WO2014124757A1 - Pyrrolotriazine derivatives as pi3k inhibitors - Google Patents

Pyrrolotriazine derivatives as pi3k inhibitors Download PDF

Info

Publication number
WO2014124757A1
WO2014124757A1 PCT/EP2014/000432 EP2014000432W WO2014124757A1 WO 2014124757 A1 WO2014124757 A1 WO 2014124757A1 EP 2014000432 W EP2014000432 W EP 2014000432W WO 2014124757 A1 WO2014124757 A1 WO 2014124757A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
amino
branched
linear
triazin
Prior art date
Application number
PCT/EP2014/000432
Other languages
French (fr)
Inventor
Montserrat Erra Sola
Joan Taltavull Moll
Original Assignee
Almirall, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Almirall, S.A. filed Critical Almirall, S.A.
Publication of WO2014124757A1 publication Critical patent/WO2014124757A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

New pyrrolotriazine 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

PYRROLOTRIAZINE DERIVATIVES AS PI3K 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, p110b, p110d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits. Whereas p110a (PI3Ka or PI3 a) and p1 10b (PI3Kb or ΡΙ3Κβ) isoforms are expressed ubiquitously, p110g (PI3Kg or ΡΙ3Κγ) and especially p110d (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 p110d has been shown to inhibit T cell proliferation and cytokine production in response to different stimuli such as anti-CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen- dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008). 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 pyrrolotriazine derivatives for use in the treatment of conditions in which targeting of the PI3K pathway or inhibition of PI3 Kinases can be therapeutically useful.
The compounds described in the present invention are potent PI3K inhibitors, particularly PI3Kd or dual PK3Kd/g inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic 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 pyrrolotriazine 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 imgf000009_0001
Formula (I) wherein, W represents a direct bond or a linker selected from a -O-(CH2)0-3- group, a -S-(CH2)0-3- group, a -(CH2)1-4- group, a -(CH2)0.3-NRa-(CH2)o-3- group, a -(CH2)0.3-NRa-C(O)-(CH2)0. 3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0.3-N(*)-(CH2) 2-4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2HCH2)o-3-C(0)-N(Ra)Rb group, a -(CH2)o.3-N[C(*)H2]-(CH2)2-4N(Ra)Rb group, a -(CH2)0.3-N(*)-(CH2)o.3-Rc group or a -(CH2)0.3-N[C(*)H2]-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched CVC4 alkyl) group; and wherein (*) represents the point of attachment to R ;
R° represents a C3-C10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C^C alkyl group; X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched Ci-C6 alkyl group, a linear or branched C^-Ce hydroxyalkyl group, a -(CH2)o-3N(Rd)Regroup, a linear or branched C Ce haloalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched Ci-C4 alkyl group; and
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)1-3CN group, a -(CH2)0-3-0-(CH2)o.3-0-R7 group, a -(CH2)o-3-0-(linear or branched C C4 alkyl) group, a -(CH2)0.3-O-(CH2)2.4- NR7R8 group, a -(CH2)0.3NR7R8 group, a -(CH2)o-3NH-(CH2) 2-4NR7R8 group, a -
0(0)-(ΟΗ2)1-3ΟΝ group, a -C(0)-0-(linear or branched C C4 alkyl) group, a - C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0-3-(linear or branched d-C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a -C(O)-O-(CH2)0-3-(phenyl) group, a - C(0)-(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-
(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one
heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-NR7[CH(C1-C2 alkyl)]o.3-(phenyl) group, a -C(0)-(CH2)o-3-NR7(CH2)o-3-(phenyl) group, a -C(O)- (CH2)o-3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o-3-NR7(CH2)o-3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o-3-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)2-6-NR7R8 group, a -C(O)-(CH2)0.3-NR7-(CH2)1- 6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0.3R8 group, a -S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0-3NR7R8 group, a -S(0)2CH2)o-3-NR7(CH2)o-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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0.3-(phenyl) group or a -(CH2)0.3-O- (CH2)0.3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group, a linear or branched Ci-C4 hydroxyalkyi group, a -(CH2)o-3-0-(linear or branched Ci- C4 alkyl) group, a -C(0)-0-(linear or branched C^C4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched Ci-C4 alkyl) group, a -C(O)-(CH2)0.3NRfR9 group, a -(CH2)0.3N(Rf)R9group, a -S(O)2(CH2)0. 3(linear or branched CVC4 alkyl) group, a -S(O)2(CH2)0.3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(0)2(CH2)o.3R9 group, a -(CH2)0.3- 0-(CH2)2.4-NRfR9 group or a -(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched (- C3 alkyl group or a -(CH2)0.3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C C4 alkyl group or a linear or branched C^C4 hydroxyalkyi group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C4 cycloalkyi group, a CVC4 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^C alkyl group, a CVC haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C7 cycloalkyi 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), a - (CH2)o-3-0-(CH2)0-3-(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), 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),
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 C^C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group or a C C4 alkoxy group;
R6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C4 alkyl group; a C!-C alkoxy group; a CrC4 haloalkyi group; a linear or branched C C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a -(CH2)0.
3NR7R8 group; a -(CH^.s-O- inear or branched C C4 alkyl group); a -(CH2)0-3-OC(O)-( linear or branched C C4 alkyl group); a -(CH2)0.3-C(O)O-(linear or branched C C4 alkyl group); a -C(O)-(CH2)0-3-NR7R8 group; or a -(CH2)0-3-C(O)OH group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched CVC4 alkyl group, a C C haloalkyi group, a linear or branched Ci-C4 hydroxyalkyl group or a CVC4 alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-2), (II-3), (II-4), (II-5), (II-6) or (II-7)
Figure imgf000013_0001
formula (11-5) formula (11-6) formula (11-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group;
R9, R11, Ri3, Ri4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched Ci-C4 alkyl group; R10 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a -0-(linear or branched C C3 alkyl) group, a -(CH2)0-3- C(O)-(CH2) 0-3-NR'R"group, a -(CH2) 0-3NR'R" group, a -(CH2)0.3- NR'-(CH2)1-6-NR'R" group, a -(CH2) 0-3-C(O)OH group, or a - (CH2)o-3NR'-S(0)2(CH2)0.3R" group, a -(CH2)0-3NR,-S(0)2(CH2)o.3 NR'R" group, a -(CH2)0.3NR'-C(O)(CH2)0.3 NR'R" group, a -(CH2)0. 3-(piperidinyl) group or a -(CH2)0.3-(piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C1-C4 alkyl group;
· L represents a direct bond or a linker selected from -0-(CH2)o-3-, -S-
(CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a -
C(0)-0- group or a -(CH2)i-4 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 and pain; cardiovascular diseases; viral infection;
metabolism/endocrine function disorders; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis,
autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, 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 C 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 Ci-C4 haloalkyl group is an alkyl group, for example a Ci-C4 or C 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 C C4 hydroxyalkyi embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted by one or more, preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
As used herein, the term CrC4 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-Ci0 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-Ci0 cycloalkenyl embraces partially unsaturated
carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A C3-C10 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 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 9- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A 5- to 14- membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
A said optionally substituted 5- to 14- membered heteroaryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. 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 monocyclic or bicyclic 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-C14 carbocyclic ring system, preferably C5-C10 carbocyclic ring system, more preferably C5-C9 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S. A heterocyclyl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom. When a 5 to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
A said optionally substituted monocyclic or bicyclic 5- to 14-membered heterocyclyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. Typically, the substituents on a 5 to 14-membered heterocyclyl radical are themselves unsubstituted. Examples of monocyclic or bicyclic 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro- oxazolyl, 2-benzofuran-1(3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza- tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 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, (1S,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 monocyclic or bicyclic 5- to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
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, po!yamine 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 11 C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, 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 PI3 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." IC5o 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 (IC50) 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), W represents a direct bond or a linker selected from a-O-(CH2)0-3- group, a -S- (CH2)0-3- group, a -(CH2)i.4- group, a -(CH2)0-3- NRa-(CH2)0-3- group, a -(CH2)0.3-NRa-C(0)-(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)o-3-N(*)-(CH2) 2.4-N(Ra)Rb group, a -(CH2)o-3-NRa-CH[C(*)H2]-(CH2)o-3-C(0)- N(Ra)Rb group, a -(CH2)0.3-N[C(*)H2]-(CH2)2^N(Ra)Rb group, a -(CH2)0.3-N(*)-(CH2)o-3-Rc group or a -(CH2)0-3-N[C(*)H2]-(CH2)0-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C1-C4 alkyl group or a -(CH2)0-3-O-(linear or branched C^CA alkyl) group; and wherein (*) represents the point of attachment to R^ and wherein R° represents a phenyl group or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N.
Typically, in the compound of formula (I), X represents a nitrogen atom or a -CR6 group. Preferably X represents a -CR6.
Typically, in the compound of formula (I), Ra and R each independently represent a hydrogen atom or a linear or branched C^-C alkyl group. Preferably Ra and Rb each independently represent a hydrogen atom, a methyl group or an ethyl group.
Typically, in the compound of formula (I) Ri represents a linear or branched C C6 alkyl group, a linear or branched C^-C6 hydroxyalkyl group, a -(CH2)0-3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C C4 alkyl group; and
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C^C hydroxyalkyi group, a C3-C4 cycloalkyl group, a -(CH2)i.3CN group, a -(CH2)o-3-0-(CH2)0-3-0-R7 group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -(CH2)0-3-O-(CH2)2-4- NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)o-3NH-(CH2) 2.4NR7R8 group, a - C(0)-(CH2)i.3CN group, a -C(0)-0-(linear or branched d-C4 alkyl) group, a - C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0-3-(linear or branched d-C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a -C(O)-O-(CH2)0.3-(phenyl) group, a - C(0)-(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one
heteroatom selected from O, S and N) group, a
Figure imgf000025_0001
alkyl)]0.3-(phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0-3-(phenyl) group, a -C(O)- (CH2)0.3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0-3-NR7(CH2)0.3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-NR7R8 group, a -C(O)-(CH2)0.3-NR7-(CH2)2-6-NR7R8 group, a -C(0)-(CH2)o.3-NR7-(CH2)i. e-NR7-(CH2)m-NR7Re group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(0)2(CH2)o.3R8 group, a -S(O)2(CH2)0-3NR7R8 group, a -S(O)2CH2)0.3-NR7(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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0.3-(phenyl) group or a -(CH2)0-3-O- (CH2)0-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group, a linear or branched C C4 hydroxyalkyi group, a -(CH2)0.3-O-(linear or branched C C4 alkyl) group, a -C(0)-0-(linear or branched d-d alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched d-d alkyl) group, a -C(0)-(CH2)o.3NRfR9 group, a -(CH2)0.3N(Rf)R9group, a -S(O)2(CH2)0. 3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(O)2(CH2)0-3R9 group, a -(CH2)0.3- 0-(CH2)2-4-NRfR9 group or a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-C3 alkyl group or a -(CH2)o-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C1-C4 alkyl group or a iinear or branched C C4 hydroxyalkyl group. Preferably, in the compound of formula (I), Ri represents a Iinear or branched C -C6 alkyl group, a Iinear or branched Ci-C6 hydroxyalkyl group, a -(CH2)o-3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, a 1 ,4-azathianyl group, a thiomorpholinyl 1 ,1-dioxide group, a 2,5- diazabicyclo[2.2.1 ]heptan-2-yl group, a 2,5-diazabicyclo[2.2.1 ]octan-2-yl group, a pyrrolidinyl-2-one group, or a pyrrolidinyl group; wherein Rd and Re each independently represents hydrogen or a Iinear or branched ( C4 alkyl group; and
wherein the cycloalkyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1 ,4-azathianyl, thiomorpholinyl 1 ,1- dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1 ]octan-2-yl, pyrrolidinyl-2-one or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a Iinear or branched (VC4 alkyl group, a C C4 haloalkyl group, a Iinear or branched C C hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3-O- (CH2)o-3-0-R7 group, a -(CH2)0-3-O-(linear or branched C1-C4 alkyl) group, a -
(CH2)o-3-0-(CH2)2-4-NR7R8 group, a -(CH2)0.3NR7R8 group, a -(CH2)o-3NH-(CH2) 2. 4NR7R8 group, a -C(0)-0-(linear or branched C1-C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0.3-(linear or branched C C4 alkyl) group, a -C(0)-(CH2)o-3-(phenyl) group, a -C(O)-O-(CH2)0-3-(phenyl) group, a -C(O)- (CH2)o.3-(piperazinyl) group, a -C(0)-(CH2)o-3-NR7[CH(CrC2 alkyl)]0.3-(phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0.3-(phenyl) group, a -C(O)-(CH2)0-3-NR7(CH2)0- 3-(piperidinyl) group, a -C(0)-(CH2)o-3-NR7(CH2)0-3-(pyridinyl) group, a -C(O)- (CH2)0-3-NR7R8 group, a -C(O)-(CH2)0-3-NR7-(CH2)2.6-NR7R8 group, a -C(O)- (CH2)o.3-NR7-(CH2)1.6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(0)2(CH2)o-3R8 group, a -S(0)2(CH2)o.3NR7R8 group, a -S(O)2CH2)0.3-
NR7(CH2)o-3-(phenyl) group, a -(CH2)0.3-(pyrrolidinyl) group, a -(CH2)0.3- (piperazinyl) group, a -(CH2)0-3-(piperidinyl) group, a -(CH2)0-3-(phenyl) group or a -(CH2)0.3-0-(CH2)o-3-(phenyl) group;
wherein each phenyl, pyridinyl, pyrrolidinyl, piperazinyl or piperidinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a Iinear or branched C C alkyl group, a Iinear or branched C C4 hydroxyalkyl group, a -(CH2)0.3-O-(linear or branched C1-C4 alkyl) group, a -C(0)-0-(linear or branched CrC4 alkyl) group, a -C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched CrC4 alkyl) group, a -C(0)-(CH2)o-3NRfR9 group, a -(CH2)o-3N(Rf)R9group, a - S(O)2(CH2)0-3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0. 3NRfR9 group, a -NRf-S(O)2(CH2)0.3NRfR9 group, a -NRf-S(O)2(CH2)0.3R9 group, a -(CH2)0-3-O-(CH2)2-4-NRfR9 group or a -(CH2)0.3-(pyridinyl) group; which pyridinyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched ( C3 alkyl group or a - (CH2)0.3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C1-C4 alkyl group or a linear or branched CVC4 hydroxyalkyl group.
In one embodiment, in the compound of formula (I), represents a linear or branched C C6 alkyl group, a linear or branched C C6 hydroxyalkyl group, C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group; wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group; a cyano group; a linear or branched CVC4 alkyl group; a C C4 haloalkyl group; a linear or branched C C hydroxyalkyl group; a C3-C4 cycloalkyl group; a -(CH2)1-3CN group; a - (CH2)o-3-0-(linear or branched C -C4 alkyl) group; a -(CH2)0-3-O-(CH2)2.4-NR7R8 group; a -(CH2)o-3NR7R8 group; a -(CH2)o.3NH-(CH2) 2-4NR7R8 group; a -C(0)-(CH2)1-3-CN group; a -C(0)-0-(linear or branched d-C4 alkyl) group; a -C(O)-(CH2)0-3-NR7R8 group; a -
C(0)-(CH2)o-3-NR7-(CH2)2.4-NR7R8 group; a -NR7-S(O)2(CH2)0.3R8 group; a -S(O)2(CH2)0. 3R8 group; a -S(O)2(CH2)0-3NR7R8 group; a -(CH2)_.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; a -(CH2)0.3- (5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; a -(CH2)0.3-(phenyl) group or a -(CH2)0-3-O-(CH2)0.3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C alkyl group or a -(CH2)0.3-O-(CH2)2.4-NR7R8 group; and wherein R7 and R8 each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a C3-C7 cycloalkyl group. In one embodiment, in the compound of formula (I) preferably represents a linear or branched Ci-C6 alkyl group, a linear or branched C C6 hydroxyalkyl group, a C3-C7 cycloalkyi group, a phenyl group, a pyridyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group; wherein the cycloalkyi, phenyl, pyridyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched CVC4 alkyl group, a Ci-C4 haloalkyl group, a linear or branched (-VC4 hydroxyalkyl group, a C3-C4 cycloalkyi group, a -(CH2)0-3-O-(linear or branched C C alkyl) group, a -(CH2)o-3-0- (CH2)2-4-NR7R8 group, a -(CH2)o.3NR7R8 group, a -(CH2)o.3NH-(CH2) 2-4NR7R8 group, a - C(0)-0-(linear or branched d-C4 alkyl) group, a -C(O)-(CH2)0.3-NR7R8 group, a -C(O)- (CH2)o-3-NR7-(CH2)2.4-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0-3R8 group, a -(CH2)0-3-(pyrrolidinyl) group, a -(CH2)0.3-(phenyl) group or a -(CH2)0-3-O-(CH2)0. 3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group or a -(CH2)0.3-O-(CH2)2-4-NR7R8 group.
Typically, in the compound of formula (I) R2 represents a hydrogen atom, a halogen atom or a linear or branched C C4 alkyl group.
Preferably, R2 represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. More preferably R2 represents a hydrogen atom.
Typically, in the compound of formula (I) R3 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C C alkyl group, a C C4 haloalkyl group, or a linear or branched C C4 hydroxyalkyl group.
Preferably, R3 represents a hydrogen atom, a halogen atom or a linear or branched C C4 alkyl group. More preferably R3 represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. Even more preferred, R3 represents a hydrogen atom.
Typically, in the compound of formula (I) R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a -(CH2)0.3-S-(CH2)0.3-(phenyl) group, a -(CH2)0-3-O-(CH2)0- 3-(phenyl) group, or a -(CH2)0.3-(phenyl) group; wherein the phenyl group is
unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C alkyl group, a Ci-C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group or a C C4 alkoxy group. Preferably, R4 represents a hydrogen atom, a branched C C4 alkyl group or a -(CH2)o- 3-(phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C4 alkyl group. More preferably R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, or a -(CH2)0-3-(phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups. Even more preferably R4 represents a hydrogen atom or a linear or branched C C4 alkyl group. Most preferably, R4 represents a hydrogen atom, a methyl group or an ethyl group.
Typically, in the compound of formula (I) R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C C alkyl group, a C C4 haloalkyl group, or a linear or branched C C4 hydroxyalkyl group. Preferably, R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group. More preferably, R6 represents a hydrogen atom, a halogen atom, hydroxyl group, a cyano group or a methyl group.
Typically, in the compound of formula (I) R7 and R8 each independently represent a hydrogen atom, a linear or branched C!-C4 alkyl group, a C C haloalkyl group, a linear or branched Ci-C4 hydroxyalkyl group, a C3-C7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C4 alkyl group, a ( C4 haloalkyl group, a linear or branched C C hydroxyalkyl group or a CrC4 alkoxy group.
Preferably R7 and R8 each independently represent a hydrogen atom, a linear or branched C^C3 alkyl group, a linear or branched C C3 hydroxyalkyl group, a C3-C cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C C4 alkoxy groups. More preferably, R7 and R8 each independently represent a hydrogen atom, a linear or branched CrC3 alkyl group, a linear or branched C C3 hydroxyalkyl group or a C3-C7 cycloalkyi group.
In one embodiment, in the compound of formula (I), R7 and R8 each independently represent a hydrogen atom, a linear or branched C^C4 alkyl group, a C3-C7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C^C4 hydroxyalkyi group or a C^C4 alkoxy group.
In one embodiment, R7 and R8 each independently preferably represent a hydrogen atom, a linear or branched ( C3 alkyl group, a C3-C4 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C^C4 alkoxy groups. More preferably, R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group or a C3-C7 cycloalkyl group.
Typically, in the compound of formula (I), R5 represents a moiety of formula (11-1 ), (II-2), (II-3), (II-4), (II-5), (II-6) or (II-7)
Figure imgf000030_0001
formula (11-1 ) formula (II-2) formula (II-3) formula (ll-4)
Figure imgf000030_0002
formula (II-5) formula (II-6) formula (I I-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9, R10, R11, R12, Ri3, Ri4, Ri5, Z and L are as defined above.
Preferably, in the compound of formula (I), R5 represents a moiety of formula (11-1), (II- 2), (II-3), (II-4), (II-5), (II-6) or (II-7)
Figure imgf000031_0001
formula (11-1) formula (II-2) formula (II-3) formula (II-4)
Figure imgf000031_0002
formula (II-5) formula (II-6) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R and to the pyrrolotriazine group;
• Z represents a nitrogen atom or a -CH group;
• R9i Rn, R13 R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyl group;
• R10 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a -0-(linear or branched C^-Cz alkyl) group, a -(CH2)o-3- C(O)-(CH2) 0-3-NR'R"group, a -(CH2) 0.3NR'R" group, a -(CH2)0-3- NR'-(CH2)1-6-NR'R" group, a -(CH2) 0-3-C(O)OH group, or a - (CH2)o-3NR'-S(0)2(CH2)o.3R" group, a -(CH2)o-3NR'-S(0)2(CH2)0-3 NR'R" group, a -(CH2)0-3NR'-C(O)(CH2)0.3 NR'R" group, a - (CH2)0-3-(piperidinyl) group or a -(CH2)0-3-(piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched CVC4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C1-C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
· L represents a direct bond or a linker selected from -0-(CH2)o-3-, -S-
(CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a -
C(0)-0- group or a -(CH2)i-4 group.
In a preferred embodiment, in the compound of formula (I), R5 represents a moiety of formula (11-1 ), (II-2
Figure imgf000032_0001
formula (11-1 ) formula (II-2) formula (II-5)
Figure imgf000032_0002
formula (II-6) formula (II-7) wherein:
· (*) represents the point of attachment of R5 to the carbon atom bonded to R and to the pyrrolotriazine group;
• Z represents a nitrogen atom;
• R9i R , R13i R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C3 alkyl group; · Rio and R12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
wherein the phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxyl group, a linear or branched 0Γ0 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a -0-(linear or branched C C3 alkyl) group, a -(CH2)o-3-C(0)-(CH2) o.3-NR'R"group, a -(CH2) o-3NR'R" group, a - (CH2)o-3-NR'-(CH2)1.6-NR'R" group, a -(CH2) 0-3-C(O)OH group, a - (CH2)o.3NR'-S(0)2(CH2)o.3R" group, a -(CH2)o-3NR'-S(0)2(CH2)o-3 NR'R" group, a -(CH2)o-3NR'-C(0)(CH2)0.3 NR'R" group, a - (CH2)o-3-(piperidinyl) group or a -(CH2)0-3-(piperazinyl) group, wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0.3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched ( C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched ( C4 alkyl group;
• L represents a direct bond.
In a preferred embodiment, in the compound of formula (I), R5 represents a moiety of formula (11-1), (II-2 -5), (II-6) or (II-7)
Figure imgf000033_0001
formula (11-1) formula (II-2) formula (II-5)
Figure imgf000033_0002
formula (II-6) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• Z represents a nitrogen atom; • R9, Rn R13i R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C3 alkyl group;
• R10 and R12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
wherein the phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched CV C4 alkyl group, a linear or branched Ci-C4 hydroxyalkyl group, a - 0-(linear or branched C C3 alkyl) group, a -(CH2) 0-3NR'R" group, a -(CI-yo-s- R'-iCHz e-NR'R" group, a -NR'-S(0)2(CH2)o.3R" group, a -NR'-S(O)2(CH2)0-3 NR'R" group, a -NR'-C(O)(CH2)0.3 NR'R" group, a -(CH2)0-3-(piperidinyl) group or a -(CH2)0.3- (piperazinyl) group, wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched 0^0 alkyl group or a -(CH2) 0- 3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched Ci-C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched ( C4 alkyl group;
• L represents a direct bond.
In a particular preferred embodiment, in the compound of formula (I), R5 represents a moiety of formula
Figure imgf000034_0001
formula (I I-5) formula (II-6) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group; Rg, Rii, Ri3, Ri4 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C1-C4 alkyl group; R10 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched C^C* hydroxyalkyl group, a - 0-(linear or branched CrC3 alkyl) group, a -(CH2)0-3-C(O)-(CH2) 0-3- NR'R"group, a -(CH2) 0-3NR'R" group, a -(CH2)0-3-NR'-(CH2)1.6-NR'R" group, a -(CH2) 0.3-C(O)OH group, or a -(CH2)0-3NR'-S(0)2(CH2)o-3R" group, a -(CH2)o.3NR'-S(0)2(CH2)o-3 NR'R" group, a -(CH2)0.3NR'- C(O)(CH2)0-3 NR'R" group, a -(CH2)o-3-(piperidinyl) group or a -(CH2)0-3- (piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched (- C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C1-C4 alkyl group.
In one embodiment, in the compound of formula (I) R5 preferably represents a moiety of formula (11-1 ), (II-5 or (II-7)
Figure imgf000035_0001
formula (11-1 ) formula (II-5) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9i R10, R11, Ri2, Ri3, Ri4, Ri5 and Z are as defined above. In one embodiment, R5 preferrably represents a moiety of formula (11-1), (II-5) or (II-7)
Figure imgf000036_0001
formula (11-1 ) formula (II-5) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group;
R9, R11, i3, Ri4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyl group; R10 and R 2each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, or a linear or branched C C4 hydroxyalkyl group.
Typically, in the compound of formula (I), L represents a direct bond or a linker selected from -0-(CH2)o-3-, -S- (CH2)0-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a -C(0)-0- group or a -(CH2)1-4 group.
Preferably, L represents a direct bond or a linker selected from -O-(CH2)0_3-, -S- (CH2)0. 3- or a -(CH2)1-4 group. Preferably, in the compound of formula (I)
W represents a direct bond or a linker selected from a -0-(CH2)o-3- group, a -S-(CH2)0.3- group, a -(CH2)i-4- group, a -(CH2)o-3-NRa-(CH2)o.3- group, a -(CH2)0.3-NRa-C(0)-(CH2)o. 3- group, a -0-(CH2)2^-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2-4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2l-(CH2)o.3-C(0)-N(Ra)Rb group, a -(CH2)0.3-N[C(*)H2]-(CH2)2-4N(Ra)Rb group, a -(CH2)o-3-N(*)-(CH2)0-3-Rc group or a -(CH2)0.3-N[C(*)H2]-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched CV C alkyl group or a -(CH2)0-3-O-(linear or branched C^C4 alkyl) group; and wherein (*) represents the point of attachment to R^
R° represents a C3-C10 cycloalkyi group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyi, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C C4 alkyl group; X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched C C6 alkyl group, a linear or branched C C6 hydroxyalkyl group, a -(CH2)0-3N(Rd)Regroup, a linear or branched C Ce haloalkyl group, a C3-C10 cycloalkyi group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C1-C4 alkyl group; and
wherein the cycloalkyi, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyi group, a -(ΟΗ2)1-3ΟΝ group, a -(CH2)0-3-0-(CH2)o-3-0-R7 group, a -(CH2)o-3-0-(linear or branched C CA alkyl) group, a -(CH2)0-3-O-(CH2)2. - NR7R8 group, a -(CH2)0.3NR7R8 group, a -(CH2)0.3NH-(CH2) 2. NR7R8 group, a -
C(0)-(CH2)1-3CN group, a -C(0)-0-(linear or branched C1-C4 alkyl) group, a - C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0.3-(linear or branched C^C* alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a -C(0)-0-(CH2)o-3-(phenyl) group, a - C(0)-(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one
heteroatom selected from O, S and N) group, a -C(0)-(CH2)o.3-NR7[CH(C1-C2 alkyl)]0.3-(phenyl) group, a -C(0)-(CH2)0.3-NR7(CH2)o-3-(phenyl) group, a -C(O)- (CH2)o-3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-NR7(CH2)0.3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0-3-NR7R8 group, a -C(0)-(CH2)o.3-NR7-(CH2)2.6-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)i. 6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(0)2(CH2)o-3R8 group, a -S(O)2(CH2)0.3R8 group, a -S(O)2(CH2)0.3NR7R8 group, a -S(O)2CH2)0.3-NR7(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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-(phenyl) group or a -(CH2)0-3-O- (CH2)o-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group, a linear or branched C C4 hydroxyalkyl group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -C(0)-0-(linear or branched C C4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0.3-(linear or branched C^C alkyl) group, a -C(O)-(CH2)0.3NRfR9 group, a -(CH2)0-3N(Rf)R9group, a -S(O)2(CH2)0- 3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(O)2(CH2)0.3NRfR9 group, a -NRf-S(O)2(CH2)0-3R9 group, a -(CH2)0.3- 0-(CH2)2- -NRfR9 group or a -(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched alkyl group or a -(CH2)o-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C -C4 alkyl group or a linear or branched C C hydroxyalkyl group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C!-C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched Ci-C hydroxyalkyi 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 CrC alkyl group, a CVC4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C7 cycloalkyl 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), 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), a -(CH2)0-3- (phenyl group), a -(C 2)o-3-(5- to 7- 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 C C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C hydroxyalkyi group or a Ci-C4 alkoxy group;
R6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched Ci-C alkyl group; a C1-C4 alkoxy group; a Ci-C4 haloalkyi group; a linear or branched C C4 hydroxyalkyi group; a C3-C7 cycloalkyl group; a -(CH2)0.
3NR7R8 group; a -(CH2)1-3-0-(linear or branched C C4 alkyl group); a -(CH2)0-3-OC(O)-( linear or branched C C4 alkyl group); a -(CH2)0-3-C(O)O-(linear or branched C C4 alkyl group); a -C(O)-(CH2)0.3-NR7R8 group; or a -(CH2)o.3-C(0)OH group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched Ci-C4 alkyl group, a C C4 haloalkyi group, a linear or branched CrC4 hydroxyalkyi group, a C3-C cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C4 alkyl group, a C C4 haloalkyi group, a linear or branched Ci-C4 hydroxyalkyi group or a Ci-C4 alkoxy group;
R5 represents a m
Figure imgf000039_0001
formula (11-1) formula (II-2) formula (II-5)
Figure imgf000040_0001
formula (11-6) formula (11-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9, R 0, R , R12, Ri3, Ri4, Ris, Z and L are as defined above.
In a particular preferred embodiment, in the compound of formula (I) W represents a direct bond or a linker selected from a-0-(CH2)o-3- group, a -S- (CH2)o-3- group, a -(CH2)i.4- group, a -(CH2)o.3-NRa-(CH2)o-3- group, a -(CH2)0.3-NRa-C(O)-(CH2)0- 3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0.3-N(*)-(CH2) 2-4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2]-(CH2)0-3-C(O)-N(Ra)Rb group, a -(CH2)o-3-N[C(*)H2]-(CH2)2.4N(Ra)Rb group, a -(CH2)o.3-N(*)-(CH2)o-3-Rc group or a -(CH2)o-3-N[C(*)H2]-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched Ci-C4 alkyl) group; and wherein (*) represents the point of attachment to R^
Rc represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
wherein the phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched Ci-C4 alkyl group;
X represents a nitrogen atom or a -CR6 group;
R-ι represents a linear or branched C Ce alkyl group, a linear or branched C C6 hydroxyalkyl group, a -(CH2)0-3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C†-C4 alkyl group; and
wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C4 alkyl group, a C C4 haloalkyi group, a linear or branched CrC4 hydroxyalkyi group, a C3-C4 cycloalkyl group, a -(CH2)o-3-0-(CH2)o-3-0-R7 group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -(CH2)0-3-O-(CH2)2.4-NR7R8 group, a -(CH2)0. 3NR7R8 group, a -(CH2)o.3 H-(CH2) 2.4NR7R8 group, a -C(0)-0-(linear or branched d-C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0. 3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a - C(O)-O-(CH2)0.3-(phenyl) group, a -C(O)-(CH2)0-3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-NR7[CH(C C2 alkyl)]0-3-(phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0-3- (phenyl) group, a -C(0)-(CH2)o-3-NR7(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a - C(0)-(CH2)0.3-NR7(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered
heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0-3-NR7R8 group, a -C(O)-(CH2)0.3-NR7-(CH2)2.6-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)1.6-NR7-(CH2)1.6-NR7R8 group, a -NR7- S(O)2(CH2)0.3R8 group, a -S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0.3NR7R8 group, a -S(0)2CH2)o-3-NR7(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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0. 3-(phenyl) group or a -(CH2)0.3-O-(CH2)0-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group, a linear or branched C C4 hydroxyalkyi group, a -(CH2)0-3-O-(linear or branched d- C alkyl) group, a -C(0)-0-(linear or branched C1-C4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched C^C alkyl) group, a -C(0)-(CH2)o.3NRfR9 group, a -(CH2)0.3N(Rf)R9group, a -S(O)2(CH2)0- 3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(0)2(CH2)o-3R9 group, a -(CH2)0-3- 0-(CH2)2-4-NRfR9 group or a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C3 alkyl group or a -(CH2)0.3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C C4 alkyl group or a linear or branched C^C4 hydroxyalkyi group; R2 represents a hydrogen atom or a linear or branched C C4 alkyl group;
R3 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched Ci-C4 alkyl group, or a -(CH2)0.3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C^C4 alkyl group;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC^ alkyl group, a C C haloalkyi group, or a linear or branched C C4 hydroxyalkyi group;
R7 and R8each independently represent a hydrogen atom, a linear or branched C C alkyl group, a linear or branched C C3 hydroxyalkyi group, a C3-C7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched CTC4 hydroxyalkyi group or a C,-C4 alkoxy group;
R5 represents a m
Figure imgf000042_0001
formula (11-1 ) formula (II-2) formula (II-5)
Figure imgf000043_0001
wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• Z represents a nitrogen atom or a -CH group;
• R9i Rn, R13i R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyl group;
• R 0 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a -0-(linear or branched ( C3 alkyl) group, a -(CH2)0-3- C(O)-(CH2) 0-3-NR'R"group, a -(CH2) 0.3NR'R" group, a -(CH2)0-3- NR'-(CH2)1-6-NR'R" group, a -(CH2) 0.3-C(O)OH group, or a - (CH2)o.3NR'-S(0)2(CH2)o-3R" group, a -(CH2)0-3NR'-S(O)2(CH2)0-3 NR'R" group, a
Figure imgf000043_0002
NR'R" group, a - (CH2)0.3-(piperidinyl) group or a -(CH2)0.3-(piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched CVC alkyl group or a -(CH2) 0.3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C1-C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C1-C4 alkyl group; • L represents a direct bond or a linker selected from -0-(CH2)o-3-, -S-
(CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH2)i-4 group. In a particularly preferred embodiment, in the compound of formula (I)
W represents a direct bond or a linker selected from a-0-(CH2)o-3- group, a -(CH2)1- - group, a -(CH2)0-3-NRa-(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)- (CH2) 2-4.N(Ra)Rb group, a -(CH2)0-3-NRa-CH[C(*)H2]-(CH2)o-3-C(0)-N(Ra)Rb group, a - (CH2)o.3-N[C(*)H2]-(CH2)MN(Ra)Rb group, a -(CH2)0.3-N(*)-(CH2)o-3-Rc group or a -
(CH2)o-3-N[C(*)H2]-(CH2)o-3-Rc group; wherein Ra and R each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment to R^ Rc represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
X represents a -CR6 group; represents a linear or branched C C6 alkyl group, a linear or branched C^Ce hydroxyalkyl group, a -(CH2)0-3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, a 1 ,4-azathianyl group, a thiomorpholinyl 1 , 1 -dioxide group, a 2,5-diazabicyclo[2.2.1 ]heptan-2-yl group, a 2,5-diazabicyclo[2.2.1]octan-2-yl group, a pyrrolidinyl-2-one group, or a pyrrolidinyl group; wherein Rd and Re each independently represents hydrogen or a linear or branched C C4 alkyl group; and
wherein the cycloalkyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1 ,4-azathianyl, thiomorpholinyl 1 , 1 - dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1 ]octan-2-yl, pyrrolidinyl-2-one or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C^C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0.3-O- (CH2)o-3-0-R7 group, a -(CH2)0-3-O-(linear or branched C C alkyl) group, a -
(CH2)o-3-0-(CH2)2.4-NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)0-3NH-(CH2) 2- 4NR7R8 group, a -C(0)-0-(linear or branched C C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(0)-(CH2)o-3-(linear or branched <-VC4 alkyl) group, a -C(0)-(CH2)o-3-(phenyl) group, a -C(O)-O-(CH2)0-3-(phenyl) group, a -C(O)- (CH2)0.3-(piperazinyl) group, a -C(O)-(CH2)0-3-NR7[CH(C C2 alkyl)]0.3-(phenyl) group, a -C(0)-(CH2)0-3-NR7(CH2)o-3-(phenyl) group, a -C(O)-(CH2)0-3-NR7(CH2)0. 3-(piperidinyl) group, a -C(0)-(CH2)o-3-NR7(CH2)0-3-(pyridinyl) group, a -C(O)-
(CH2)o-3-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)2.6-NR7R8 group, a -C(O)- (CH2)0.3-NR7-(CH2)1.6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(0)2(CH2)o.3R8 group, a -S(O)2(CH2)0.3NR7R8 group, a -S(O)2CH2)0-3- NR7(CH2)o-3-(phenyl) group, a -(CH2)0-3-(pyrrolidinyl) group, a -(CH2)0.3- (piperazinyl) group, a -(CH2)0.3-(piperidinyl) group, a -(CH2)0.3-(phenyl) group or a -(CH2)o.3-0-(CH2)o.3-(phenyl) group;
wherein each phenyl, pyridinyl, pyrrolidinyl, piperazinyl or piperidinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C^C4 alkyl group, a linear or branched CVC4 hydroxyalkyl group, a -(CH2)0.3-O-(linear or branched C C4 alkyl) group, a -C(0)-0-(linear or branched C C4 alkyl) group, a -C(0)-OH group, a -C(O)-(CH2)0.3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0.3NRfR9 group, a -(CH2)0-3N(Rf)R9group, a - S(0)2(CH2)o.3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0- 3NRfR9 group, a -NRf-S(O)2(CH2)0-3NRfR9 group, a -NRf-S(O)2(CH2)0.3R9 group, a -(CH2)0-3-O-(CH2)2.4-NRfR9 group or a -(CH2)0-3-(pyridinyl) group; which pyridinyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C3 alkyl group or a - (CH2)o-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C C4 alkyl group or a linear or branched C C hydroxyalkyl group;
R2 represents a hydrogen atom; R3 represents a hydrogen atom;
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, or a -(CH2)0.3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched C!-C3 alkyl group; R7 and R8 each independently represent a hydrogen atom, a linear or branched C C3 alkyl group, a linear or branched C^Cs hydroxyalkyi group, a C3-C4 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more Ci- C4 alkoxy groups;
R5 represents a m
Figure imgf000046_0001
formula (11-1 ) formula (II-2) formula (I I-5)
Figure imgf000046_0002
formula (II-6) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom;
R-, ii, Ri3, Ri4 and R 5 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C3 alkyl group;
R10 and R12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
wherein the phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C4 alkyl group, a C C haloalkyl group, a linear or branched C C4 hydroxyalkyi group, a -0-(linear or branched ( C3 alkyl) group, a -(CH2)o-3-C(0)-(CH2) o.3-NR'R"group, a -(CH2) 0.3NR'R" group, a - (CH2)0.3-NR'-(CH2)1.6-NR'R" group, a -(CH2) 0.3-C(O)OH group, a - (CH2)o-3NR'-S(0)2(CH2)0.3R" group, a -(CH2)0-3NR'-S(O)2(CH2)0.3 NR'R" group, a -(CH2)o.3NR'-C(0)(CH2)o-3 NR'R" group, a - (CH2)o-3-(piperidinyl) group or a -(CH2)0-3-(piperazinyl) group, wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C†-C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
L represents a direct bond.
