 3- heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg oleic acid or lecithin) and cosolvens (eg ethanol). Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1 -10 μπι, preferably 2-5 μπι. Particles having a size above 20 μπι are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.
Achieving high dose reproducibility with micronised powders is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient such as lactose or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, preferably crystalline alpha lactose monohydrate.
Pressurized aerosol compositions will generally be filled into canisters fitted with a valve, especially a metering valve. Canisters may optionally be coated with a plastics material e. g. a fluorocarbon polymer as described in W096/32150. Canisters will be fitted into an actuator adapted for buccal delivery. iv) Nasal mucosal administration
The compounds of the invention may also be administered via the nasal mucosal. Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents. v) Parenteral Administration
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. vi) Topical Administration
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis,
phonophoresis, sonophoresis and microneedle or needle-free injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. vii) Rectal/lntravaginal Administration
Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. viiQ Ocular Administration
Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. ix) Other Technologies
Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
Preferably, the the pharmaceutical compositions of the invention are made up in a form suitable for oral, inhalation or topical administration, being particularly preferred oral or inhalation administration.
The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
The following preparations forms are cited as formulation examples:
Formulation Examples
Formulation Example 1 (Oral suspension)
Ingredient Amount
Active Compound 3 mg
Citric acid 0,5 g
Sodium chloride 2,0 g
Methyl paraben 0,1 g
Granulated sugar 25 g
Sorbitol (70% solution) 1 1 g
Veegum K 1 ,0 g
Flavoring 0,02 g
Dye 0,5 mg Distilled water q.s. to 100 ml_
Formulation Example 2 (Hard gelatine capsule for oral administration)
Figure imgf000174_0001
Formulation Example 3 (Gelatin cartridge for inhalation)
Figure imgf000174_0002
Formulation Example 4 (Formulation for inhalation with a DPI)
Figure imgf000174_0003
Formulation Example 5 (Formulation for a MDI)
Figure imgf000174_0004
In all the formulation examples, active compound is 2-((4-Amino-3-(3-hydroxyphenyl)- 1 H-pyrazolo[3!4-d]pyrimidin-1 -yl)methyl)-5-methyl-3-(o-tolyl)pyrrolo[2!1-f][1 !2,4]triazin- 4(3H)-one. Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention.

Claims

Claims
1. A compound of formula (I), or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof:
Figure imgf000176_0001
Formula (I) wherein, n represents 0, 1 , 2 or 3; X represents N or CH;
Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group; Ri represents a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, aryl, 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-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)i-3CN group, a -(CH2)o-30R9 group, a -(CH2)o-3N R9Rio group, a -C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0.3-R9 group, a -C(0)-(CH2)o-3-NR9Rio group, a -S(CH2)0.3R9 group, a -S(0)(CH2)o-3R9 group, a -S(0)(CH2)0.3NR9Rio group, a -S(O)2(CH2)0-3R9 group, a -S(0)2(CH2)0-3NR9Rio group or
a -(CH2)0-3(phenyl)-OR9 group;
R2 and Rs each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C1-C4 alkoxy group, a -NH2 group, a -N(CH3)H group or a -N(CH3)2 group;
R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a - (CH2)0-3-O(Ci-C4 alkyl) group, a -(CH2)0-3-S-(CH2)0-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, a -(CH2)0-3-O- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3NR9R10 group, a -(CH2)o-3-0(CrC4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Rii group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-SH group, a -(CH2)0-3-S- (CH2)o-3-Rii group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)o-3-(phenyl) group, a -(CH2)o-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)o-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-
0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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;
R6 and R7 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a - C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0-3-R' group, a -C(O)-(CH2)0.3-NR'R", a -(CH2)0. 3NR'R" group, or a linear or branched C1-C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group or a linear or branched d- C4 alkyl group;
R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group, a -(CH2)0-3-O(Ci-C4 haloalkyi) group, a -(CH2)o.3-0-(CH2)i.3-0(Ci-C4 alkyl) group, a -(CH2)0.3-O- (CH2)i-3-0(Ci-C4 haloalkyi) group, a -(CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)o-3- 0-(CH2)i-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a - (CH2)0-3-C(0)-(CH2) o-3-NR'R"group, a -(CH2)0-3-C(0)0-(CH2) o-3R' group, a - (CH2) o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Rii group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)o-3-Ri i group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C4 alkyi group, a -(CH2)i-3NRaRb 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 Ci-C4 hydroxyalkyi group, a Ci-C4 haloalkyi group, a Ci-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a CrC4 haloalkyi group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C C4 alkoxy group, a -NH2 group, a -NH(C C4 alkyi) group, a - NH-S(0)2-(C C4 alkyi) group,
R-I2 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)1-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyi group, and R'" represents a linear or branched Cr C4 alkyi group.