In one particular embodiment, in the compound of formula (I)
W represents a direct bond or a linker selected from a -O-(CH2)0-3- group, a -S- (CH2)0- 3- group, a -(CH2)1-4- group, a -(CH2)o.3-NRa-(CH2)0.3- group, a -(CH2)0-3-NRa-C(O)- (CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0.3-N(*)-(CH2) 2.4-N(Ra)Rb group or a -(CH2)o-3-N(*)-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched Ci-C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen
Rc represents a C3-C10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C C4 alkyl group;
X represents a nitrogen atom or a -CR6 group; -i represents a linear or branched C -C& alkyl group; a linear or branched C C6 hydroxyalkyl group, a linear or branched C -C6 haloalkyl group, a C3-C10 cycloalkyl group, a C3-Ci0 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group; a cyano group; a linear or branched Ci-C4 alkyl group; a C C4 haloalkyi group; a linear or branched C^C4 hydroxyalkyl group; a C3-C4 cycloalkyl group; a -(CH2)i-3CN group; a -(CH2)o-3-0-(linear or branched C C4 alkyl) group; a -(CH2)o-3-0-(CH2)2-4-NR7 8 group; a -(CH2)0-3NR7R8 group; a -(CH2)o-3NH-(CH2) 2.4NR7R8 group; a -C(0)-(CH2)1-3-CN group; a -C(0)-0-
(linear or branched C1-C4 alkyl) group; a -C(O)-(CH2)0.3-NR7R8 group; a -C(O)- (CH2)0.3-NR7-(CH2)2.4-NR7R8 group; a -NR7-S(O)2(CH2)0.3R8 group; a - S(0)2(CH2)o-3R8 group; a -S(O)2(CH2)0.3NR7R8 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-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; a -(CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)o.3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group or a - (CH2)o-3-0-(CH2)2.4-NR7R8 group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C4 haloalkyi group, or a linear or branched C C4 hydroxyalkyl group;
R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C cycloalkyl group, a -(CH2)o-3-S-(CH2)o-3-(phenyl group), a -(CH2)o-3-0-(CH2)0-3-(phenyl group), or a -(CH2)o-3-(phenyl group);
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C^C4 haloalkyi group, a linear or branched C^C4 hydroxyalkyl group or a C C4 alkoxy group; R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, or a linear or branched C^C4 hydroxyalkyl group; R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C^-C* alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group or a C C4 alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
Figure imgf000049_0001
formula (11-1) formula (II-5) formula (II-7)
wherein:
• (*) represents the point of attachment of Rs to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9 R 0, Rii Ri2 i3 i4, i5, Z and L are as defined above.
In another particular preferred embodiment, in the compound of formula (I)
W represents a direct bond or a linker selected from a -0-(CH2)o-3- group, a -S- (CH2)o- 3- group, a -(CH2)M- group, a -(CH2)o.3-NRa-(CH2)o-3- group, a -(CH2)0-3-NRa-C(O)- (CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2.4.N(Ra)Rb group or a -(CH2)o-3-N(*)-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R^
Rc represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C1-C4 alkyl group; X represents a nitrogen atom or a -CR6 group; represents a linear or branched Ci-C6 alkyl group, a linear or branched C^Ce hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C C haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3-O-(linear or branched C1-C4 alkyl) group, a -(CH2)o- 3-0-(CH2)2-4-NR7R8 group, a -(CH2)o-3NR7R8 group, a -(CH2)0-3NH-(CH2) 2-4NR7R8 group, a -C(0)-0-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0-3-NR7R8 group, a -C(O)-(CH2)0-3-NR7-(CH2)2-4-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0.3R8 group, a -(CH2)0-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a - (CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)0.3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C -C4 alkyl group or a -(CH2)o-3-0-(CH2)2-4-NR7R8 group;
R2 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R3 represents a hydrogen atom or a linear or branched C!-C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched C!-C alkyl group, or a -(CH2)0-3- (phenyl) group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C alkyl group;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CTC4 alkyl group, a C C haloalkyi group, or a linear or branched C C4 hydroxyalkyl group; R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched CrC alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group or a CVC4 alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
Figure imgf000051_0001
formula (11-1) formula (II-5) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• Z represents a nitrogen atom or a -CH group;
• Rg, Rn, R13, R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyl group;
• R10 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched CVC4 alkyl group, a C C4 haloalkyl group, or a linear or branched CVC hydroxyalkyl group;
• L represents a direct bond or a linker selected from -O-(CH2)0-3-, -S- (CH2)o-3- a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH2)i-4 group.
In another embodiment, it is preferred that in the compound of formula (I)
W represents a direct bond or a linker selected from a-O-(CH2)0-3- group, a -(CH2)1-4- group, a -(CH2)0-3-NRa-(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)- (CH2) 2-4-N(Ra)Rb group or a -(CH2)o.3-N(*)-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched CVC4 alkyl group or a -(CH2)0. 3-0-(linear or branched C^C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R^
Rc represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
X represents a -CR6 group;
Ri represents a linear or branched C C6 alkyl group, a linear or branched C^C6 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group;
wherein the cycloalkyl, phenyl, pyridyl, piperidinyl, piperazinyl,
tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C,-C4 alkyl group, a C^-C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a - (CH2)o-3-0-(linear or branched d-C4 alkyl) group, a -(CH2)o-3-0-(CH2)2-4-NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)o-3NH-(CH2) 2. NR7R8 group, a -C(0)-0- (linear or branched C C4 alkyl) group, a -C(0)-(CH2)o-3-NR7R8 group, a -C(O)- (CH2)o-3-NR7-(CH2)2-4-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a - S(0)2(CH2)o-3R8 group, a -(CH2)0-3-(pyrrolidinyl) group, a -(CH2)o-3-(phenyl) group or a -(CH2)o.3-0-(CH2)o-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C C4 alkyl group or a -(CH2)o-3-0-(CH2)2-4- NR7R8 group; R2 represents a hydrogen atom;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom, a linear or branched C C alkyl group, or a -(CH2)0.3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups; R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched ( C3 alkyl group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched Ci alkyl group, a C3-C4 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C^-CA alkoxy groups;
R5 represents a moiety of formula (11-1 ), (H-5) or (II-7)
Figure imgf000053_0001
formula (11-1 ) formula (II-5) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• Z represents a nitrogen atom;
· R9 Rn R 3 R and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C1-C3 alkyl group;
• R10 and R12 each independently represent a phenyl group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C3 alkyl group;
• L represents a direct bond.
Particular individual compounds of the invention include:
1. (S)-Tert-butyl 4-(((2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl)oxy)methyl)piperidine-1 -carboxylate;
2. (S)-4-Amino-6-((1-(4-(pipehdin-4-ylmethoxy)pyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
3. (S)-4-Amino-6-((1 -(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 4. (S)-4-Amino-6-((1-(4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
5. (S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)methoxy)pyrrolo[2, 1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
6. (S)-4-Amino-6-((1-(4-isopropoxypyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
7. (S)-4-Amino-6-((1-(5-bronrio-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
8. (S)-2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-((tetrahydro-2H-pyran- 4-yl)methoxy)pyrrolo[2, 1 -f][1 ,2,4]triazine-5-carbonitrile;
9. (S)-4-Amino-6-((1 -(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
10. (S)-4-Amino-6-((1 -(5-bromo-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
1 1. (S)-Tert-butyl 4-((2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- bromopyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)piperidine-1-carboxylate;
12. (S)-4-Amino-6-((1-(5-bromo-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
13. (S)-4-Amino-6-((1 -(5-methyl-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
14. (S)-4-Amino-6-((1-(4-(4-methylpiperazin-1-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
15. (S)-Tert-butyl 4-((2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)piperidine-1-carboxylate;
16. (S)-4-Amino-6-((1-(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
17. (S)-4-Amino-6-((1 -(4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
18. (S)-3-(4-Amino-6-((1 -(5-methyl-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol;
19. (S)-3-(4-Amino-6-((1-(5-methyl-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluoropheno
20. (S)-4-Amino-6-((1 -(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
21. (S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 22. (S)-4-Amino-6-((1-(4-(3-(hydroxymethyl)phenoxy)-5-rnethylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)et yl)amino)pyrimidine-5-carbonitrile;
23. (S)-4-Amino-6-((1-(4-(3-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
24. (S)-4-Amino-6-((1 -(4-(4-hydroxyphenyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
25. 3-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrinnidin-3-yl)-5-fluorophenol;
26. (S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
27. 3-(4-Amino-1 -((4-(3-fluoro-5-hydroxyphenyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
28. 4-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol;
29. (S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)arriino)ethyl)-5-rriethylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-hydroxybenzamide;
30. (S)-4-Amino-6-((1-(4-(2-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
31. (S)-4-Amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
32. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
33. (S)-4-Amino-6-((1-(4-(3,5-dihydroxyphenoxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
34. (S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide;
35. (S)-4-Amino-6-((1-(4-(5-amino-6-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
36. (S)-4-Amino-6-((1 -(4-(5-hydroxypyridin-3-yl)-5-methylpyrrolo[2, 1 -f][ ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
37. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
38. (S)-4-Amino-6-((1-(4-(3-((2-(dimethylamino)ethyl)amino)phenoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
39. (S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 40. (S)-4-Amino-6-((1 -(4-(4-(3-hydroxybenzyl)piperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
41. (S)-4-Amino-6-((1-(4-(3,5-difluoro-4-hydroxyphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
42. 3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
43. (S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
44. (S)-4-Amino-6-((1-(4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
45. 3-(4-Amino-1 -((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
46. 3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
47. (S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
48. 3-(4-Amino-1 -((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyriiTiidin-3-yl)-5-fluorophenol;
49. (S)-4-Amino-6-((1-(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
50. (S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-cyclopropyl-5-hydroxybenzamide;
51. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- methoxyphenyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimi 5-carbonitrile;
52. (S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(2-morpholinoethyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
53. (S)-N-(3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide;
54. 3-(4-Amino-1 -((4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
55. 3-(4-Arnino-1-((4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2^]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
56. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- hydroxyphenyl)amino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile; 57. (S)-4-Amino-6-((1-(4-(4-hydroxy-3-(2-hydroxypropan-2-yl)phenyl)-5- methylpyrrolo[2 -f][1 ,2,4]iriazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
58. (S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)-4- methoxybenzenesulfonamide;
59. (S)-N-(5-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-2-hydroxypyridin-3-yl)-4- methoxybenzenesulfonamide;
60. 3-(4-amino-1 -((4-(4-(2-hydroxyethyl)piperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5-fluorophenol;
61. (S)-4-amino-6-((1-(4-((3-methoxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
62. 3-(4-amino-1-((5-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
63. (S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
64. 3-(4-amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2^]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
65. (S)-4-amino-6-((2-(3-hydroxyphenyl)-1 -(4-(4-isopropylpiperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
66. 4-amino-6-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
67. (S)-4-amino-6-((1 -(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
68. (S)-4-amino-6-((1 -(5-methyl-4-(4-(pyrrolidin-1 -ylmethyl)piperidin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
69. (S)-4-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile;
70. (S)-4-amino-6-((1-(5-methyl-4-(2-morpholinoethyl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
71. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazin-1- yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
72. 3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)- H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
73. (S)-4-amino-6-((1-(4-((2-hydroxyethyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 74. (S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(2-methoxyethyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboniirile;
75. (S)-4-amino-6-((1-(5-methyl-4-(methyl(1-methylpiperidin-4-yl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirnidine-5-carbonitrile;
76. 4-amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)-2-(3-hydroxyphenyl)ethyl)amino)pyrimidine-5-carbonitrile;
77. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arriino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-hydroxybenzarnide;
78. 4-amino-6-(((S)-1 -(5-methyl-4-(methyl((1 S,2S)-2-
(methylamino)cyclohexyl)amino)pyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimi 5-carbonitrile;
79. (S)-4-amino-6-((1 -(4-(dimethylamino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
80. (S)-4-amino-6-((1-(4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
81. 3-(4-amino-1 -((4-((3S,5R)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1 -yl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
82. (S)-4-amino-6-((1-(4-((2-aminoethyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
83. (S)-4-amino-6-((1 -(5-methyl-4-((2-(methylamino)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
84. (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
85. N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
86. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrim 5-carbonitrile;
87. N-(3-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
88. N-(3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide; 89. 4-amino-6-(((S)-1 -(4-((3R,5S)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyi)amino)pyrimidine-5-carbonitrile;
90. 5-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol ;
91. 4-(((S)-1-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-6-aminopyrimidine-5-carbonitrile;
92. (S)-4-amino-6-((1-(4-((3-aminopropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
93. (S)-4-amino-6-((1-(5-methyl-4-((3-(methylamino)propyl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
94. 4-amino-6-(((S)-1 -(4-((2S,6R)-2,6-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
95. 3-(4-amino-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)- 1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
96. 3-(4-amino-1-((5-methyl-4-thiomorpholinopyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)- 1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
97. 3-(4-amino-1 -((5-methyl-4-((2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
98. (S)-4-amino-6-((1-(4-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)anriino)pyrimidine-5-carbonitrile;
99. (S)-methyl 4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-2,6-dimethylbenzoate;
100. 3-(1 -((4-((1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
101. 3-(4-amino-1-((4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3^-d]pyrimidin-3-yl)-5-fluorophenol;
102. 3-(4-amino-1 -((5-methyl-4-(2,2,6,6-tetramethylmorpholino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirnidin-3-yl)-5-fluorophenol;
103. (S)-methyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
104. (S)-4-amino-6-((1 -(4-(3-cyano-5-hydroxyphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
105. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid;
106. 1-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)piperidin-4-ol; 107. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-methylbenzaiTiide;
108. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-rnethylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide;
109. 4-amino-6-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
110. N-(3-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide
111. 4-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)piperazin-2-one;
112. 1 -(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)piperidine-4-carboxamide ;
113. 3-(4-amino-1-((5-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
114. 4-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)thiomorpholine 1 ,1 -dioxide;
115. 3-(1 -((4-(1 ,4-diazepan-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-4- amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
116. (S)-4-amino-6-((1 -(4-(3-hydroxy-5-methylphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
117. 3-(1-((4-((1 R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
118. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5-methylbenzamide;
119. (S)-4-amino-6-((1 -(5-methyl-4-(2-(4-methylpiperazin-1 -yl)pyridin-4- yl)pyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirnidine-5-carbonitrile;
120. (S)-4-amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
121. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide;
122. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5-methylbenzamide
123. 3-(4-amino-1-((5-methyl-4-((1 S,4S)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.2]octan-2-yl)pyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-fluorophenol; 124 N-((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
125. 3-(4-amino-1-((4-((2-(dimethylamino)ethyl)(tetrahydro-2H-pyran-4-yl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
126. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzarriide;
127. 3-(4-amino-1-((5-methyl-4-((1 R,4R)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-fluorophenol;
128. (S)-2-((2-((S)-1 -((6-amino-5-cyanopyriinidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)amino)-3-(4-hydroxyphenyl)propanamide;
129. N-(3-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide;
130. (S)-4-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide;
131. N-(5-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxypyridin-3- yl)methanesulfonamide;
132. 3-(4-amino-1-((5-methyl-4-(2-morpholinoethoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
133. 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
134. (S)-4-amino-6-((1 -(4-(3-cyano-5-(3-hydroxypropoxy)phenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
135. 5-(5-amino-6-methoxypyridin-3-yl)-N-((S)-1-(4-((2S,6R)-2,6- dimethylmorpholino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
136. N-(3-(4-amino-1 -((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide;
137. (S)-4-amino-6-((1-(4-(3-cyano-5-((4-(methylsulfonyl)benzyl)oxy)phenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
138. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-(methylsulfonamido)benzyl)benzamide; 139. (S)-methyl 4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoate;
140. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-5- methylbenzamide;
141. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxyphenyl)-5-methylbenzamide;
142. (S)-4-((3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoic acid;
143. ethyl 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4- carboxylate;
1 4. N-(4-(4-(((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
145. (S)-N-(3-(4-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide;
146. (S)-3-aminophenyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
147. (S)-3-(2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
148. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-N,5-dimethylbenzamide;
149. 3-(4-amino-1 -((R)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5-fluorophenol;
150. 3-(4-amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
151. 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylic acid;
152. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(4-((2-hydroxyethyl)carbamoyl)benzyl)-5-methylbenzamide;
153. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-(sulfamoylamino)benzyl)benzamide;
154. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-methoxy-5-(methylsulfonamido)benzyl)-5-methylbenzamide; 155. (S)-methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-cyanobenzoate;
156. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-cyanobenzoic acid;
157. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(3-methoxy-4-(methylsulfonamido)benzyl)-5-methylbenzamide;
158. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-cyano-N-(4-sulfamoylbenzyl)benzamide;
159. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxy-5-(methylsulfonamido)benzyl)-5-methylbenzarriide;
160. (S)-4-amino-6-((1-(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirriidine-5-carbonitrile;
161. (S)-2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-6-methyl-N-(4-sulfamoylbenzyl)pyrimidine-4-carboxamide;
162. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5-methylbenzenesulfonamide;
163. (S)-4-amino-6-((1 -(4-((2-(dimethylamino)ethyl)(4-(4-methylpiperazin-1 - yl)benzyl)amino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
164. 3-(2-((S)-1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-((S)-1-(3-hydroxyphenyl)ethyl)-5-methylbenzamide;
165. (S)-4-sulfamoylbenzyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
166. (S)-4-amino-6-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)pyridin-4-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
167. (S)-4-amino-6-((1 -(4-(2-(4-(4-(dimethylamino)-6-methylpyridin-2-yl)piperidin-1 - yl)pyridin-4-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
168. (S)-4-amino-6-((1-(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4- yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
169. 5-(2-aminopyridin-4-yl)-N-((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
170. 5-(6-aminopyridin-3-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
171. ethyl 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzoate; 172. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyi)-5-methyipyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
173. 2-(dimethylamino)-N-(3-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) hydroxyphenyl)ethanesulfonamide;
174. (S)-4-amino-6-((1 -(4-((2-(dimethylamino)ethyl)(4-(4-(dimethylamino)piperidin-1 - yl)benzyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
175. N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
176. 3-(4-amino-1 -((4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5- methylpyrrolo[2 ,1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
177. (S)-4-amino-6-((1 -(5-methyl-4-((4-(4-methylpiperazin-1 -yl)benzyl)(2-(pyrrolidin- 1 -yl)ethyl)amino)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
178. (S)-4-amino-6-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)-6-methylpyridin-4-yl)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
179. 5-(2-aminopyridin-4-yl)-N-((S)-1 -(4-((2S,6R)-2,6- dimethylmorpholino)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin amine;
180. (1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidin-4-yl)(4- methylpiperazin-1 -yl)methanone;
181. 5-(2-(4-(dimethylamino)piperidin-1-yl)pyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
182. 5-(2-(dimethylamino)pyridin-4-yl)-N-((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 - yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amin
183. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-4-yl)-N-(3-(4-(dimethylamino)piperidi yl)propyl)-5-methylbenzamide;
184. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(3-((3- (dimethylamino)propyl)(methyl)amino)propyl)-5-methylbenzamide;
185. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid; 186. (S)-3-(2-(1-((6-amino-5-cyanopyrirnidin-4-yl)amino)ethyl)pyrrolo[2,1- f]i1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide;
187. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arriino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide;
188. (S)-4-amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
189. (S)-4-amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
190. (S)-4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide;
191. N-(3-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorphol^
yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonarriide;
192. N-(4-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6- yl)methanesulfamide;
193. (S)-N-(4-(4-((1 -(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2^-d]pyrimidin-5-yl)-1 H-indol-6-yl)methanesulfarriide;
194. (S)-N-(4-(4-((1 -(5-methyl-4-(2-(pyrrolidin-1 -yl)ethoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin- 2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl)methanesulfamide;
195. (S)-5-(2-aminopyridin-4-yl)-N-(1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
196. (S)-3-(4-(4-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) pyrazol-1 -yl)propan-1 -ol;
197. (S)-1-(5-(4-((1-(4-(2-(4-(dimethylamino)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxypyridin-3-yl)urea;
198. N1 -(4-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-N2,N2- dimethylethane-1 ,2-diamine;
199. N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-5-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
200. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(1 -(3- (dimethylamino)propyl)piperidin-4-yl)-5-methylbenzamide; 201. 3-(4-amino-1 -((4-(2-((3-(dimethylamino)propyl)(methyl)amino)ethoxy)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)^^
fluorophenol;
202. 3-(4-amino-1-((4-(2-(4-((dimethylamino)methyl)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
203 3-(4-amino-1-((4-(3-(4-(dimethylarnino)piperidin-1-yl)propoxy)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
204. 3-(4-amino-1-((4-(2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)ethoxy)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
205. 3-(4-amino-1-((5-methyl-4-((1-(3-(piperidin-1-yl)propyl)piperidin-4- yl)oxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
206. 3-(4-amino-1 -((5-methyl-4-(methyl(2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
207. 3-(4-amino-1 -((4-(2-(dimethylamino)ethoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
208. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
209. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbon^
210. 4-amino-6-(((S)-1 -(4-((3S,5R)-4-(3-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amin
5-carbonitrile; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
Examples of the preferred compounds are:
9. (S)-4-Amino-6-((1 -(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
17. (S)-4-Amino-6-((1 -(4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
20. (S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile; 21. (S)-4-Amino-6-((1 -(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
29. (S)-4-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-2-hydroxybenzamide;
31. (S)-4-Amino-6-((1 -(4-(3-aminophenoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
32. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
34. (S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide; 37. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
39. (S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
40. (S)-4-Amino-6-((1-(4-(4-(3-hydroxybenzyl)piperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
41. (S)-4-Amino-6-((1-(4-(3,5-difluoro-4-hydroxyphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
42. 3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
45. 3-(4-Amino-1 -((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
46. 3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
47. (S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dirnethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
48. 3-(4-Amino-1 -((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
49. (S)-4-Amino-6-((1-(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
50. (S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-cyclopropyl-5-hydroxybenzamide;
51. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- methoxyphenyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidi^ 5-carbonitrile;
53. (S)-N-(3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide; 54. 3-(4-Amino-1-((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
55. 3-(4-Amino-1-((4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5- fluorophenol;
56. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- hydroxyphenyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidi carbonitrile;
60. 3-(4-amino-1 -((4-(4-(2-hydroxyethyl)piperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
62. 3-(4-amino-1 -((5-methyl-4-(4-(methylsulfonyl)piperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
63. (S)-4-amino-6-((1 -(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyriiTiidine-5-carbonitrile;
64. 3-(4-amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)arnino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
66. 4-amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
67. (S)-4-amino-6-((1 -(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
69. (S)-4-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyriiTiidine-5- carbonitrile;
72. 3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
85. N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
87. N-(3-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
88. N-(3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide;
90. 5-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidiri-3-yl)pyridin-3-ol; 97. 3-(4-amino-1 -((5-methyl-4-((2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5-fluorophenol;
99. (S)-methyl 4-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-2,6-dimethylbenzoate;
100. 3-(1-((4-((1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
101. 3-(4-amino-1-((4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
108. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-rnethylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide;
110. N-(3-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide;
120. (S)-4-amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
121. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide;
122. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5-methylbenzamide;
131. N-(5-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxypyridin-3^ yl)methanesulfonamide;
144. N-(4-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
145. (S)-N-(3-(4-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide; 147. (S)-3-(2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
150. 3-(4-amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
159. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxy-5-(methylsulfonamido)benzyl)-5-methylbenzamide;
163. (S)-4-amino-6-((1 -(4-((2-(dimethylamino)ethyl)(4-(4-methylpiperazin-1 - yl)benzyl)amino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile; 164. 3-(2-((S)-1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-((S)-1-(3-hydroxyphenyl)ethyl)-5-methylbenzamide;
169. 5-(2-aminopyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5-dirnethylpiperazin-1-yl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ami
170. 5-(6-aminopyridin-3-yl)-N-((S)-1-(4-((3S,5R)-3,5-dirnethylpiperazin-1-yl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
172. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
176. 3-(4-amino-1 -((4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
179. 5-(2-aminopyridin-4-yl)-N-((S)-1-(4-((2S,6R)-2,6- dimethylmorpholino)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
181. 5-(2-(4-(dimethylamino)piperidin-1 -yl)pyridin-4-yl)-N-((S)-1 -(4-((3S,5R)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
182. 5-(2-(dimethylamino)pyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1- yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-am or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
In one embodiment, particular individual compounds of the invention include:
(S)-Tert-butyl 4-(((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)oxy)methyl)piperidine-1 -carboxylate;
(S)-4-Amino-6-((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-((1 -isopropylpiperidin-4-yl)methoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-Amino-6-((1-(4-isopropoxypyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimid 5-carbonitrile;
(S)-4-Amino-6-((1-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2, 1 -f][1 ,2,4]triazine-5-carbonitrile;
(S)-4-Amino-6-((1 -(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(5-bromo-4-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-Tert-butyl 4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- bromopyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate;
(S)-4-Amino-6-((1-(5-bromo-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-Tert-butyl 4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate;
(S)-4-Amino-6-((1-(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2 -f][1 ,2,4]triazi 2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(4-Amino-6-((1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2 -f][1 ,2,4]triazi yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol;
(S)-3-(4-Amino-6-((1 -(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirnidin-5-yl)-5-fluorophenol;
(S)-4-Amino-6-((1 -(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(3-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(3-hydroxyphenyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-Amino-6-((1-(4-(4-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
3-(4-Amino-1 -((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1 -(4-(3-hydroxyphenoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
3- (4-Amino-1 -((4-(3-fluoro-5-hydroxyphenyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H- pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
4- (4-Amino-1 -((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol;
(S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-hydroxybenzamide;
(S)-4-Amino-6-((1-(4-(2-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2, 1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3,5-dihydroxyphenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide;
(S)-4-Amino-6-((1 -(4-(5-amino-6-hydroxypyridin-3-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)arriino)pyrirnidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(5-hydroxypyridin-3-yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(3-((2-(dimethylamino)ethyl)amino)phenoxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)arnino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(4-(3-hydroxybenzyl)piperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3,5-difluoro-4-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1 -(4-((3- ydroxyphenyl)amino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
3-(4-Amino-1 -((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dimethylphenyl)-5-rriethylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2 -n[1 ,2,4]triazin-
2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1-(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-cyclopropyl-5-hydroxybenzamide;
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5-methoxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(2-morpholinoethyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-N-(3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide;
3- (4-Amino-1 -((4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3-(4-Amino-1-((4-((2-(dimethylarriino)ethyl)(3-hydroxyphenyl)aiTiino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5-hydroxyphenyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(4-hydroxy-3-(2-hydroxypropan-2-yl)phenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-N-(5-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)-4-rriethoxybenzenesulfonamide;
(S)-N-(5-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-2-hydroxypyridin-3-yl)-4-methoxybenzenesulfonamide; 3-(4-amino-1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2 -f][1 ,2,4]tri
2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-amino-6-((1-(4-((3-methoxyphenyl)(methyl)amino)-5-iTiethylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
3- (4-amino-1 -((5-methyl-4-(4-(methylsulfonyl)piperazin-1 -yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
3- (4-amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-amino-6-((2-(3-hydroxyphenyl)-1-(4-(4-isopropylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
4- amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1 -(5-methyl-4-(4-(pyrrolidin-1 -ylmethyl)piperidin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-((1 -(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(5-methyl-4-(2-morpholinoethyl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
4-amino-6-(((S)-1-(4-((3S,5R)-4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirriidine-5-carbonitrile;
3- (4-amino-1 -((4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-amino-6-((1 -(4-((2-hydroxyethyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(2-methoxyethyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(5-methyl-4-(methyl(1-methylpiperidin-4-yl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
4- amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)-2-(3-hydroxyphenyl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-rriethylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-hydroxybenzamide; 4- amino-6-(((S)-1 -(5-methyl-4-(methyl((1 S,2S)-2- (methylamino)cyclohexyi)amino)pyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amin
5- carbonitrile;
(S)-4-amino-6-((1-(4-(dimethylamino)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
3-(4-amino-1-((4-((3S,5R)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
5-(4-amino-1 -((4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol;
3-(4-amino-1 -((5-methyl-4-(methyl(2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirnidin-3-yl)-5-fluorophenol;
3-(4-amino-1-((5-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3- (4-amino-1 -((4-(2-(dimethylamino)ethoxy)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
4- amino-6-(((S)-1-(4-((3S,5R)-4-(4-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
4- amino-6-(((S)-1-(4-((3S,5R)-4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-
5- carbonitrile;
4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitn
4- amino-6-(((S)-1-(4-((3S,5R)-4-(3-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-
5- carbonitrile; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
Examples of the preferred compounds in this embodiment are:
(S)-4-Amino-6-((1 -(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)oxy
2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-hydroxybenzamide;
(S)-4-Amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1 -(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide;
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(4-(3-hydroxybenzyl)piperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-Amino-6-((1-(4-(3,5-difluoro-4-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-
2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
3- (4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3-(4-Amino-1 -((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3-(4-Amino-1 -((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-
2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-Amino-6-((1-(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-cyclopropyl-5-hydroxybenzamide; (S)-4-Amino-6-((1-(4-((2-(dimethyla^
methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrirnidine-5-carbonitrile;
(S)-N-(3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide;
3-(4-Amino-1-((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazi yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3-(4-Amino-1-((4-((2-(dimethylamino)ethyl)(3-hydroxyph
methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl^ fluorophenol;
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5-hydroxyphenyl)amin methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbon^
3-(4-amino-1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]tri
2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
3- (4-amino-1 -((5-methyl-4-(4-(methylsulfonyl)piperazin-1 -yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
(S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
3-(4-amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 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 and pain; cardiovascular diseases; viral infection;
metabolism/endocrine function disorders; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis,
autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, 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 alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1 ,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert- butyldimethylsilyl (TBS); and the like.
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 alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
Compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1 , from compounds of Formula (IV). Thus, compounds of Formula (IV) can be converted in compounds of Formula (III) by treatment of compounds of Formula (IV) with an appropriate reagent such as phosphorus oxychloride or phosphorus pentachloride or thionyl chloride or mixtures of them at temperatures ranging from room temperature to reflux with or without the presence of an appropriate solvent such as methylene chloride. In the particular case of compounds of Formula (I) where W represents a direct bond, compounds of Formula (III) can be treated with the corresponding boronic acids or boronic esters in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions, which are widely described in the literature. Alternatively, they can be prepared by reaction of compounds of Formula (III) with the corresponding organotin derivatives, in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Stille coupling conditions.
In the particular case of compounds of Formula (I) where W represents a linker selected from -O-(CH2)0.3-, -S- (CH2)M-, -NRa-(CH2)0.3-, -O-(CH2)0-3-N(*)Ra, -N(*)- (CH2)0-3-N(Ra)Rb and -N(*)-(CH2)0-3-Rc, compounds of Formula (III) can be treated with the corresponding R^WH group in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as tert-butanol, /V,/V-dimethylformamide, tetrahydrofurane or acetone at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
Figure imgf000080_0001
Formula (IV) Formula (III)
Formula (I)
Scheme 1
In one embodiment of the present invention compounds of Formula (IV) can be obtained from compounds of Formula (V) where is an -NH2 group by treatment with compounds of Formula (11-1 ) (II-2) (II-3) (II-4) (II-5) (II-6) as shown in Scheme 2, in the presence of a suitable base such as potassium carbonate or diisopropylethylamine in an appropriate solvent such as tert-butanol, Λ/,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation and with or without the use of a suitable catalyst such as caesium fluoride.
In another embodiment of the present invention, compounds of general Formula (IV) may be prepared from compounds of Formula (V), where the group represents a halogen atom such as chlorine, bromine and iodine or another suitable leaving group such as methanesulfonate or trifluoromethanesulfonate or other groups such as hydroxyl, that can be converted to suitable leaving groups by standard methods described in the literature, such as the Mitsunobu reaction and others, by treatment of compounds of Formula (V) with compounds of Formula (11-7) using the same conditions described above.
When 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.
Compounds of Formula (II) can either be commercial or prepared by synthetic methods well described in the literature.
Figure imgf000081_0001
Scheme 2 Alternatively, compounds of Formula (IV) can be obtained in a two steps synthesis as shown in Scheme 3, by treatment of compounds of Formula (V) with compounds of Formula (VII-1 ) (VII-2) (VII-3) in the presence of a suitable base such as potassium carbonate or diisopropylethylamine in an appropriate solvent such as terf-butanol, N,N- dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation and with or without the use of a suitable catalyst such as caesium fluoride.
In the particular case of compounds of general Formula (IV) where R5 represents a moiety of formula (11-1), (II-2) or (II-4), wherein L represents a direct bond or a -(CH2)i-4 group, compounds of Formula (IV) can be prepared from compounds of Formula (VI-1 ) (VI-2) (VI-3) where Z3 represents a halogen atom by reaction with the corresponding boronic acids or boronic esters in the presence of a suitable catalyst such as a palladium (0) catalyst under standard Suzuki coupling conditions. In the particular case of compounds of general Formula (IV) where R5 represents a moiety of formula (11-1 ), (II-2) or (M-4), wherein L represents a linker selected from -O- (CH2)o-3- or -S-(CH2)o-3-, compounds can be obtained from compounds of Formula (VI- 1 ) (VI-2) (VI-3) by reacting with the corresponding thiols or alcohols of formula HL-R10 or HL-R12 by using copper or palladium catalysed coupling methods or any other method well known for those skilled in the art.
Boronic acids or esters, thiols and alcohols can be commercial or prepared by standard methods and can be used in a protected form to prevent certain functional groups from undergoing undesired reactions. In these cases, standard methods for the removal of these protecting groups can be used at the most suitable step of the synthesis.
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.
In the particular case of compounds of general Formula (IV) where R5 represents a moiety of formula (11-1), (II-2) or (M-4), wherein L represents a -C(0)-NH- group or a - C(0)-0- group, compounds of Formula (IV) can be prepared from compounds of Formula (VI-1 ) (VI-2) (VI-3), where Z3 represents a carboxylic acid, by preparing the corresponding amide or ester by treatment of the carboxylic acid with an activating agent by methods and conditions well described in the literature, for example using T3P®, EDC or HATU as an activating agent in a solvent such as dimethylformamide, tetrahydrofurane, ethyl acetate or dichloromethane at temperatures ranging from room temperature to 80 °C
Figure imgf000083_0001
Figure imgf000083_0002
Formula (IV)
Scheme 3 Compounds of general Formula (V) can be prepared from compounds of Formula (IX) as illustrated in Scheme 4, where Z2 represents a -NH2 group or a protected amino group, such as -NHBz(OMe) or -NHBz(OMe)2 or a -O-alkyl group.
Compounds of Formula (IX) can be transformed in amides of Formula (VIII) by treatment of compounds with Formula (IX) with the appropriate acid chlorides of Formula (X) in a solvent such as acetic acid, toluene, xylene, dioxane or methylene chloride at a temperature ranging from room temperature to 50 °C in the presence or not of a suitable base such as triethylamine or pyridine.
Alternatively, compounds of Formula (IX) can be transformed in amides of Formula (VIII) by treatment with carboxylic acids of Formula (XI) in the presence of an activating agent by methods and conditions well described in the literature, for example using T3P®, EDC or HATU as an activating agent in a solvent such as dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
Compounds of Formula (VIII) where Z2 is a -NH2 group or a protected amino group, such as -NHBz(OMe) or -NHBz(OMe)2 groups, can be transformed in compounds of Formula (V) by treatment with acetic acid at a temperature ranging from room temperature to 150 °C or by treatment with pyridinium p-toluenesulfonate in an appropriate solvent such as toluene or xylene at a temperature ranging from room temperature to 150 °C.
Deprotection of benzyl groups can be performed at this or at another convenient step of the synthesis by standard methods well described in the literature, such as Pd- catalysed hydrogenolysis or acid-promoted debenzylation with trifluoroacetic acid. Compounds of Formula (VIII) where Z2 is a -O-alkyl group can be transformed in compounds of Formula (V) by treatment of compounds of Formula (VIII) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with a subsequent treatment with concentrated ammonium hydroxide or a solution of ammonia in an organic solvent such as methanol or dioxane at a temperature ranging from room temperature to 150 °
Figure imgf000084_0001
Scheme 4 Compounds of general Formula (IX) can be obtained from compounds of Formula (XII) as shown in Scheme 5. Thus, compounds of general Formula (XII) can be aminated on the nitrogen atom in position 1 with one of the aminating agents described in the literature, such as 0-(mesitylenesulfonyl)hydroxylamine, O-(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 W,W-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 dialkyi ethers and adding a phase transfer catalyst such as Aliquat 336® at temperatures ranging from 0 °C to room temperature.
Figure imgf000085_0001
Formula (XII) Formula (IX)
Scheme 5
Compounds of general Formula (XII) can either be commercial or can be prepared by known synthetic routes described elsewhere in the literature and will be apparent to those versed in the art.
Figure imgf000085_0002
In the particular case of compounds of Formula (I) where X represents CR6 being R6 a C3-C7 cycloalkyl group, or a linear or branched C C4 alkyl group, compounds of Formula (lb) can be prepared, as illustrated in Scheme 6, from compounds of Formula (lc) by Suzuki or Stille coupling with the corresponding boronic acids or organotin compound in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate with or without an appropriate base such as potassium carbonate or caesium carbonate and in a suitable solvent such as toluene or dioxane or /V,/V-dimethylformamide at temperatures ranging from 60°C to 150°C.
In the particular case where X represents CR6, being R6 a trifluoromethyl group, the bromine atom of compound of Formula (lc) can be converted first into a iodine atom by treatment of (lc) with sodium iodide in the presence of a catalysts such as copper (I) iodide and a chelating amine such as frans-1 ,2-bis(methylamino)cyclohexane in an appropriate solvent such as 1 ,4-dioxane at a temperature ranging from 60°C to reflux. Next, treatment of the iodine intermediate with methyl 2,2-difluoro-2- (fluorosulfonyl)acetate or any other trifluoro methylating 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 Ν,Ν'- dimethylformamide to afford the desired compounds.
In the particular case where R6 is a cyano group, the bromine atom of compound of Formula (lc) can be converted first into a iodine with the methods previously described or treated directly with dicyanozinc in the presence of a palladium catalyst such as tetrakis(triphenylphoshane) palladium (0) in an appropriate solvent such as Ν,Ν'- dimethylformamide at a temperature ranging from 60°C to 150°C or by using copper cyanide in a solvent such pyridine at temperatures ranging from 60°C to 150°C.
EXAMPLES General
The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the following Examples (1 -210) (including Preparation
Examples (Preparations 1-146)) 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 BCichi rotatory evaporator.
Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 prn) with the solvent system indicated. Purifications in reverse phase were made in a Biotage SP1® automated purification system equipped with a 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 appropriate fractions were collected and the solvents evaporated under reduced pressure and/or lyophilized.
Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep C18 (19 x 300 mm, 7 pm) column or an XBridge Prep C18 (19 x 100 mm, 5 pm) column. The mobile phase was formic acid (0.4 ml_), ammonia (0.1 ml_), methanol (500 ml_) and acetonitrile (500 ml_) (B) and formic acid (0.5 ml_), ammonia (0.125 ml.) and water (1000 ml_) (A), the specific gradients used are specified in each particular case. The flow rate was 20 mL/min.
Purity and MS identification was performed in a Waters 2795 system coupled to a 2996 Diode array detector and to a Waters ZQ mass spectrometer detector or in a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector. The injection volume was 5 microliter on the HPLC and 0.5 microliter on the UPLC. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization. The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A) and a gradient between 0 to 95% of B was used. Columns: HPLC: Waters Symmetry (2.1x50mm, 3.5 Dm); UPLC: ACQUITY UPLC BEH C-18 (2.1x50mm, 1.7 Dm)
1H Nuclear Magnetic Resonance Spectra were recorded on a Varian Gemini-2000 spectrometer operating at a frequency of 300 MHz for the H spectra or in a Varian Mercury plus operating at a frequency of 400 MHz for the 1H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.
Abbreviations:
DMSO Dimethylsulfoxide
CDCI3 Deuterated chloroform
CD30D Deuterated methanol NMR Nuclear magnetic resonance
s Singlet
d Doublet
dd Double doublet
td Triple doublet
br Broad
q Quartet
t Triplet
m Multiplet
LRMS Low resolution mass spectrometry
h hour(s)
min minutes
DMF Λ/,/V-Dimethylformamide
DC dichloromethane, methylene chloride
AcOEt ethyl acetate
DMSO Dimethylsulfoxide
DMTBE Dimethyl-terf-buthylether
Et20 Diethylether
EtOH Ethanol
EDC■ HCI 3-((ethylimino)methyleneamino)-/V,/V-dimethylpropan-1 -aminium chloride
THF tetrahydrofurane
DIEA diisopropylethyamine
HOBt 1-Hydroxybenzotriazole hydrate
MeOH methanol
iPrOH isopropanol, propan-2-ol, 2-propanol
DPPOONH2 (aminooxy)diphenylphosphine oxide
PPTS pyridinium p-toluenesulphonate
PPh3 Triphenylphosphine
Pd(PPh3)4 Tetrakis(triphenylphosphane) palladium(O)
PdCI2dppf DCM [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane
dppf 1 ,1 '-Bis(diphenylphosphino)ferrocene
Celite® diatomaceous earth
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 PREPARATION 1
(S)-2-(1 -Aminoethyl)pyrrolo[2,1 ,2,4]triazin-4(3H)-one a) (S)-ferf-butyl (1 -((2-carbamoyl-1 H-pyrrol-1 -yl)amino)-1 -oxopropan-2- yl)carbamate
8.50 g (22.35 mmol) of HATU and 4.00 g (21.14 mmol) of (S)-2-((tert- butoxycarbonyl)amino)propanoic acid (purchased from Aldrich® cat. no. 15380) were dissolved in 50 ml of a 1 :1 mixture of DCM and DMF. 4.0 ml (22.9 mmol) of DlEA were added and the resulting solution was stirred at room temperature for 1 hour. Then 2.55 g (20.4 mmol) of 1-amino-1 -/-pyrrole-2-carboxamide1 were added and the reaction mixture was stirred for an additional 3 hours. Then the solvents were removed under vacuum and the residue was suspended in water and filtered to furnish 3.41 g of the title compound as a brown solid. The aqueous solution was extracted with methylene chloride, washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. This crude product was purified by flash chromatography (0% to 100% hexanes/AcOEt) to yield additional 2.65 g of the title compound. Total yield: 95%.
LRMS (m/z): 297 (M+1)+. b) (S)-rerf-butyl (1-(4-oxo-3,4-dihydropyrrolo[2,1-/J[1,2,4]triazin-2- yl)ethyl)carbamate
2.65 g (8.94 mmol) of (S)-terf-butyl (1-((2-carbamoyl-1 H-pyrrol-1-yl)amino)-1- oxopropan-2-yl)carbamate and 2.25 g (8.95 mmol) PPTS were suspended in 105 ml xylene and the resulting mixture was stirred at 140 °C overnight. The solvent was then removed under reduced pressure 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 removed. 320 mg (8% yield) of the title compound were obtained.
LRMS (m/z): 279 (M+1)+. c) (S)-2-(1 -Aminoethyl)pyrrolo[2,1 ,2,4]triazin-4(3W)-one
786 mg (2.82 mmol) of (S)-terf-butyl (1-(4-oxo-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)carbamate were dissolved in 30 ml of a 4M solution of hydrochloric acid in dioxane. The solution was stirred at room temperature overnight and the volatiles were removed under vacuum. 606 mg (100% yield) of the title compound were obtained as a white solid (hydrochloric salt).
LRMS (m/z): 179 (M+1)+. PREPARATION 2
(S)-4-Amino-6-((1-(4-chloropyrrolo[2,1 -^[1,2,4]triazin-2-yl)ethyl)amino)pyrimidi 5-carbonitrile a) (S)-4-Amino-6-((1 -(4-oxo-3,4-dihydropyrrolo[2,1-/l[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
606 mg (2.82 mmol) of (S)-2-(1-Aminoethyl)pyrrolo[2,1-^[1 ,2,4]triazin-4(3H)-one (hydrochloric salt) and 480 mg (3.11 mmol) of 4-amino-6-chloropyrimidine-5- carbonitrile2 were suspended in 50 ml fe/t-butanol. 2.46 ml (1 1.75 mmol) of DIEA were added and the resulting suspension was stirred in a sealed vessel at 120 °C overnight. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to yield 600 mg (72% yield) of the title compound as a white solid.
LRMS (m/z): 297 (M+1)+. b) (S)-4-Amino-6-((1-(4-chloropyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
600 mg (2.03 mmol) of (S)-4-amino-6-((1-(4-oxo-3,4-dihydropyrrolo[2,1-r][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile were stirred in 10 ml phosphorus oxychloride at reflux temperature for 2 hours. The volatiles were then removed under vacuum and the residue was partitioned between water and methylene chloride. The aqueous layers were extracted three times with DCM and the combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent removed under vacuum to obtain 179 mg (28% yield) of the title compound as a white solid.
LRMS (m/z): 315 (M+1)+. PREPARATION 3
Methyl 1 -amino-3-bromo-1 H-pyrrole-2-carboxylate a) Methyl 3-bromo-1H-pyrrole-2-carboxylate
29.5 g (85.6 mmol) of methyl 3-bromo-1-(phenylsulfonyl)-1 H-pyrrole-2-carboxylate3 were dissolved in 560 ml of methanol and cooled in an ice bath under nitrogen atmosphere. 6.79 g (123 mmol) of sodium methoxide were added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into a saturated solution of ammonium chloride and ice and the product was extracted with diethylether. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The residue was re-dissolved in a mixture of 140 ml of methanol and 140 ml of concentrated ammonia and was stirred at room temperature for 1 hour. Then it was poured into a 1 :1 mixture of water and brine and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 15.1 g (88% yield) of the title product as a white solid.
LRMS (m/z): 204, 206 (M+1)+. b) Methyl 1 -amino-3-bromo-1 H-pyrrole-2-carboxylate
2.43 g (60.7 mmol) of sodium hydride (60% dispersion in mineral oil) were suspended in 225 ml anhydrous DMF and cooled in an ice bath. A solution of 7.50 g (36.8 mmol) of methyl 3-bromo-1H-pyrrole-2-carboxylate in 75 ml DMF was then added drop-wise under nitrogen atmosphere and the mixture was stirred at 0 °C for 30 min. Then it was diluted with 115 ml DMF and 13.7 g (58.8 mmol) DPPOONH2 were added in two portions. The resulting mixture was stirred at room temperature for 3 h and then poured into 500 ml of a 10% aqueous solution of sodium thiosulfate. The product was extracted with diethylether and the organics were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 7.1 g of the title product as an oil, with a purity of 66%, which was used with no further purification in the next step. Yield: 59%.
LRMS (m/z): 219, 221 (M+1 )+.
PREPARATION 4
(S)-2-(1 -Aminoethyl)-5-bromopyrrolo[2,1 ,2,4]triazin-4(3AY)-one a) (S)-Methyl 3-bromo-1-(2-((ferf-butoxycarbonyl)amino)propanamido)-1H- pyrrole-2-carboxylate
The crude product obtained in Preparation 3b (18.38 mmol) was dissolved in 40 ml ethyl acetate. 3.50 g (18.5 mmol) of (S)-2-((fert-butoxycarbonyl)amino)propanoic acid (purchased from Aldrich®, cat. no. 15380) were added and the resulting mixture was cooled in an ice bath under argon. Then 10.6 ml (60.9 mmol) of DIEA were added and after 15 min, 15.3 ml (25.7 mmol) of T3P® (50% solution in AcOEt) were added drop- wise. The mixture was first stirred at 0 °C for 20 min and then at room temperature for 1 hour. To isolate the product, the solution was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 25% hexane/AcOEt) to yield 4.34 g (61 % yield) of the title compound as a solid.
LRMS (m/z): 390, 392 (M+1)+. b) (S)-rerf-butyl (1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)carbamate
1.0 g (2.56 mmol) of (S)-methyl 3-bromo-1-(2-((tert- butoxycarbonyl)amino)propanamido)-1 /- -pyrrole-2-carboxylate were stirred in a 7 M solution of ammonia in methanol in a sealed tube at 85 °C overnight. The volatiles were removed under vacuum and the crude product was purified by flash chromatography (0% to 50% hexane/AcOEt) to yield 360 mg (39% yield) of the title compound as a solid.
LRMS (m/z): 357, 359 (M+1)+. c) (S)-2-(1-Aminoethyl)-5-bromopyrrolo[2,1-fl[1,2,4]triazin-4(3H)-one
360 mg (1.01 mmol) of (S)-fert-butyl (1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)carbamate were stirred at room temperature in a 4M solution of hydrochloric acid in dioxane overnight. The volatiles were removed under vacuum and the residue was dissolved in water and the solution basified with a saturated aqueous solution of sodium carbonate. The product was extracted with methylene chloride and the aqueous layer was saturated with sodium chloride and extracted again. The combined organic solutions were dried over magnesium sulphate, filtered and the solvents were removed in vacuo to give 220 mg (85% yield) of the title compound as a solid.
LRMS (m/z): 257, 259 (M+1)+.
PREPARATION 5
(S)-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[2,1-fl[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a) (S)-4-Amino-6-((1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
1.07 g (4.16 mmol) of (S)-2-(1-aminoethyl)-5-bromopyrrolo[2,1-/][1 ,2,4]triazin-4(3H)- one and 710 mg (4.59 mmol) of 4-amino-6-chloropyrimidine-5-carbonitrile2 were suspended in 50 ml terf-butanol. 2.90 ml (16.65 mmol) of DIEA were added and the resulting suspension was stirred in a sealed vessel at 120 °C overnight. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to yield 980 mg (63% yield) of the title compound as a brownish solid.
LRMS (m/z): 375, 377 (M+1 )+. b) (S)-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[2,1 -f|[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
980 mg (2.61 mmol) of (S)-4-amino-6-((1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were stirred in 15 ml phosphorus oxychloride at reflux temperature for 3 hours. The volatiles were then removed under vacuum and the residue was suspended in water and stirred overnight. Then THF was added to the suspension until complete dissolution of the solid was observed. The solution was neutralized to pH = 7 with aqueous solution of potassium carbonate and stirred for 4 hours at room temperature. The product was then extracted with methylene chloride and the combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent removed under vacuum to give 741 mg (72% yield) of the title compound as a brown solid.
LRMS (m/z): 393, 395 (M+1 )+.
PREPARATION 6
(S)-2-(1 -Aminoethyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4(3W)-one a1 ) Ethyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate
3.39 g (84.7 mmol) of sodium hydride (60% dispersion in mineral oil) were suspended in 550 ml anhydrous DMF and cooled in an ice bath. A solution of 10.0 g (65.3 mmol) of ethyl 3-methyl-1 H-pyrrole-2-carboxylate (purchased from Astatech®, cat. no. 59362) in 200 ml DMF was added during 30 min under nitrogen atmosphere and the mixture was stirred mechanically at 0 °C for 30 min. Then 24.36 g (104 mmol) DPPOONH2 were added in 5 portions. The resulting mixture was stirred at room temperature for 4 h and then poured into 500 ml of a 10% aqueous solution of sodium thiosulfate. The product was extracted with diethylether and the organics were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 10.23 g of the title product as an oil of 66% purity, which was used with no further purification in the next step. Yield: 72%.
LRMS (m/z): 169 (M+1)+. b1 ) (S)-Ethyl 1 -(2-((tert-butoxycarbonyi)amino)propanamido)-3-methy!-1 H- pyrrole-2-carboxylate
12.66 g (66.9 mmol) of (S)-2-((ferf-butoxycarbonyl)amino)propanoic acid (purchased from Aldrich®, cat. no. 15380) and 25.44 h (66.9 mmol) HATU were dissolved in a mixture of 40 ml DMF and 40 ml DCM. The solution was cooled in an ice bath, 1 1.65 ml (66.9 mmol) of DIEA were added and the resulting mixture was stirred at room temperature for 1 h. Then 10.23 g (46.8 mmol) of ethyl 1-amino-3-methyl-1 H-pyrrole-2- carboxylate (crude product obtained in the previous step, 66% purity) were added and the reaction was stirred at room temperature for 2 hours. The solvents were evaporated under vacuum and the residue was partitioned between water and AcOEt. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo to give 16.04 g of the title compound as a white solid with a purity of 81 % (82% yield), which was used with no further purification in the next step.
LRMS (m/z): 340 (M+1 )+. c1 ) (S)-rerf-butyl (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-fl[1 ,2,4]triazin-2- yl)ethyl)carbamate
24.8 g (94.5 mmol) of PPh3 were dissolved in 200 ml methylene chloride and cooled in an ice bath. Then 4.84 ml (94.5 mmol) of bromine were added and the resulting solution was stirred at room temperature for 30 min. Then were added 33 ml (238 mmol) of triethylamine and a solution of 16.07 g (38.4 mmol) of (S)-ethyl 1-(2-((tert- butoxycarbonyl)amino)propanamido)-3-methyl-1 H-pyrrole-2-carboxylate (crude product obtained in the previous step, 81 % purity) in 100 ml methylene chloride. The resulting solution was stirred at room temperature for 2 h and the volatiles were removed under reduced pressure. The residue was suspended in 250 ml of concentrated aqueous ammonia and the resulting suspension was stirred at 100 °C in a sealed reactor overnight. Once the mixture reached room temperature, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and AcOEt. The organic layers were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. 40.51 g of a mixture of (S)-tert-butyl (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)ethyl)carbamate and triphenylphosphine oxide were obtained, which was used with no further purification in the next step.
LRMS (m/z): 293 (M+1 )+. d1 ) (S)-2-(1 -Aminoethyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4(3H)-one 40.51 g of the crude product obtained in the previous step were stirred in 300 ml of a 4 M solution of hydrogen chloride in dioxane for 1 h. Then the volatiles were removed under reduced pressure and the residue was partitioned between 2 M aqueous solution of hydrochloric acid and AcOEt. The aqueous layer was washed two times more with AcOEt and basified to pH= 8-9 with concentrated aqueous sodium hydroxide. The product was then extracted with methylene chloride (x3), the organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated. 5.68 g of a brownish solid were obtained, free from triphenylphosphine. Yield: 47% (in two steps).
LRMS (m/z): 193 (M+1 )+. a2) Methyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate
3.74 g (93.5 mmol) of sodium hydride (60% dispersion in mineral oil) were suspended in 550 ml anhydrous DMF and cooled in an ice bath. A solution of 10.0 g (65.3 mmol) of methyl 3-methyl-1 - -pyrrole-2-carboxylate (purchased from Otava Chemicals®, cat. no. 1056278) in 200 ml DMF was added during 30 min under nitrogen atmosphere and the mixture was stirred mechanically at 0 °C for 30 min. Then 26.8 g (115 mmol) DPPOONH2 were added in 5 portions. The resulting mixture was stirred at room temperature for 5 h and then poured into 500 ml of a 10% aqueous solution of sodium thiosulfate. The product was extracted with diethylether and the organics were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 19.5 g of an oil that contained a mixture of 70% of the product and 30% of starting material. This crude was dissolved in diethylether and the product was extracted twice with a 2 M aqueous solution of hydrochloric acid. The aqueous solution was then neutralized with a 2 M solution of sodium hydroxide and the product was extracted again with diethylether (x3). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 5.90 g (53% yield) of the title product were isolated as a white solid.
LRMS (m/z): 155 (M+1)+. b2) (S)-Methyl 1-(2-((tert-butoxycarbonyl)amino)propanamido)-3-methyl-1H- pyrrole-2-carboxylate
The title compound was prepared following the experimental procedure described in Preparation 6b1 , from 2.53 g (16.41 mmol) of methyl 1-amino-3-methyl-1H-pyrrole-2- carboxylate. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to yield 4.98 g (93% yield) of the title compound as a white solid.
LRMS (m/z): 326 (M+1 )+. c2) (S)-rerf-butyl (l -iS-methy -oxo-S^-dihydropyrrolo^.l- lll^.^triazin^- yl)ethyl)carbamate
The title compound was prepared following the experimental procedure described in Preparation 6c1 , from 914 mg (2.81 mmol) of (S)-methyl 1-(2-((tert- butoxycarbonyl)amino)propanamido)-3-methyl- H-pyrrole-2-carboxylate. The crude product was purified by flash chromatography (0% to 40% hexane/AcOEt) to yield 381 mg (46% yield) of the title compound as a white solid.
LRMS (m/z): 293 (M+1 )+. d2) (S)-2-(1 -Aminoethyl)-5-methylpyrrolo[2,1 -f\[1 ,2,4]triazin-4(3W)-one
The title compound was prepared following the experimental procedure described in Preparation 6d1 , from (S)-tert-butyl (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)carbamate. 196 mg (79% yield) of the title product were obtained as a white solid.
LRMS (m/z): 193 (M+1)+.
PREPARATION 7
(S)-4-Amino-6-((1 -(4-chloro-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a) (S)-4-Amino-6-((1 -(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1 -f [1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
870 mg (4.53 mmol) of (S)-2-(1-aminoethyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-4(3H)- one and 770 mg (4.98 mmol) of 4-amino-6-chloropyrimidine-5-carbonitrile2 were suspended in 30 ml terf-butanol. 2.37 ml (13.6 mmol) of DIEA were added and the resulting suspension was stirred in a sealed vessel at 120 °C overnight. 770 mg excess of 4-amino-6-chloropyrimidine-5-carbonitrile and 2.37 ml DIPEA were added and the reaction was stirred at 120 °C for another 24 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 876 mg (62% yield) of the title compound as a white solid.
LRMS (m/z): 311 (M+1)+. b) (S)-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-f|[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
700 mg (2.26 mmol) of (S)-4-amino-6-((1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrirriidine-5-carbonitrile were suspended in 15 ml of phosphorus oxychloride and stirred at reflux temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was suspended in a saturated bicarbonate solution. The pH was adjusted at 7 with a saturated potassium carbonate solution and the suspension was stirred vigorously for 4 hours. The product was then extracted twice with ethyl acetate, the combined organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 316 mg (43% yield) of the title product as a pale solid.
LRMS (m/z): 329 (M+1 )+.
PREPARATION 8
6-Chloro-5-iodopyrimidin-4-amine
To a solution of 3.03 g (23.4 mmol) of 6-chloropyrimidin-4-amine (purchased from Aldrich®, cat. no. 735272) in 60 ml of DMF was added drop-wise a solution of 2.34 ml (46.7 mmol) of iodine monochloride in 40 ml DMF and the mixture was stirred at 45 °C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM and a saturated solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuo. The product was purified by flash chromatography (0% to 20% DCM/MeOH) to obtain 4.28 g (72% yield) of the title compound.
LRMS (m/z): 256 (M+1 )+.
PREPARATION 9
(S)- V4-(1-(4-Chloro-5-methylpyrrolo[2,1-/|[1 ,2,4]triazin-2-yl)ethyl)-5- iodopyrimidine-4,6-diamine a) (S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ,2,4]triazin-4(3H)-one
280 mg (1.46 mmol) of (S)-2-(1-aminoethyl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-4(3H)- one (Preparation 6), 744 mg (2.91 mmol) of 6-Chloro-5-iodopyrimidin-4-amine, 422 mg (2.91 mmol) of caesium fluoride and 1.27 ml (7.29 mmol) of DIEA were suspended in 8 ml of tert-butanol and heated at 140 °C in a sealed vessel for 16 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 422 mg (71 % yield) of the title compound.
LRMS (m/z): 412 (M+1 )+. b) (S)-Ar'-(l -(4-Chloro-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl)-5- iodopyrimidine-4,6-diamine
422 mg (1.03 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3/-/)-one were suspended in 5 ml of phosphorus oxychloride and stirred at 100 °C for 1 hour. The volatiles were removed under reduced pressure and the residue was suspended in a mixture of methylene chloride and aqueous saturated solution of sodium bicarbonate and it was stirred vigorously for 30 min. The product was then extracted twice methylene chloride, and the combined organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (40% to 100% hexane/AcOEt) to obtain 210 mg (43% yield) of the title product as a pale yellow solid.
LRMS (m/z): 430 (M+1 )+.
PREPARATION 10
(S^S-lodo-A/ -il-fS-methyM-^-meth^^
yl)ethyl)pyrimidine-4,6-diamine 54 mg (0.13 mmol) of (S)-W*-(1 -(4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)- 5-iodopyrimidine-4,6-diamine and 70 μΙ (0.63 mmol) of 1-methylpiperazine were dissolved in 3 ml of THF and stirred at reflux for 1 h. The solvent was removed under reduced pressure 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 to give 64 mg (100% yield) of the title compound as a white solid.
LRMS (m/z): 494 (M+1 )+.
PREPARATION 1 1
(SJ-S-lodo-Af'-il-iS-methyl^itetrahydro^H-pyran^-yOmethoxyJpyrrolo^.l- ][1 ,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine 1 12 mg (0.96 mmol) of (tetrahydro-2H-pyran-4-yl)methanol (purchased from Maybridge int.®, cat. no. CC29909DA) were added to a suspension of 19 mg (0.48 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF and were stirred under nitrogen atmosphere for 30 min. Then this solution was poured into a solution of 188 mg (0.44 mmol) of (S)-A/4-(1 -(4-chloro-5-methylpyrrolo[2, 1 - r [1 ,2,4]triazin-2-yl)ethyl)-5-iodopyrimidine-4,6-diamine in 3 ml of THF and the resulting mixture was stirred at room temperature for 2 hours. To isolate the product, the reaction mixture 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 reverse phase chromatography (C- 18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 135 mg (61 % yield) of the title product as a white solid.
LRMS (m/z): 510 (M+1 )+.
PREPARATION 12
2-(Chloromethyl)pyrrolo[2,1 ,2,4]triazin-4(3H)-one a) 1 -(2-Chloroacetamido)-1 H-pyrrole-2-carboxamide
3.00 g (24.0 mmol) of 1 -amino-1 H-pyrrole-2-carboxamide1 were dissolved in 45 ml of glacial acetic acid and cooled in an ice bath. 2.80 ml (35.1 mmol) of 2-chloroacetyl chloride were added drop-wise and the reaction mixture was stirred at room temperature for 90 min. The precipitate that formed was collected by filtration, was washed with cyclohexane and was dried in a stream of air. 4.43 g (92% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 202 (M+1 )+. b) 2-(Chloromethyl)pyrrolo[2,1 ,2,4]triazin-4(3H)-one
4.43 g (22.0 mmol) of 1-(2-Chloroacetamido)-1 H-pyrrole-2-carboxamide were suspended in 160 ml of xylene and 5.50 g (22.0 mmol) of PPTS were added. The mixture was stirred at 140 °C for 1 hour 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 3.10 g (72% yield) of the title compound.
LRMS (m/z): 184 (M+1 )+.
PREPARATION 13 l-ii^Chloropyrrolo^.l-ZHI^^ltriazin-a-y methy -S-iodo-IH-pyrazoloIS^- d]pyrimidin-4-amine a) 2-((4-Amino-3-iodo-1H-pyrazolo[3,4-o]pyrimidin-1-yl)methyl)pyrrolo[2,1- J[1,2,4]triazin-4(3H)-one
3.80 g (14.6 mmol) of 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (purchased from Ark Pharm®, cat. no. AK-32203) were dissolved in 45 ml of DMF and cooled in an ice bath. To this solution were added 2.0 g (14.6 mmol) of potassium carbonate and then a solution of 2.90 g (14.6 mmol) of 2-(chloromethyl)pyrrolo[2,1-r][1 ,2,4]triazin-4(3H)-one drop-wise. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and AcOEt and the solid that formed was filtered, washed with water and dried in the oven to give 490 mg of the title product. The aqueous layer was adjusted to pH = 7 and was extracted with AcOEt. The combined organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain an additional 730 mg of the title compound. Overall yield: 19%.
LRMS (m/z): 409 (M+1)+. b) 1-((4-Chloropyrrolo[2,1-fl[1,2,4]triazin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-4-amine
490 mg (1.04 mmol) of 2-((4-amino-3-iodo-1W-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)pyrrolo[2,1- [1 ,2,4]triazin-4(3 - )-one were suspended in 3 ml of phosphorus oxychloride and stirred at 100 °C for 2 hours. The volatiles were removed under reduced pressure and the residue was suspended in a mixture of methylene chloride and water. Solid sodium bicarbonate was added until neutral pH was reached and the organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 477 mg (88% yield) of the title product were obtained as a pale yellow solid.
LRMS (m/z): 427 (M+1)+.
PREPARATION 14
3-lodo-1 -((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1 ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine The title compound was prepared following the experimental procedure described in Preparation 11 from 238 mg (0.56 mmol) of 1-((4-chloropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 285 mg (2.45 mmol) of (tetrahydro-2H-pyran-4-yl)methanol. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 89 mg (32% yield) of the title product as a white solid.
LRMS (m/z): 283 (M+1 )+.
PREPARATION 15
1 -Amino-/V-(2,4-dimethoxybenzyl)-3-methyl-1 H-pyrrole-2-carboxamide a) 3-Methyl-1 H-pyrrole-2-carboxylic acid
10.0 g (65.3 mmol) of ethyl 3-methyl-1 /- -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.
LR S (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/- -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 drop-wise, 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- V-(2,4-dimethoxybenzyl)-3-methyl-1 V-pyrrole-2-carboxamide
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 drop-wise (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 16
2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin- 4(3W)-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 drop-wise 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-/J[1 ,2,4]triazin- 4(3W)-one
5.24 g (14.3 mmol) of 1-(2-chloroacetamido)-/V-(2,4-dimethoxybenzyl)-3-methyl-1 /-/- 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 17
1-((4-Chloro-5-methylpyrrolo[2,1-/l[1,2,4]triazin-2-yl)methyl)-3-iodo-1H- pyrazolo[3,4-d]pyrimidin-4-amine a) 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-(2,4- dimethoxybenzyl)-5-methylpyrrolo[2,1- |[1,2,4]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(3H)-one in DMF (180 ml) were added 4.12 g (15.8 mmol) of 3-iodo-1 H-pyrazolo[3,4-d]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)+. b) 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c(]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1- ][1,2,4]triazin-4(3H)-one
3.27 g (5.71 mmol) of 2-((4-amino-3-iodo-1 -/-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3- (2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-4(3H)-one were dissolved in 50 ml of trifluoroacetic acid. 18 ml (28 mmol) of anisole were added and the mixture was stirred at 75 °C for 5.5 hours and then the volatiles were removed under reduced pressure. The residue was suspended in 50 ml of hexane and the mixture was stirred vigorously overnight. The solid that formed was filtered, washed with hexane and dried under a team of air to obtain 2.33 g (97% yield) of the title compound.
LRMS (m/z): 423 (M+1 )+. c) 1 -((4-Chloro-5-methylpyrrolo[2,1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-d)pyrimidin-4-amine
2.33 g (5.52 mmol) of 2-((4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrirnidin-1 -yl)methyl)-5- methylpyrrolo[2, 1 -/][1 ,2,4]tnazin-4(3H)-one were suspended in 15 ml of phosphorus oxychloride and stirred at 80 °C for 2 hours. The volatiles were removed under reduced pressure and the residue was suspended in a saturated solution of sodium bicarbonate. After 30 min. stirring, the product was extracted with ethyl acetate and the organic solution was, washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 1.59 g (66% yield) of the title product was obtained as a pale brown solid.
LRMS (m/z): 441 (M+1 )+.
PREPARATION 18
3-lodo-1 -((4-(4-isopropylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)methyl)-1 W-pyrazolo[3,4-cdpyrimidin-4-amine
100 mg (0.23 mmol) of 1 -((4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 97 mg (0.76 mmol) of 1 - isopropylpiperazine were dissolved in 2 ml of acetone and stirred at reflux for 1 hour. The reaction mixture was partitioned between water and ethyl acetate, the organic layers were washed with water and bine, dried over magnesium sulphate, filter and the solvent was removed under reduced pressure to obtain 92 mg (76% yield) of the title compound as a pale orange solid.
LRMS (m/z): 533 (M+1 )+.
PREPARATION 19
3-lodo-1-((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4- /|pyrimidin-4-amine The title compound was prepared following the experimental procedure described in Preparation 1 1 from 102 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1 - /][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-amine and 1 14 mg (0.98 mmol) of (tetrahydro-2H-pyran-4-yl)methanol. After isolation, 92 mg (76% yield) of the title compound were obtained as a pale orange solid, pure enough to be used in the next step with no need of purification.
LRMS (m/z): 521 (M+1 )+. PREPARATION 20
1 -((4-((2S,6 ?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)methyl)-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-arnine The title compound was obtained from 100 mg (0.23 mmol) of 1 -((4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /-/-pyrazolo[3,4-cf]pyrimidin-4- amine and 140 μΙ (1.14 mmol) of c/'s-2,6-dimethylmorpholine following the experimental procedure described in Preparation 18. 102 mg (87% yield) of the pure title compound were obtained as a light brown solid.
LRMS (m/z): 520 (M+1 )+.
PREPARATION 21
A/-Cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzamide a) 3-Bromo-/V-cyclopropyl-5-hydroxybenzamide
100 mg (0.46 mmol) of 3-bromo-5-hydroxybenzoic acid (purchased from Aldrich®, cat. no. 686417), 58 μΙ (0.83 mmol) of cyclopropanamine (purchased from Aldrich®, cat. no. 125504), 263 mg (0.69 mmol) of HATU and 281 μΙ (1.61 mmol) of DIEA were dissolved in 2 ml of DMF under nitrogen atmosphere and stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was re-dissolved in AcOEt. The resulting organic solution was washed with saturated solution of sodium bicarbonate, water and brine, dried over magnesium sulphate, filtered and the solvent evaporated to give 320 mg of a crude product that contained the title compound with a purity of 60%.
LRMS (m/z): 257 (M+1)+. b) /V-Cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzamide
The crude product of Preparation 21 a was dissolved in dioxane (20 ml) and to this solution were added 371 mg (1 .46 mmol) of 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 , 3,2- dioxaborolane), 30 mg (0.04 mmol) of PdCI2dppf DCM , 20 mg (0.04 mmol) of dppf and 215 mg (2.19 mmol) of potassium acetate. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. An additional 30 mg of the palladium catalyst was added and the reaction was allowed to proceed for 24 hours more. After cooling, the reaction mixture was filtered through a bed of Celite® and the solid was washed abundantly with ethyl acetate. The filtered organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 244 mg of a dark oil containing a 48% of the title product were isolated and used with no further purification.
LRMS (m/z): 222 (M+1 )+.
PREPARATION 22
yV-(3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide a) A/-(3-Hydroxyphenyl)methanesulfonamide
500 mg (4.58 mmol) of 3-Aminophenol were dissolved in 8 ml of tetrahydrofurane. 747 μΙ (9.16 mmol) of pyridine and 425 μΙ (5.49 mmol) of methanesulfonyl chloride were added. The mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. Then it was cooled at 0 °C and 7 ml of 1 N hydrochloric acid was added. The mixture was stirred for 5 min and was poured into water. The product was extracted with ethyl acetate, dried over sodium sulphate, filtered and concentrated under reduced pressure to give 980 mg (99% yield) of the title compound as an oil.
LRMS (m/z): 188 (M+1)+. b) /V-(3-Bromo-5-hydroxyphenyl)methanesulfonamide
857 mg (4.58 mmol) of A/-(3-hydroxyphenyl)methanesulfonamide were suspended in 10 ml of acetic acid. The mixture was cooled at 0 °C and 281 μΙ (5.49 mmol) of bromine were added drop-wise. The reaction mixture was stirred for 4 h. Diethyl ether was added and the organic was washed with 4% sodium bicarbonate solution, water and brine. The aqueous layer was extracted with ethyl acetate and the organics were combined, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to give 451 mg (37% yield) of the title compound as a solid.
LRMS (m/z): 267 (M+1)+. c) /V-(3-Hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide
451 mg (1.68 mmol) of V-(3-bromo-5-hydroxyphenyl)methanesulfonamide were treated with 430 mg (1.69 mmol) of 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), 703 mg (5.09 mmol) of potassium acetate, 60 mg (2.13 mmol) of PdCI2dppf DCM and 60 mg (0.09 mmol) of dppf according to the method described in Preparation 21 b. The crude product was purified by flash chromatography (0% to 100% hexane/AcOEt) to obtain 260 mg (49% yield) of the title compound. Purity: 100%.
LRMS (m/z): 314 (M+1 )+.
PREPARATION 23
3-lodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)- 1 V-pyrazolo[3,4- ]pyrimidin-4-amine a) Terf-butyl 4-((2-((4-amino-3-iodo-1H-pyrazolo[3,4-iy|pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1 -r][1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate
The title compound was prepared following the experimental procedure described in Preparation 11 from 200 mg (0.45 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- r][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /- -pyrazolo[3,4-d]pyrimidin-4-amine and 183 mg (0.91 mmol) of tert-butyl 4-hydroxypiperidine-1 -carboxylate (purchased from Aldrich®, cat. no. 495484). The reaction was completed in 16 hours and the crude product was used in the next step with no further purification.
LRMS (m/z): 606 (M+1)+. b) 3-lodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)- 1W-pyrazolo[3,4-cflpyrimidin-4-amine
The crude terf-butyl 4-((2-((4-amino-3-iodo-1 /- -pyrazolo[3,4-c]pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate obtained in Preparation 23a was treated with 10 ml of 4 M solution of hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature overnight and the volatiles were removed under reduced pressure. The residue was partitioned between DCM and diluted aqueous HCI solution and the two layers were separated. The aqueous layer was basified with 2 M sodium hydroxide solution and the product was extracted twice with AcOEt. The combined organic solutions were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain
39 mg (17% yield in two steps) of the title compound as a white solid.
LRMS (m/z): 506 (M+1)+.
PREPARATION 24 3-lodo-1 -((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
39 mg (0.08 mmol) of 3-iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-4-aiTiine were suspended in 2 ml of acetonitrile. 17 mg (0.11 mmol) of sodium iodide, 27 mg (0.20 mmol) of potassium carbonate and 11 μΙ (0.12 mmol) of 2-bromopropane were added. The resulting mixture was heated for 2 hours at 140 °C using microwaves irradiation. The reaction mixture was partitioned between aqueous 2 M hydrochloric acid and methylene chloride and the organic layer was discarded. The aqueous solution was adjusted to pH = 8-9 with 8 M sodium hydroxide and the product was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 27 mg (64% yield) of the title product were isolated as a white solid.
LRMS (m/z): 548 (M+1 )+.
PREPARATION 25
3-((2-((4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)(2-(dimethylamino)ethyl)amino)phenol
96 mg (0.22 mmol) 1-((4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl)-3-iodo- 1H-pyrazolo[3,4-d]pyrimidin-4-amine and 82 mg (0.45 mmol) of 3-((2- (dimethylamino)ethyl)amino)phenol4 were suspended in 1 ml of acetone and heated for 20 min. at 150 °C using microwaves irradiation. To the reaction mixture was added ethyl acetate and a precipitate was formed. The solid was filtered and washed with more ethyl acetate, and it was dried in a stream of air to give 26 mg (75% yield) of the title compound.
LRMS (m/z): 585 (M+1)+. PREPARATION 26
2-(2-Hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 4-Bromo-2-(2-hydroxypropan-2-yl)phenol
1.00 g (4.65 mmol) of 1-(5-bromo-2-hydroxyphenyl)ethanone (purchased from Aldrich®, cat. no. 383406) were dissolved in 15 ml of THF and cooled in an ice bath under nitrogen atmosphere. 4.65 ml (13.9 mmol) of a 3 M solution of methylmagnesium bromide in diethylether were added drop-wise and the resulting mixture was stirred at 0 °C for 3 hours. The reaction mixture was poured into a mixture of 15 ml water and 15 ml saturated ammonium chloride solution and the product was extracted with diethylether. The organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. 1.27 g of a pale pink solid, which contained a 71% of the crude title product, were obtained and used with no need of further purification in the next synthetic step. Yield: 84%.
LRMS (m/z): 231 , 233 (M+1 )+. b) 2-(2-Hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol The title compound was prepared following the experimental procedure described in Preparation 21 b from 1.27 g (3.90 mmol) of the crude product of Preparation 26a. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 900 mg of a white solid that contained a 34% of the title compound and was used with no further purification in the next synthetic step. Yield: 28%.
LRMS (m/z): 279 (M+1 )+.
PREPARATION 27
2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine a) 5-Bromo-2-methoxypyridin-3-amine
2.0 g (8.58 mmol) of 5-bromo-2-methoxy-3-nitropyridine (purchased from Combi- blocks®, cat. no. PY-7161 ), 2.0 g (35.8 mmol) of iron and 2.0 g (37.4 mmol) of ammonium chloride were stirred in 15 ml of a 1 :1 mixture of water/EtOH at 95 °C for 75 min. After cooling, the reaction mixture was filtered through a layer of Celite® and the volatiles were removed under reduced pressure. The residue was suspended in water and basified with sodium bicarbonate solution and the product was extracted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulphate, filtered and the solvents were removed in vacuo. 1.73 g of a dark oil were obtained, which contained 80% of the title compound wad was used with no further purification in the next step.
LRMS (m/z): 204 (M+1)+. b) 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine
The title compound was prepared following the experimental method described in Preparation 21 b from 1.73 g (6.82 mmol) of the crude 5-bromo-2-methoxypyridin-3- amine obtained in Preparation 27a. The reaction was completed in 2 hours at 80°C. The crude product was purified by flash chromatography (0% to 20% hexane/AcOEt) to obtain 1.43 g (55% yield) of the title compound as a solid.
L MS (m/z): 251 (M+1 )+.
PREPARATION 28
yV-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl)methanesulfonamide 940 mg (3.76 mmol) of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-3-amine were dissolved in 20 ml of pyridine and cooled in an ice bath. 600 μΙ (7.75 mmol) of methanesulfonyl chloride were added drop-wise and the reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between DCM and a saturated sodium bicarbonate solution. The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was treated with a mixture of diethylether and isopropylether and was stirred until a solid precipitated. The product was filtered and dried in a stream of air to obtain 720 mg (58% yield) of the title compound.
LRMS (m/z): 329 (M+1)+.