2. A compound according to claim 1 , wherein n represents 0, 1 , 2 or 3; X represents N or CH; Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, aryl, 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 C4 haloalkyi group, a C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)i-3CN group, a -(CH2)0-3OR9 group, a -(CH2)o-3N R9Rio group, a -C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0.3-R9 group, a -C(O)-(CH2)0-3-N R9R10 group, a -S(CH2)0.3R9 group, a -S(0)(CH2)o-3R9 group, a -S(O)(CH2)0.3N R9R10 group, a -S(O)2(CH2)0-3R9 group, a -S(O)2(CH2)0-3N R9R10 group or
a -(CH2)0-3(phenyl)-OR9 group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C1-C4 alkoxy group, a -NH2 group, a -N(CH3)H group or a -N(CH3)2 group;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, a -(CH2)o-3-0- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9Rio group, a -(CH2)o-3-0(C C4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Ri i group, a -(CH2)0-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3-SH group, a -(CH2)o-3-S- (CH2)o-3-Ri i group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)o-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C4 alkyl group, a Ci-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a C C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a - C(0)-(CH2)i-3-CN group, a -C(O)-(CH2)0-3-R' group, a -C(O)-(CH2)0-3-NR'R", a -(CH2)o- 3NR'R" group, or a linear or branched C1-C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group or a linear or branched Cr C4 alkyl group; R8 represents a monocyclic or bicyclic C6-C-|4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a -(CH2)o-3-0(Ci-C4 alkyi) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR'R" group, a -(CH2)o-3-C(0)-(CH2) o-3-N R'R"group, a -(CH2) o-3N R'- S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)0-3-SH group, or a - (CH2)o-3-S-(CH2)o-3-Ri i group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi 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 C1-C4 hydroxyalkyi group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH2 group, a -NH(CrC4 alkyi) group or a - NH-S(0)2-(CrC4 alkyi) group; L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched Ci-C4 alkyi group, and R'" represents a linear or branched C C4 alkyi group.
3. A compound according to claim 1 , wherein n represents 0, 1 , 2 or 3; X represents N or CH;
Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from 0, S and N, or a 5- to 10- membered heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N;
wherein the cycloalkyl, phenyl, heteroaryl or heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(0)(CH2)o-3R9 group, a -S(0)(CH2)o-3NR9R10 group, a -
S(0)2(CH2)o-3R9 group, a -S(O)2(CH2)0-3N R9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R 0 each independently represent a hydrogen atom or a C1-C4 alkyl group; R2 and R3 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C C3 alkoxy group, a linear or branched C1-C4 alkyl group, a C1-C3 haloalkyi group, a C3-C4 cycloalkyl group or a -NH2 group;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-(C3-C4 cycloalkyl) group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-S-(CH2)0-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)0-3-O- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9Rio group, a -(CH2)o-3-0(C C4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Ri i group, a -(CH2)0-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3-SH group, a -(CH2)o-3-S- (CH2)o-3-Ri i group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)o-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group,
wherein the 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 C4 alkyl group, a Ci-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and
N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -C(0)-(CH2)o-3-(CrC4 alkyl) group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group;
R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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-C4 alkyi group, a CrC4 haloalkyi group, a C1-C4 hydroxyalkyi group, a -(CH2)o-3-0(Ci-C4 alkyi) group, a -(CH2)o-3-0(Ci-C haloalkyi) group, a -(CH2)o-3-0-(CH2)i-3-0(Ci-C4 alkyi) group, a -(CH2)0.3-O- (CH2)1-3-0(Ci-C4 haloalkyi) group, a -(CH2)o-3-0-(CH2) 0-3R12 group, a -(CH2)0-3-
0-(CH2)i-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a - (CH2)o-3-C(0)-(CH2)o-3-NR'R"group, a -(CH2)o-3-C(0)0-(CH2) o-3R' group, a - (CH2)o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Rn group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)o-3-Rii group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched C C4 alkyi group, a -(CH2)1-3NRaR 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 C C4 hydroxyalkyi group, a C C4 haloalkyi group, a C C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a C C4 haloalkyi group, a C1-C4 hydroxyalkyi group or a linear or branched Ci-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH2 group, a -NH(CrC4 alkyi) group, a - NH-S(0)2-(C C4 alkyi) group,
Ri2 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched Cr C4 alkyl group.