PREPARATION 29
4-Methoxy-W-(2-methoxy-5-(4,4,5,5 etramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide
200 mg (0.80 mmol) of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-3-amine were dissolved in 10 ml of pyridine and cooled in an ice bath. 331 mg (1.60 mmol) of 4-methoxybenzene-1 -sulfonyl chloride (purchased from Aldrich®, cat. no. M10204), dissolved in 5 ml of pyridine, were added drop-wise and the reaction mixture was stirred for 2 hours at room temperature. The volatiles were removed under reduced pressure and the residue was partitioned between diethylether and a saturated sodium bicarbonate solution. The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. 304 mg (90% yield) of the title compound were obtained.
LRMS (m/z): 421 (M+1)+.
PREPARATION 30 2- (4-(2-((4-Amino-3-iodo-1H-pyrazolo[3,4-o]pyrimidin-1-yl)methyl)-5- methylpyrroio[2,1-f][1,2,4]triazin-4-yi)piperazin-1-yi)ethanol
100 mg (0.23 mmol) of 1 -((4-chloro-5-methylpyrrolo[2, 1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 1 14 mg (0.88 mmol) of 2-(piperazin-1- yl)ethanol (purchased from Aldrich®, cat. no. H28807) were stirred in 2 ml of acetone at reflux temperature for 90 minutes. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 90 mg (68% yield) of the title compound as a white solid. Purity: 92%.
LRMS (m/z): 535 (M+1 )+.
PREPARATION 31
3- lodo-1 -((5-methyl-4-(4-(methylsulfonyl)piperazin-1 -yl)pyrrolo[2,1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-cQpyrimidin-4-amine
100 mg (0.23 mmol) of 1 -((4-chloro-5-methylpyrrolo[2, 1-r][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 123 mg (0.75 mmol) of 1- (methylsulfonyl)piperazine (purchased from ABCR®, cat. no. AB169005) were stirred in 2 ml of acetone at reflux temperature for 75 minutes. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 63 mg (49% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 569 (M+1 )+.
PREPARATION 32
Wi-(2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)-/V\A/2,W2-trimethylethane-1 ,2-diamine
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 -/-pyrazolo[3,4-d]pyrimidin-4-amine and 77 mg (0.75 mmol) of N1,N N2- trimethylethane-1 ,2-diamine were stirred in 2 ml of acetone at reflux temperature for 90 minutes. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 90 mg (67% yield) of the title compound were obtained and were used in the next step without further purification. Purity: 86%.
LRMS (m/z): 507 (M+1 )+.
PREPARATION 33
(S)-3-(3-(Benzyloxy)phenyl)-2-((ferf-butoxycarbonyl)amino)propanoic acid a) (S)-Methyl 2-amino-3-(3-hydroxyphenyl)propanoate hydrochloride
1.08 g (6.0 mmol) of (S)-2-amino-3-(3-hydroxyphenyl)propanoic acid (purchased from Alfa Aesar® cat. no. H27224) were suspended in 20 ml methanol and cooled in an ice bath. Then 872 μΙ (12 mmol) of thionyl chloride were added and the resulting solution was stirred at room temperature overnight and then at 50 °C for 4 hours. The volatiles were then removed under reduced pressure and 1.38 g of the title compound (100% yield) were isolated as a yellowish solid.
LRMS (m/z): 196 (M+1)+. b) (S)-Methyl 2-(iert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate
1.38 g (6.0 mmol) of (S)-methyl 2-amino-3-(3-hydroxyphenyl)propanoate hydrochloride were suspended in 10 ml THF. 1.66 ml (12 mmol) of triethylamine and 1.30 g (6.0 mmol) of di-te/f-butyl dicarbonate were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and the resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed under reduced pressure. 1.80 g (100% yield) of the title compound were obtained and were used without further purification in the next step.
LRMS (m/z): 296 (M+1)+. c) (S)-Methyl 3-(3-(benzyloxy)phenyl)-2-(fert-butoxycarbonylamino)propanoate To a solution of 1.76 g (5.9 mmol) of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3- hydroxyphenyl)propanoate in 20 ml of acetone were added 2.47 g (18 mmol) of potassium carbonate, 90 mg (0.6 mmol) of sodium iodide and 1.42 ml (12 mmol) of benzyl bromide. The resulting mixture was stirred at reflux for 16 hours and then it was partitioned between ethyl acetate and water. The two layers were separated and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed under reduced pressure. The crude product was purified by flash chromatography (0% to 100% hexanes/DCM) to yield 1.37 g (60% yield) of the title compound as a colourless oil, which turned to a white solid after a while.
LRMS (m/z): 386 (M+1 )+. d) (S)-3-(3-(Benzyloxy)phenyl)-2-((ferf-butoxycarbonyl)amino)propanoic acid
To a solution of 1.37 g (3.6 mmol) of (S)-methyl 3-(3-(benzyloxy)phenyl)-2-(terf- butoxycarbonylamino)propanoate in 20 ml of tetrahydrofurane was added a solution of 180 mg (4.3 mmol) of lithium hydroxide monohydrate in 20 ml of water. The combined solution was stirred at room temperature for 4 hours and then diluted with a saturated solution of ammonium chloride. A few drops of a 2N aqueous solution of hydrochloric acid were added and the reaction product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed under reduced pressure. 1.32 g (100% yield) of the title compound were obtained and were used in the next step without further purification.
LRMS (m/z): 372 (M+1 )+.
PREPARATION 34
(S)-2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- l[1 ,2,4]triazin- 4(3H)-one a) (S)-Ethyl 1-(3-(3-(benzyloxy)phenyl)-2-((iert- butoxycarbonyl)amino)propanamido)-3-methyl-1H-pyrrole-2-carboxylate
1.32 g (3.6 mmol) of (S)-3-(3-(benzyloxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid and 1.36 g (3.6 mmol) HATU were dissolved in a mixture of 10 ml DMF and 10 ml DCM. The solution was cooled in an ice bath, 620 μΙ (3.6 mmol) of DIEA were added and the resulting mixture was stirred at room temperature for 1 h. Then 1 .2 g (7.2 mmol) of ethyl 1 -amino-3-methyl-1 H-pyrrole-2- carboxylate were added and the reaction was stirred at room temperature for 4 hours. The solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography (0% to 25% hexanes/AcOEt) to yield 1.42 g (76% yield) of the title compound.
LRMS (m/z): 522 (M+1 )+. b) (S)-Terf-butyl (2-(3-(benzyloxy)phenyl)-1 -(5-methyl-4-oxo-3,4- dihydropyrrolo[2,1-f|[1 ,2,4]triazin-2-yl)ethyl)carbamate 1.79 g (6.8 mmol) of PPh3 were dissolved in 20 ml methylene chloride and cooled in an ice bath. Then 348 μΙ (6.8 mmol) of bromine were added and the resulting solution was stirred at room temperature for 30 min. Then were added 2.3 ml (16.4 mmol) of triethylamine and a solution of 1.42 g (2.7 mmol) (S)-ethyl 1-(3-(3-(benzyloxy)phenyl)- 2-((fe -butoxycarbonyl)amino)propanamido)-3-methyl-1 /- -pyrrole-2-carboxylate in 10 ml methylene chloride. The resulting solution was stirred at room temperature for 2 h and the volatiles were removed under reduced pressure. The residue was suspended in diethyl ether and evaporated twice, until a solid formed after evaporation of the solvent. Then the solid was suspended in 25 ml of concentrated aqueous ammonia and the resulting suspension was stirred at 100 °C in a sealed reactor overnight. Once the mixture reached room temperature, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and AcOEt. The organic layers were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. 3.22 g of a mixture of (S)-tert-butyl (2-(3- (benzyloxy)phenyl)-1 -(5-methyl-4-oxo-3,4-dihydropyrrolo[2, 1 -f [\ ,2,4]triazin-2- yl)ethyl)carbamate and triphenylphosphine oxide were obtained, which was used with no further purification in the next step.
LRMS (m/z): 475 (M+1 )+. c) (S)-2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one
3.22 g of the crude product obtained in the previous step were stirred in 30 ml of a 4 M solution of hydrogen chloride in dioxane for 2 hours. The solid that formed was filtered and washed with hexane. 396 mg (39% yield, 2 steps) of the title compound (hydrochloride) were obtained as a pure, white solid.
LRMS (m/z): 375 (M+1)+.
PREPARATION 35
(S)-4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5-methylpyrrolo[2,1- ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile a) (S)-4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(5-methyl-4-oxo-3,4- dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
396 mg (0.96 mmol) of (S)-2-(1-amino-2-(3-(benzyloxy)phenyl)ethyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one hydrochloride and 164 mg (1.1 mmol) of 4- amino-6-chloropyrimidine-5-carbonitrile2 were suspended in 15 ml tert-butanol. 0.84 ml (4.8 mmol) of DIEA were added and the resulting suspension was stirred in a sealed vessel at 120 °C for 48 hours. The solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to yield 245 mg (52% yield) of the title compound as a yellowish solid.
LRMS (m/z): 493 (M+1)+. b) (S)-4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
215 mg (0.44 mmol) of (S)-4-amino-6-((2-(3-(benzyloxy)phenyl)-1-(5-methyl-4-oxo-3,4- dihydropyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were suspended in 3 ml of phosphorus oxychloride and stirred at 80 °C for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 250 mg (92% yield) of the title product as a solid.
LRMS (m/z): 511 (M+1)+.
PREPARATION 36
(S)-4-Amino-6-((2-(3-(benzyloxy)phenyl)-1 -(4-(4-isopropylpiperazin-1 -yl)-5- methylpyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
36 mg (0.07 mmol) of (S)-4-amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 30 μΙ (0.21 mmol) of 1-isopropylpiperazine were dissolved in 2 ml of acetone and stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between HCI 5N and methylene chloride. The aqueous layer was separated and treated with an 8N aqueous solution of sodium hydroxide until basic pH was reached. The product was then re-extracted with ethyl acetate and the combined organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 25 mg (59% yield) of the title compound as a pale solid.
LRMS (m/z): 603 (M+1)+. PREPARATION 37
(2S,6R)-2,6-Dimethylpiperazine 250 mg (1.17 mmol) of (3S,5f?)-terf-butyl 3,5-dimethylpiperazine-1-carboxylate (purchased from AK Scientific® 166098) were suspended in 5 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 218 mg (100% yield) of the title compound (dihydrochloride) were obtained and used without any further purification.
LRMS (m/z): 1 15 (M+1 )+.
PREPARATION 38
(S)-4-((1-(4-Chloro-5-methylpyrrolo[2,1-/l[1 ,2,4]triazin-2-yl)ethyl)amino)-7H- pyrrolo[2,3-cQpyrimidine-5-carbonitrile a) (S)-4-((1 -(5-Methyl-4-oxo-3,4-dihydropyrrolo[2,1 -f\[1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-o]pyrimidine-5-carbonitrile
133 mg (0.69 mmol) of (S)-2-(1-aminoethyl)-5-methylpyrrolo[2, 1-^[1 ,2,4]triazin-4(3H)- one and 121 mg (0.69 mmol) of 4-chloro-7/-/-pyrrolo[2,3-d]pyrimidine-5-carbonitrile6 were suspended in 4 ml tert-butanol. 290 μΙ (1.66 mmol) of DIEA were added and the resulting suspension was stirred in a sealed vessel at 120 °C overnight. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (1% to 10% DCM/MeOH) to yield 62 mg (27% yield) of the title compound as a solid.
LRMS (m/z): 335 (M+1)+. b) (S)-4-((1 -(4-Chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)-7H- pyrrolo[2,3-d]pyrimidine-5-carbonitrile
62 mg (0.17 mmol) of (S)-4-((1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-c/]py midine-5-carbonitrile were stirred in 2 ml phosphorus oxychloride at 70 °C for 7.5 hours. The volatiles were then removed under vacuum and the residue was treated with ice-water and neutralised with an aqueous saturated NaHC03 solution. The aqueous suspension was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent removed under vacuum. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to yield 23 mg (39% yield) of the title compound as a solid.
LRMS (m/z): 353 (M+1 )+. PREPARATION 39
(S)-4-Amino-6-((1 -(5-methyl-4-vinylpyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
300 mg (0.91 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/ [1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 62 mg (0.28 mmol) of palladium (II) acetate and 145 mg (0.55 mmol) of triphenylphosphine were dissolved in 6 ml anhydrous tetrahydrofurane under argon. The solution was stirred at room temperature for 5 minutes and then 320 μΙ (1.07 mmol) of tributyl(vinyl)stannane were added. The reaction mixture was stirred at reflux temperature for 2 hours and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (1 % to 5% DCM/MeOH) to yield 198 mg (68% yield) of the title compound as a solid.
LRMS (m/z): 321 (M+1)+.
PREPARATION 40
(2S,6R)-1-(2-(Benzyloxy)ethyl)-2,6-dimethylpiperazine a) (3S,5/?)-7e/ -butyl 4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazine-1 -carboxylate
160 mg (0.75 mmol) of (3S,5f?)-tert-butyl 3,5-dimethylpiperazine-1 -carboxylate (purchased from AK Scientific® 166098) were dissolved in 2.5 ml of D F. 142 μΙ (0.90 mmol) of ((2-bromoethoxy)methyl)benzene (Aldrich®, ref. no. 47,481-9) and 114 mg (0.82 mmol) of potassium carbonate were added and the reaction mixture was stirred at 120 °C overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 121 mg (60% purity, 28% yield) of the title compound as a colourless oil with the main impurity being ((2- bromoethoxy)methyl)benzene.
LRMS (m/z): 349 (M+1)+. b) (2S,6 ?)-1-(2-(Benzyloxy)ethyl)-2,6-dimethylpiperazine
121 mg of impure (3S,5f?)-Terf-butyl 4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazine-1- carboxylate obtained in the previous step were suspended in 4 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature overnight and then the volatiles were removed under reduced pressure. The residue was redissolved in 20 ml of 2M hydrochloric acid and the aqueous solution was washed with methylene chloride. Then aqueous 23% sodium hydroxide solution was added until the solution reached a basic pH. The product was then extracted with ethyl acetate and the combined organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. 42 mg (81 % yield) of the pure title compound were obtained and used without any further purification.
LRMS (m/z): 249 (M+1 )+.
PREPARATION 41
1-((4-((3S,5 ?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f|[1 ,2,4]triazin-2- yl)methyl)-3-iodo-1H-pyrazolo[3,4-cflpyrimidin-4-amine
100 mg (0.23 mmol) of 1 -((4-chloro-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 51 mg (0.27 mmol) of (2S,6f?)-2,6- dimethylpiperazine (dihydrochloride) were dissolved in 5 ml of acetone and stirred at room temperature for overnight. The solvents were removed and the residue was partitioned between water and ethyl acetate, the organic layers were washed with water and bine, dried over magnesium sulphate, filter and the solvent was removed under reduced pressure. The crude product purified by flash chromatography (100% DCM to 100% DCM/MeOH/NHa, 100:8:1 ) to yield 79 mg (67% yield) of the title compound as a white solid.
LRMS (m/z): 519 (M+1 )+.
PREPARATION 42
3-((2-Methoxyethyl)amino)phenol 1.00 g (9.16 mmol) of 3-aminophenol and 2.6 ml (28.5 mmol) of 1-chloro-2- methoxyethane were dissolved in 2.5 ml of water. The solution was heated at 150 °C for 20 minutes. Then 1.3 ml (9.18 mmol) of triethylamine were added and the solvent was evaporated under reduced pressure. The crude product was then directly purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 770 mg (50% yield) of the title compound as a light yellow oil.
LRMS (m/z): 168 (M+1 )+. PREPARATION 43
4- Amino-6-(((S)-2-(3-(benzyloxy)phenyl)-1-(4-((3S,5 ?)-3,5-dimethylpiperazin-1-yl)-
5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Preparation 36 from 100 mg (0.20 mmol) of (S)-4-amino-6-((2-(3-(benzyloxy)phenyl)-1- (4-chloro-5-methylpyrrolo[2, 1 -f\ \ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile. The reaction was done at room temperature for 3 hours. The crude product was used in the next step without further purification.
LRMS (m/z): 589 (M+1 )+.
PREPARATION 44
Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate
1.0 g (4.3 mmol) of methyl 3-bromo-5-hydroxybenzoate (purchased from Alfa Aesar® cat. no. H51724) were treated with 2.2 g (8.7 mmol) of 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane), 1.3 g (13 mmol) of potassium acetate, 177 mg (0.22 mmol) of PdCI2dppf DCM and 120 mg (0.22 mmol) of dppf according to the method described in Preparation 21 b. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 783 mg (65% yield) of the title compound as a white solid.
LRMS (m/z): 279 (M+1 )+.
PREPARATION 45
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f|[1 ,2,4]triazin-4-yl)-5-hydroxybenzoic acid a) (S)-Methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)-5-hydroxybenzoate
350 mg (1.1 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 492 mg (2.1 mmol) of methyl 3-hydroxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate, 62 mg (0.05 mmol) of Pd(PPh3)4 and 338 mg (3.2 mmol) of sodium carbonate were suspended in a mixture of 12 ml of dioxane and 0.5 ml of water. The mixture was stirred under argon atmosphere at 90 °C overnight. Then the reaction mixture was filtered over Celite® and diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 130 mg of the title compound as an oil of 60% purity, which was used directly in the next step.
LRMS (m/z): 445 (M+1)+. b) (S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 - ][1,2,4]triazin-4-yl)-5-hydroxybenzoic acid
The crude product of the previous step was dissolved in 3.5 ml of THF and a solution of 61 mg (1.5 mmol) of lithium hydroxide in 2.5 ml of water was added. The reaction mixture was stirred at room temperature for 4 hours and the volatiles were removed under reduced pressure. The residue was diluted with water and 2N hydrochloric acid was added until a solid precipitated. The product was extracted with ethyl acetate and the organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/ eOH) to obtain 42 mg of the title compound as a yellow solid.
LRMS (m/z): 431 (M+1)+. PREPARATION 46
1-((4-((3S,5R)-3,5-Dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
100 mg (0.19 mmol) of 1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine were dissolved in 2 ml of anhydrous methylene chloride. 55 μΙ (0.39 mmol) of triethylamine and 18 μΙ (0.23 mmol) of methanesulfonyl chloride were added and the mixture was stirred at room temperature for 1 hour. The solution was then diluted with methylene chloride and it was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 20 mg (17% yield) of the title compound as a pale solid.
LRMS (m/z): 597 (M+1)+. PREPARATION 47
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cnpyrimidine 344 mg (8.6 mmol) of sodium hydride (60 % dispersion in mineral oil) was suspended in 10 ml dimethylformamide. The mixture was cooled at 0 °C in an ice bath and a solution of 2.0 g (7.2 mmol) of 4-chloro-5-iodo-7 - -pyrrolo[2,3-c |pyrimidine (purchased from Aldrich® cat. no. 699497) in 10 ml of dimethylformamide was added dropwise. The resulting mixture was stirred for 30 min. at 0 °C and then a solution of 1.6 ml (9.0 mmol) of [2-(chloromethoxy)ethyl](trimethyl)silane (purchased from Aldrich® cat. no. 238902) in 10 ml of dimethylformamide was added dropwise and stirred at room temperature overnight. The mixture was poured into water, a solution of potassium carbonate was added until basic pH was reached and the product was extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The residue was treated with hexane and the solid that remained was filtered, washed with more hexane and dried under air stem. 2.2 g (71 % yield) of the title compound were obtained as a white solid.
LRMS (m/z): 410 (M+1)+.
PREPARATION 48
4-Chloro-5-(1 -methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7W- pyrrolo[2,3- ]pyrimidine 500 mg (1.2 mmol) of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine, 310 mg (1.5 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /- -pyrazole (purchased from Aldrich® cat. no. 595314), 315 mg (1.5 mmol) of potassium phosphate and 95 mg (0.12 mmol) of PdCI2dppf DCM were suspended in a mixture of 16 ml of tetrahydrofurane and 1.6 ml of water. 1.0 ml (7.2 mmol) of triethylamine were added and the resulting mixture was heated at reflux for 3 hours under nitrogen atmosphere. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 20% DCM/EtOAc) to obtain 380 mg (84% purity, 72% yield) of the title compound, which was used without further purification.
LRMS (m/z): 364 (M+1)+.
PREPARATION 49
(S)-W-(1 -(4-Chloro-5-methylpyrrolo[2,1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H- pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c |pyrimidin-4- amine a) (S)-5-Methyi-2-(1 -((5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cf]pyrimidin-4- yl)amino)ethyl)pyrrolo[2,1-/][1,2,4]triazin-4(3H)-one
93 mg (0.48 mmol) of (S)-2-(1-aminoethyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)- one, 190 mg (0.52 mmol) of 4-chloro-5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-d]pyrimidine, 190 mg (1.3 mmol) of caesium fluoride and 450 μΙ (2.6 mmol) of DIEA were stirred in 5 ml of iert-butanol at reflux temperature for 48 hours. The volatiles were removed and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 50% DCM/EtOAc) to obtain 53 mg (25% yield) of the title compound.
LRMS (m/z): 520 (M+1)+. b) (S)-/V-(1-(4-Chloro-5-methylpyrrolo[2,1- [1,2,4]triazin-2-yl)ethyl)-5-(1-methyl- 1W-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7W-pyrrolo[2,3-cnpyrimidin-4- amine
53 mg (0.1 mmol) of (S)-5-Methyl-2-(1 -((5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- /]pyrimidin-4-yl)amino)ethyl)pyrrolo[2, 1 - f\[\ ,2,4]triazin-4(3/-/)-one were suspended in 2 ml of phosphorus oxychloride. The mixture was stirred at 70 °C for 1 hour and the volatiles were removed under reduced pressure. The solid residue was suspended in 20 ml of water-ice and the product was extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. 48 mg (87% yield) of the title compound were obtained as a solid.
LRMS (m/z): 538 (M+1)+.
PREPARATION 50
A/-((S)-1-(4-((3S,5/?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c/lpyrimidin-4-amine
48 mg (0.09 mmol) of (S)-/\/-(1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)- 5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 33 mg (0.29 mmol) of (2S,6f?)-2,6-dimethylpiperazine (dihydrochloride) and 800 μΙ (4.6 mmol) of diisopropylethylamine were stirred in 5 ml of acetone at room temperature for 30 minutes. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 63 mg (87% purity, 100% yield) of the title compound were obtained and used in the next step without any further purification.
LRMS (m/z): 616 (M+1 )+.
PREPARATION 51
4-(2-(Dimethylamino)ethoxy)benzaldehyde
1.0 g (8.2 mmol) of 4-hydroxybenzaldehyde (purchased from Aldrich® cat. no. 144088), 1.77 g (12.3 mmol) of 2-chloro-A/,/V-dimethylethanamine hydrochloride (purchased from Aldrich® cat. no. D141208) and 4.5 g (33 mmol) of potassium carbonate were stirred in 20 ml of DMF at 80 °C for 4 hours. The solution was partitioned between water and diethylether and the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed to obtain 950 mg (60% yield) of the title compound as a yellowish oil.
LRMS (m/z): 194 (M+1 )+.
PREPARATION 52
2-(4-(((2R,6S)-2,6-Dimethylpiperazin-1 -yl)methyl)phenoxy)-/V,/V- dimethylethanamine a) (3/?,5S)-rerf-butyl 4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazine-1-carboxylate
To a mixture of 250 mg (1.2 mmol) of (3 5S)-terf-butyl 3,5-dimethylpiperazine-1 - carboxylate (purchased from AK Scientific® 166098) and 270 mg (1.4 mmol) of 4-(2- (dimethylamino)ethoxy)benzaldehyde in 10 ml of methylene chloride was added 300 mg (1.4 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at 40 °C overnight, an additional 300 mg of sodium triacetoxyborohydride were added and the stirring continued at 40 °C for another 48 hours. Then the mixture was filtered through Celite® and washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 146 mg (32% yield) of the title compound were obtained as a yellowish oil.
LRMS (m/z): 392 (M+1)+. b) 2-(4-(((2R,6S)-2,6-Dimethylpiperazin-1-yl)methyl)phenoxy)-A/,A - dimethylethanamine dihydrochloride.
146 mg (0.37 mmol) of (3ft,5S)-terf-butyl 4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazine-1-carboxylate were suspended in 5 ml of a 4 M solution of hydrochloric acid in dioxane. The suspension was stirred for 10 minutes and then 2 ml of water were added. The clear solution was then stirred at room temperature for 1 hour. The volatiles were then removed under reduced pressure and the residue was treated with diethylether and evaporated in vacuo twice. 136 mg (100% yield) of the title compound were obtained as a brownish solid.
LRMS (m/z): 292 (M+1)+.
PREPARATION 53
(S)-(9H-Fluoren-9-yl)methyl (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)carbamate
1.4 g (6.4 mmol) of (S)-2-(1-aminoethyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one were dissolved in 12 ml of methylene chloride and cooled in an ice bath. Then 2.0 ml of an aqueous saturated solution of sodium bicarbonate and 2.0 g (7.7 mmol) of (9H- fluoren-9-yl)methyl carbonochloridate were added. The mixture was stirred at room temperature for 10 minutes and it was diluted with methylene chloride. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 20% DCM/EtOAc and then to 100% to recover the remaining starting material) to obtain 1.21 g (46% yield) of the title compound as a white solid.
LRMS (m/z): 415 (M+1)+.
PREPARATION 54
(S)-(9/7-Fluoren-9-yl)methyl (1-(3-(2,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4- dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl)carbamate a) (S)-(9H-Fluoren-9-yl)methyl (1 -((2-((2,4-dimethoxybenzyl)carbamoyl)-3-methyl- 1 W-pyrrol-1 -yl)amino)-1 -oxopropan-2-yl)carbamate
20.4 g (65 mmol) of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid and 13.0 g (68 mmol) of EDC HCI were suspended in 300 ml of DMF and stirred at room temperature for 30 minutes. Then a solution of 18.1 g (63 mmol) of 1-amino-/V- (2,4-dimethoxybenzyl)-3-methyl-1H-pyrrole-2-carboxamide in 145 ml of DMF were added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into 1000 ml of water and the solid that formed was filtered, washed with water and diethylether and dried under a stream of air and then in the vacuum oven. 10.9 g (30% yield) of the title compound were obtained as a white solid, which was used directly in the next step without any further purification.
LRMS (m/z): 583 (M+1 )+. b) (S)-(9H-Fluoren-9-yl)methyl (1 -(3-(2,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4- dihydropyrrolo[2,1 ,2,4]triazin-2-yl)ethyl)carbamate
10.9 g of the crude (S)-(9H-Fluoren-9-yl)methyl (1-((2-((2,4- dimethoxybenzyl)carbamoyl)-3-methyl-1 - -pyrrol-1 -yl)amino)-1 -oxopropan-2- yl)carbamate obtained in Preparation 54a were suspended in 450 ml of toluene and heated at 150 °C in the presence of 7.5 g of PPTS for 16 hours, using a Dean-Stark head to remove the traces of water from the reaction mixture. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed to give 13.1 g of crude (S)-(9H-fluoren-9-yl)methyl (1-(3-(2,4- dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)carbamate, which was used in the next step without any further purification.
LRMS (m/z): 565 (M+1)+.
PREPARATION 55
(S)-(9H-Fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1-fl[1 ,2,4]triazin-2- yl)ethyl)carbamate a) (S)-(9W-Fluoren-9-yl)methyl (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)carbamate
13.1 g of the crude (S)-(9H-fluoren-9-yl)methyl (1-(3-(2,4-dimethoxybenzyl)-5-methyl-4- oxo-3,4-dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)carbamate obtained in Preparation 54b were dissolved in 176 ml of trifluoroacetic acid and heated at 70 °C for 6 hours in the presence of 68 ml of anisole. The volatiles were removed under reduced pressure and the residue was suspended in 200 ml of hexane and stirred vigorously at room temperature overnight. The solid that formed was filtered and washed with hexane and dried under a stream of air to give 7.5 g (87%) yield, two steps) of the title compound as a pale brown solid.
LRMS (m/z): 415 (M+1)+. b) (S)-(9W-Fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1-f|[1 ,2,4]triazin-2- yl)ethyl)carbamate
7.47 g (18 mmol) of (S)-(9H-fluoren-9-yl)methyl (1-(5-methyl-4-oxo-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)carbamate obtained in Preparation 55a were suspended in 90 ml of phosphorus oxychloride. The mixture was heated at 70 °C for 2.5 hours and then the volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 4.5 g (58% yield) of the title compound.
LRMS (m/z): 433 (M+1)+.
PREPARATION 56
(S)-1-(4-((3S,5/?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-^[1,2,4]triazin-2- yl)ethanamine a) (9H-Fluoren-9-yl)methyl ((S)-1 -(4-((3S,5A?)-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl)carbamate
87 mg (0.46 mmol) of (2S,6f?)-2,6-dimethylpiperazine dihydrochloride were suspended in 10 ml of acetone. 250 μΙ (1.44 mmol) of DIEA were added and the mixture was stirred for 10 minutes. To this mixture, a solution of 100 mg (0.23 mmol) of (S)-(9H- fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)carbamate in 2 ml of acetone were added and the resulting suspension was stirred at room temperature for 90 minutes. Then the volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed to obtain 117 mg (89% purity, 89% yield) of the title compound.
LRMS (m/z): 415 (M+1)+. b) (S)-1-(4-((3S,5/?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- |[1 ,2,4]triazin- 2-yl)ethanamine
The crude product of the previous step was dissolved in 2 ml of dioxane. 20 μΙ (23 mmol) of morpholine were added and the mixture was heated at reflux temperature for 2.5 hours. The volatiles were removed under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 26 mg (44% yield) of the title compound as a pale solid.
LRMS (m/z): 289 (M+1 )+. PREPARATION 57
W-(3-(4-Chloro-7-((2-(trimethylsilyl)eta
yl)phenyl)methanesulfonamide
300 mg (0.73 mmol) of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine, 326 mg (1.1 mmol) of A/-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide (purchased from Aldrich® cat. no. 63,603-7), 54 mg (0.07 mmol) of PdCI2dppf DCM, 187 mg (0.88 mmol) of potassium phosphate and 561 μΙ (4.0 mmol) of triethylamine were suspended in a mixture of 10 ml of tetrahydrofurane and 1 ml of water. The reaction mixture was stirred under nitrogen atmosphere at reflux temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/EtOAc) to obtain 196 mg (59% yield) of the title compound.
LRMS (m/z): 454 (M+1 )+.
PREPARATION 58
A/-(3-(4-(((S)-1 -(4-((3S,5fl)-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-cdpyrimidin-5-yl)phenyl)methanesulfonamide
26 mg (0.09 mmol) of (S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethanamine, 62 mg (0.14 mmol) of A/-(3-(4-chloro- 7-((2-(trimethylsilyl)ethoxy)methyl)-7 - -pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide, 42 mg (0.28 mmol) of caesium fluoride and 100 μΙ (0.57 mmol) of DIEA were suspended in 2 ml of te/f-butanol. The mixture was heated at 130 °C for 6 hours using microwave irradiation. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 50% DCM/EtOAc) to obtain 28 mg (44% yield) of the title compound.
LRMS (m/z): 706 (M+1 )+. PREPARATION 59
4- (Hydroxymethyl)benzenesulfonamide
A solution of 1.0 g (4.97 mmol) of 4-sulfamoylbenzoic acid (purchased from Aldrich® cat. no C1 , 180-4) in 80 ml of THF was cooled in an ice bath under nitrogen atmosphere. Then 20 ml (20 mmol) of a 1 M solution of borane in THF was added dropwise and the reaction mixture was stirred at 0 °C for 30 minutes and at room temperature overnight. An additional 20 ml of the borane solution was added dropwise at 0 °C and the mixture was stirred for another 72 hours at room temperature. Then the solution was cooled to 0 °C and 50 ml of methanol were added to quench the reaction and then 50 ml of 2M hydrochloric acid. The solution was stirred at room temperature for 3 hours and the volatiles were removed under reduced pressure. The residue was treated with water and the product was extracted with ethyl acetate (x6) The combined organic fractions were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was treated with methylene chloride and the insoluble solid was filtered and dried under a stream of air. 900 mg (95% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 188 (M+1 )+.
PREPARATION 60
W-(3-(4-(((S)-1-(4-((2S,6fl)-2,6-Dimet
yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)m
yl)phenyl)methanesulfonamide
5- Bromo-/V-((S)-1 -(4-((2S,6ft)-2,6-dimethylmorpholino)pyrrolo[2, 1 - ][1 ,2,4]triazin-2- yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cf]pyrimidin-4-amine (333 mg, 0.55 mmol) was placed in a sealed tube in a mixture of dimethoxyethane (28 ml) and water (6 ml) under nitrogen atmosphere. Then /V-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide (424 mg, 1.42 mmol), sodium carbonate (147 mg, 1 .38 mmol) and PdCI2dppf.CH2CI2 (135 mg, 0.16 mmol) were successively added and the mixture was heated at 70 °C overnight. The reaction mixture was poured into a saturated solution of ammonium chloride and was extracted with ethyl acetate and washed successively with water and brine, dried with sodium sulphate and the solvent was removed in vacuo. The crude was purified by flash chromatography (20% to 80% petroleum ether/AcOEt) to give 209 mg (55% yield) of the title compound as a pale orange solid.
LRMS (m/z): 693 (M+1)+.
PREPARATION 61
(2S,6 ?)-2,6-Dimethyl-1-(methylsulfonyl)piperazine a) (3S,5R)-7eri-butyl 3,5-dimethyl-4-(methylsulfonyl)piperazine-1 -carboxylate
500 mg (2.33 mmol) of (3S,5f?)-fe/f-butyl 3, 5-dimethylpiperazine-1 -carboxylate (purchased from AK Scientific® 166098) were dissolved in 10 ml of anhydrous methylene chloride. 650 μΙ (4.7 mmol) of triethylamine and 216 μΙ (2.8 mmol) of methanesulfonyl chloride were added and the mixture was stirred at room temperature for 3 hours. Then the organic solution was washed with 1 M hydrochloric acid solution, water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was treated with diethylether and the insoluble solid was filtered and dried under air steam. 379 mg (56% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 293 (M+1)+. b) (2S,6/?)-2,6-Dimethyl-1 -(methylsulfonyl)piperazine hydrochloride
379 mg (1.3 mmol) of (3S,5f?)-fert-butyl 3,5-dimethyl-4-(methylsulfonyl)piperazine-1- carboxylate were suspended in 5.5 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 249 mg (100% yield) of the title compound were obtained and used without any further purification.
LRMS (m/z): 193 (M+1)+.
PREPARATION 62
5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol a) 5-Bromopyridin-3-ol
4.0 g (20.6 mmol) of 3-bromo-5-methoxypyridine were treated with 19 ml of concentrated hydrobromic acid (48% solution) and 16 ml of glacial acetic acid and stirred at 120 °C for 4 days, with additions of 9 ml hydrobromic acid every 24 hours. After completion of the reaction, the solution was poured into ice and taken to pH = 6 with a concentrated solution of sodium hydroxide. The product was extracted with ethyl acetate and the combined organic solution was washed with water and brine, dried over sodium sulphate, filtered and the solvent was removed. 3.15 g (90% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 172, 174 (M-1)+. b) 5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol
550 mg (3.2 mmol) of 5-bromopyridin-3-ol, 1.6 g (6.3 mmol) of 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), 258 mg (0.32 mmol) of PdCI2dppf DCM, 175 mg (0.32 mmol) of dppf and 930 mg (9.5 mmol) of potassium acetate were suspended in 25 ml of dioxane under nitrogen atmosphere. The mixture was heated at 90 °C overnight. The suspension was then filtered and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 270 mg (39% yield) of the title compound.
LRMS (m/z): 222 (M+1)+.
PREPARATION 63
1-((2S,6 ?)-2,6-Dimethylpiperazin-1-yl)ethanone hydrochloride a) (3S,5fi)-rert-butyl 4-acetyl-3,5-dimethylpiperazine-1-carboxylate
100 mg (0.47 mmol) of (3S,5f?)-terf-butyl 3,5-dimethylpiperazine-1-carboxylate (purchased from AK Scientific® 166098) and 156 μΙ (1.1 mmol) of triethylamine were dissolved in 3 ml of dioxane. A solution of 40 μΙ (2.8 mmol) of methanesulfonyl chloride in 1 ml of dioxane was added and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with 2 M hydrochloric acid solution, water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. 107 mg (92% purity, 82% yield) of the title compound were obtained as oil, which was used without additional purification in the next step.
LRMS (m/z): 257 (M+1)+. b) 1-((2S,6 ?)-2,6-Dimethylpiperazin-1-yl)ethanone hydrochloride
104 mg (0.41 mmol) of (3S,5f?)-te/f-butyl 4-acetyl-3,5-dimethylpiperazine-1-carboxylate were suspended in 2 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature overnight and then the volatiles were removed under reduced pressure. 63 mg (100% yield) of the title compound were obtained and used without any further purification.
LRMS (m/z): 157 ( +1 )+. PREPARATION 64
(3S,5 ?)-7ert-butyl 4-(2-((S)-1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)-3,5-dimethylpiperazine-1 -carboxylate
30 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 59 mg (0.27 mmol) of (3S,5R)-ferf-butyl 3,5-dimethylpiperazine-1 -carboxylate (purchased from AK Scientific® 166098) were stirred in 0.6 ml of methylisobutylcetone at 150 °C for 17 hours using microwaves irradiation. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 8 mg (17% yield) of the title compound.
LRMS (m/z): 507 (M+1)+.
PREPARATION 65
3-lodo-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1 -fl[1 ,2,4]triazin-2-yl)methyl)-1H- pyrazolo[3,4-cdpyrimidin-4-amine
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 22 mg (0.25 mmol) of piperazine and 120 μΙ (0.57 mmol) of DIEA were stirred in 20 ml of acetone at room temperature for 24 hours. The suspension that formed was filtered and washed with ether and acetone to obtain 111 mg (100% yield) of the title compound, which was used in the next step without further purification.
LRMS (m/z): 491 (M+1)+.
PREPARATION 66
3-lodo-1-((5-methyl-4 hiomorpholinopyrrolo[2,1 - ][1,2,4]triazin-2-yl)methyl)-1 W- pyrazolo[3,4-d]pyrimidin-4-amine 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1/-/-pyrazolo[3,4-d]pyrimidin-4-amine, 24 μΙ (0.23 mmol) of thiomorpholine and 120 μΙ (0.57 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. The suspension that formed was filtered and washed with ether and acetone to obtain 115 mg (100% yield) of the title compound, which was used in the next step without further purification.
LRMS (m/z): 508 (M+1 )+.
PREPARATION 67
3-lodo-1-((5-methyl-4-((2-(pyrrolidin-1-yl)ethyl)amino)pyrrolo[2,1-^[1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-d]pyhmidin-4-amine, 32 μΙ (0.27 mmol) of 2-(pyrrolidin-1- yl)ethanamine and 120 μΙ (0.57 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. Additional 16 μΙ of the amine were added and the mixture was stirred at room temperature for 8 hours more and then at 55 °C for 16 hours. The suspension was allowed to cool and the solid that formed was filtered and washed with ether and acetone to obtain 90 mg (77% yield) of the title compound, which was used in the next step without further purification.
LRMS (m/z): 519 (M+1)+.
PREPARATION 68
(1 S,4S)-7eri-butyl 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- o |pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-/|[1,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate a) (1 S,4S)-7e/ -butyl 5-(2-((4-amino-3-iodo-1 /Y-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 50 mg (0.25 mmol) of (1 S,4S)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 120 μΙ (0.57 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. The suspension that formed was filtered and washed with ether and acetone to obtain 50 mg (36% yield) of the title compound, which was used in the next step without further purification.
LRMS (m/z): 603 (M+1)+. b) (1 S,4S)-7eri-butyl 5-(2-((4-amino-3-(3-fiuoro-5-hydroxyphenyi)-1 H-pyrazolo[3,4- cQpyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-/|[1,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
40 mg (0.07 mmol) of (1 S,4S)-tert-butyl 5-(2-((4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate, 20 mg (0.13 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid and 6 mg (0.007 mmol) of PdCI2dppf DCM were suspended in dioxane. 0.1 ml of a 2M aqueous solution of sodium carbonate were added and the resulting mixture was heated at 80 °C for 20 hours under argon atmosphere. After two additions of excess boronic acid and catalyst the reaction was completed after a total time of 82 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over sodium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (3% DCM/MeOH) to obtain 16 mg (41% yield) of the title compound.
LRMS (m/z): 587 (M+1 )+.
PREPARATION 69
3-((2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)(methyl)amino)propan-1-ol
75 mg (0.17 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]thazin-2-yl)methyl)-3- iodo-1/-/-pyrazolo[3,4-cf]pyrimidin-4-amine, 23 μΙ (0.25 mmol) of 3- (methylamino)propan-l-ol and 89 μΙ (0.51 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. The volatiles were removed under reduced pressure and the residue was treated with diethylether and the insoluble solid was filtered and dried to obtain 73 mg (87% yield) of the title compound as a solid, which was used in the next step without further purification.
LRMS (m/z): 494 (M+1)+.
PREPARATION 70
3-lodo-1 -((5-methyl-4-(2,2,6,6-tetramethylmorpholino)pyrrolo[2,1 ,2,4]triazin-2- yl)methyl)-1 y-pyrazolo[3,4-d]pyrimidin-4-amine
75 mg (0.17 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1/-/-pyrazolo[3,4-af]pyrimidin-4-amine, 46 mg (0.25 mmol) of 2,2,6,6- tetramethylmorpholine and 89 μΙ (0.51 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. The volatiles were removed under reduced pressure and the residue was treated with diethylether and the insoluble solid was filtered and dried to obtain 63 mg (68% yield) of the title compound as a solid, which was used in the next step without further purification.
LRMS (m/z): 548 (M+1)+.
PREPARATION 71
1 -(2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)piperidin-4-ol
75 mg (0.17 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 23 μΙ (0.25 mmol) of piperidin-4-ol and 89 μΙ (0.51 mmol) of DIEA were stirred in 4 ml of acetone at room temperature for 24 hours. The volatiles were removed under reduced pressure and the residue was treated with diethylether and the insoluble solid was filtered and dried to obtain 86 mg (100% yield) of the title compound as a solid, which was used in the next step without further purification.
LRMS (m/z): 506 (M+1)+.
PREPARATION 72
W-(3-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-5-hydroxyphenyl)methanesulfonamide 500 mg (1.2 mmol) of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-d]pyrimidine, 575 mg (1.8 mmol) of A/-(3-hydroxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide, 92 mg (0.11 mmol) of PdCI2dppf DCM, 315 mg (1.5 mmol) of potassium phosphate and 1000 μΙ (7.2 mmol) of triethylamine were suspended in a mixture of 160 ml of tetrahydrofurane and 16 ml of water. The reaction mixture was stirred under nitrogen atmosphere at reflux temperature for 3 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to obtain 410 mg (72% yield) of the title compound.
LRMS (m/z): 469 (M+1)+. PREPARATION 73
W-(3-(4-(((S)-1 -(4-((3S,5fl)-3,5-Dimethylpiperazin-1 -yi)-5-methyipyrrolo[2,1 - ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-djpyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide
29 mg (0.10 mmol) of (S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethanamine, 90 mg (0.19 mmol) of A/-(3-(4-chloro- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide, 50 mg (0.33 mmol) of caesium fluoride and 100 μΙ (0.57 mmol) of DIEA were suspended in 2 ml of terf-butanol. The mixture was heated at reflux temperature overnight. An additional 90 mg of the chloro starting material and 100 μΙ of DIEA were added and the reaction mixture was stirred for 4 hours more until no starting material was detected. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 50% DCM/EtOAc) to obtain 34 mg (47% yield) of the title compound.
LRMS (m/z): 721 (M+1)+. PREPARATION 74
4-(2-((4-Amino-3-iodo-1H-pyrazolo[3,4-d|pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1 -f|[1 ,2,4]triazin-4-yl)piperazin-2-one
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-c/]pyrimidin-4-amine, 35 mg (0.35 mmol) of piperazin-2-one (purchased from Aldrich® cat. no. 641065) and 160 μΙ (0.91 mmol) of DIEA were stirred in a mixture of 2 ml of THF and 2 ml of acetone at 60 °C for 24 hours. The reaction mixture was filtered and the solid washed with acetonitrile and ether. 105 mg (92% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 505 (M+1)+.
PREPARATION 75
1-(2-((4-Amino-3-iodo-1H-pyrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)piperidine-4-carboxamide
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-c ]pyrimidin-4-amine, 45 mg (0.35 mmol) of piperidine-4- carboxamide (purchased from Aldrich® cat. no. 11 ,790-7) and 160 μΙ (0.91 mmol) of DIEA were stirred in a mixture of 3 ml of THF and 3 ml of acetone at 60 °C for 24 hours. The reaction mixture was filtered and the solid washed with acetonitrile and ether. 115 mg (95% yield) of the title compound were obtained as a white solid.
LRMS (m/z): 553 (M+1 )+.
PREPARATION 76
3- lodo-1 -((5-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1-/l[1 ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-cdpyrimidin-4-amine
53 μΙ (0.45 mmol) of 2-(pyrrolidin-1-yl)ethanol were dissolved in 2 ml of anhydrous THF. 14 mg (0.35 mmol) of sodium hydride (60% dispersion in mineral oil) were added. The reaction mixture was stirred at room temperature for 30 minutes and 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-cflpyrimidin-4-amine were added and the resulting reaction mixture was stirred at room temperature overnight and then at 60 °C for 24 hours. An extra addition of a solution of 53 μΙ of 2-(pyrrolidin-1-yl)ethanol and 14 mg of sodium hydride was done and after 4 hours more at 60 °C the reaction was allowed to reach room temperature. The mixture was filtered and the filtrates were evaporated under reduced pressure to give 55 mg (44% yield) of the title compound as a pure white solid.
LRMS (m/z): 520 (M+1 )+.
PREPARATION 77
4- (2-((4-Amino-3-iodo-1W-pyrazolo[3,4-clpyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-4-yl)thiomorpholine 1 ,1 -dioxide
100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-rl[1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 /-/-pyrazolo[3,4-cf]pyrimidin-4-amine, 47 mg (0.35 mmol) of thiomorpholine 1 ,1- dioxide (purchased from TCI® cat. no. T2193) and 160 μΙ (0.91 mmol) of DIEA were stirred in a mixture of 3 ml of THF and 3 ml of acetone at 50 °C for 24 hours. An additional 47 mg of the amine was added and the reaction proceeded for 16 hours more. The reaction mixture was filtered and the solid washed with ether. Most of the desired product was in the solution, so the solvents were removed under reduced pressure to give 164 mg of a mixture of the title compound and the excess of amine, which was used in the next step without further purification.
LRMS (m/z): 540 (M+1)+. PREPARATION 78
1 -((*-( 1 ,4-Diazepan-1 -yl)-5-methylpyrrolo[2,1 -/J[1 ,2,4]triazin-2-yl)methyl)-3-iodo- 1H-pyrazolo[3,4-d]pyrimidin-4-amine 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1/-/-pyrazolo[3,4-d]pyrimidin-4-amine, 28 mg (0.28 mmol) of 1 ,4-diazepane (purchased from Aldrich® cat. no. H1 , 660-4) and 160 μΙ (0.91 mmol) of DIEA were stirred in a mixture of 4 ml of THF and 4 ml of acetone at room temperature for 40 hours. The reaction mixture was filtered and the solid washed with ether. Most of the desired product was in the solution, so the solvents were removed under reduced pressure to give 28 mg (24% yield) of the title compound as a solid.
LRMS (m/z): 505 (M+1)+.
PREPARATION 79
Terf-butyl 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-^[1,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate a) Terf-butyl 5-(2-((4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate
150 mg (0.34 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 110 mg (0.52 mmol) of tert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate (purchased from J&W Pharmalab® cat. no. 65- 0429) and 240 μΙ (0.48 mmol) of DIEA were stirred in a mixture of 5 ml of THF and 5 ml of acetone at 60 °C for 24 hours. The reaction mixture was filtered and the solid washed with THF. Most of the desired product was in the solution, so the solvents were removed under reduced pressure to give 210 mg (100% yield) of the title compound as a solid.
LRMS (m/z): 617 (M+1)+. b) Terf-butyl 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- <^pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate
200 mg (0.32 mmol) of tert-butyl 5-(2-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2- carboxylate, 100 mg (0.64 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 26 mg (0.032 mmol) of PdCI2dppf DCM and 480 μΙ (0.96 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 15 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was directly purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 110 mg (57% yield) of the title compound.
LRMS (m/z): 602 (M+1 )+.
PREPARATION 80
(S)-4-Amino-6-((1-(4-(4-formyl-3,5-dimethylphenyl)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
250 mg (0.76 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 271 mg (1.52 mmol) of (4-formyl-3,5- dimethylphenyl)boronic acid (purchased from Combi-blocks®, cat. no. BB-6256), 62 mg (0.08 mmol) of PdCI2dppf DCM and 1.14 ml (2.3 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 8.5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The reaction mixture was filtered through Celite® and the solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified first by flash chromatography (0% to 16% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 164 mg (57% yield) of the title compound as a yellowish solid.
LRMS (m/z): 427 (M+1)+.
PREPARATION 81
5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cqpyrimidine
The title compound was prepared from 6.0 g (25.8 mmol) of 5-bromo-4-chloro-7H- pyrrolo[2,3-cf]pyrimidine (purchased from Aldrich® cat. No. 720194) and 5.4 g (32.4 mmol) of (2-(chloromethoxy)ethyl)trimethylsilane following the experimental procedure described in Example 47. The crude product was treated with hexane and the solid that remained was filtered, washed with more hexane and dried under air steam. 6.5 g of the title compound were obtained as a white solid. The filtrates were evaporated and the residue was purified by flash chromatography (0% to 30% hexane/Et20) to obtain additional 2.1 g (91% global yield) of the title compound as a white solid.
LRMS (m/z): 362, 364 (M+1)+. PREPARATION 82
5-Bromo-W-((S)-1-(4-((2S,6 ?)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- /J[1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- cdpyrimidin-4-amine a) (S)-1-(4-((2S,6 ?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1-^[1,2,4]triazin-2- yl)ethanamine
520 mg (1.2 mmol) of (S)-(9H-fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)carbamate was dissolved in 36 ml of acetone. 152 mg (1.32 mmol) of (2S,6ft)-2,6-dimethylmorpholine and 630 μΙ (3.6 mmol) of DIEA were added and the mixture was stirred for 2.5 hours at room temperature. Then the solvent was removed under reduced pressure and the residue was redissolved in 10 ml of dioxane. 691 mg (6 mmol) of (2S,6R)-2,6-dimethylmorpholine were added and the resulting mixture was heated to 100 °C for 1 hour. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 186 mg (89% yield) of the title compound.
LRMS (m/z): 290 (M+1)+. b) 5-Bromo-/V-((S)-1 -(4-((2S,6f?)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1 - /J[1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
186 mg (0.64 mmol) of (S)-1-(4-((2S,6 )-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethanamine was dissolved in 14 ml of terf-butanol. 466 mg (1.28 mmol) of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- c/]pyrimidine, 39 mg (0.26 mmol) of caesium fluoride and 1 ml (5.8 mmol) of DIEA were added and the resulting mixture was stirred at 100 °C for 48 hours. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (0% to 20% hexane/EtOAc) to give 370 mg (93% yield) of the title compound as a pale solid.
LRMS (m/z): 616, 618 (M+1)+.
PREPARATION 83
/V-((S)-1 -(4-((2S,6R)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2)1 ,2,4]triazin- 2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-cflpyrimidin-4-amine 29 mg (0.05 mmol) of 5-bromo-/v-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)ethyi)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-c0pyrimidin-4-amine, 20 mg (0.10 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (purchased from Aldrich®, cat. no. 595314), 4 mg (0.005 mmol) of PdCI2dppf DCM and 72 μΙ (0.14 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The volatiles were removed and the crude product was purified by flash chromatography (0% to 50% hexane/AcOEt) to obtain 15 mg (49% yield) of the title compound.
LRMS (m/z): 618 (M+1)+.
PREPARATION 84
/V1,/V1-Dimethyl-/V2-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine 200 mg (2.0 mmol) of dihydro-2H-pyran-4(3H)-one were added to a solution of 270 μΙ (2.9 mmol) of /V1,A/ -dimethylethane-1 ,2-diamine in dichloroethane. The mixture was stirred at room temperature for 1 hour and then 636 mg (3.0 mmol) of sodium triacetoxyhydroborate were added. The reaction mixture was stirred at room temperature for 60 h and then it was diluted with a 10% aqueous solution of ammonium hydroxide. The product was extracted with methylene chloride and the combined organic fraction was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 50 mg (14% yield) of the title compound were obtained as a colourless oil.
LRMS (m/z): 173 (M+1)+.
PREPARATION 85
W1-(2-((4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)^
yl)ethane-1,2-diamine
85 mg (0.19 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 50 mg (0.29 mmol) of /\/1,/V1-dimethyl-A/2- (tetrahydro-2H-pyran-4-yl)ethane-1 ,2-diamine and 160 μΙ (0.91 mmol) of DIEA were stirred in a mixture of 2 ml of THF and 2 ml of acetone at 60 °C for 24 hours. The reaction mixture was filtered and the solid washed with THF. Most of the desired product was in the solution, so the solvents were removed under reduced pressure to give 94 mg (85% yield) of the title compound as a soiid.
LRMS (m/z): 577 (M+1 )+. PREPARATION 86
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-/V-(piperidin-4-ylmethyl)benzamide a) (S)-rerf-butyl 4-((3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2 - ][1,2,4]triazin-4-yl)-5-methylbenzamido)methyl)piperidine-1- carboxylate
50 mg (0.12 mmol) of (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 38 mg (0.18 mmol) of tert- butyl 4-(aminomethyl)piperidine-1-carboxylate (purchased from Maybridge Int.® cat. no. KM10802DA), 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride at room temperature overnight. Additional 38 mg of 4-(aminomethyl)piperidine-1 - carboxylate were added and the reaction mixture was stirred for another 2 hours. Then it was diluted with methylene chloride and washed with a saturated solution of sodium hydrogencarbonate, water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to afford 62 mg (85% yield) of the title compound.
LRMS (m/z): 626 (M+1 )+. b) (S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 - f)[1,2,4]triazin-4-yl)-5-methyl-/V-(piperidin-4-ylmethyl)benzamide hydrochloride
To a solution of 60 mg (0.10 mmol) of (S)-tert-butyl 4-((3-(2-(1 -((6-amino-5- cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-4-yl)-5- methylbenzamido)methyl)piperidine-1-carboxylate in 1 ml of methylene chloride were added 2 ml of a 4M solution of hydrochloric acid in dioxane. The reaction mixture was stirred at room temperature for 1 h and then the volatiles were removed under reduced pressure. The crude product was treated with acetonitrile and the solid was filtered and washed with acetonitrile. 45 mg (90% yield) of the title compound were obtained.
LRMS (m/z): 526 (M+1 )+.
PREPARATION 87
(1f?,4R)-2-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane a) (1 R,4f?)-7"ert-butyl 5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate
To a solution of 200 mg (1.0 mmol) of (1 R,4f?)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (purchased from Aldrich® cat. no. CDS019057) in methylene chloride were added 350 μΙ (2.0 mmol) of DIEA and 120 μΙ (1.5 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at room temperature for 48 hours and then 4 hours more after a second addition of both reagents. The volatiles were then removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with diluted hydrochloric acid and brine, dried over sodium sulphate, filtered and the solvent was removed to give 230 mg (83% yield) of the title compound.
LRMS (m/z): 277 (M+1 )+. b) (1 ?,4f?)-2-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane
225 mg (0.81 mmol) of (1 R4f?)-7ert-butyl 5-(methylsulfonyl)-2,5- diazabicyclo[2.2.1 ]heptane-2-carboxylate were dissolved in 4 ml of a 4M solution of hydrochloric acid in dioxane and the solution was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and 173 mg (100% yield) of the title compound were obtained as hydrochloride.
LRMS (m/z): 177 (M+1 )+.
PREPARATION 88
3-lodo-1 -((5-methyl-4-((1A?,4A?)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrrolo[2,1- |[1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-cnpyrimidin-4-amine
1 10 mg (0.25 mmol) of 1-((4-chloro-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 171 mg (1.26 mmol) of (1 R,4f?)-2- (methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride and 220 μΙ (1.27 mmol) of DIEA were stirred in a mixture of 3 ml of THF and 3 ml of acetone at 60 °C for 60 hours. The reaction mixture was filtered and the solid washed with THF. Most of the desired product was in the solution, so the solvents were removed under reduced pressure to give 195 mg of a crude sample in which the title compound was the main component. This crude was used directly in the next step.
LRMS (m/z): 581 (M+1 )+.
PREPARATION 89 W-(3-(4-(((S)-1-(4-((2S,6 )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f][1,2,4]triazin-2-yi)ethyi)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 - pyrrolo[2,3-c/]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide 100 mg (0.16 mmol) of 5-bromo-/\/-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5- methylpyrrolo[2 -/][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 102 mg (0.33 mmol) of /V-(3-hydroxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide, 14 mg (0.016 mmol) of PdCI2dppf DCM and 245 μΙ (0.49 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. Then a second addition of all the reagents was needed and the reaction was stirred at 100 °C for 24 hours more. The volatiles were removed and the crude product was purified by flash chromatography (0% to 70% hexane/AcOEt) to obtain 63 mg (53% yield) of the title compound.
LRMS (m/z): 723 (M+1 )+.
PREPARATION 90
W-(2-Hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide a) 4-Bromo-/V-(2-hydroxyethyl)-2,6-dimethylbenzamide
To a suspension of 500 mg (2.2 mmol) of 4-bromo-2,6-dimethylbenzoic acid in 15 ml of methylene chloride were added 5 drops of DMF and 320 μΙ (4.4 mmol) of thionyl chloride. The resulting solution was stirred at reflux temperature for 1 hour and then the volatiles were removed under reduced pressure. The residue was redissolved in 15 ml of THF and to this solution 190 μΙ (1.1 mmol) of DIEA and 265 μΙ (4.4 mmol) of 2- aminoethanol were added. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 439 mg (74% yield) of the title compound as a colourless oil.
LRMS (m/z): 272, 274 (M+1 )+. b) /V-(2-Hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzamide 439 mg (1.6 mmol) of 4-bromo-A/-(2-hydroxyethyl)-2,6-dimethylbenzamide, 819 mg (3.2 mmol) of 4,4,4',4,,5,5,5',5'-octamethy!-2,2'-bi(1 ,3,2-dioxaborolane), 132 mg (0.16 mmol) of PdCI2dppf DCM, 89 mg (0.16 mmol) of dppf and 475 mg (4.8 mmol) of potassium acetate were suspended in 20 ml of anhydrous dioxane. The reaction mixture was stirred at 90 °C for 16 hours and then it was allowed to cool to room temperature. The suspension was filtered through Celite® and the filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to obtain 446 mg (87% yield) of the title compound.
LRMS (m/z): 320 (M+1)+.
PREPARATION 91
A/-(5-(4-(((S)-1-(4-((2/?,6S)-2,6-Dimethylmorpholino)-5-met ylpyrrolo[2,1- fJ[1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7W- pyrrolo[2,3-c ]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide
109 mg (0.17 mmol) of 5-bromo-/V-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5- methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-d]pyrimidin-4-amine, 102 mg (0.33 mmol) of A/-(2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide, 14 mg (0.016 mmol) of PdCI2dppf DCM and 250 μΙ (0.50 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The volatiles were removed and the crude product was purified by flash chromatography (0% to 70% hexane/AcOEt) to obtain 86 mg (70% yield) of the title compound.
LRMS (m/z): 738 (M+1)+.
PREPARATION 92
3-lodo-1 -((5-methyl-4-(2-morpholinoethoxy)pyrrolo[2,1 -f [1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine
55.6 μΙ (0.45 mmol) of 2-morpholinoethanol (purchased from Aldrich®, cat. no. H2,820- 3) were added to a suspension of 8 mg (0.20 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 30 min and a solution of 100 mg (0.23 mmol) of 1-((4-chloro-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /-/-pyrazolo[3,4-c(]pyrimidin-4- amine in 3 ml of THF were added. The resulting mixture was stirred at room temperature for 20 hours. Then two extra additions of reagents were done, preparing a solution of 55.6 μΙ of 2-morpholinoethanol and 8 mg of sodium hydride and stirring for 30 min. and then adding this solution to the reaction mixture. Once the reaction was completed, the solvent was removed under reduced pressure and the residue was treated with acetonitrile. The solid that remained was filtered and the filtrates that contained the desired product were evaporated under vacuo to obtain 190 mg of a crude residue in which the title compound was the main product. This crude was used directly in the next step without any further purification.
LRMS (m/z): 536 (M+1)+.
PREPARATION 93
1 -(2-((2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-cQpyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 -/][1 ,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one 51 μΙ (0.45 mmol) of 1-(2-hydroxyethyl)pyrrolidin-2-one (purchased from Aldrich®, cat. no. 33,047-7) were added to a suspension of 8 mg (0.20 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 30 min and a solution of 100 mg (0.23 mmol) of 1-((4- chloro-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H-pyrazolo[3,4- cf]pyrimidin-4-amine in 3 ml of THF were added. The resulting mixture was stirred at room temperature for 20 hours. Then an extra addition of reagents was done, preparing a solution of 55.6 μΙ of 2-morpholinoethanol and 8 mg of sodium hydride and stirring for 30 min. and then adding this solution to the reaction mixture. Once the reaction was completed, the solvent was removed under reduced pressure and the residue was treated with acetonitrile. The solid that remained was filtered and dried under air stem to obtain 103 mg (85% yield) of the title compound.
LRMS (m/z): 534 (M+1)+.
PREPARATION 94
5-(5-Amino-6-methoxypyridin-3-yl)- V-((S)-1-(4-((2R,6S)-2,6-dimethylmorpholino)- 5-methylpyrrolo[2,1-/|[1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-cQpyrimidin-4-amine
100 mg (0.16 mmol) 5-bromo-/\/-((S)-1-(4-((2S,6f?)-2,6-dimethylmorpholino)-5- methylpyrrolo[2, 1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-o|pyrimidin-4-amine, 82 mg (0.33 mmol) of 2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine, 14 mg (0.016 mmol) of PdCI2dppf DCM and 245 μΙ (0.49 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The volatiles were removed and the crude product was purified by flash chromatography (0% to 70% hexane/AcOEt) to obtain 43 mg (40% yield) of the title compound.
LRMS (m/z): 660 (M+1 )+.
PREPARATION 95
5-(2-Aminopyridin-4-yl)-N-((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)pyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
5-Bromo-/\/-((S)-1 -(4-((2S,6f?)-2,6-dimethylmorpholino)pyrrolo[2, 1-/][1 ,2,4]triazin-2- yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- ]pyrimidin-4-amine (550 mg, 0.91 mmol) was placed in a sealed tube in dimethoxyethane (1 1 ml) and water (1.1 ml) under nitrogen atmosphere. Then 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-amine (300 mg, 1.36 mmol), sodium carbonate (240 mg, 2.2 mmol) and PdCI2dppf.CH2CI2 (40 mg, 0.05 mmol) were added and the mixture was heated at 90 °C overnight. The reaction mixture was cooled down to room temperature, ethyl acetate was added and the resulting suspension was filtered through Celite®. After evaporation, the crude product was purified by a first flash chromatography (0% to 50% petroleum ether/AcOEt) and then by a second flash chromatography (0% to 5%
DCM/MeOH) to give 53 mg (10% yield) of the title compound.
LRMS (m/z): 616 (M+1 )+.
PREPARATION 96
Ethyl 1 -(2-hydroxyethyl)piperidine-4-carboxylate
To a solution of 3.5 ml (32 mmol) of 2-bromoethanol In acetonitrile, 2.46 g (16 mmol) of ethyl piperidine-4-carboxylate (purchased from Aldrich® cat. no. E3, 350-5) were added. The resulting solution was heated at 85 °C for 3 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and diethylether. The organic layer was extracted with a 5% aqueous solution of citric acid and then the aqueous extracts were basified to pH = 1 1 with a 1 M aqueous solution of sodium hydroxide. The product was re-extracted with diethylether and the combined organic solution was dried over sodium sulphate, filtered and the solvent removed to give 1.87 g (42% yield) of the title compound. LRMS (m/z): 202 (M+1)+.
PREPARATION 97
Ethyl 1 -(2-((2-((4-amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylate
540 mg (2.7 mmol) of ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylate were added to a suspension of 90 mg (2.3 mmol) of sodium hydride (60% dispersion in mineral oil) in 20 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 5 min and a suspension of 400 mg (0.9 mmol) 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin- 2-yl)methyl)-3-iodo-1/-/-pyrazolo[3,4-d]pyrimidin-4-amine in 10 ml of THF was added. The resulting mixture was stirred at room temperature for 16 hours. Once the reaction was completed, the suspension was filtered and the solid washed with THF. The filtrates contained the desired product and were evaporated to give 350 mg (64% yield) of the title compound.
LRMS (m/z): 606 (M+1 )+.
PREPARATION 98
W-(4-(4-(((S)-1-(4-((2S,6 ?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide
76 mg (0.12 mmol) of 5-bromo-A/-((S)-1-(4-((2S,6f?)-2,6-dimethylmorpholino)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/- - pyrrolo[2,3-cf]pyrimidin-4-amine, 92 mg (0.31 mmol) of A/-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide (purchased from Combi-blocks® cat. no. PN-2165), 30 mg (0.04 mmol) of PdCI2dppf DCM and 32 mg of sodium carbonate were dissolved in a mixture of 32 ml of dimethoxyethane and 7 ml of water. The mixture was stirred under nitrogen atmosphere at 100 °C for 24 hours. After addition of an extra equivalent of all reagents, the mixture was heated for an additional 24 hours. Then it was let to cool to room temperature and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 100% DCM/AcOEt) to obtain 73 mg of a solid that contained the title compound in a purity of 44% and was used in the next step without any further purification. LRMS (m/z): 707 (M+1)
PREPARATION 99
(S)-1 -(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethanamine a) (S)-(9H-Fluoren-9-yl)methyl (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)carbamate
512 mg (1.2 mmol) of (S)-(9H-fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)carbamate, 540 mg (2.3 mmol) of 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (purchased from Combi-blocks®, cat. no. PN-5673), 95 mg (0.12 mmol) of PdCI2dppf DCM and 1.75 ml (3.5 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 8.5 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 100 °C overnight. The reaction mixture was filtered through Celite® and the solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 100% DCM/EtOAc) to obtain 288 mg (48% yield) of the title compound as a solid.
LRMS (m/z): 585 (M+1)+. b) (S)-1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-r][1,2,4]triazin-2- yl)ethanamine
288 mg (0.56 mmol) of (S)-(9H-fluoren-9-yl)methyl (1-(4-(2,6-dimethylpyridin-4-yl)-5- methylpyrrolo[2,1-/|[1 ,2,4]triazin-2-yl)ethyl)carbamate and 2.45 ml (28 mmol) of morpholine were dissolved in 5 ml of dioxane and stirred at reflux temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layer was separated and the organic fraction was washed with more water, brine, dried over magnesium sulphate, filtered and the solvent was removed to obtain 270 mg (29% purity, 50% yield) of a mixture of the title compound and the 9-methylene-9/-/-fluorene derived from the protecting group. This crude product was used in the next step without further purification.
LRMS (m/z): 282 (M+1)+.
PREPARATION 100 (S)-5-Bromo-A/-(1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-^[1 ,2,4]triazm 2-yl)ethyl)-7-((2-(trimethyisiiyl)ethoxy)methyi)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
157 mg (0.16 mmol) of impure (S)-1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethanamine (see Preparation 99b), 117 mg (0.32 mmol) of 5-bromo- 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, 9.8 mg (0.06 mmol) of caesium fluoride and 254 μg (1.46 mmol) of DIEA were dissolved in 3 ml of ferf-butanol and stirred in a sealed vessel at 130 °C overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate, the aqueous phase was basified with saturated solution of sodium carbonate and the two layer were separated. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 100% DCM/EtOAc) to obtain 83 mg (78% yield) of the title compound.
LRMS (m/z): 609 (M+1)+.
PREPARATION 101
(S)-W-(3-(4-((1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2- yl)ethyl)amino)-7-((2-(trimethylsilyl)ethox
yl)-5-hydroxyphenyl)methanesulfonamide
83 mg (0.13 mmol) of (S)-5-bromo-/\/-(1-(4-(2,6-dimethylpyridin-4-yl)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 126 mg (0.31 mmol) of A/-(3-hydroxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide, 31 mg (0.04 mmol) of PdCI2dppf DCM and 33 mg (0.31 mmol) of sodium carbonate were dissolved in a mixture of 32 ml of dimethoxyethane and 7 ml of water. The mixture was stirred under nitrogen atmosphere at 100 °C for 24 hours. Then it was let to cool to room temperature and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 100% DCM/AcOEt) to obtain 42 mg of a solid that contained the title compound in a purity of 74% and was used in the next step without any further purification.
LRMS (m/z): 714 (M+1)+. PREPARATION 102
(S)- ethyl 3-(2-(1-aminoethyl)-5-methylpyrroioi2,1-/][1,2)4]triazin-4-yl)-5- methylbenzoate 260 mg (0.45 mmol) of (S)-(9H-fluoren-9-yl)methyl (1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)carbamate, 250 mg (0.91 mmol) of methyl 3-methyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (purchased from Combi-blocks®, cat. no. PN-5549), 37 mg (0.05 mmol) of PdCI2dppf DCM and 680 μΙ (1.4 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 100 °C overnight. The solvents were removed under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 24 mg (10% yield) of (S)-methyl 3-(2-(1- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-5-methylpyrrolo[2, -f][1 ,2,4]triazin-4- yl)-5-methylbenzoate
LRMS (m/z): 547 (M+1 )+.
and 132 mg (90% yield) of the title compound as a solid.
LRMS (m/z): 325 (M+1 )+. PREPARATION 103
(S)-3-(2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- cnpyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- |[1,2,4]triazin-4-yl)-5- methylbenzoic acid a) (S)-Methyl 3-(2-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- o pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- |[1,2,4]triazin-4-yl)-5- methylbenzoate
93 mg (0.29 mmol) of (S)-methyl 3-(2-(1-aminoethyl)-5-methylpyrrolo[2,1- /)[1 ,2,4]triazin-4-yl)-5-methylbenzoate, 209 mg (0.57 mmol) of 5-bromo-4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c ]pyrimidine, 17.5 mg (0.12 mmol) of caesium fluoride and 451 pg (2.58 mmol) of DIEA were dissolved in 3 ml of te/t-butanol and stirred at 100 °C for 40 hours. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 300% hexane/EtOAc) to obtain 119 mg (49% yield) of the title compound.
LRMS (m/z): 650, 652 (M+1)+. b) (S)-3-(2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- c |pyrimidin-4-yi)amino)ethyi)-5-methylpyrrolo[2,1-/][1,2,4]triazin-4-y!)-5- methylbenzoic acid
1 19 mg (0.18 mmol) of (S)-methyl 3-(2-(1 -((5-bromo-7-((2- (trimethylsNyl)ethoxy)methyl)-7H-pyrrolo[2,3-(¾pyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1-r][1 ,2,4]triazin-4-yl)-5-methylbenzoate were dissolved in 5 ml of THF and 732 μΙ (0.73 mmol) of a 1 M aqueous solution of lithium hydroxide were added. The resulting solution was stirred at room temperature overnight. Another 730 μΙ (0.73 mmol) of the 1 M aqueous solution of lithium hydroxide were added and the mixture was stirred for 24 hours more. Then the diluted hydrochloric acid was added and the product was extracted with ethyl acetate, the organic solution was dried over magnesium sulphate, filtered and the solvents were removed to give 109 mg (94% yield) of the title compound.
LRMS (m/z): 634 (M-1 )\
PREPARATION 104
(S)-3-(2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- c(jpyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-W-(2- hydroxyethyl)-5-methylbenzamide
109 mg (0.17 mmol) of (S)-3-(2-(1 -((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 -/][1 ,2,4]triazin-4-yl)-5- methylbenzoic acid, 12 μΙ (0.20 mmol) of 2-aminoethanol, 39 mg (0.20 mmol) of EDC HCI, 31 mg (0.20 mmol) of HOBt and 59 μΙ (0.42 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride and a few drops of DMF at room temperature for 6 hours. An excess of all reagents was added and the mixture was stirred for an additional 16 hours, then it was treated with an aqueous sodium bicarbonate solution, the organic layer was separated and washed with brine, dried over magnesium sulphate, filtered and the solvents were removed. 96 mg (83% yield) of the title compound were isolated, pure enough to use directly in the next step without any additional purification step.
LRMS (m/z): 679 (M+1)+.
PREPARATION 105
(S)-3-(2-(1 -((5-(5-Amino-6-methoxypyridin-3-yl)-7-((2-
(trimethylsilyl)ethoxy)methyl)-7W-pyrrolo[2,3-oQpyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-fj[1,2,4]triazin-4-yl)-/V-(2-hydroxyethyl)-5-methylbenzamide 90 mg (0.13 mmol) of (S)-3-(2-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-o]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin
hydroxyethyl)-5-methylbenzamide, 66 mg (0.26 mmol) of 2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine, 11 mg (0.013 mmol) of PdCI2dppf DCM and 200 μΙ (0.40 mmol) of a 2M aqueous solution of caesium carbonate were stirred in 10 ml of dioxane under argon atmosphere at 100 °C overnight. The volatiles were removed under reduced pressure and the crude product was directly purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 46 mg (48% yield) of the title compound.
LRMS (m/z): 724 (M+1)+.
PREPARATION 106
3-((Methylamino)methyl)phenol
1.0 g (8.2 mmol) of 3-hydroxybenzaldehyde (purchased from Aldrich® cat. no. H19808) and 1.15 ml of a 33% solution of methanamine in ethanol (commercially available from Fluka® cat. no. 65590) were mixed and stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was redissolved in 5 ml of ethanol and cooled in an ice bath. 1.0 g (26 mmol) of sodium borohydride was added as a solid and the resulting solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 950 mg (84% yield) of the title compound were obtained.
LRMS (m/z): 138 (M+1)+.
PREPARATION 107
2-(4-Amino-3-iodo-1 H-pyrazolo[3,4-cflpyrimidin-1 -yl)propanoic acid a) Ethyl 2-(4-amino-3-iodo-1 H-pyrazolo[3,4-cQpyrimidin-1 -yl)propanoate
2.0 g (7.7 mmol) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (purchased from Ark Pharm® cat. no. AK-32203) and 1.1 g (8.1 mmol) of (f?)-ethyl 2-chloropropanoate (purchased from Santai Labs® cat. no. ADH-2600) were dissolved in 120 ml of DMF. 2.1 g (15.3 mmol) of potassium carbonate were added and the mixture was stirred at °C for 5 hours and then at room temperature for 3 days. The volatiles were removed under reduced pressure and the residue was treated with water and the insoluble solid was filtered, washed with water and dried first under air steam and then in a vacuum oven at 50 °C for 2 hours. 2.8 g (100% yield) of the title compound were obtained as a racemic mixture of the two possible isomers.
LRMS (m/z): 362 (M+1)+. b) 2-(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)propanoic acid
1.4 g (3.9 mmol) of racemic ethyl 2-(4-amino-3-iodo-1 H-pyrazolo[3,4- |pyrimidin-1- yl)propanoate were dissolved in a mixture of 100 ml of methanol and 40 ml of THF. A solution of 1.5 g (35 mmol) of lithium hydroxide monohydrate in 20 ml of water was added and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was acidified with 2M hydrochloric acid until a pale solid appeared. The product was filtered, washed with water and dried first under air steam and then in a vacuum oven at 50 °C. 1.03 g (79% yield) of the title compound were obtained.
LRMS (m/z): 332 (M-1)\
PREPARATION 108
1-(1-(4-Chloro-5-methylpyrrolo[2,1- |[1,2,4]triazin-2-yl)ethyl)-3-iodo-1W- pyrazoio[3,4-d]pyrimidin-4-amine a) 1 -(2-(4-Amino-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)propanamido)-W-(2,4- dimethoxybenzyl)-3-methyl-1H-pyrrole-2-carboxamide
210 mg (0.67 mmol) of 1-amino-/\/-(2,4-dimethoxybenzyl)-3-methyl-1 /-/-pyrrole-2- carboxamide, 267 mg (0.80 mmol) of 2-(4-amino-3-iodo-1 - -pyrazolo[3,4- |pyrimidin-1- yl)propanoic acid, 134 mg (1.1 mmol) of EDC HCI and 95 mg (1.1 mmol) of HOBt were suspended in 4 ml of DMF and stirred at 50 °C overnight. The mixture was diluted with ethyl acetate and the resulting solution was washed with 2M hydrochloric acid, water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 110 mg (25% yield) of the title compound.
LRMS (m/z): 605 (M+1)+. b) 2-(1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5- methylpyrrolo[2,1- j[1,2,4]triazin-4(3H)-one
310 mg (0.51 mmol) of 1-(2-(4-amino-3-iodo-1 /- -pyrazolo[3,4-d]pyrimidin-1- yl)propanamido)-A/-(2,4-dimethoxybenzyl)-3-methyl-1 H-pyrrole-2-carboxamide were suspended in 70 ml of toluene. 194 mg (0.77 mmol) of PPTS were added and the resulting mixture was heated at 150 °C for 4 days, using a Dean-Stark head to remove the traces of water from the reaction mixture. The volatiles were then removed and the residue was redissolved in ethyl acetate and this solution was washed with a 4% aqueous solution of sodium carbonate, water and brine. The volatiles were removed and the residue was treated with 33% ammonium hydroxide and heated at 80 °C overnight. Once the mixture reached room temperature, it was neutralized with 5M hydrochloric acid and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed to give 230 mg (82% yield) of the title compound as a white solid.
LRMS (m/z): 437 (M+1 )+. c) 1 -(1 -(4-Chloro-5-methylpyrrolo[2,1 ,2,4]triazin-2-yl)ethyl)-3-iodo-1 H- pyrazolo[3,4-rf]pyrimidin-4-amine
230 mg (0.53 mmol) of 2-(1 -(4-amino-3-iodo-1 H-pyrazolo[3,4-c]pyrimidin-1-yl)ethyl)-5- methylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3/-/)-one were suspended in 5 ml of phosphorus oxychloride and heated at 80 °C for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate and the mixture was stirred vigorously for 30 minutes. Then the two layers were separated and the organic fraction was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. 192 mg (80% yield) of the title compound were obtained as a brown solid.
LRMS (m/z): 455 (M+1 )+.