4. A compound according to claim 2, wherein n represents 0, 1 , 2 or 3; X represents N or CH; Ra and Rb each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, or a 5- to 10- membered heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N;
wherein the cycloalkyl, phenyl, heteroaryl or heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -
S(CH2)o-3R9 group, a -S(O)(CH2)0-3R9 group, a -S(0)(CH2)o-3NR9Rio group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R 0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
R2 and R3 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C3 alkoxy group, a linear or branched C1-C4 alkyl group, a C1-C3 haloalkyi group, a C3-C4 cycloalkyl group or a -NH2 group; R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a - (CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)0-3-(phenyl) group, a -(CH2)o-3-0- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3NR9Rio group, a -(CH2)o-3-0(CrC4 alkyl) group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-SI-l group, a -(CH2)o-3-S- (CH2)o-3-Rii group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-0-(CH2)o-3-(phenyl) group, a -(CH2)0-3-0-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)o-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -C(0)-(CH2)o-3-(CrC4 alkyi) group, a -N H2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyi group;
R8 represents a monocyclic or bicyclic C6-Ci4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N ,
wherein the aryl , heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group 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 alkyi group, a C C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a -(CH2)o-3-0(C C4 alkyi) group, a C3-C7 cycloalkyl group, a -(CH2) o-3NR'R" group, a -(CH2)0-3-C(O)-(CH2) 0-3-NR'R"group, a -(CH2) 0-3NR'- S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0-3-Rn group, a -(CH2)0-3-SH group, or a - (CH2)o-3-S-(CH2)o-3-Rii group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi 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 C1-C4 hydroxyalkyi group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Ri0 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group;
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH2 group, a -N H(CrC4 alkyi) group or a - NH-S(0)2-(Ci-C4 alkyi) group;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched CrC4 alkyi group, and R'" represents a linear or branched d- C4 alkyi group.
5. A compound according to any one of claims 1 to 4, wherein Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from 0, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(0)(CH2)o-3R9 group, a -S(O)(CH2)0-3NRgR10 group, a - S(0)2(CH2)o-3R9 group, a -S(O)2(CH2)0-3N R9R10 group or a -(CH2)0-3(phenyl)-OR group; wherein R9 and R-i0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
and
wherein more preferably represents a phenyl, which phenyl is unsubstituted or substituted by one, two or three substituents selected from a halogen atom or a linear or branched C1-C3 alkyl group; and wherein preferably said phenyl group is directly bonded to the pyrrolotriazinone group.
6. A compound according to any one of the preceding claims, wherein R2 represents a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group.
7. A compound according to any one of the preceding claims, wherein R3 represents a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group.
8. A compound according to any one of the preceding claims, wherein R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH2)o-3-(C3-C4 cycloalkyl) group, a -(CH2)0-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-0-(CH2)o-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyi group, a Ci-C4 hydroxyalkyi group or a C1-C4 alkoxy group.