PREPARATION 109
1 -(1 -(4-((3S,5 ?)-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine 190 mg (0.42 mmol) of 1 -(1 -(4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)-3- iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine were suspended in 10 ml of acetone. 1 17 mg (0.63 mmol) of (2S,6ft)-2,6-dimethylpiperazine dihydrochloride and 364 μΙ (2.1 mmol) of DIEA were added and the resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and methylene chloride/methanol. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 52 mg (23% yield) of the title compound as a white solid.
LRMS (m/z): 533 (M+1 )+.
PREPARATION 1 10
4-(Sulfamoylamino)benzylamine a) Terf-butyl 4-(sulfamoylamino)benzylcarbamate
To a solution of 196 mg (0.88 mmol) of te/f-butyl 4-aminobenzylcarbamate (purchased from Aldrich® cat. no. 525626) in 2 ml of DMA were added 204 mg (1.76 mmol) of sulfamoyl chloride and the resulting reaction mixture was stirred at room temperature for 64 hours. Then it was diluted with ethyl acetate it was washed with 1 M hydrochloric acid and water, dried over magnesium sulphate, filtered and the solvents were removed to afford 80 mg (30% yield) of the title compound.
LRMS (m/z): 300 (M-1 )\ b) 4-(Sulfamoylamino)benzylamine hydrochloride
A solution of 80 mg (0.27 mmol) of te/rf-butyl 4-(sulfamoylamino)benzylcarbamate in 2 ml of a 4M solution of hydrochloric acid in dioxane was stirred at room temperature for 90 minutes. The volatiles were removed under reduced pressure and the residue was suspended in diethylether and stirred vigorously. The insoluble solid was filtered and washed with ether and dried to give 60 mg (95% yield) of the title compound.
LRMS (m/z): 202 (M+1 )+.
PREPARATION 1 1 1
/V-(3-(Aminomethyl)-5-methoxyphenyl)methanesulfonamide a) 3-Amino-5-methoxybenzonitrile
A solution of 500 mg (2.47 mmol) of 3-bromo-5-methoxyaniline in anhydrous 5 ml of N- methyl-2-pyrrolidinone and 288 mg (3.21 mmol) of cyanocopper was heated overnight at 200°C. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of sodium hydrogencarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to afford 256 mg (70% yield) the title compound.
LRMS (m/z): 149 (M+1)+. b) A -(3-Cyano-5-methoxyphenyl)methanesulfonamide
A solution of 256 mg (1.7 mmol) of 3-amino-5-methoxybenzonitrile in 6 ml of pyridine was cooled at 0 °C. 275 μΙ (3.6 mmol) of methanesulfonyl chloride were added and the solution was stirred at room temperature overnight. Then the mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to afford 293 mg (75% yield) of the title compound as a solid.
LRMS (m/z): 225 (M-1 )\ c) A/-(3-(Aminomethyl)-5-methoxyphenyl)methanesulfonamide
200 mg (0.88 mmol) of A/-(3-Cyano-5-methoxyphenyl)methanesulfonamide, 420 mg (1.7 mmol) of cobalt (II) chloride hexahydrate and 334mg (8.8 mmol) of sodium borohydride were dissolved in 10 ml of methanol and stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain a solid that was treated with dioxane and stirred at room temperature overnight. The solid that remained was filtered and the solvent was removed from the filtrate under reduced pressure to give 73 mg (35% yield) of the title compound.
LRMS (m/z): 231 (M+1 )+.
PREPARATION 1 12
/V-(4-(Aminomethyl)-2-methoxyphenyl)methanesulfonamide a) 4-Amino-3-methoxybenzonitrile
A solution of 400 mg (2.0 mmol) of 4-bromo-2-methoxyaniline in anhydrous 4 ml of N- methyl-2-pyrrolidinone and 233 mg (2.6 mmol) of cyanocopper was heated overnight at 150°C. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of sodium hydrogencarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to afford 100 mg (34% yield) the title compound.
LRMS (m/z): 149 (M+1 )+. b) W-(4-Cyano-2-methoxyphenyl)methanesulfonamide A solution of 100 mg (0.67 mmol) of 4-amino-3-methoxybenzonitrile in 3 ml of pyridine was cooled at 0 °C. 260 μΙ (3.4 mmol) of methanesulfonyl chloride were added and the solution was stirred at room temperature overnight. Then the mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to afford 130 mg (85% yield) of the title compound.
LRMS (m/z): 225 (M-1 )\ c) /V-(4-(Aminomethyl)-2-methoxyphenyl)methanesulfonamide
100 mg (0.44 mmol) of A/-(4-Cyano-2-methoxyphenyl)methanesulfonamide, 210 mg (0.88 mmol) of cobalt (II) chloride hexahydrate and 167 mg (4.4 mmol) of sodium borohydride were dissolved in 5 ml of methanol and stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 60 mg (59% yield) of the title compound.
LRMS (m/z): 231 (M+1)+.
PREPARATION 113
/V-(3-(Aminomethyl)-5-hydroxyphenyl)methanesulfonamide
2.2 ml (2.2 mmol) of a 1 M solution of boron tribromide in methylene chloride were added dropwise to a solution of 100 mg (0.44 mmol) of A/-(3-(aminomethyl)-5- methoxyphenyl)methanesulfonamide in 3 ml of methylene chloride cooled in an ice bath. The resulting mixture was stirred at room temperature overnight and then the volatiles were removed under reduced pressure and the crude product was directly purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 29 mg (31 % yield) of the title compound.
LRMS (m/z): 217 (M+1 )+.
PREPARATION 1 14
2- ethyl-4-(4-methylpiperazin-1-yl)-6-(trimethylstannyl)pyrimidine a) 4-Chloro-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine
1.00 g (6.1 mmol) of 4,6-dichloro-2-methylpyrimidine (purchased from Aldrich® cat. no. 596728) was dissolved in 2 ml of tert-butanol and 819 μΙ (7.4 mmol) of 1- methylpiperazine were added. The reaction mixture was stirred at 100 °C overnight and the volatiies were removed under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 902 mg (65% yield) of the title compound.
LRMS (m/z): 227 (M+1)+. b) 2-Methyl-4-(4-methylpiperazin-1-yl)-6-(trimethylstannyl)pyrimidine
250 mg (1.1 mmol) of 4-chloro-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine, 128 mg (0.1 mmol) of Pd(PPh3)4 and 457 μΙ (2.2 mmol) of 1 ,1 ,1 ,2,2,2-hexamethyldistannane were stirred in 5 ml of THF at 100 °C in a sealed tube under nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature and then filtered through Celite® to obtain 530 mg of a crude product that was used in the next step without further purification.
LRMS (m/z): 356 (M+1 )+.
PREPARATION 115
Methyl 6-methyl-2-(trimethylstannyl)pyrimidine-4-carboxylate
200 mg (1.1 mmol) of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (purchased from Aldrich® cat. no. 716588), 124 mg (0.11 mmol) of Pd(PPh3)4 and 703 μΙ (3.4 mmol) of 1 ,1 ,1 ,2,2,2-hexamethyldistannane were stirred in 5 ml of THF at 100 °C in a sealed tube under nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature and then filtered through Celite® and the volatiies were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 60% hexane/EtOAc) to obtain 49 mg (15% yield) of the title compound as a colourless oil.
LRMS (m/z): 316 (M+1)+.
PREPARATION 116
(S)-2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid a) (S)-Methyl 2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylate 50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 48 mg (0.15 mmol) of methyl 6-methyl-2- (trimethylstannyl)pyrimidine-4-carboxylate, 18 mg (0.02 mmol) of Pd(PPh3)4 and 15 mg (0.08 mmol) of copper (I) iodide were stirred in 2 ml of DMF at 100 °C for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 35 mg (52% yield) of the title compound as a pale solid.
LRMS (m/z): 445 (M+1)+. b) (S)-2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid
35 mg (0.08 mmol) of (S)-methyl 2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)- 5-methylpyrrolo[2, 1 -t7[1 ,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylate were dissolved in 5 ml of methanol. 281 μΙ (0.56 mmol) of a 2M aqueous solution of sodium hydroxide were added and the resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was diluted with water and washed with methylene chloride. Then the aqueous solution was acidified to pH = 3 and the product was extracted with methylene chloride. The combined organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed to obtain 10 mg (29% yield) of the title compound.
LRMS (m/z): 429 (M-1)\
PREPARATION 117
W-(3-Hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenesulfonamide a) 3-Bromo-/V-(3-hydroxybenzyl)-5-methylbenzenesulfonamide
500 mg (1.9 mmol) of 3-bromo-5-methylbenzene-1-sulfonyl chloride (purchased from Astatech® cat. no. CL8741 ) were dissolved in 30 ml of chloroform. 520 μΙ (3.7 mmol) of triethylamine and 300 mg (2.4 mmol) of 3-(aminomethyl)phenol were added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 111 mg (17% yield) of the title compound.
LRMS (m/z): 354, 356 (M-1)\ b) A/-(3-Hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide
243 mg (0.68 mmol) of 3-Bromo-Ay-(3-hydroxybenzyl)-5-methylbenzenesulfonamide, 346 mg (1.4 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), 56 mg (0.07 mmol) of PdCI2dppf DCM, 38 mg (0.07 mmol) of dppf and 201 mg (2.1 mmol) of potassium acetate were suspended in 10 ml of dioxane under nitrogen atmosphere. The mixture was heated at 80 °C overnight. The suspension was then diluted with ethyl acetate, filtered through Celite® and the filtrate was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc and then 0% to 5% EtOAc/ eOH) to obtain 166 mg (60% yield) of the title compound.
LRMS (m/z): 404 (M+1)+.
PREPARATION 118
V1,/V1-Dimethyl-/V2-(4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine a) 4-(4- ethylpiperazin-1 -yl)benzaldehyde
1.0 g (8.1 mmol) of 4-fluorobenzaldehyde, 1.52 ml (13.7 mmol) of 1-methylpiperazine and 1.28 g (12.1 mmol) of sodium carbonate were stirred in 10 ml of water at 100 °C overnight. The reaction mixture was diluted with water and the product was extracted with methylene chloride. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. 1.59 g (97% yield) of the title compound were obtained as a pale solid.
LRMS (m/z): 205 (M+1)+. b) W^^-Dimethyl-W^^-methylpiperazin-l-y benzylJethane-l^-diamine
1.59 g (7.8 mmol) of 4-(4-methylpiperazin-1-yl)benzaldehyde and 900 μΙ (8.2 mmol) of A/\/V1-dimethylethane-1 ,2-diamine were stirred in 40 ml of methanol for 30 min. Then the volatiles were removed under reduced pressure and the residue was redissolved in 40 ml of methanol. The resulting solution was cooled in an ice bath and 150 mg (4.0 mmol) of sodium borohydride were added portionwise. The mixture was stirred at room temperature for 2 hours and the solvent was removed. The residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed to obtain 2.1 g (97% yield) of the title compound as a colourless oil.
LRMS (m/z): 277 (M+1 )+. PREPARATION 119
(S)-3-(1 -Aminoethyl)phenol
A solution of 250 mg (1.65 mmol) of (S)-1-(3-methoxyphenyl)ethanamine (purchased from Aldrich® cat. no. 727199) in 12.5 ml of methylene chloride was cooled to -78 °. 3.3 ml (3.3 mmol) of a 1 M solution of boron tribromide in methylene chloride were added dropwise and the resulting reaction mixture was stirred at room temperature for 2 hours. 30 ml of methanol were added to quench the reaction and then the volatiles were removed under reduced pressure. The title product was obtained as a white solid and was used in the next step without further purification.
LRMS (m/z): 138 (M+1)+.
PREPARATION 120
W,A/-Dimethyl-1-(4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine a) 1-(4-Bromopyridin-2-yl)-/V,A/-dimethylpiperidin-4-amine
1.00 g (5.7 mmol) of 4-bromo-2-chloropyridine (purchased from Aldrich® cat. no. 646318), 874 μΙ (6.8 mmol) of A/,A/-dimethylpiperidin-4-amine and 2.36 g (17 mmol) of potassium carbonate were dissolved in 5 ml of DMSO and heated at 100 °C overnight. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 1.57 g (92% yield) of the title compound were obtained as a yellowish oil.
LRMS (m/z): 284, 286 (M+1)+. b) /V,A/-Dimethyl-1 -(4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine
300 mg (1.0 mmol) of 1-(4-bromopyridin-2-yl)-/\/,/V-dimethylpiperidin-4-amine, 115 mg (0.10 mmol) of Pd(PPh3)4 and 411 μΙ (2.0 mmol) of 1 ,1 ,1 ,2,2,2-hexamethyldistannane were stirred in 7.5 ml of THF at 100 °C in a sealed tube under nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 50%) to obtain 152 mg (42% yield) of the title compound as a colourless oil.
LRMS (m/z): 369 (M+1)+.
PREPARATION 121
A/,W,2-Trimethyl-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin yl)piperidin-4-yl)pyridin-4-amine a) 2-(1-(4-Bromopyridin-2-yl)piperidin-4-yl)-/V,A/,6-trimethylpyridin-4-amine
A mixture of 96 mg (0.55 mmol) of 4-bromo-2-fluoropyridine (purchased from Aldrich® cat. no. 722421), 144 mg (0.65 mmol) of A/,Ay,2-trimethyl-6-(piperidin-4-yl)pyridin-4- amine (purchased from Asinex® cat. no. 27288294) and 226 mg (1.6 mmol) of potassium carbonate in 0.5 ml of DMSO was stirred at 100 °C overnight. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvents were removed. 131 mg (64% yield) of the title product were obtained as an oil.
LRMS (m/z): 376 (M+1)+. b) W,A/,2-Trimethyl-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperidin-4-yl)pyridin-4-amine
131 mg (0.30 mmol) of 2-(1-(4-bromopyridin-2-yl)piperidin-4-yl)-/\/,/\/,6-trimethylpyridin- 4-amine, 150 mg (0.59 mmol) of 4,4,4,,4',5,5,5',5,-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane), 15 mg (0.02 mmol) of PdCI2dppf DCM and 87 mg (0.9 mmol) of potassium acetate were suspended in 2.5 ml of dioxane under argon atmosphere. The mixture was heated at 120 °C in three cycles of 20 minutes, adding 15 mg of the catalyst after each heating cycle. Once the reaction was completed, the suspension was diluted with DCM, filtered through Celite® and the filtrate was washed with water. The product was extracted into the aqueous phase and this solution was injected directly into the reverse phase purification system (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 80 mg (54% yield) of the title compound as a solid.
LRMS (m/z): 423 (M+1)+. PREPARATION 122
1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperazine a) 1 -(4-Bromo-6-methylpyridin-2-yl)-4-methylpiperazine
200 mg (0.97 mmol) of 4-bromo-2-chloro-6-methylpyridine (purchased from Combi- blocks® cat. no. PY-1965), 129 μΙ (1.2 mmol) of 1-methylpiperazine, 506 μΙ (2.9 mmol) of DIEA and 147 mg (0.97 mmol) of caesium fluoride were suspended in 8 ml of tert- butanol and heated at 100 °C overnight, then at 120 °C for 4 hours, then at 130 °C for 16 hours more and finally at 180 °C in a pressure-proof sealed vessel for 16 hours. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 42 mg (18% yield) of the title compound.
LRMS (m/z): 270, 272 (M+1)+. b) 1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperazine
47 mg (0.17 mmol) of 1-(4-bromo-6-methylpyridin-2-yl)-4-methylpiperazine, 20 mg (0.02 mmol) of Pd(PPh3)4 and 72 μΙ (0.35 mmol) of 1 ,1 ,1 ,2,2,2-hexamethyldistannane were stirred in 3 ml of THF at 100 °C overnight in a sealed tube under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered through Celite®. The solvents were removed and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to give 54 mg (88% yield) of the title compound as a colourless oil.
LRMS (m/z): 355 (M+1 )+.
PREPARATION 123
5-Bromo-/V-((S)-1 -(4-((3S,5/?)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 - /][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsiIyl)ethoxy)methyl)-7W-pyrrolo[2,3- cflpyrimidin-4-amine
170 mg (0.59 mmol) of (S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethanamine, 290 mg (0.80 mmol) of 5-bromo-4- chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, 35 mg (0.23 mmol) of caesium fluoride and 0.91 ml (5 mmol) of DIEA were suspended in 10 ml of terf-butanol. The reaction mixture was stirred at 100 °C for 24 hours. The volatiles were removed under reduced pressure and the crude product was directly purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 96 mg (34% yield) of the title compound as a white solid.
LRMS (m/z): 615 (M+1)+. PREPARATION 124
5-(2-Aminopyridin-4-yl)-A/-((S)-1-(4-((3S,5/?)-3,5-dimethylpipera2in-1-yl)-5- methylpyrrolo[2,1- [1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-c |pyrimidin-4-amine
96 mg (0.16 mmol) of 5-bromo-A/-((S)-1-(4-((3S,5 )-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-d]pyrimidin-4-amine, 60 mg (0.28 mmol) of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (purchased from Combi-blocks® cat. no. PN-0151), 12 mg (0.014 mmol) of PdCI2dppf DCM and 225 μΙ of an aqueous 2M solution of caesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred under argon at 100 °C for 16 hours. Then the solvents were removed and the crude product was directly purified by flash chromatography (100% DC to 100% DCM/MeOH/NH3, 90:8:1) to obtain 70 mg (65% yield) of the title compound as a white solid.
LRMS (m/z): 629 (M+1)+.
PREPARATION 125
5-(6-Aminopyridin-3-yl)-W-((S)-1-(4-((3S,5 ?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7W-pyrrolo[2,3-cflpyrimidin-4-amine
40 mg (0.07 mmol) of 5-bromo-/V-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -/][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 -/- pyrrolo[2,3-cf]pyrimidin-4-amine, 36 mg (0.16 mmol) of 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (purchased from Fluorochem® cat. no. 021607), 6 mg (0.007 mmol) of PdCI2dppf DCM and 100 μΙ of an aqueous 2M solution of caesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred under argon at 100 °C for 16 hours. Then the solvents were removed and the crude product was directly purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8:1) to obtain 70 mg (32% yield) of the title compound as a white solid.
LRMS (m/z): 629 (M+1)+.
PREPARATION 126
4-Chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1- ]t1,2,4]triazine a) A/-(2,4-Dimethoxybenzyl)-1 -(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2- carboxamide
3.8 g (13 mmol) of 1-amino-/\/-(2I4-dirnethoxybenzyl)-3-rnethyl-1H-pyrrole-2- carboxamide were dissolved in acetic acid and cooled in an ice bath. 1.3 ml (14.3 mmol) of 2-methoxyacetyl chloride were added dropwise and the mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and methylene chloride. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 3.4 g (72% yield) of the title compound as an oil.
LRMS (m/z): 362 (M+1 )+. b) 3-(2,4-Dimethoxybenzyl)-2-(methoxymethyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4(3H)-one
3.4 g (9.4 mmol) of A/-(2,4-dimethoxybenzyl)-1 -(2-methoxyacetamido)-3-methyl-1 -/- pyrrole-2-carboxamide were suspended in 300 ml of toluene. 4.7 g (19 mmol) of PPTS were added and the resulting mixture was heated at 160 °C for 6 hours, using a Dean- Stark head to remove the traces of water from the reaction mixture. The volatiles were then removed and the residue was redissolved in ethyl acetate and this solution was washed with water and brine. The volatiles were removed and the residue was redissolved in ethyl acetate. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 2.7 g (85% yield) of the title compound as a colourless oil.
LRMS (m/z): 344 (M+1 )+. c) 2-(Methoxymethyl)-5-methylpyrrolo[2,1- ][1,2,4]tria2in-4(3H)-one
To a solution of 2.7 g (7.9 mmol) of 3-(2,4-dimethoxybenzyl)-2-(methoxymethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one in TFA, 24 ml of anisole were added. The reaction mixture was stirred at 80°C for 9 hours. Then the solvents were removed and the crude product was triturated with hexane and the solid filtered and dried under air stream to give 1.43 g (90% yield) of the title compound as a grey solid.
LRMS (m/z): 194 (M+1)+. d) 4-Chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1-/][1,2,4]triazine
1.43 g (7.4 mmol) of 2-(methoxymethyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4(3H)-one were suspended in 24 ml of phosphorus oxychloride and stirred at 80 °C for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH = 7 with a saturated solution of sodium hydrogencarbonate and the layer was separated. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to obtain 1.31 g (83% yield) of the title product as a solid.
LRMS (m/z): 212 (M+1 )+.
PREPARATION 127
Methyl 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4-yl)-5- methylbenzoate
315 mg (1.5 mmol) of 4-chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazine, 624 mg (2.3 mmol) of methyl 3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (purchased from Combi-blocks®, cat. no. PN-5549), 93 mg (0.11 mmol) of PdCI2dppf DCM and 1.7 ml (3.4 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The solvents were removed and the crude product was purified directly by flash chromatography (0% to 50% hexane/EtOAc) to obtain 291 mg (78% yield) of the title compound as a solid.
LRMS (m/z): 326 (M+1)+.
PREPARATION 128
Methyl 3-(2-((4-amino-3-iodo-1H-pyrazolo[3,4-£/|pyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1-fj[1 ,2,4]triazin-4-yl)-5-methylbenzoate a) Methyl 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-4-yl)-5- methylbenzoate
291 mg (0.89 mmol) of methyl 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin- 4-yl)-5-methylbenzoate were dissolved in 10 ml of methylene chloride. The solution was cooled at -78 °C and then 2.7 ml (2.7 mmol) of a 1 M solution of boron tribromide in methylene chloride were added dropwise. The reaction mixture was stirred at room temperature for 90 minutes and then the reaction was quenched by addition of methanol. The volatiles were removed under reduced pressure and the residue was redissolved in 20 ml of methanol and 600 μΙ of concentrated sulphuric acid were added. The solution was stirred at room temperature overnight. The solvent was then removed and the residue partitioned between ethyl acetate and saturate solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. 228 mg (82% yield) of the title compound were obtained as a solid.
LRMS (m/z): 312 (M+1)+. b) Methyl 3-methyl-5-(5-methyl-2-(((methylsulfonyl)oxy)methyl)pyrrolo[2,1- ,2,4]triazin-4-yl)benzoate
To a solution of 77 mg (0.25 mmol) of methyl 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-4-yl)-5-methylbenzoate in anhydrous DCM, 40 μΙ (0.28 mmol) of triethylamine and 20 μΙ of methanesulfonyl chloride were added. The reaction mixture was stirred for 2 hours at room temperature. Then an excess of reagents was added and the mixture was stirred for an additional 6 hours. The solution was then washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed to give 84 mg (87% yield) of the title compound as a yellow oil.
LRMS (m/z): 390 (M+1 )+. c) Methyl 3-(2-((4-amino-3-iodo-1 H-pyrazolo[3,4-cflpyrimidin-1 -yl)methyl)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-4-yl)-5-methylbenzoate
83.7 mg (0.21 mmol) of methyl 3-methyl-5-(5-methyl-2- (((methylsulfonyl)oxy)methyl)pyrrolo[2,1- |[1 ,2,4]triazin-4-yl)benzoate, 72 mg (0.28 mmol) of 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine and 38 mg (0.28 mmol) of potassium carbonate were dissolved in DMF. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude product was purified by flash chromatography (0% to 20% DCM/MeOH) to obtain ,100 mg (84% yield) of the title compound as a yellowish solid.
LRMS (m/z): 555 (M+1)+.
PREPARATION 129
3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d|pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4-yl)-5-methylbenzoic acid
98 mg (0.18 mmol) of methyl 3-(2-((4-amino-3-iodo-1 /-/-pyrazolo[3,4-c ]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoate, 42 mg (0.27 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid and 14.7 mg (0.27 mmol) of PdCI2dppf DCM were dissolved in 5 ml of ethanol in a sealed reactor. 270 μΙ (0.54 mmol) of a 2M aqueous solution of caesium carbonate (0.27 ml, 0.54 mmol) was added and then the reaction mixture was degassed with argon and stirred at 80 °C overnight. The solvent was evaporated and the crude was partitioned between water and ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid and the product precipitated while it was being extracted with methylene chloride. The solid was filtered and dried under a stream of air to give 54 mg (55% yield) of the title compound as a white solid.
LRMS (m/z): 523 (M-1 )\
The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed to give the main by-product ethyl 3-(2-((4- amino-3-(3-fluoro-5-hydroxyphenyl)-1 /- -pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoate, which was isolated and purified as described in Example 171.
PREPARATION 130
2-(Dimethylamino)-W-(3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethanesulfonamide a) W-(3-Bromo-5-hydroxyphenyl)ethenesulfonamide
To a solution of 465 mg (2.47 mmol) of 3-amino-5-bromophenol and 817 μΙ (8.2 mmol) of 4-methylmorpholine in 13 ml of methylene chloride, cooled in an ice bath, was added a solution of 387 μΙ (3.7 mmol) of 2-chloroethanesulfonyl chloride in 7 ml of methylene chloride dropwise. The resulting solution was stirred at room temperature for 2 hours and then the volatiles were removed. The residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 640 mg (63% purity, 60% yield) of crude product were obtained, which were used in the next step without any further purification.
LRMS (m/z): 278, 280 (M+1 )+. b) W-(3-Bromo-5-hydroxyphenyl)-2-(dimethylamino)ethanesulfonamide
The crude product isolated in Preparation 130a was dissolved in 13 ml of methanol and 2.9 ml of a 2M solution of dimethylamine in tetrahydrofurane was added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 500 mg (83% purity, 88% yield) of crude product were obtained, which were used in the next step without any further purification.
LRMS (m/z): 323, 325 (M+1)+. c) 2-(Dimethylamino)-W-(3-hydroxy-5-(4,4,5,5-tetramethyi-1,3,2-dioxaborolan-2- yl)phenyl)ethanesulfonamide
335 mg (1.0 mmol) of A/-(3-bromo-5-hydroxyphenyl)-2- (dimethylamino)ethanesulfonamide, 791 mg (3.1 mmol) of 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane), 170 mg (0.21 mmol) of PdCI2dppf DCM and 612 mg (6.2 mmol) of potassium acetate were suspended in 14 ml of dioxane under argon atmosphere. The mixture was heated at 100 °C for 16 hours. The volatiles were removed and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 200 mg (69% yield) of the title compound as a white solid.
LRMS (m/z): 371 (M+1)+.
PREPARATION 131
2-(Dimethylamino)- V-(3-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-/|[1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c |pyrimidin-5-yl)-5- hydroxyphenyl)ethanesulfonamide
50 mg (0.08 mmol) of 5-bromo-/V-((S)-1-(4-((3S,5 )-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 100 mg (0.27 mmol) of 2-(dimethylamino)-/V-(3- hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide, 6 mg (0.007 mmol) of PdCI2dppf DCM and 100 μΙ of a 2M aqueous solution of caesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred under argon at 100 °C for 16 hours. Then the solvents were removed and the crude product was directly purified by flash chromatography (0% to 20% DCM/MeOH) to obtain 15 mg (23% yield) of the title compound as a white solid.
LRMS (m/z): 779 (M+1)+.
PREPARATION 132
A/^4-(4-(Dimethylamino)piperidin-1-yl)benzyl)^ a) 4-(4-(Dimethylamino)piperidin-1 -yl)benzaldehyde The title compound was prepared from 500 mg (4.0 mmol) of 4-fluorobenzaldehyde and 878 mg (6.9 mmol) of A/,A/-dimethylpiperidin-4-amine following the experimental procedure described in Preparation 118a. 907 mg (97% yield) of the title compound were obtained as a colourless oil.
LRMS (m/z): 233 (M+1 )+. b) /V1-(4-(4-(Dimethylamino)piperidin-1 -yl)benzyl)-W2,/V2-dimethylethane-1 ,2- diamine
The title compound was prepared from 907 mg (3.9 mmol) of 4-(4- (dimethylamino)piperidin-1-yl)benzaldehyde and 451 μΙ (4.1 mmol) of Λ/1,Λ/1- dimethylethane-1 ,2-diamine following the experimental procedure described in Preparation 1 18b. 1.18 g (99% yield) of the title compound were obtained as a yellowish oil.
LRMS (m/z): 305 (M+1 )+.
PREPARATION 133
/V-((S)-1-(4-((3S,5A?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- [1,2,4]triazin-2-yl)ethyl)-7-((2-(tri^
/lpyrimidin-4-amine
The title compound was obtained as a side product in Suzuki reactions like those described in Preparation 124, Preparation 125 and Preparation 131. In some of the cases, the title compound was the main product of the reaction and was isolated from the reaction crude during the purification of the desired products of those reactions.
LRMS (m/z): 336 (M+1)+.
PREPARATION 134
2-(4-(Dimethylamino)piperidin-1-yl)ethanol 400 mg (3.1 mmol) of A/,A/-dimethylpiperidine-4-amine were dissolved in acetonitrile. 1.3 g (9.4 mmol) of potassium carbonate and 450 μΙ (2.0 mmol) of bromoethanol were added and the mixture was stirred at 80 °C for 3 hours and then at room temperature for 20 hours. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was diluted with the minimum amount of water and some drops of 1 N NaOH was added to reach a clearly basic pH. The aqueous layer was extracted with methylene chloride (x6) and the combined organic extracts were dried over sodium sulphate, filtered and the solvent removed to give 100 mg (19% yield) of the title compound as an oil.
LRMS (m/z): 173 (M+1 )+. PREPARATION 135
1-((4-(2-(4-(Dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4- /|pyrimidin-4-amine
45 mg (0.26 mmol) of 2-(4-(dimethylamino)piperidin-1-yl)ethanol were added to a suspension of 10 mg (0.26 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 5 min and 51 mg (0.12 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)- 3-iodo-1 H-pyrazolo[3,4-c/]pyrimidin-4-amine were added. The resulting mixture was stirred at room temperature for 16 hours. Once the reaction was completed, the suspension was filtered and the solid washed with THF. The filtrates contained the desired product and were evaporated to give 67 mg (100% yield) of the title compound.
LRMS (m/z): 577 (M+1)+.
PREPARATION 136
A/-(4-(4-Methylpiperazin-1-yl)benzyl)-2-(pyrrolidin-1-yl)ethanamine
The title compound was prepared from 150 mg (0.68 mmol) of 4-(4-methylpiperazin-1- yl)benzaldehyde and 90 μΙ (0.71 mmol) of 2-(pyrrolidin-1-yl)ethanamine following the experimental procedure described in Preparation 118b. 207 mg (100% yield) of the title compound were obtained as a yellowish oil.
LRMS (m/z): 303 (M+1)+.
PREPARATION 137
W,W-Dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amin a) 1-(4-Bromo-6-methylpyridin-2-yl)-/V,/V-dimethylpiperidin-4-amine
250 mg (1.21 mmol) of 4-bromo-2-chloro-6-methylpyridine (purchased from Combi- blocks® cat. no. PY-1965), 186 mg (1.45 mmol) of A/,/V-dimethylpiperidin-4-amine, 633 μΙ (3.6 mmol) of DIEA and 184 mg (1.21 mmol) of caesium fluoride were suspended in 10 ml of fert-butanol and heated at 180 °C overnight in a pressure-proof sealed vessel. Additional amounts of reagents were needed every 24 hours until no starting material was left (3 extra additions in successive days). Then the solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 249 mg (69% yield) of the title compound as a yellowish oil.
LRMS (m/z): 298, 300 (M+1)+. b) /V,/V-Dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine
249 mg (0.83 mmol) of 1-(4-bromo-6-methylpyridin-2-yl)-/\/,/\/-dimethylpiperidin-4- amine, 97 mg (0.08 mmol) of Pd(PPh3)4 and 346 μΙ (1.67 mmol) of 1 ,1 ,1 ,2,2,2- hexamethyldistannane were stirred in 36 ml of THF at 100 °C overnight in a sealed tube under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered through Celite®. The solvents were removed and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to give 300 mg (94% yield) of the title compound as a colourless oil.
LRMS (m/z): 383 (M+1)+.
PREPARATION 138
A/,W-Dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperidin-4-amine
425 mg (1.5 mmol) of 1-(4-bromopyhdin-2-yl)-/V,/V-dimethylpiperidin-4-amine, 460 mg (1.8 mmol) of 4,4,4',4',5,5,5,,5,-octamethyl-2,2,-bi(1 ,3,2-dioxaborolane), 60 mg (0.07 mmol) of PdCI2dppf DCM and 440 mg (4.5 mmol) of potassium acetate were suspended in 15 ml of dioxane under argon atmosphere. The mixture was heated at 80 °C for 16 hours. A further equivalent of all reagents was added and the mixture was heated at 80 °C for an additional 4 hours. Once the reaction was completed, the suspension was diluted with diethylether, filtered through Celite® and the volatiles were removed. The residue was treated with hexane and stirred vigorously for 1 hour. The remaining solid that mainly contained impurities was filtered and the solvent was removed to obtain 490 mg (99% yield) of the title compound, which was used in the next step without any further purification.
LRMS (m/z): 332 (M+1 )+. PREPARATION 139 5-(2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl)-/V-((S)-1-(4-((3S,5 ?)-3,5- dimethyipiperazin-1-yi)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yi)ethyl)-7-((2-
(trimethylsilyl)ethoxy)methyl)-7W-pyrrolo[2,3-c^pyrimidin-4-amine 100 mg (0.16 mmol) of 5-bromo-/\/-((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 159 mg (0.48 mmol) of A/,/\/-dimethyl-1-(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-amine, 20 mg (0.024 mmol) of PdCI2dppf DCM and 400 μΙ of an aqueous 2M solution of caesium carbonate were dissolved in 6 ml of dioxane. The mixture was stirred under argon at 100 °C for 20 hours. Then the solvents were removed and the crude product was directly purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8:1 ) to obtain a solid that was dissolved in DCM and washed with 1 N aqueous solution of sodium hydroxide (x3), water and brine. The organic solution was dried over magnesium sulphate, filtered and the solvent removed. Finally, the obtained solid was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 50 mg (42% yield) of the title compound as a white solid.
LRMS (m/z): 740 (M+1)+.
PREPARATION 140
5-(2-(Dimethylamino)pyridin-4-yl)-AM(S)^^
5-methylpyrrolo[2,1- |[1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-cQpyrimidin-4-amine
100 mg (0.16 mmol) of 5-bromo-/\/-((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-t][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-d]pyrimidin-4-amine, 121 mg (0.48 mmol) of /V,/\/-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine, 21 mg (0.025 mmol) of PdCI2dppf DCM and 410 μΙ of an aqueous 2M solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon at 100 °C for 18 hours. Then the solvents were removed and the crude product was directly purified first by flash chromatography (0% to 10% DCM//MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 45 mg (42% yield) of the title compound as a white solid.
LRMS (m/z): 657 (M+1)+. PREPARATION 141
1-(3-Aminopropyl)-W,/V-dimethylpiperidin-4-amine a) 3-(4-(Dimethylamino)piperidin-1-yl)propanenitrile
500 mg (3.9 mmol) of W,A/-dimethylpiperidin-4-amine and 575 mg (4.23 mmol) of 3- bromopropanenitrile were dissolved in 7.5 ml of anhydrous acetonitrile. 1.18 g (8.6 mmol) of potassium carbonate were added and the reaction mixture was stirred overnight at room temperature, and then at 50 °C for 5 hours. The reaction mixture was filtered through Celite® and after evaporation of the volatiles under reduced pressure. 700 mg (100% yield) of the title compound were obtained.
LRMS (m/z): 182 (M+1)+. b) 1 -(3-Aminopropyl)-/V,W-dimethylpiperidin-4-amine
440 mg (11.6 mmol) of lithium aluminium hydride in 18 ml of anhydrous THF were degassed with nitrogen. A solution of 700 mg (3.86 mmol) of 3-(4- (dimethylamino)piperidin-1-yl)propanenitrile 5 ml anhydrous was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. To quench the reaction, 3 ml of water and 3 ml of a 2N solution of sodium hydroxide were added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then filtered through Celite® and the solvents removed. The residue was redissolved in methylene chloride and washed with brine, dried over magnesium sulphate, filtered and concentrated to afford 385 mg (54% yield) of the title compound, which was used in the next step without further purification.
LRMS (m/z): 186 (M+1)+.
PREPARATION 142
1-(3-Aminopropyl)-W,A/-dimethylpiperidin-4-amine a) 3-((3-(Dimethylamino)propyl)(methyl)amino)propanenitrile
350 mg (80% yield) of the title compound were obtained from 300 mg (2.6 mmol) of A/\A/\/V3-trimethylpropane-1 ,3-diamine and 247 μΙ (2.84 mmol) of 3- bromopropanenitrile following the experimental procedure described in Preparation 141a.
LRMS (m/z): 170 (M+1)+. b) ^-(S-Aminopropy -^^.y^-trimethylpropane-l ,3-diamine 250 mg (69% yield) of the title compound were obtained from 350 mg (2.1 mmol) of 3- ((3-(dimethyiamino)propyi)(methyl)amino)propanenitrile following the experimental procedure described in Preparation 141 b.
LRMS (m/z): 174 (M+1)+.
PREPARATION 143
(S)-Methyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1 - f\ [1 , 2,4]triazi n-4-y I )-5-methy I benzoate (S)-4-Amino-6-((1-(4-chloropyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile (1.3 g, 4.1 mmol) was dissolved in 26 ml of dioxane. 1.0 g (5.1 mmol) of (3- (methoxycarbonyl)-5-methylphenyl)boronic acid, 340 mg (0.41 mmol) of PdCI2dppf.CH2CI2 and 4.1 ml (8.2 mmol) of a 2M solution of caesium carbonate 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 crude product was purified by flash chromatography (0% to 1% DCM/MeOH) to give 1.06 g (60% yield) of the title compound as a pale yellow solid.
LRMS (m/z): 429 (M+1)+.
PREPARATION 144
(S)-4-Amino-6-((1-(4-(4-formyl-3,5-dimethylphenyl)pyrrolo[2,1-fj[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
(S)-4-Amino-6-((1-(4-chloropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile (200 mg, 0.63 mmol) was dissolved in dioxane (4 mL). (4-Formyl-3,5- dimethylphenyl)boronic acid (170 mg, 0.93 mmol), PdCI2dppf.CH2CI2 (52 mg, 0.06 mmol) and a 2M solution of caesium carbonate (0.64 ml, 1.28 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 flash chromatography (0% to 50% petroleum ether/AcOEt) to give 30 mg (11 % yield) of the title compound as a yellow solid.
LRMS (m/z): 413 (M+1 )+. PREPARATION 145
(S)-Benzyl (1-(4-oxo-3,4-dihydropyrroio[2,1- ][1,2,4]triazin-2-yi)ethyi)carbamaie a) (S)-Benzyl (1 -((2-carbamoyl-1 H-pyrrol-1 -yl)amino)-1 -oxopropan-2-yl)carbamate 10.4 g (83 mmol) of 1-amino-1H-pyrrole-2-carboxamide were added to a mixture of 19.4 g (86 mmol) of (S)-2-(((benzyloxy)carbonyl)amino)propanoic acid, 34.9 g (91 mmol) of HATU and 16.3 ml (173 mmol) of DIEA in 100 ml of methylene chloride and 100 ml of DMF. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and then the residue was triturated with 750 ml of ethyl acetate to give a white solid, which was filtered off and dried in a vacuum oven at 50 °C to give 26.3 g (95% yield) of the title compound.