9. A compound according to any one of the preceding claims, wherein R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched
C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0_3- S(0)2(CH2)o_3-(phenyl) group, a -(CH2)0-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH2)o-3- S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C4 alkyl group, a C1-C4 haloalkyi group, a
C1-C4 hydroxyalkyi group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o-4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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.
10. A compound according to any one of the preceding claims, wherein R8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a -(CH2)o-3-0(Ci-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2)i-3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O- (CH2)1-3-0(Ci-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3- 0-(CH2)i-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a - (CH2)o-3-C(0)-(CH2) o-3-NR'R"group, a -(CH2)0-3-C(0)0-(CH2) o-3R' group, a -
(CH2) o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Ri i group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)0-3-Rn group; wherein R' and R" each
independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH2)i-3NRaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
and wherein R12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N.
1 1. A compound according to any one of claims 1 to 8, wherein R8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)o-3-0(Ci-C4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH2) 0.3N R'R" group, a -(CH2)0-3-C(O)-(CH2) 0-3-N R'R"group or a - (CH2) o-3NR'-S(0)2R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 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, a cyano group, a C1-C4 hydroxy alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C3-C4 cycloalkyl group or a linear or branched alkyl group.
12. A compound of according to claim 1 , wherein n represents 0, 1 , or 2; X represents N or CH;
Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from 0, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
tetrahydropyranyl group, a tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(0)(CH2)o-3R9 group, a -S(0)(CH2)o-3NR9R10 group, a -
S(0)2(CH2)o-3R9 group, a -S(O)2(CH2)0-3N R9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R 0 each independently represent a hydrogen atom or a C1-C4 alkyl group; R2 and R3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH2)0.3-(C3- C4 cycloalkyl) group, a -(CH2)0-3-S-(CH2)0-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)0-3-S-(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)o.4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C C4 alkyl group, a phenyl group, a -
(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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;
R6 and R7 each independently represent a hydrogen atom, a -N H2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched Ci-C4 alkyl group;
R8 represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched Ci-C4 alkyl group, a C1-C4 haloalkyl group, a
C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group, a -(CH2)o-3-0(Ci-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2)i.3-0(Ci-C4 alkyl) group, a -(CH2)0-3-O- (CH2)i-3-0(Ci-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2) o-3Ri2 group, a -(CH2)0-3- 0-(CH2)i-3NR'R" group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a - (CH2)o-3-C(0)-(CH2) o-3-NR'R"group, a -(CH2)o-3-C(0)0-(CH2) 0-3R' group, a -
(CH2) o-3NR'-S(0)2R" group, a -(CH2)0-3- S(O)2(CH2)0.3-Ri i group, a -(CH2)0-3-SH group, or a -(CH2)0-3-S-(CH2)o.3-Ri i group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH2)i-3NRaRb 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 C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C3-C4 cycloalkyl group;
R9 and Rio each independently represent a hydrogen atom or a linear or branched Ci- C4 alkyl group;
R12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C C4 alkyl group.
13. A compound according to claim 12, wherein: n is 0 or 1 ;
X represents N or CH;
Ra and Rb each independently represent a hydrogen atom or C1-C4 alkyl group;
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 ,1 -dioxide group,
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C3 alkyl group, a C1-C3 alkoxy group, a -S(Ci-C4 alkyl) group, a - S(0)(Ci-C4 alkyl) group, or a -S(0)2(Ci-C4 alkyl) group; R2 and Rs each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-S(0)2-(CH2)o-3-(phenyl) group or a -(CH2)o-3-S-(CH2)o-3-(phenyl) group;
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C1-C4 alkyl group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH2)o-4-C(0)-N(H)-(CH2)o-4-(morpholinyl) group, a -(CH2)0-4-C(0)-N-[(CH2)o-3-0(C1-C4 alkyl)]2 group or a -(CH2)0-4-C(0)-(CH2)o-4- (isopropylpiperazinyl) group; R6 and R7 each independently represent a hydrogen atom, a -N H2 group, or a linear or branched C1-C4 alkyl group;
R8 represents 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a -(CH2)0.3-O(Ci- C4 alkyl) group, a -(CH2)o-3-0(C1-C4 haloalkyl) group, a -(CH2)o-3-0-(CH2) 0-3- (morpholinyl) group, a -(CH2)o-3-0-(CH2)1-3NR' R" group, a -(CH2) 0-3NH2 group, a -(CH2) o-3NH-(CH2)1 -3N R'R" group, a -(CH2) o-3N R'-S(0)2(Ci-C4 alkyl) group, a -
(CH2)0-3-C(O)-(CH2) 0-3-NH-(CH2)1.3NH2 group, a -(CH2)0-3-C(0)0-(CH2) o-3(C1-C4 alkyl) group, a -(CH2)0-3-C(O)OH grup, or a -(CH2) 0-3NR'-S(O)2(phenyl) group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group or a C1-C4 alkoxy group; and wherein R' and R" each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
L represents a direct bound or -S-.