LRMS (m/z): 331(M+1)+.
b) (S)-Benzyl (1-(4-oxo-3,4-dihydropyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)carbamate Pyridinium p-toluenesulfonate (4.28g, 17 mmol) was added to a stirred mixture of (S)- benzyl (1-((2-carbamoyl-1/-/-pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate (4.08 g, 12 mmol) and 4A molecular sieves (small spoon amount) in anhydrous toluene (80 ml). The resulting mixture was heated under reflux with a Dean-Stark for 15 hours. Then the solvent was removed under reduced pressure. The resulting solid was treated with water (100 ml) and then extracted with ethyl acetate (3 X 100 ml). An insoluble white solid was filtered off and dried in a vacuum oven at 50 °C to give 1.93 g (54% yield) of the title compound. The ethyl acetate extracts were dried with sodium sulphate, filtered and the solvent removed to give 1.92 g (53% yield) of a yellowish-white solid. Total amount: 3.85 g (quantitative yield).
LRMS (m/z): 313 (M+1)+.
PREPARATION 146
5-Bromo-A -((S)-1-(4-((2S,6/?)-2,6-dimethylmo
yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)meth^ a) Benzyl ((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)pyrrolo[2,1 -/][1 ,2,4]triazin-2- yl)ethyl)carbamate
(S)-Benzyl (1-(4-oxo-3,4-dihydropyrrolo[2,1-r][1 ,2,4]triazin-2-yl)ethyl)carbamate (1.0 g, 3.2 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.7 g, 3.8 mmol) were dissolved in THF (100 ml). The mixture was heated to enable a better dissolution. When cooled down to room temperature, 1 ,8-diazabiciclo[5.4.0]undec-7-eno was added, followed after few minutes by (2 6S)- 2,6-dimethylmorpholine (0.75 ml, 4.8 mmol). The mixture was stirred at room temperature overnight. Tetrahydrofurane was concentrated under reduced pressure. Ethyl acetate was then added and the organic phase was successively washed with water and brine, dried with sodium sulphate and evaporated. The crude product was purified by flash chromatography (0% to 30% petroleum ether/AcOEt) to give 1.39 g (100% yield) of the title compound.
LRMS (m/z): 410 ( +1)+. b) (S)-1-(4-((2S,6 ?)-2,6-Dimethylmorpholino)pyrrolo[2,1-fl[1,2,4]triazin-2- yl)ethanamine
A solution of benzyl ((S)-1-(4-((2S,6f?)-2,6-dimethylmorpholino)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)carbamate (1.39 g, 3.3 mmol) and palladium on carbon 10 wt.% (130 mg) in ethanol (130 ml) was degased and an hydrogen balloon was loaded. The reaction was stirred at room temperature for 4 h. The mixture was then filtered on a pad of Celite®. The solvent was removed to give 948 mg (100% yield) of the title compound as an oil.
LRMS (m/z): 276 (M+1)+. c) 5-Bromo-/V-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7W-pyrrolo[2,3- cf]pyrimidin-4-amine
(S)-1-(4-((2S,6/?)-2,6-Dimethylmorpholino)pyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethanamine (720 mg, 2.6 mmol), 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-cf]pyrimidine (1.42 g, 3.9 mmol), diisopropylethylamine (3.2 ml, 17 mmol) and caesium fluoride (396 mg, 2.6 mmol) were combined in a sealed tube and the mixture was heated at 110 °C overnight. The mixture was partitioned between ethyl acetate (100 ml) and a 4% aqueous solution of NaHC03 (50 ml). The organic phase was then washed with brine, dried with sodium sulphate, filtered and evaporated. The crude product was purified by flash chromatography (0% to 100% petroleum ether/AcOEt) to give 976mg (62% yield) as a yellow solid.
LRMS (m/z): 602, 604 (M+1)+.
EXAMPLE 1
(S)-Teri-butyl 4-(((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- ][1,2,4]triazin-4-yl)oxy)methyl)piperidine-1-carboxylate 239 mg (1.11 mmol) of te/t-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (purchased from Aldrich®, cat. no. 556017) were added to a suspension of 27 mg (0.68 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 15 min. and a solution of 175 mg (0.56 mmol) of (S)-4-amino-6-((1-(4-chloropyrrolo[2,1-r][1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile in 3 ml of THF was added. The resulting mixture was stirred at room temperature for 3 hours, until the starting material was consumed. The solvent was then removed under reduced pressure 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 reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 133 mg (49% yield) of the title product as a white solid. Purity: 98.5%.
LRMS (m/z): 494 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 8.00 (s, 1 H), 7.90 (dd, 1H), 7.39 (d, 1 H), 7.32 (s, 2H), 6.80 (ddd, 2H), 5.35 - 5.22 (m, 1 H), 4.48 - 4.24 (m, 2H), 4.05 - 3.86 (m, 2H), 2.84 - 2.56 (m, 2H), 1.97 (s, 1 H), 1.76 - 1.61 (m, 2H), 1.56 (d, 3H), 1.39 (s, 9H).
EXAMPLE 2
(S)-4-Amino-6-((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile 125 mg (0.25 mmol) of (S)-rert-butyl 4-(((2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)pyrrolo[2, 1 -r][1 ,2,4]triazin-4-yl)oxy)methyl)piperidine-1 -carboxylate were stirred in 6.3 ml of a 4 M solution of hydrogen chloride in dioxane for 3 hours, until all the starting material was consumed. Then the volatiles were removed under reduced pressure and the residue was partitioned between saturated solution of potassium carbonate and methylene chloride. After a second extraction with methylene chloride, the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated. 100 mg (100% yield) of the title product were isolated as a white solid. Purity: 98.6%.
LRMS (m/z): 394 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.00 (s, 1 H), 7.90 (dd, 1 H), 7.48 - 7.17 (m, 3H),
6.79 (ddd, 2H), 5.36 - 5.21 (m, 1 H), 4.36 (ddd, 2H), 2.94 (d, 2H), 2.48 - 2.37 (m, 2H), 1.95 - 1.80 (m, 1 H), 1.63 (d, 2H), 1.55 (d, 3H). EXAMPLE 3
(S)-4-Amino-6-((1-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 1 from 62 mg (0.20 mmol) of (S)-4-amino-6-((1-(4-chloropyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 46 mg (0.40 mmol) of (tetrahydro-2H-pyran-4-yl)methanol. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 45% B to 75% B, in a 20 min. gradient). 2.0 mg (3% yield) of the title compound were obtained as a white solid. Purity: 98.8%.
LRMS (m/z): 395 (M+1)+.
EXAMPLE 4
(S)-4-Amino-6-((1 -(4-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)pyrrolo[2,1 - r][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
45 mg (0.11 mmol) of (S)-4-amino-6-((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in methylene chloride (5 ml). 32 μΙ (0.23 mmol) of triethylamine were added and the solution was cooled in an ice bath. Then 10 μΙ (0.13 mmol) of methanesulfonyl chloride were added and the reaction mixture was stirred at 0 °C for 1 hour. Once the reaction was completed, the mixture was partitioned between water and methylene chloride and the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to obtain 48 mg (91% yield) of the title compound as a white solid. Purity: 99.4%.
LRMS (m/z): 472 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.67 (dd, 1 H), 6.81 (dd, 1 H), 6.74 (dd, 1 H), 6.43 (d, 1 H), 5.45 - 5.33 (m, 1 H), 5.29 (s, 2H), 4.67 - 4.34 (m, 2H), 3.87 (d, 2H), 2.80 (s, 3H), 2.78 - 2.65 (m, 2H), 2.11 - 1.91 (m, 3H), 1.61 (d, 3H).
EXAMPLE 5 (S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)methoxy)pyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyi)amino)pyrimidine-5-carbonitrile
45 mg (0.11 mmol) of (S)-4-amino-6-((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1- r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 21 mg (0.14 mmol) of sodium iodide, 13 μΙ (0.14 mmol) of 2-bromopropane and 38 mg (0.27 mmol) of potassium carbonate were suspended in acetonitrile (10 ml). The mixture was stirred overnight at reflux temperature. An excess of 400 μΙ of 2-bromopropane and 5 ml of acetone as a co-solvent were added and the reaction was refluxed for an additional 16 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude that was obtained contained the title product as a minor component and was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 4 mg (8% yield) of the title compound as a white solid. Purity: 79%.
LRMS (m/z): 436 (M+1)+.
1H N R (400 MHz, DMSO) δ 7.99 (s, 1 H), 7.90 (dd, 1 H), 7.38 (d, 1 H), 7.31 (s, 2H), 6.93 - 6.66 (m, 2H), 5.44 - 5.12 (m, 1 H), 3.54 - 3.37 (m, 2H), 2.76 (d, 2H),
2.65 (dd, 1 H), 2.15 - 2.00 (m, 2H), 1.84 - 1.60 (m, 4H), 1.55 (d, 3H), 0.95 (d, 6H).
EXAMPLE 6
(S)-4-Amino-6-((1 -(4-isopropoxypyrrolo[2,1 -/J[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
23 mg (59% yield) of the title compound were obtained as the side-product in the experimental procedure described in Example 5. Purity: 96.2%.
LRMS (m/z): 339 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 8.00 (s, 1 H), 7.88 (t, 1 H), 7.39 - 7.24 (m, 2H), 6.79 - 6.74 (m, 2H), 5.61 - 5.43 (m, 1 H), 5.35 - 5.18 (m, 1 H), 1.56 (d, 3H), 1.45 - 1.28 (m, 6H).
EXAMPLE 7
(S)-4-Amino-6-((1-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 1 from 310 mg (0.79 mmol) of (S)-4-amino-6-((1-(5-bromo-4- chloropyrrolo[2,1-r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 183 mg (1.58 mmol) of (tetrahydro-2/7-pyran-4-yl)methanol. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 200 mg (54% yield) of the title compound as a white solid. Purity: 93.2%.
LRMS (m/z): 473, 475 (M+1)+.
H NMR (400 MHz, DMSO) δ 7.99 (s, 1 H), 7.93 (d, 1 H), 7.37 (s, 1 H), 7.29 (s, 2H), 6.91 (d, 1 H), 5.33 - 5.17 (m, 1 H), 4.39 (tt, 2H), 3.87 (d, 2H), 2.12 - 1.97 (m, 1 H), 1.72 - 1.61 (m, 2H), 1.55 (d, 3H), 1.46 - 1.31 (m, 2H). EXAMPLE 8
(S)-2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2,1-/][1,2,4]triazine-5-carbonitrile
50 mg (0.11 mmol) of (S)-4-amino-6-((1-(5-bromo-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 25 mg (0.21 mmol) of dicyanozinc and 12 mg (0.010 mmol) of Pd(PPh3)4 were suspended in 2 ml of DMF. The mixture was stirred under nitrogen atmosphere at 120 °C overnight. The reaction mixture was partitioned between water and methylene chloride, a small amount of methanol was added and the two layers were separated. The organic solution was washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%). The product thus obtained was treated with diethylether and stirred vigorously for 3 hours at room temperature and then the insoluble solid was filtered, washed with diethylether and dried under a stream of air to obtain 20 mg (45% yield) of the title product as a white solid. Purity: 95.8%.
LRMS (m/z): 420 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.07 (d, 1 H), 7.98 (s, 1 H), 7.48 (d, 1 H), 7.36 (d, 1 H), 7.30 (s, 2H), 5.42 - 5.24 (m, 1 H), 4.55 - 4.37 (m, 2H), 3.87 (d, 2H), 2.13 -
1.98 (m, 1 H), 1.72 - 1.61 (m, 2H), 1.57 (d, 3H), 1.46 - 1.26 (m, 2H). EXAMPLE 9
(S)-4-Amino-6-((1-(5-methyi-4-((tetrahydro-2H-pyran-4-y!)methoxy)pyrroio[2,1- /][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 60 mg (0.13 mmol) of (S)-4-amino-6-((1-(5-bromo-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 155 μΙ (0.14 mmol) of 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (purchased from Aldrich®, cat. no. 323136), 5.20 mg (0.006 mmol) of PdCI2dppf DCM and 53 mg (0.38 mmol) of potassium carbonate were suspended in 1.5 ml of 1 ,2-dimethoxyethane. The mixture was heated under nitrogen atmosphere at 120°C for 30 min using microwaves irradiation. The reaction mixture was partitioned between water and methylene chloride and the two layers were separated. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified first by flash chromatography (0% to 5% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 32 mg (62% yield) of the title compound as a pale brown solid. Purity: 97.4%.
LRMS (m/z): 409 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.00 (s, 1 H), 7.74 (d, 1 H), 7.36 - 7.23 (m, 3H), 6.58 (d, 1 H), 5.31 - 5.14 (m, 1 H), 4.49 - 4.23 (m, 2H), 3.87 (d, 2H), 2.42 (s,
3H), 2.12 - 1.98 (m, 1 H), 1.69 - 1.57 (m, 2H), 1.53 (d, 3H), 1.44 - 1.27 (m, 2H).
EXAMPLE 10
(S)-4-Amino-6-((1-(5-bromo-4-(4-methylpiperazin-1-yl)pyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
100 mg (0.25 mmol) of (S)-4-amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- ][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 84 μΙ (0.76 mmol) of 1-methylpiperazine were dissolved in 5 ml of THF and stirred for 1 hour (until the reaction was completed) at 70°C. The volatiles were removed under reduced pressure and the residue was re- dissolved in 2M hydrochloric acid. The solution was washed twice with methylene chloride and then basified with an 8 M sodium hydroxide solution. The product was extracted twice from the aqueous solution with methylene chloride and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. 79 mg (68% yield) of the title product were isolated as a white solid. Purity: 98.8%.
LRMS (m/z): 457, 459 (M+1)+. 1H NMR (400 MHz, DMSO) δ 8.02 (s, 1 H), 7.82 (d, 1 H), 7.30 (s, 2H), 7.16 (d, 1 H), 6.88 (d, 1 H), 5.28 - 5.07 (m, 1 H), 3.76 - 3.52 (m, 4H), 2.48 - 2.42 (m, 4H), 2.21 (s, 3H), 1.50 (d, 3H). EXAMPLE 1 1
(S)-rert-butyl 4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- bromopyrrolo[2,1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate
The title compound was prepared following the experimental procedure described in Example 1 from 641 mg (1.63 mmol) of (S)-4-amino-6-((1 -(5-bromo-4- chloropyrrolo[2, 1-^[1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 984 mg (4.88 mmol) of tert-butyl 4-hydroxypiperidine-1 -carboxylate (purchased from Aldrich®, cat. no. 495484). The crude product was purified by reverse phase chromatography (C- 18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 209 mg (23% yield) of the title compound as a white solid. Purity: 95.7%.
LRMS (m/z): 558, 560 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.20 (s, 1 H), 7.57 (d, 1 H), 6.74 (d, 1 H), 6.29 (d, 1 H), 5.73 - 5.59 (m, 1 H), 5.40 - 5.31 (m, 1 H), 5.29 (s, 2H), 3.80 - 3.44 (m, 4H), 2.09 - 1.84 (m, 4H), 1.59 (d, 3H), 1.48 (s, 9H).
EXAMPLE 12
(S)-4-Amino-6-((1-(5-bromo-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrrolo[2,1 - l[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile
The title compound was prepared following the experimental procedure described in Example 10 from 26 mg (0.066 mmol) of (S)-4-amino-6-((1 -(5-bromo-4- chloropyrrolo[2,1-r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 12 μΙ (0.1 1 mmol) of (tetrahydro-2H-pyran-4-yl)methanamine (purchased from Acros®, cat. no. 38521 ). 1 1 mg (64% yield) of the title compound were obtained as a white solid. Purity: 94.2%.
LRMS (m/z): 472, 474 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.21 (s, 1 H), 7.43 (d, 1 H), 6.72 (t, 1 H), 6.60 (d, 1 H), 5.29 (s, 2H), 5.27 - 5.14 (m, 1 H), 4.09 - 3.88 (m, 2H), 3.72 - 3.50 (m, 2H),
3.48 - 3.34 (m, 2H), 2.05 - 1.89 (m, 1 H), 1.74 (d, 2H), 1.57 (d, 3H), 1.53 - 1.35 (m, 2H). EXAMPLE 13
(S)-4-Amino-6-((1 -(5-methyl-4-(4-methylpiperazin-1 -yl)pyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 9 from 40 mg (0.087 mmol) of (S)-4-amino-6-((1-(5-bromo-4-(4- methylpiperazin-1-yl)pyrrolo[2, 1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile and 16 mg (0.13 mmol) of 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 40% B, in a 15 min. gradient) to obtain 7 mg (20% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 393 (M+1 )+.
EXAMPLE 14
(S)-4-Amino-6-((1-(4-(4-methylpiperazin-1-yl)pyrrolo[2,1- |[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
10 mg (30% yield) of the title compound were obtained as a side-product in the experimental procedure described in Example 13. Purity: 99.1 %.
LRMS (m/z): 379 (M+1 )+. EXAMPLE 15
(S)-rerf-butyl 4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate
The title compound was prepared following the experimental procedure described in Example 9 from 70 mg (0.13 mmol) of (S)-terf-butyl 4-((2-(1 -((6-amino-5- cyanopyrimidin-4-yl)amino)ethyl)-5-bromopyrrolo[2, 1 -f \ ,2,4]triazin-4-yl)oxy)piperidine- 1-carboxylate and 53 μΙ (0.38 mmol) of 2,4,6-trimethyl-1 , 3,5,2,4, 6-trioxatriborinane. 54 mg (87% yield) of the title compound were obtained as a white solid. Purity: 100%.
LRMS (m/z): 494 (M+1 )+.
EXAMPLE 16 (S)-4-Amino-6-((1 -(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 2 from 122 mg (0.25 mmol) of (S)-ferf-butyl 4-((2-(1-((6-amino-5- cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 ,2,4]triazin-4-yl)oxy)piperidine- 1-carboxylate. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol [non buffered] as eluents 0% to 100%) to obtain 52 mg (54% yield) of the title compound were obtained as a white solid. Purity: 100%.
LRMS (m/z): 394 (M+1 )+.
EXAMPLE 17
(S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
27 mg (0.07 mmol) of (S)-4-amino-6-((1-(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 21 mg (0.14 mmol) of sodium iodide, 26 μΙ (0.28 mmol) of 2-bromopropane and 38 mg (0.27 mmol) of potassium carbonate were suspended in acetonitrile (2 ml). The mixture was heated for 2 hours at 140°C using microwaves irradiation. Then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol [non buffered] as eluents 0% to 100%) to obtain 22 mg (74% yield) of the title compound as a white solid. Purity: 98.1 %.
LRMS (m/z): 436 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.01 (s, 1 H), 7.74 (d, 1 H), 7.30 (s, 2H), 7.22 (d, 1 H), 6.58 (d, 1 H), 5.34 - 5.15 (m, 2H), 2.80 - 2.59 (m, 3H), 2.47 - 2.33 (m, 5H), 2.08 - 1.86 (m, 2H), 1.86 - 1.61 (m, 2H), 1.54 (d, 3H), 0.99 (d, 6H).
EXAMPLE 18
(S)-3-(4-Amino-6-((1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol
55 mg (0.1 1 mmol) of (S)-5-iodo-/S/4-(1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine, 26 mg (0.17 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid (purchased from Combi-blocks®, cat. no. BB-2773) and 10.0 mg (0.01 1 mmol) of PdCI2dppf DCM were suspended in 5 ml of dioxane. 167 μΙ (0.33 mmol) of a 2 M aqueous solution of sodium carbonate were added and the reaction mixture was stirred under argon at 100 °C overnight. A further equivalent of boronic acid and catalyst was added and the reaction kept at 100 °C until the starting material was consumed. Then the solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The two layers were separated and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified first by flash chromatography (3% to 10% DCM/MeOH) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 44% B, in a 14 min. gradient) to obtain 13 mg (24% yield) of the title compound as a pale brown solid. Purity: 100%.
LRMS (m/z): 478 (M+1 )+.
EXAMPLE 19
(S)-3-(4-Amino-6-((1-(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol The title compound was obtained following the experimental procedure described in Example 18 from 135 mg (0.27 mmol) of (S)-5-iodo-A/*-(1 -(5-methyl-4-((tetrahydro-2H- pyran-4-yl)methoxy)pyrrolo[2, 1-/][1 ,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine and 83 mg (0.53 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 50 mg (38% yield) of the title compound as a white solid. Purity: 96.5%.
LRMS (m/z): 494 (M+1 )+.
EXAMPLE 20
(S)-4-Amino-6-((1 -(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2,1-f|[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 1 from 50 mg (0.15 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 34 mg (2.03 mmol) of resorcinol. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 23 mg (38% yield) of the title compound as a white solid. Purity: 98.5%.
LRMS (m/z): 403 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.61 (d, 1 H), 7.32 (t, 1 H), 6.98 (dd, 1 H), 6.87 (dd, 1 H), 6.77 (dd, 1 H), 6.60 (d, 1 H), 6.25 (d, 1 H), 5.43 - 5.18 (m,
3H), 2.59 (s, 3H), 1.43 (d, 3H).
EXAMPLE 21
(S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1- [1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a) (S)-4-Amino-6-((1-(4-((3-((rer--butyldimethylsilyl)oxy)benzyl)oxy)-5- methylpyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile.
72 mg (0.30 mmol) of (3-((feri-butyldimethylsilyl)oxy)phenyl)methanol5 were added to a suspension of 7 mg (0.18 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of anhydrous THF. The mixture was stirred under nitrogen atmosphere for 30 min and a solution of 50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile in 3m of THF were added. The resulting mixture was stirred at room temperature for 3 hours, until the starting material was consumed. The reaction mixture was partitioned between diluted sodium bicarbonate solution 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 100% hexane/AcOEt) to obtain 35 mg (43% yield) of (S)-4-amino-6-((1-(4-((3-((teAt-butyldimethylsilyl)oxy)benzyl)oxy)- 5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile.
LRMS (m/z): 531 (M+1)+. b) (S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1-/][1,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile
35 mg (0.07 mmol) of (S)-4-amino-6-((1-(4-((3-((terf-butyldimethylsilyl)oxy)benzyl)oxy)- 5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2 ml of anhydrous THF and 73 μΙ (0.07 mmol) of a of tetrabutylammonium fluoride in THF were added. The mixture was stirred at room temperature for 2 hours and then 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 reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 20 mg (73% yield) of the title compound as a white solid. Purity: 99.5%.
LRMS (m/z): 417 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.52 (d, 1 H), 7.27 (t, 1 H), 7.06 (d, 1 H), 7.01 (s, 1 H), 6.83 (dd, 1 H), 6.49 (d, 1 H), 6.36 (d, 1 H), 5.79 (d, 1 H), 5.53 -
5.22 (m, 4H), 2.50 (s, 3H), 1.57 (d, 3H).
EXAMPLE 22
(S)-4-Amino-6-((1 -(4-(3-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2,1 - fj[1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound (14 mg) was obtained as a side-product in the experimental procedure of Example 21 a. Purity: 97.9%.
LRMS (m/z): 417 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.16 (s, 1 H), 7.62 (d, 1 H), 7.45 (t, 1 H), 7.34 (d,
1 H), 7.10 (dd, 1 H), 6.61 (dd, 1 H), 6.01 (d, 1 H), 5.40 - 5.09 (m, 3H), 4.84 - 4.60
(m, 2H), 2.60 (s, 3H), 1.42 (d, 3H).
EXAMPLE 23
(S)-4-Amino-6-((1-(4-(3-hydroxyphenyl)-5-methylpyrrolo[2,1 - l[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 32 mg (0.23 mmol) of 3-hydroxyphenylboronic acid, 12 mg (0.015 mmol) of PdCI2dppf DCM and 48 mg (0.45 mmol) of sodium carbonate were suspended in 2 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 100 °C overnight. Another 32 mg of the boronic acid, 24 mg of the palladium catalyst and 50 mg of sodium carbonate were added and the reaction was heated for another 24 hours until most of the starting material was consumed. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 10% DCM/MeOH) to obtain 17 mg (29% yield) of the title compound as a pale yellow solid. Purity: 98.9%.
LRMS (m/z): 387 (M+1)+. 1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.80 (d, 1 H), 7.36 (t, 1 H), 7.28 - 7.27 (m, 1 H), 7.22 - 7.14 (m, 1 H), 7.02 (ddd, 1 H), 6.97 (d, 1 H), 6.79 - 6.71 (m, 1 H), 5.53 - 5.38 (m, 1 H), 5.33 (s, 2H), 2.18 (s, 3H), 1.66 (d, 3H). EXAMPLE 24
(S)-4-Amino-6-((1-(4-(4-hydroxyphenyl)-5-methylpyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 42 mg (0.30 mmol) of 4-hydroxyphenylboronic acid, 37 mg (0.045 mmol) of PdCI2dppf DCM and 228 μΙ (0.46 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 10% DCM/MeOH) to obtain 30 mg (51% yield) of the title compound as a solid. Purity: 99.7%.
LRMS (m/z): 387 (M+1)+.
H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.78 (d, 1 H), 7.59 (d, 2H), 6.94 (d, 2H), 6.72 (s, 1 H), 6.66 (d, 1 H), 6.09 (s, 1 H), 5.56 - 5.42 (m, 1 H), 5.31 (s, 2H), 2.16 (s, 3H), 1.66 (d, 3H).
EXAMPLE 25
3-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- |[1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol 45 mg (0.088 mmol) of 3-iodo-1-((4-((tetrahydro-2 -/-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 41 mg (0.26 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 3.6 mg (0.045 mmol) of PdCI2dppf DCM and 88 μΙ (0.18 mmol) of a 2 M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C for 40 hours. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 6 mg (14% yield) of the title compound as a white solid. Purity: 97%.
LRMS (m/z): 491 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.20 (s, 1 H), 8.27 (s, 1 H), 7.92 (s, 1 H), 6.94 -
6.74 (m, 4H), 6.63 (d, 1 H), 5.52 (s, 2H), 4.11 (d, 2H), 3.74 (d, 2H), 3.21 - 3.02
(m, 3H), 1.76 (s, 1 H), 1.35 (d, 2H), 1.19 - 1.00 (m, 2H).
EXAMPLE 26
(S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1- ][1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 20 from 45 mg (0.12 mmol) of (S)-4-amino-6-((1-(4-chloropyrrolo[2,1- /][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 68 mg (0.62 mmol) of resorcinol. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 41 mg (82% yield) of the title compound. Purity: 96%.
LRMS (m/z): 389 (M+1)+.
1H NMR (400 MHz, DMSO) δ 9.77 (s, 1 H), 8.01 (s, 1 H), 7.94 (s, 1 H), 7.37 - 7.16 (m, 4H), 6.92 (s, 1 H), 6.89 (s, 1 H), 6.71 (s, 1 H), 6.69 (s, 2H), 5.24 - 5.01 (m, 1 H), 1.46 (d, 3H). EXAMPLE 27
3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)pyrrolo[2,1-/l[1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-dlpyrimidin-3-yl)-5-fluorophenol
The title compound was prepared following the experimental procedure described in Example 25 from 50 mg (0.12 mmol) of 1-((4-chloropyrrolo[2,1- ][1 ,2,4]triazin-2- yl)methyl)-3-iodo-1H-pyrazolo[3,4-c/]pyrimidin-4-amine and 75 mg (0.48 mmol) of (3- fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 9 mg (19% yield) of the title compound. Purity: 100%.
LRMS (m/z): 487 (M+1 )+. 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1 H), 10.20 (s, 1 H), 8.28 (s, 1 H), 8.17 (s, 1 H), 7.33 (s, 1 H), 7.24 - 7.16 (m, 2H), 7.11 (d, 1 H), 6.96 - 6.77 (m, 4H), 6.65 (d, 1 H), 5.74 (s, 2H). EXAMPLE 28
4-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- ][1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol
45 mg (0.088 mmol) of 3-iodo-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 41 mg (0.26 mmol) of (3-fluoro-4-hydroxyphenyl)boronic acid (purchased from Apollo Scientific®, cat. no. PC1628), 3.6 mg (0.045 mmol) of PdCI2dppf DCM and 7 mg (0.18 mmol) of sodium hydroxide were mixed together in 2 ml of DMF. The mixture was stirred under nitrogen atmosphere at 120 °C for 40 hours. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 40% B to 85% B, in a 12 min. gradient) to obtain 1.8 mg (4% yield) of the title compound. Purity: 86%.
LRMS (m/z): 491 (M+1)+.
EXAMPLE 29
(S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-2-hydroxybenzamide
The title compound was prepared following the experimental procedure described in Example 24 from 33 mg (0.10 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 36 mg (0.20 mmol) of (4-carbamoyl-3-hydroxyphenyl)boronic acid6. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 12 mg (28% yield) of the title compound as a pale yellow solid. Purity: 96.7%.
LRMS (m/z): 430 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 12.28 (s, 1 H), 8.21 (s, 1 H), 7.82 (d, 1 H), 7.58 (d,
1 H), 7.17 (dd, 1 H), 6.75 (d, 1 H), 6.56 (d, 1 H), 5.57 - 5.45 (m, 1 H), 5.43 (s, 2H), 2.14 (s, 3H), 1.66 (d, 3H). EXAMPLE 30
(S)-4-Amino-6-((1 -(4-(2-hydroxyphenyl)-5-methylpyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 39 mg (0.20 mmol) of 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (purchased from Aldrich®, cat. no. 522554). The reaction was completed after 2 hours and the crude product that was isolated was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 18 mg (53% yield) of the title compound as a pale yellow solid. Purity: 100%.
LRMS (m/z): 387 (M+1)+.
1H NMR (400 MHz, DMSO) δ 9.89 (s, 1 H), 8.01 (s, 1 H), 7.96 (d, 1 H), 7.46 - 7.22 (m, 5H), 7.02 - 6.90 (m, 2H), 6.76 (s, 1 H), 5.45 - 5.27 (m, 1 H), 1.94 (s, 3H), 1.57 (d, 3H). EXAMPLE 31
(S)-4-Amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2,1- j[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2 ml of dioxane. 50 mg (0.46 mmol) of 3-aminophenol and 137 μΙ (0.27 mmol) of a 2 M aqueous solution of caesium carbonate were added and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 14 mg (37% yield) of the title compound. Purity: 96%.
LRMS (m/z): 402 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.95 (s, 1 H), 7.85 (d, 1 H), 7.36 - 7.16 (m, 3H), 7.03 (t, 1 H), 6.68 (d, 1 H), 6.49 - 6.43 (m, 2H), 6.39 (d, 1 H), 5.28 (s, 2H), 5.07 (m, 1 H), 1.43 (d, 3H). EXAMPLE 32
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2,1- f|[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 37 mg (0.18 mmol) of (3-hydroxy-5-(trifluoromethyl)phenyl)boronic acid (purchased from Combi-blocks®, cat. no. BB-5075). The reaction was completed after 2 hours and the crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 15% DCM/MeOH) to obtain 11 mg (27% yield) of the title compound as a pale yellow solid. Purity: 100%.
LRMS (m/z): 455 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.62 (s, 1 H), 8.08 (d, 1 H), 8.00 (s, 1 H), 7.46 (d, 1 H), 7.42 - 7.16 (m, 5H), 6.88 (s, 1 H), 5.42 - 5.32 (m, 1 H), 2.03 (s, 3H), 1.58
(d, 3H).
EXAMPLE 33
(S)-4-Amino-6-((1-(4-(3,5-dihydroxyphenoxy)-5-methylpyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 20 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 57 mg (0.46 mmol) of benzene-1 ,3,5-triol. The reaction was stirred at room temperature and then at reflux until most of the starting material was consumed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 17 mg (44% yield) of the title compound. Purity: 96%.
LRMS (m/z): 419 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 9.57 (s, 2H), 7.95 (s, 1 H), 7.84 (d, 1 H), 7.35 - 7.18 (m, 3H), 6.68 (s, 1 H), 6.16 (s, 3H), 5.07 (s, 1 H), 1.44 (d, 3H). EXAMPLE 34
(S)-/V-(5-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- |[1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-^[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 72 mg (0.22 mmol) of A/-(2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide, 6.4 mg (0.01 mmol) of PdCI2(PPh3)2 and 120 μΙ (0.22 mmol) of a 2 M aqueous solution of sodium carbonate were dissolved in 2 ml of 1 ,2-dimethoxyethane. The mixture was stirred under nitrogen atmosphere at 70 °C for 5 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 9 mg (20% yield) of the title compound as a solid. Purity: 95%.
LRMS (m/z): 495 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.16 (s, 1 H), 8.04 (s, 1 H), 8.00 (s, 1 H), 7.83 (s, 1 H), 7.68 - 7.38 (m, 2H), 7.30 (s, 1 H), 6.85 (s, 1 H), 5.44 - 5.28 (m, 1 H), 3.98 (s,
3H), 2.99 (s, 3H), 2.15 (s, 3H), 1.58 (d, 3H).
EXAMPLE 35
(S)-4-Amino-6-((1-(4-(5-amino-6-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was obtained as a side-product of the reaction described in Example 34. 5 mg (14% yield) of the title compound were isolated as a white solid. Purity: 96%.
LRMS (m/z): 403 (M+1)+.
EXAMPLE 36
(S)-4-Amino-6-((1 -(4-(5-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 24 from 50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2 -][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carb and 42 mg
(0.30 mmol) of (5-hydroxypyridin-3-yl)boronic acid (purchased from Anichem ®, cat. no. NP2179). The reaction was completed after 2 hours and the crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8:1 ) to obtain 24 mg (41 % yield) of the title compound as a pale yellow solid. Purity: 97.7%.
LRMS (m/z): 388 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 10.38 (s, 1 H), 8.36 - 8.24 (m, 2H), 8.07 (d, 1 H), 8.00 (s, 1 H), 7.49 - 7.38 (m, 2H), 7.30 (s, 2H), 6.88 (d, 1 H), 5.45 - 5.29 (m, 1 H), 2.06 (s, 3H), 1.58 (d, 3H).
EXAMPLE 37
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 20 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 76 mg (0.54 mmol) of 5-(hydroxymethyl)benzene-1 ,3-diol. The reaction was stirred at room temperature and then at reflux until most of the starting material was consumed. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 16 mg (41% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 433 (M+1)+.
H NMR (400 MHz, CDCI3) δ 8.16 (s, 1 H), 7.61 (d, 1 H), 6.88 (s, 1 H), 6.80 -
6.70 (m, 2H), 6.59 (dd, 1H), 6.15 (d, 1 H), 5.55 (s, 2H), 5.38 - 5.22 (m, 1 H), 4.67 (s, 2H), 2.57 (s, 3H), 1.44 (d, 3H).
EXAMPLE 38
(S)-4-Amino-6-((1-(4-(3-((2-(dimethylamino)ethyl)amino)phenoxy)-5- methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 82 mg (0.45 mmol) of 3-((2- (dimethylamino)ethyl)amino)phenol4 and 25 mg (0.18 mmol) of potassium carbonate were stirred in 2 ml of 3,3-dimethylbutan-2-one at reflux temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 35 mg (81 % yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 473 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.15 (s, 1 H), 7.61 (d, 1 H), 7.23 (t, 1 H), 6.61 - 6.52 (m, 3H), 6.47 (t, 1 H), 6.19 (d, 1 H), 5.46 (s, 2H), 5.33 - 5.19 (m, 1 H), 4.48 (s, 1 H), 3.17 (t, 2H), 2.65 - 2.55 (m, 5H), 2.27 (s, 6H), 1.47 (d, 3H).
EXAMPLE 39
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 82 mg (0.45 mmol) of 3-((2- (dimethylamino)ethyl)amino)phenol4 were heated for 20 min in 0.5 ml of acetone at 150 °C using microwaves irradiation. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 20 mg (46% yield) of the title compound as a white solid. Purity: 98.4%.
LRMS (m/z): 473 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1 H), 7.50 (d, 1 H), 7.10 (t, 1 H), 6.69 (s, 1 H), 6.62 (d, 1 H), 6.58 (d, 1 H), 6.53 (d, 1 H), 6.28 (d, 1 H), 5.43 - 5.20 (m, 3H), 4.32 - 4.17 (m, 2H), 2.81 - 2.67 (m, 2H), 2.37 (s, 6H), 1.62 (d, 3H), 1.45 (s, 3H).
EXAMPLE 40
(S)-4-Amino-6-((1 -(4-(4-(3-hydroxybenzyl)piperazin-1 -yl)-5-methylpyrrolo[2,1 - f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 36 mg (0.14 mmol) of 3-(piperazin-1- ylmethyl)phenol dichlorohydrate (purchased from ChemBridge®, cat. no. 4039846) and 38 μΙ (0.27 mmol) of triethylamine were stirred in 2 ml of acetone at reflux temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic solution was washed twice with ammonium chloride solution, water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 35 mg (79% yield) of the title compound as a white solid. Purity: 99.2%.
LRMS (m/z): 485 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 9.32 (s, 1 H), 8.03 (s, 1 H), 7.65 (d, 1 H), 7.31 (s, 2H), 7.17 - 7.00 (m, 2H), 6.83 - 6.69 (m, 2H), 6.64 (d, 1 H), 6.54 (d, 1 H), 5.24 -
4.97 (m, 1 H), 3.68 - 3.52 (m, 4H), 2.38 (s, 3H), 1.49 (d, 3H).
EXAMPLE 41
(S)-4-Amino-6-((1-(4-(3,5-difluoro-4-hydroxyphenyI)-5-methylpyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 24 from 70 mg (0.21 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 77 mg (0.44 mmol) of (3,5-difluoro-4-hydroxyphenyl)boronic acid (purchased from Combi- Blocks ®, cat. no. BB-1093). The reaction was completed after 16 hours and the crude product that was isolated was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 12% DCM/MeOH) to obtain 25 mg (28% yield) of the title compound as a pale yellow solid. Purity: 100%.
LRMS (m/z): 423 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.90 (s, 1 H), 8.05 (s, 1 H), 8.00 (s, 1 H), 7.45 - 7.39 (m, 3H), 7.31 (s, 1H), 6.86 (s, 1 H), 5.41 - 5.28 (m, 1 H), 2.13 (s, 3H), 1.57 (d, 3H).
EXAMPLE 42
3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-fj[1,2,4]triazin-2- yl)methyl)-1AY-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
94 mg (0.18 mmol) of 3-iodo-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 83 mg (0.53 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 30 mg (0.04 mmol) of PdCI2dppf DCM and 443 μΙ (0.89 mmol) of a 2 M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 80 °C for 16 hours. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 5% DCM/MeOH) to obtain 30 mg (33% yield) of the title compound as a white solid. Purity: 99%.
LRMS (m/z): 517 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.19 (s, 1 H), 8.25 (s, 1 H), 7.63 (s, 1 H), 6.91 (s, 1 H), 6.84 (d, 1 H), 6.65 (d, 1 H), 6.52 (s, 1 H), 5.42 (s, 2H), 2.35 (s, 3H), 2.34 - 2.25 (m, 5H), 0.90 (s, 6H).
EXAMPLE 43
(S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 50 mg (0.46 mmol) of 3-aminophenol were stirred in 2 ml of acetone at 100 °C in a sealed vessel for 16 hours. The volatiles were removed under reduced pressure and the untreated residue was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1%* v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 12% DCM/MeOH) to obtain 17 mg (46% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 402 (M+1)+.
1H NMR (400 MHz, DMSO) δ 9.43 (s, 1 H), 8.23 (s, 1 H), 8.00 (s, 1 H), 7.61 (d, 1 H), 7.41 - 7.03 (m, 6H), 6.60 - 6.40 (m, 2H), 5.26 - 5.08 (m, 1 H), 2.60 (s, 3H),
1.52 (d, 3H).