14. A compound of according to claim 1 or claim 2, wherein n represents 0, 1 , or 2;
X represents N or CH; Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing 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 tetrahydrothiopyranyl group or a morpholinyl group,
wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - S(CH2)o-3R9 group, a -S(0)(CH2)o-3R9 group, a -S(0)(CH2)o-3NR9R10 group, a - S(0)2(CH2)o-3R9 group, a -S(0)2(CH2)o-3NR9R10 group or a -(CH2)0-3(phenyl)-OR9 group; wherein R9 and R 0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group; R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH2)0.3-(C3- C4 cycloalkyl) group, a -(CH2)0-3-S-(CH2)0-3-(phenyl) group, a -(CH2)0-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-O-(CH2)0-3-(phenyl) group, or a -(CH2)0-3-O-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH2)o-3-(phenyl) group, a -(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S(0)2(CH2)o-3-(phenyl) group, a -(CH2)0-3-S(0)2(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)o-3-S-(CH2)o-3-(phenyl) group, a -(CH2)o-3-S-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, wherein the 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C C alkyl group, a C C4 haloalkyl group, a C C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH2)o-4-C(0)-N(R')-(CH2)0.4-R" group, a -(CH2)0-4-C(0)-(CH2)o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3- 0(Ci-C4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and
N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are 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; R6 and R7 each independently represent a hydrogen atom, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group;
Rs represents a phenyl group or a 5- to 10- 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 cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH2)0-3-O(Ci-C4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH2) 0-3NR'R" group, a -(CH2)0-3-C(O)-(CH2) 0-3-NR'R"group or a - (CH2)o-3NR'-S(0)2R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 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, a cyano group, a C1-C4 hydroxy alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C3-C4 cycloalkyl group or a linear or branched alkyl group. R9 and Rio each independently represent a hydrogen atom or a linear or branched Ci- C4 alkyl group;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH2)i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched Cr C4 alkyl group.
15. A compound according to claim 14, wherein: n is O or l ;
X represents N or CH;
Ra and Rb each independently represent a hydrogen atom or C1-C4 alkyl group;
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 ,1 -dioxide group,
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a -S(d-C4 alkyl) group, a -S(0)(C C4 alkyl) group, or a -S(0)2(Ci-C4 alkyl) group;
R2 and Rs each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH2)0-3-(phenyl) group, a -(CH2)o-3-S(0)2-(CH2)0-3-(phenyl) group or a -(CH2)0-3-S-(CH2)0-3-(phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C1-C4 alkyl group;
and wherein the alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH2)o-4-C(0)-N(H)-(CH2)o-4-(morpholinyl) group, a
-(CH2)o-4-C(0)-N-[(CH2)o-3-0(Ci-C4 alkyl)]2 group or a -(CH2)0-4-C(O)-(CH2)0-4- (isopropylpiperazinyl) group;
F¾ and R7 each independently represent a hydrogen atom, a -NH2 group, or a linear or branched C1-C4 alkyl group;
R8 represents 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 C1-C4 alkyl group, a C1-C4 haloalkyl group, a -(CH2)0-3-O(Ci- C4 alkyl) group, a -(CH2) 0-3NH2 group or a -(CH2) o-3NR'-S(0)2(Ci-C4 alkyl) group, wherein R' represents a hydrogen atom or a linear or branched C C4 alkyl group;
L represents a direct bound or -S-.
16. A compound according to claim 1 , which is one of: 2-((4-Amino-3-(3-hydroxyphenyl)-1 - -pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-methyl-3- (o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3/- )-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 -/-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 -/-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-3- (o-tolyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-iH-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 -/-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5- bromo-3-(3-(methylthio)phenyl)pyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 /-/-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-5- (trifluoromethyl)pyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one; 2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1 --pyrazolo[3,4-c]pyrimidin-1- yl)methyl)pyrrolo[2,1-f|[1,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfinyl)phenyl)pyrrolo[2, 1 -f \ ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)- 1 --pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-3- (3-(methylsulfinyl)phenyl)pyrrolo[2,1-][1,2,4]triazin-4(3/-)-one;
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)- 1 --pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-/][1,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3:4-(^pyrimidin-1-yl)methyl)-3- phenyl-5-(trifluoromethyl)pyrrolo[2,1-/][1,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1/-/-pyrazolo[3,4-<]pyrimidin-1-yl)methyl)-3- phenylpyrrolo^ -lfl^^^riazin^CSHJ-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-<]pyrimidin-1-yl)methyl)-5- methyl-S-im-toly pyrrolo^ -flfl^^ltriazin^CSHJ-one;
2-((4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(m-tolyl)pyrrolo[2,1-][1!2!4]triazin-4(3-)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylthio)pyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-o^pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2!4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -|[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-apyrimidin-1-yl)methyl)-5- methyl-3-(o-tolyl)pyrrolo[2,1-|[1,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-chloro-5-hydroxyphenyl)-1H-pyrazolo[3,4-<^pyrimidin-1-yl)met yl)-5- methyl-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2, 1 -|[1 ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-((3-hydroxyphenyl)thio)-1H-pyrazolo[3,4-G]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3/-/)-one;
2-((4-Amino-3-(3,4-difluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-/]pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f[\ ,2,4]triazin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- ethynyl-3-phenylpyrrolo[2,1-|[1,2,4]triazin-4(3-)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(tetrahydro-2H-thiopyran-4-yl)pyrrolo[2,1-][1,2,4]triazin-4(3H)-one; 2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-o0pyrimidin-1-yl)methyl)-3- (1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-methylpyrrolo[2, 1 -|[1 ,2,4]triazin-4(3H)-one; (S)-2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-
3- (1 -phenylethyl)pyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-/]pyrimidin-1- yl)methyl)-3-(1-phenylethyl)pyrrolo[2,1-f|[1,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-3-(1-phenylethyl)pyrrolo[2,1-|[1,2,4]triazin-4(3H)-one;
(S)-N-(5-(4-amino-1-((4-oxo-3-(1-phenylethyl)-3,4-dihydropyrrolo[2,1-/][1,2,4]tnazin-2- yl)methyl)-1H-pyrazolo[3,4-c/]pyrimidin-3-yl)-2-methoxypyridin-3- yl)methanesulfonamide;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- phenyl-5-(phenylsulfonyl)pyrrolo[2,1-][1,2,4]triazin-4(3H)-one;
6-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f|[1,2,4]triazin-5-yl)-N,N-bis(2-methoxyethyl)hex-
5- ynamide;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-
((3-hydroxyp enyl)thio)-3-phenylpyrrolo[2,1-|[1,2,4]triazin-4(3-/)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylthio)phenyl)pyrrolo[2,1-][1!2!4]triazin-4(3-)-one;
2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- methyl-3-(3-(methylsulfonyl)phenyl)pyrrolo[2,1-|[1!2!4]triazin-4(3-)-one;
2-((4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-o^pyrimidin-1- yl)methyl)-3-phenylpyrrolo[2,1-/][1!2!4]triazin-4(3/- -one;
2-((4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-c]pynmidin-1-yl)methyl)- S-phenyl-S-itrifluoromethy pyrrolo^ -flfl^^ltriazin^iSH^one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-][1 ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-c/]pyrimidin-3-yl)-2-hydroxypyridin-3-yl)-4- methoxybenzenesulfonamide;
(R)-2-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-c/]pyrimidin-1-yl)ethyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f[\ ,2,4]triazin-4(3/-/)-one;
(S)-2-(1 -(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c]pyrimidin-1 -yl)ethyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f[\ ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5- (6-(4-isopropylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-3-phenylpyrrolo[2,1-/][1,2,4]triazin- 4(3H)-one; 6-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-
4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f|[1 ,2,4]triazin-5-yl)-N-(2-morpholinoethyl)hex-5- ynamide;
2-((4,6-diamino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-c^pynmidin-1 -yl)methyl)-
5- methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-5-(3-fluoro-5-hydroxyphenyl)-7H-pyrrolo[2,3-(^pyrimidin-7-yl)methyl)-3- (1 -phenylethyl)pyrrolo[2, 1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-
(3-hydroxybenzyl)-3-phenylpyrrolo[2,1- |[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-5-
((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2, 1 -f\ \ ,2,4]triazin-4(3H)-one;
N-(3-(4-amino-1-((5-((4-hydroxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- f|[1 ,2,4]tnazin-2-yl)methyl)-1 H-pyrazolo[3,4-c ]pyrimidin-3- yl)phenyl)methanesulfonamide;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)-5- methyl-3-phenylpyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one;
(S)-2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-c ]pynmidin-1 -yl)methyl)-3-(1- phenylethyl)pyrrolo[2, 1 - |[1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(2-aminopyridin-4-yl)-1 H-pyrazolo[3,4-oGpyrimidin-1-yl)methyl)-5-( hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3/- )-one;
2-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)methyl)-
5-((4-hydroxyphenyl)thio)-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]triazin^4(3 -/)-one;
2-((4-amino-3-(1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-o^pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4 ]pyrimidin-1-yl)methyl)-5-((4- hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)-3-
(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 -/][1 ,2!4]triazin-4(3 -/)-one;
2- ((4-amino-3-(3,5-dihydroxyphenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)-5-methyl-
3- phenylpyrrolo[2,1- ][1 ,2,4]triazin-4(3 - )-one;
2-((4-amino-3-(3-hydroxy-5-methoxyphenyl)-1 H-pyrazolo[3,4- /]pyrimidin-1-yl)methyl)- 5-methyl-3-phenylpyrrolo[2, 1 -f [\ ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3- (2,4-dihydroxybenzyl)-5-methylpyrrolo[2,1-f|[1 ,2,4]tnazin-4(3H)-one;
N-(3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-c ]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonarriide; 2-((4-amino-3-(3-(2-(dimethylamino)ethoxy)-5-hydroxyphenyl)-1 --pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-(^pyrimidin-1-yl)methyl)-3-
(2-hydroxy-4-methoxybenzyl)-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
(S)-N-(3-(4-amino-1-((4-oxo-3-(1-phenylethyl)-3,4-dihydropyrrolo[2,1-/][1,2,4]tnazin-2- yl)methyl)-1H-pyrazolo[3,4-c]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonarriide;
2-((4-amino-3-(3-hydroxy-5-(2-methoxyethoxy)phenyl)-1H-pyrazolo[3,4-oGpyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1:2,4]triazin-4(3-/)-one;
2-((4-amino-3-(3,5-bis(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-(^pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2!4]triazin-4(3-/)-one;
(S)-2-(1-(4-amino-3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c^pyrimidin-
1 -yl)ethyl)-5-methyl-3-phenylpyrrolo[2, 1 -f|[1 ,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(3,4-difluoro-5-hydroxyphenyl)-1 /--pyrazolo[3,4-c/]pyrimidin-1 - yl)ethyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2,4]triazin-4(3H)-one;
(S)-2-(1 -(4-amino-3-(5-hydroxypyridin-3-yl)-1 H-pyrazolo[3,4-c]pyrimidin-1 -yl)ethyl)-5- methyl-3-phenylpyrrolo[2, 1 -|[1 ,2,4]triazin-4(3H)-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-|[1 ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-c/]pyrimidin-3-yl)pyridin-3-yl)acetarriide;
methyl 3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-|[1 ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxybenzoate;
2- ((4-amino-3-(3-((ethylamino)methyl)-5-hydroxyphenyl)-1H-pyrazolo[3,4-c|pyrimidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2!4]triazin-4(3H)-one;
3- (4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-oi]pyrimidin-3-yl)-5-hydroxybenzoic acid;
3-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-/]pyrimidin-3-yl)-N-(2-aminoethyl)-5-hydroxybenzamide; 2-((4-amino-3-(3-(aminomethyl)-5-hydroxyphenyl)-1 --pyrazolo[3,4-oi]pyrimidin-1- y methy -S-methyl-S-phenylpyrrolop.l-flCl^^^riazin^iSH^one;
2-((4-amino-3-(3-(((2-aminoethyl)amino)methyl)-5-hydroxyphenyl)-1 -/-pyrazolo[3,4- d]pyrimidin-1-yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2,4]triazin-4(3-)-one;
2-((4-amino-3-(1 H-pyrazol-4-yl)-1/-/-pyrazolo[3,4- ]pyrimidin-1-yl)methyl)-5-methyl-3- phenylpyrrolo[2,1-|[1,2,4]triazin-4(3-)-one;
N-(5-(4-amino-1-((5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-][1 ,2,4]triazin-2- yl)methyl)-1/-/-pyrazolo[3,4-c]pyrimidin-3-yl)pyridin-3-yl)methanesulfonamide;
2-((4-amino-3-(5-(2,2-difluoroethoxy)pyridin-3-yl)-1 --pyrazolo[3,4-c]pynmidin-1- yl)methyl)-5-methyl-3-phenylpyrrolo[2,1-/][1,2,4]triazin-4(3-/)-one; 2-((4-amino-3-(1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methyl-3-phenylpyrrolo[2, 1 -/][1 ,2,4]triazin-4(3H)-one;
2-((4-amino-3-(3-hydroxy-5-(trifluoromethoxy)phenyl)-1 H-pyrazolo[3,4-(^pyrimidin-1^ yl)methyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3 - -one; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
17. A compound according to any one of claims 1 to 16, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of
Phosphoinositide 3-Kinase (PI3K).
18. A compound according to claim 17, wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome;
myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.
19. A compound according to claims 17 or 18, wherein the pathological condition or disease is 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 keratosis.
20. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 16 in association with a pharmaceutically acceptable diluent or carrier.
21. Use of a compound as defined in any one of claims 1 to 16, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in any one of claims 17 to 19.
22. A method for treating a subject afflicted with a pathological condition or disease as defined in any one of claims 17 to 19 which comprises administering to said subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 16, or a pharmaceutical composition as defined in claim 20.
23. A combination product comprising (i) a compound as defined in any one of claims 1 to 1 6; and (ii) another compound selected from the group consisting of an Adenoside A2A agonist, an agent for treating cardiovascular disorders, an agent for treating diabetes, and an agent for treating liver disease, an anti-allergic agent, an anticholinergic agent, an anti-inflammatory agent, an anti-infective agent, a p2-adrenergic agonist, a Chemoattractant receptor homologous molecule expressed on TH2 cells (C TH2) inhibitor, a chemotherapeutic agent, a corticosteroid, an ΙΚΚβ/ΙΚΒΚΒ (IkB kinase beta or IKK2) inhibitor, an immunosuppressant, a Janus kinase (JAK) inhibitor, a topically acting p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitor, a
Phosphosdiesterase (PDE) IV inhibitor, and a Spleen tyrosine kinase (Syk) inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body.
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