EXAMPLE 44
(S)-4-Amino-6-((1-(4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 29 mg (0.18 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid (purchased from Combi-Blocks ®, cat. no. BB-2773). The reaction was completed after 16 hours and the crude product that was isolated was purified first by flash chromatography (0% to 16% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 2 mg (5% yield) of the title compound. Purity: 89%.
LRMS (m/z): 405 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.38 (s, 1 H), 8.06 (s, 1 H), 8.00 (s, 1 H), 7.44 (d, 1 H), 7.31 (s, 2H), 6.95 - 6.83 (m, 3H), 6.79 (d, 1 H), 5.45 - 5.27 (m, 1 H), 2.06 (s, 3H), 1.57 (d, 3H). EXAMPLE 45
3-(4-Amino-1-((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-5-fluorophenol
92 mg (0.18 mmol) of 3-iodo-1-((5-methyl-4-((tetrahydro-2/- -pyran-4- yl)methoxy)pyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 84 mg (0.54 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 29 mg (0.04 mmol) of PdCI2dppf DCM and 441 μΙ (0.88 mmol) of a 2 M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 80 °C for 16 hours. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 5% DCM/MeOH) to obtain 15 mg (17% yield) of the title compound as a white solid. Purity: 96%.
LRMS (m/z): 505 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.19 (s, 1 H), 8.27 (s, 1 H), 7.76 (s, 1 H), 6.97 - 6.52 (m, 4H), 5.51 (s, 2H), 4.19 - 4.05 (m, 2H), 3.84 - 3.69 (m, 2H), 3.21 - 3.10 (m, 2H), 1.85 - 1.71 (m, 1 H), 1.51 - 1.32 (m, 2H), 1.31 - 1.06 (m, 3H).
EXAMPLE 46 3-(4-Amino-1 -((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yi)methyl)-1H-pyrazolo[3,4- /|pyrimidin-3-yl)-5-fiuorophenoi
The title compound was prepared following the experimental procedure described in Example 45 from 101 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- i][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /-/-pyrazolo[3,4-c ]pyrimidin-4-amine and 177 mg (1.14 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 18 mg (16% yield) of the title compound as a pale yellow solid. Purity: 95.9%.
LRMS (m/z): 501 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 8.26 (s, 1 H), 8.04 (d, 1 H), 6.94 - 6.72 (m, 7H), 6.66 (d, 1 H), 5.66 (s, 2H), 2.04 (s, 3H). EXAMPLE 47
(S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 24 from 100 mg (0.30 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 110 mg (0.61 mmol) of (4-methoxy-3,5-dimethylphenyl)boronic acid (purchased from Aldrich®, cat. no. 598062). The reaction was completed after 16 hours and the crude product that was isolated was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (0% to 16% DCM/MeOH) to obtain 85 mg (65% yield) of the title compound. Purity: 100%.
LRMS (m/z): 429 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.02 (s, 2H), 7.57 - 7.20 (m, 5H), 6.85 (s, 1 H), 5.34 (s, 1 H), 3.74 (s, 3H), 2.32 (s, 6H), 2.09 (s, 3H), 1.58 (d, 3H).
EXAMPLE 48
3-(4-Amino-1-((4-((2S,6 ?)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
The title compound was prepared from 102 mg (0.20 mmol) of 1-((4-((2S,6R)-2,6- dimethylmorpholino)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-c ]pyrimidin-4-amine and 94 mg (0.39 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. The reaction was completed in 2 hours and the isolated crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol [non buffered] as eluents 0% to 100%). The product obtained after purification was recrystallized in hot isopropylether and the precipitated white solid was filtered and dried in a stream of air to obtain 25 mg (25% yield) of the title compound. Purity: 96.1 %.
LRMS (m/z): 504 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 10.20 (s, 1 H), 8.27 (s, 1 H), 7.66 (d, 1 H), 6.89 (s,
1 H), 6.82 (d, 1 H), 6.65 (d, 1 H), 6.54 (d, 1 H), 5.43 (s, 2H), 3.68 (d, 2H), 2.70 -
2.59 (m, 2H), 2.34 (s, 3H), 0.95 (d, 6H).
EXAMPLE 49
(S)-4-Amino-6-((1 -(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
60 mg (0.14 mmol) of (S)-4-amino-6-((1-(4-(4-methoxy-3,5-dimethylphenyl)-5- methylpyrrolo[2, 1 -f\ \ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2 ml of methylene chloride. 420 μΙ (0.42 mmol) of a commercial 1 M solution of boron tribromide in methylene chloride were added and the mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride and the resulting solution was washed with a concentrated solution of sodium bicarbonate, water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 55 mg (95% yield) of pure product were isolated. Purity: 95%.
LRMS (m/z): 415 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.02 (s, 1 H), 7.98 (d, 1 H), 7.43 - 7.27 (m, 4H), 6.82 (d, 1 H), 5.36 - 5.26 (m, 1 H), 2.25 (s, 6H), 2.13 (s, 3H), 1.57 (d, 3H).
EXAMPLE 50
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)-/V-cyclopropyl-5-hydroxybenzamide
The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2 - ][1 l2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbo and 1 15 mg (0.18 mmol) of A/-cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzamide. The reaction was completed after 40 hours and the crude product that was isolated was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 8 mg (18% yield) of the title compound.- Purity: 94%.
LRMS (m/z): 470 (M+1 )+.
EXAMPLE 51
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5-methoxyphenyl)amino)- 5-methylpyrrolo[2 - ][1 ,2,4]triazin-2-yl)ethyl)am
The title compound was prepared following the experimental procedure of Example 39 from 100 mg (0.30 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 129 mg (0.61 mmol) of N1- (3-fluoro-5-methoxyphenyl)-/V2, A/2-dimethylethane-1 ,2-diamine4. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 88 mg (57% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 505 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.39 (s, 2H), 8.21 (s, 1 H), 7.57 (d, 1 H), 6.79 (d, 1 H), 6.53 - 6.34 (m, 4H), 5.57 (s, 2H), 5.46 - 5.33 (m, 1 H), 4.55 - 4.29 (m, 2H), 3.75 (s, 3H), 2.66 (s, 6H), 1.62 (d, 3H), 1.55 (s, 3H). EXAMPLE 52
(S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(2-morpholinoethyl)amino)-5- methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure of Example 39 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2,1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 100 mg (0.45 mmol) of 3- ((2-morpholinoethyl)amino)phenol4. The reaction was completed after 40 min. at 150 °C and 2 hours at 160 °C under microwaves irradiation. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 16 mg (34% yield) of the title compound as a white solid. Purity: 95.2%.
LRMS (m/z): 515 (M+1 )+. 1H NMR (400 MHz, CDCI3) δ 8.39 (s, 2H), 8.21 (s, 1 H), 7.57 (d, 1 H), 6.79 (d, 1 H), 6.53 - 6.34 (m, 4H), 5.57 (s, 2H), 5.46 - 5.33 (m, 1 H), 4.55 - 4.29 (m, 2H), 3.75 (s, 3H), 2.66 (s, 6H), 1.62 (d, 3H), 1.55 (s, 3H). EXAMPLE 53
(S)-A/-(3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 ^
[1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide
The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 73 mg (0.23 mmol) of A/-(3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide. The reaction was completed after 16 hours and the crude product that was isolated was purified first by flash chromatography (0% to 100% hexane/AcOEt) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 4 mg (9% yield) of the title compound. Purity: 100%.
LRMS (m/z): 480 (M+1)+.
H NMR (400 MHz, CDCI3/MeOD) δ 8.30 (s, 1 H), 8.04 (s, 1 H), 7.74 (d, 1 H), 6.94 - 6.89 (m, 1 H), 6.87 (t, 1 H), 6.81 - 6.76 (m, 1 H), 6.68 (d, 1 H), 5.47 -
5.28 (m, 1 H), 2.96 (s, 3H), 2.07 (s, 3H), 1.57 (d, 3H).
EXAMPLE 54
3-(4-Amino-1 -((4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- f [i ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
27 mg (0.05 mmol) of 3-iodo-1-((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1-][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-c/]pyrimidin-4-amine, 15 mg (0.10 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 4 mg (0.01 mmol) of PdCI2dppf DCM and 74 μΙ (0.15 mmol) of a 2M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 100 °C for 16 hours until the starting material were consumed. Then the reaction mixture was diluted with ethyl acetate and extracted twice with 2 M hydrochloric acid. The aqueous solution was adjust to pH= 9 with 8 M sodium hydroxide solution and re-extracted twice with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 60% B, in a 20 min. gradient). 8 mg (31% yield) of the title compound were obtained as a white solid. Purity: 99.1%.
LRMS (m/z): 533 (M+1 )+. EXAMPLE 55
3-(4-Amino-1-((4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2,1-^[1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-c ]pyrimidin-3-yl)-5- fluorophenol The title compound was prepared from 50 mg (0.09 mmol) of 3-((2-((4-amino-3-iodo- 1 -/-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)(2- (dimethylamino)ethyl)amino)phenol and 27 mg (0.17 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol [non buffered] as eluents 0% to 100%) to obtain 8 mg (16% yield) of the title compound as a white solid. Purity: 96.5%.
LRMS (m/z): 569 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.19 (s, 1 H), 9.50 (s, 1 H), 8.27 (s, 1 H), 8.16 (s, 1 H), 7.66 (d, 1 H), 7.10 (t, 1 H), 6.90 (s, 1 H), 6.83 (d, 1 H), 6.65 (d, 1 H), 6.57 (d, 2H), 6.48 (s, 1 H), 6.37 (s, 1 H), 5.49 (s, 2H), 3.75 (t, 2H), 2.07 (t, 2H), 1.85 (s,
6H), 1.33 (s, 3H).
EXAMPLE 56
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5-hydroxyphenyl)amino)- 5-methylpyrrolot2,1-fl[1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
78 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-fluoro-5- methoxyphenyl)amino)-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile were dissolved in 2 ml of methylene chloride. 464 μΙ (0.46 mmol) of a commercial 1 M solution of boron tribromide in methylene chloride were added and the mixture was stirred at room temperature for 40 hours. The solid formed was filtered and washed with methylene chloride and purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 26 mg (34% yield) of the title compound as a pale brown solid. Purity: 100%.
LRMS (m/z): 491 (M+1)+. EXAMPLE 57
(S)-4-Amino-6-((1-(4-(4-hydroxy-3-(2-hydroxypropan-2-yl)pheny!)-5- methylpyrrolo[2 -/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-t [1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 109 mg (0.39 mmol) of 2-(2-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenol. The reaction was completed after 16 hours and the crude product was purified first by flash chromatography (0% to 16% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 10 mg (25% yield) of the title compound. Purity: 100%.
LRMS (m/z): 445 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 9.35 (s, 1 H), 8.21 (s, 1 H), 7.77 (d, 1 H), 7.54 (dd,
1 H), 7.47 (d, 1 H), 7.01 (t, 1 H), 6.75 - 6.64 (m, 2H), 5.56 - 5.40 (m, 1 H), 5.26 (s, 2H), 2.58 (s, 1 H), 2.18 (s, 3H), 1.75 (d, 6H), 1.65 (d, 3H).
EXAMPLE 58
(S)-A/-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- r][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)-4-methoxybenzenesulfonamide
The title compound was prepared following the experimental procedure described in Example 24 from 70 mg (0.21 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 199 mg (0.43 mmol) of 4-methoxy-A/-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-3-yl)benzenesulfonamide. The reaction was completed after 16 hours and the crude product that was isolated was purified first by flash chromatography (0% to 16% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 48 mg (36% yield) of the title compound. Purity: 94.8%.
LRMS (m/z): 588 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.19 (d, 2H), 8.03 (s, 1 H), 7.86 - 7.72 (m, 3H), 7.26 (s, 1 H), 7.09 (s, 1 H), 6.93 (d, 2H), 6.74 (s, 1 H), 6.43 (d, 1 H), 5.57 - 5.46 (m, 1 H), 5.41 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 2.15 (s, 3H), 1.67 (s, 3H).
EXAMPLE 59 (S)-W-(5-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2][1 ,2,4]triazin-4-yi)-2-hydroxypyridin-3-yi)-4-methoxybenzenesuifonamide
45 mg (0.7 mmol) of (S)-/V-(5-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -r][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)-4- methoxybenzenesulfonamide were dissolved in 1 .5 ml of methylene chloride. 218 μΙ (0.22 mmol) of a commercial 1 M solution of boron tribromide in methylene chloride were added and the mixture was stirred at room temperature in a sealed vessel overnight. The reaction mixture was diluted with methylene chloride and the resulting solution was washed with a solution of sodium bicarbonate, water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 4 mg (9% yield) of the title compound as a solid. Purity: 91 %.
LRMS (m/z): 573 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.23 (s, 1 H), 7.92 - 7.74 (m, 4H), 7.67 (s, 1 H),
6.91 (d, 2H), 6.77 (s, 1 H), 6.66 (d, 1 H), 5.77 (s, 2H), 5.47 - 5.33 (m, 1 H), 3.81 (s, 3H), 2.28 (s, 3H), 1.65 (d, 3H).
EXAMPLE 60
3-(4-Amino-1 -((4-(4-(2-hydroxyethyl)piperazin-1 -yl)-5-methylpyrrolo[2,1 - j[1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
The title compound was prepared following the experimental procedure described in Example 24 from 90 mg (0.17 mmol) of 2-(4-(2-((4-amino-3-iodo-1 /- -pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2,1 -/][1 ,2,4]triazin-4-yl)piperazin-1 -yl)ethanol, and 79 mg (0.51 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 30 mg (32% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 565 (M+1 )+.
1H NMR (400 MHz, DMSO) δ 8.25 (s, 1 H), 8.19 (s, 1 H), 7.61 (d, 1 H), 6.93 - 6.88 (m, 1 H), 6.88 - 6.79 (m, 1 H), 6.65 (dt, 1 H), 6.54 - 6.49 (m, 1 H), 5.42 (s, 2H), 3.47 (t, 2H), 3.39 (s, 4H), 2.35 (s, 4H), 2.33 (d, 3H). EXAMPLE 61
(S)-4-Amino-6-((1-(4-((3-methoxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure of Example 39 from 100 mg (0.30 mmol) of (S)-4-amino-6-(1-(4-chloro-5-methylpyrrolo[1 ,2- /][1 ,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile and 80 mg (0.61 mmol) of 3- methoxy-A/-methylaniline. The reaction was completed after 20 min. at 120 °C heating with microwaves irradiation. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 93 mg (62% yield) of the title compound as a white solid. Purity: 97%.
LRMS (m/z): 430 (M+1)+.
EXAMPLE 62
3-(4-Amino-1 -((5-methyl-4-(4-(methylsulfonyl)piperazin-1 -yl)pyrrolo[2,1 - /][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-dlpyrimidin-3-yl)-5-fluorophenol
The title compound was prepared following the experimental procedure described, in Example 24 from 63 mg (0.11 mmol) of 3-iodo-1-((5-methyl-4-(4- (methylsulfonyl)piperazin-l -yl)pyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)methyl)-1 -/-pyrazolo[3,4- d]pyrimidin-4-amine and 50 mg (0.32 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 30 mg (47% yield) of the title compound as a white solid. Purity: 95%.
LRMS (m/z): 553 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.19 (s, 1 H), 8.27 (s, 1 H), 7.66 (d, 1 H), 6.91 (s, 1 H), 6.85 (d, 1 H), 6.65 (d, 1 H), 6.56 (d, 1 H), 5.46 (s, 2H), 3.52 (s, 4H), 3.07 (s, 4H), 2.81 (s, 3H), 2.38 (s, 3H).
EXAMPLE 63
(S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
83 mg (0.19 mmol) of (S)-4-amino-6-((1-(4-((3-methoxyphenyl)(methyl)amino)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2.7 ml of methylene chloride. 580 μΙ (0.57 mmol) of a commercial 1 M solution of boron tribromide in methylene chloride were added and the mixture was stirred at room temperature in a sealed vessel overnight. The solid that precipitated was collected by filtration and washed several times with methylene chloride and dried under a stream of air. 73 mg (93% yield) of the title compound were obtained as a pale yellow solid. Purity: 100%.
LRMS (m/z): 416 (M+1)+.
1H NMR (400 MHz, DMSO) δ 8.21 (s, 1 H), 8.05 (s, 1 H), 7.92 (s, 2H), 7.65 (d, 1 H), 7.15 (t, 1 H), 6.67 - 6.57 (m, 2H), 6.53 (t, 1 H), 6.38 (dd, 1 H), 5.33 - 5.23
(m, 1 H), 3.45 (s, 3H), 1.60 (d, 3H), 1.41 (s, 3H).
EXAMPLE 64
3-(4-Amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4- |pyrimidin-3-yl)-5-fluorophenol
The title compound was prepared following the experimental procedure described in Example 24 from 90 mg (0.18 mmol) of A/i-(2-((4-amino-3-iodo-1 /--pyrazolo[3,4- <^pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-/\/i,/\/2,/V2- trimethylethane-1 ,2-diamine and 83 mg (0.53 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid. The crude product was purified first by flash chromatography (0% DCM to 100% DCM/MeOH/NH3, 100:8:1 ) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 7 mg (8% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 491 (M+1)+.
1H NMR (400 MHz, DMSO) δ 10.17 (s, 1 H), 8.25 (s, 1 H), 7.60 (s, 1 H), 6.89 (s, 1 H), 6.83 (d, 1 H), 6.65 (d, 1 H), 6.50 (s, 1 H), 5.36 (s, 2H), 3.43 (s, 2H), 3.14 (s, 3H), 2.37 (s, 3H), 1.98 (s, 6H).
EXAMPLE 65
(S)-4-Amino-6-((2-(3-hydroxyphenyl)-1-(4-(4-isopropylpiperazin-1-yl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 25 mg (0.04 mmol) of (S)-4-amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-(4- isopropylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile were dissolved in a mixture of 10 ml of methanol and 10 ml of ethyl acetate. 15 mg (0.01 mmol) of 10% palladium (0) on charcoal were added and the mixture was stirred under hydrogen atmosphere (60 psi) for 40 hours. Then the catalyst was removed by filtration and the volatiles were evaporated under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3 (100:8:1)) to yield 9 mg (42% yield) of the title compound. LRMS (m/z): 513 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.19 (s, 1 H), 7.46 (d, 1 H), 7.03 (t, 1 H), 6.64 (d, 1 H), 6.61 - 6.49 (m, 3H), 6.45 (s, 1 H), 5.55 - 5.41 (m, 1 H), 5.32 (s, 2H), 3.64 (d, 4H), 3.23 (ddd, 2H), 2.81 - 2.70 (m, 1 H), 2.64 (s, 4H), 2.43 (s, 3H), 1.09 (d, 6H).
EXAMPLE 66
4-Amino-6-(((S)-1-(4-((3S,5A?)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 17 mg (0.15 mmol) of (2R,6S)-2,6- dimethylpiperazine dihydrochloride and 52 μΙ (0.30 mmol) of diisopropylethylamine were stirred in 2 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and methylene chloride. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 100:8:1) to obtain 25 mg (82% yield) of the title compound as a white solid. Purity: 98.2%.
LRMS (m/z): 407 (M+1)+.
1H NMR (400 MHz, CDCI3) δ 8.21 (s, 1 H), 7.53 (d, 1 H), 6.64 (d, 1 H), 6.48 (d, 1 H), 5.35 (s, 2H), 5.29 - 5.16 (m, 1 H), 4.10 (t, 2H), 3.13 (br s, 2H), 2.85 (br s, 2H), 2.44 (s, 3H), 1.56 (d, 3H), 1.23 (d, 6H).
EXAMPLE 67
(S)-4-Amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-/][1,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 24 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and 28 mg (0.18 mmol) of 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (purchased from Combi-blocks®, cat. no. PN-5673). The reaction proceeded overnight and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 23 mg (63% yield) of the title compound as a pale yellow solid. Purity: 100%.
LRMS (m/z): 400 (M+1 )+.
1H NMR (400 MHz, CDCI3) δ 8.21 (s, 1 H), 7.82 (d, 1 H), 7.23 - 7.21 (m, 2H), 6.76 (s, 1 H), 6.47 (d, 1 H), 5.62 - 5.42 (m, 1 H), 5.27 (s, 2H), 2.09 (s, 3H), 1.66
(d, 3H), 1.25 (s, 6H).
EXAMPLE 68
(S)-4-Amino-6-((1-(5-methy -(4-(pyrrolidin-1-ylmethyl)piperidin-1 -yl)pyrrolo[2,1^ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 26 mg (0.1 1 mmol) of 4-(pyrrolidin-1 - ylmethyl)piperidine dihydrochloride (purchased from ChemBridge®, cat. no. 4010589) and 48 μΙ (0.28 mmol) of diisopropylethylamine were stirred in 5 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 30 mg (71 % yield) of the title compound were obtained as a white solid. Purity: 95.0%.
LRMS (m/z): 461 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.22 (s, 1 H), 7.49 (s, 1 H), 6.76 (d, 1 H), 6.46 (s, 1 H), 5.38 - 5.08 (m, 3H), 4.20 (d, 2H), 3.04 (t, 2H), 2.51 (s, 4H), 2.44 (s, 3H), 2.40 (d, 2H), 1.96 (d, 2H), 1.85 - 1.69 (m, 6H), 1.56 (d, 3H), 1.46 - 1.29 (m, 2H).
EXAMPLE 69
(S)-4-((1 -(4-((2-(Dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2,1 -fl[1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-cqpyrimidine-5- carbonitrile
23 mg (0.07 mmol) of (S)-4-((1-(4-chloro-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-2- yl)ethyl)amino)-7/-/-pyrrolo[2,3-d]pyrimidine-5-carbonitrile and 24 mg (0.13 mmol) of 3- ((2-(dimethylamino)ethyl)amino)phenol4 were heated for 20 min in 0.4 ml of acetone at 150 °C using microwaves irradiation. The solvent was removed under reduced pressure and the crude product was purified first by flash chromatography (5% to 20% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 6 mg (17% yield) of the title compound. Purity: 94%.
LRMS (m/z): 497 (M+1 )+.
1H NMR (400 MHz, dmso) δ 12.81 (s, 1 H), 9.54 (s, 1 H), 8.34 (s, 1 H), 8.20 (s, 1 H), 7.62 (s, 1 H), 7.14 (t, 1H), 6.73 - 6.45 (m, 4H), 6.38 (s, 1 H), 5.45 - 5.25
(m, 1 H), 4.37 - 4.14 (m, 1 H), 4.14 - 3.90 (m, 1 H), 2.14 (s, 6H), 1.66 (d, 3H), 1.39 (s, 3H).
EXAMPLE 70
(S)-4-Amino-6-((1-(5-methyl-4-(2-morpholinoethyl)pyrrolo[2,1- l[1,2)4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
20 mg (0.06 mmol) of (S)-4-amino-6-((1-(5-methyl-4-vinylpyrrolo[2,1- ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 5 ml of ethanol under inert atmosphere. 15 μΙ (0.11 mmol) of triethylamine and 50 μΙ (0.58 mmol) of morpholine were added and the resulting solution was stirred at reflux temperature for 4 hours. Then the volatiles were removed under reduced pressure and 26 mg (99%) of the title compound were obtained. Purity: 96.4%.
LRMS (m/z): 408 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.64 (d, 1 H), 6.65 (d, 1 H), 6.60 (d,
1 H), 5.39 (t, 1 H), 5.32 (s, 2H), 3.80 - 3.69 (m, 4H), 3.35 - 3.20 (m, 2H), 2.95 (t, 2H), 2.67 - 2.47 (m, 7H), 1.60 (d, 3H).
EXAMPLE 71
4-Amino-6-(((S)-1 -(4-((3S,5/?)-4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 45 mg (0.18 mmol) of (2S,6R)-1-(2- (benzyloxy)ethyl)-2,6-dimethylpiperazine and 79 μΙ (0.45 mmol) of diisopropylethylamine were stirred in 5 ml of acetone at room temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 57 mg (69% yield) of the title compound as a white solid. Purity: 98%. LRMS (m/z): 541 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.51 (d, 1 H), 7.32 (d, 5H), 6.66 (d, 1 H), 6.46 (d, 1 H), 5.30 - 5.15 (m, 3H), 4.52 (s, 2H), 4.01 (t, 2H), 3.56 (t, 2H), 3.00 (t, 2H), 2.86 (dd, 4H), 2.43 (s, 3H), 1.55 (d, 3H), 1.17 (d, 6H).
EXAMPLE 72
3-(4-Amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- ^[1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol The title compound was prepared following the experimental procedure described in Example 25 from 79 mg (0.15 mmol) of 1-((4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 - -pyrazolo[3,4-c ]pyrimidin-4- amine and 48 mg (0.31 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid at 80 °C overnight. An additional addition of 30 mg of boronic acid was needed and after 6 hours at 80 °C the reaction was completed. The crude product was purified first by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 100:8:1) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 36 mg (47% yield) of the title compound as a white solid. Purity: 97%.
LRMS (m/z): 503 (M+1 )+.
H NMR (400 MHz, cdcl3) δ 8.44 (s, 1 H), 7.48 (d, 1 H), 6.97 - 6.84 (m, 2H), 6.63 (d, 1 H), 6.43 (d, 1 H), 5.58 (s, 1 H), 5.55 (s, 1 H), 3.89 (d, 2H), 2.99 (t, 2H), 2.63 (t, 2H), 2.38 (s, 3H), 1.00 (d, 6H). EXAMPLE 73
(S)-4-Amino-6-((1-(4-((2-hydroxyethyl)(methyl)amino)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 71 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 8.8 μΙ (0.1 1 mmol) of 2-(methylamino)ethanol. The crude oil obtained was stirred with hexanes and the white solid that precipitated was filtered and air-dried. 35 mg (100% yield) of the title compound were obtained. Purity: 96%.
LRMS (m/z): 368 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.53 (d, 1 H), 6.55 (d, 1 H), 6.48 (d, 1 H), 5.27 (s, 2H), 5.24 - 5.16 (m, 1 H), 3.95 (t, 2H), 3.82 (dd, 2H), 3.34 (s, 3H), 2.49 (s, 3H), 1.56 (br s, 3H).
EXAMPLE 74
(S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(2-methoxyethyl)amino)-5- methylpyrrolo[2,1-^[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 32 mg (0.18 mmol) of 3-((2- methoxyethyl)amino)phenol were heated for 30 min in 0.5 ml of acetone at 150 °C using microwaves irradiation. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by flash chromatography (0% to 16% DCM/MeOH), then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and finally by preparative HPLC (Symmetry Prep® Ci8 column, mixture of eluents A B from 55% A to 55% B, in a 32 min. isocratic gradient) to obtain 2.1 mg (5% yield) of the title compound. Purity: 100%.
LRMS (m/z): 460 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.49 (s, 1 H), 7.13 (t, 1 H), 6.81 - 6.68
(m, 2H), 6.61 (dd, 2H), 6.28 (s, 1 H), 5.38 (s, 2H), 5.34 - 5.25 (m, 1 H), 4.29 (dd, 2H), 3.67 (d, 2H), 3.35 (s, 3H), 1.60 (d, 3H), 1.45 (s, 3H).
EXAMPLE 75
(S)-4-Amino-6-((1-(5-methyl-4-(methyl(1-methylpiperidin-4-yl)amino)pyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 71 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 16 μΙ (0.11 mmol) of /V,1-dimethylpiperidin-4-amine (purchased from Aldrich®, cat. no. 22,140-6). The crude product was purified by flash chromatography (0% to 20% DCM/MeOH to obtain 29 mg (75% yield) of the title compound. Purity: 100%.
LRMS (m/z): 421 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.48 (d, 1 H), 6.60 (d, 1 H), 6.44 (d,
1 H), 5.34 (s, 2H), 5.27 - 5.11 (m, 1 H), 4.30 (t, 1 H), 3.13 (s, 3H), 3.01 (d, 2H), 2.44 (s, 3H), 2.36 (s, 3H), 2.25 (d, 2H), 2.06 (d, 2H), 1.87 (s, 2H), 1.54 (d, 3H). EXAMPLE 76
4-Amino-6-(((S)-1 -(4-((3S,5/?)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - /][1,2,4]triazin-2-yl)-2-(3-hydroxyphenyl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 65 from 30 mg (0.09 mmol) of 4-amino-6-(((S)-2-(3-(benzyloxy)phenyl)-1-(4- ((3S,5 )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 -/][1 ,2,4]tnazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 26 mg (32% yield) of the title compound. Purity: 98%.
LRMS (m/z): 499 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.44 (s, 1 H), 7.48 (d, 1 H), 6.97 - 6.84 (m, 2H), 6.63 (d, 1 H), 6.43 (d, 1 H), 5.73 - 5.41 (m, 4H), 3.89 (d, 2H), 3.06 - 2.93 (m, 2H),
2.63 (t, 2H), 2.38 (s, 3H), 1.00 (d, 6H).
EXAMPLE 77
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1 ,2,4]triazin-4-yl)-/V-(2-(dimethylamino)ethyl)-5-hydroxybenzamide
21 mg (0.05 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-^][1 ,2,4]triazin-4-yl)-5-hydroxybenzoic acid, 1 1 mg (0.06 mmol) of EDC HCI and 6.6 mg (0.05 mmol) of HOBt were dissolved in 0.2 ml of DMF and stirred for 15 min. Then 22 μΙ (0.20 mmol) of 4-methylmorpholine and 5.3 μΙ (0.05 mmol) of /V\/V1-dimethylethane-1 ,2-diamine (purchased from Aldrich®, cat. no. D158003) were added and the reaction mixture was stirred at room temperature for 48 hours. Then excess 22 μΙ (0.20 mmol) of 4-methylmorpholine and 5.3 μΙ (0.05 mmol) of Λ/1,Λ/1- dimethylethane-1 ,2-diamine were added and the mixture was stirred for 24 hours more. Then the reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with 4% aqueous solution of sodium hydrogencarbonate, water and brine, dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (100% DCM to 100% DCM/MeOH/NHa, 100:8: 1 ) to obtain 19 mg (15% yield) of the title compound. Purity: 96%. LRMS (m/z): 501 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.85 (s, 1 H), 7.80 (d, 1 H), 7.71 (s, 1 H), 7.62 (s, 1 H), 7.31 (s, 1 H), 6.95 (d, 1 H), 6.75 (s, 1 H), 5.61 (s, 2H), 5.42 (d, 1 H), 4.20 (dd, 1 H), 3.73 (d, 2H), 2.90 (t, 2H), 2.55 (s, 6H), 2.19 (s, 3H), 1.65 (d, 6H).
EXAMPLE 78
4-Amino-6-(((S)-1-(5-methyl-4-(methyl((1 S,2S)-2- (methylamino)cyclohexyl)amino)pyrrolo[2,1 - |[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 26 mg (0.18 mmol) of (1 S,2S)-/V1,/V2- dimethylcyclohexane-1 ,2-diamine (purchased from Aldrich® cat. no. 669660) and 80 μΙ (0.46 mmol) of diisopropylethylamine were stirred in 5 ml of acetone at room temperature overnight. An excess of 26 mg of the diamine and 240 μΙ diisopropylethylamine were added and the mixture was stirred at room temperature for an additional 64 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) and then by flash chromatography (100% DCM to 10% DCM/MeOH/NH3, 100:8:1) to obtain 3 mg (5% yield) of the title compound. Purity: 94%.
LRMS (m/z): 435 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.48 (s, 1 H), 6.60 (d, 1H), 6.44 (s, 1 H), 5.31 (s, 2H), 5.24 - 5.14 (m, 1 H), 4.12 (s, 1 H), 3.13 (s, 3H), 2.64 (s, 1 H), 2.47 (s, 3H), 2.33 (s, 3H), 2.09 (dd, 2H), 1.92 - 1.58 (m, 6H), 1.54 (d, 3H), 1.19 (dd, 2H).
EXAMPLE 79
(S)-4-Amino-6-((1-(4-(dimethylamino)-5-methylpyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
9 mg of the title compound were obtained and isolated as a side product of the experimental procedure described in Example 78. Purity: 94%. LRMS (m/z): 338 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.49 (d, 1 H), 6.86 (d, 1 H), 6.45 (d, 1 H), 5.31 - 5.11 (m, 3H), 3.22 (s, 6H), 2.47 (s, 3H), 1.57 (s, 3H). EXAMPLE 80
(S)-4-Amino-6-((1-(4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 71 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1-r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 10.6 μΙ (0.11 mmol) of 3-(methylamino)propan-1-ol. The reaction mixture was stirred at room temperature overnight and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 23 mg (67% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 382 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.51 (d, 1 H), 6.79 (d, 1 H), 6.46 (d, 1 H), 5.38 - 5.11 (m, 3H), 3.94 - 3.60 (m, 4H), 3.28 (s, 3H), 2.47 (s, 3H), 2.07 - 1.88 (m, 2H).
EXAMPLE 81
3-(4-Amino-1-((4-((3S,5f?)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5- methylpyrrolo[2,1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-cr]pyrimidin-3-yl)-5- fluorophenol
The title compound was prepared from 20 mg (0.03 mmol) of 1-((4-((3S,5f?)-3,5- dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)methyl)-3-iodo-1H-pyrazolo[3,4-cQpyrimidin-4-amine and 1 1 mg (0.07 mmol) of (3- fluoro-5-hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. After 16 hours of reaction, an additional 10 mg of the boronic acid and 5 mg of the palladium catalyst were added and the mixture stirred at 100 °C for 48 hours more. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 18 mg (82% yield) of the title compound as a white solid. Purity: 95%.
LRMS (m/z): 581 (M+1 )+. EXAMPLE 82
(S)-4-Amino-6-((1-(4-((2-aminoethy!)(methyl)amino)-5-methylpyrro!o[2,1-][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile The title compound was prepared following the experimental procedure described in Example 71 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1 -(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 7 μΙ (0.08 mmol) of A/1-methylethane-1 ,2-diamine. The reaction mixture was stirred at room temperature overnight and the crude product was purified first by flash chromatography (100% DCM to 100% DCM/MeOH/NHa, 100:8: 1 ) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 40% B, in a 14 min. gradient) to obtain 4 mg (13% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 367 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.50 (d, 1 H), 6.77 (d, 1 H), 6.50 - 6.42
(m, 1 H), 5.29 (s, 2H), 5.25 - 5.12 (m, 1 H), 3.83 - 3.63 (m, 2H), 3.28 (s, 3H), 3.05 (t, 2H), 2.47 (s, 3H), 1.55 (d, 3H).
EXAMPLE 83
(S)-4-Amino-6-((1 -(5-methyl-4-((2-(methylamino)ethyl)amino)pyrrolo[2,1 -][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
6 mg of the title compound were obtained and isolated as a side product of the experimental procedure described in Example 82. Purity: 98%.
LRMS (m/z): 367 (M+1 )+.
H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.36 (d, 1 H), 6.88 (d, 1 H), 6.35 (s, 2H), 5.33 - 5.08 (m, 3H), 3.82 - 3.61 (m, 2H), 2.93 (t, 2H), 2.52 (s, 3H), 2.48 (s, 3H). EXAMPLE 84
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 35 μΙ (0.30 mmol) of N N N2- trimethylethane-1 ,2-diamine were stirred in 0.6 ml of acetone at 55 °C for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 16% DCM/MeOH) to obtain 33 mg (92% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 395 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.49 (d, 1 H), 6.67 (d, 1 H), 6.44 (d, 1 H), 5.33 (s, 2H), 5.28 - 5.1 1 (m, 1 H), 3.78 (ddq, 2H), 3.28 (s, 3H), 2.65 (t, 2H), 2.46 (s, 3H), 2.28 (s, 6H), 1.56 (d, 3H).
EXAMPLE 85
/V-((S)-1-(4-((3S,5 ?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-cnpyrimidin-
4-amine
63 mg (0.1 mmol) of A/-((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -/][1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7/- -pyrrolo[2,3-c]pyrimidin-4-amine were treated with 1.5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure and the residue was treated with 1.5 ml of a 7 M solution of ammonia in methanol. The solution was stirred at room temperature for 30 min., then the volatiles were removed under reduced pressure and the residue was partitioned between basic water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 11 mg (24% yield) of the title compound as a white solid. Purity: 92%.
LRMS (m/z): 486 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 10.99 (s, 1 H), 8.33 (s, 1 H), 7.76 (s, 1 H), 7.57 (d,
1 H), 7.53 (s, 1 H), 6.96 (s, 1 H), 6.52 (d, 1 H), 6.45 (d, 1 H), 5.34 (m, 1 H), 4.15 (br. s, 1 H), 4.06 - 3.82 (m, 5H), 3.12 - 2.87 (m, 2H), 2.75 - 2.55 (m, 2H), 2.42 (s, 3H), 1.59 (d, 3H), 1.11 (t, 6H). EXAMPLE 86 4-Amino-6-(((S)-1-(4-((3S,5R)-4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 -f|[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile 40 mg (0.12 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 43 mg (0.15 mmol) of 2-(4-(((2f?,6S)-2,6- dimethylpiperazin-1-yl)methyl)phenoxy)-/\/,/\/-dimethylethanamine (dihydrochloride) and 85 μΙ (0.49 mmol) of DIEA were stirred in 4 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium hydroxide buffered] 0% to 100%) to obtain 11 mg (14% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 584 (M+1)+.
H NMR (400 MHz, cdcl3) δ 8.42 (s, 1 H), 8.19 (s, 1 H), 7.49 (d, 1 H), 7.29 (d, 2H), 6.84 (d, 2H), 6.64 (d, 1 H), 6.45 (d, 1 H), 5.45 (s, 2H), 5.30 - 5.11 (m, 1 H), 4.19 (t, 2H), 4.03 (t, 2H), 3.84 (s, 2H), 3.16 - 2.69 (m, 6H), 2.56 (s, 6H), 2.42 (s, 3H), 1.53 (d, 3H), 1.21 - 1.07 (m, 6H).
EXAMPLE 87
A/-(3-(4-(((S)-1 -(4-((3S,5 ?)-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - ^[1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide
28 mg (0.04 mmol) of A/-(3-(4-(((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide were treated with 1.0 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure and the residue was dissolved in 2 ml of methanol and 1.5 ml of a 7 M solution of ammonia in methanol was added. The solution was stirred at room temperature for 30 min., the volatiles removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium hydroxide buffered] 0% to 100%) to obtain 13 mg (52% yield) of the title compound as a white solid. Purity: 92%.
LRMS (m/z): 575 (M+1 )+.
1H NMR (400 MHz, CD30D) δ 8.19 (s, 1 H), 7.43 (t, 1 H), 7.39 (d, 1 H), 7.38 -
7.34 (m, 1 H), 7.34 - 7.26 (m, 2H), 7.14 (s, 1 H), 6.51 (dd, 1 H), 5.21 (q, 1 H), 4.00 - 3.86 (m, 2H), 3.24 - 2.99 (m, 2H), 2.89 (s, 3H), 2.71 (dd, 2H), 2.42 (s, 3H), 1.53 (d, 3H), 1.15 (t, 6H). EXAMPLE 88
/V-(3-(4-Amino-1-((4-((3S,5 ?)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1-
/][1 ,2,4]triazin-2-yl)methyl)-1W-pyrazolo[3,4-cdpyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide The title compound was prepared from 50 mg (0.10 mmol) of 1 -((4-((3S,5f?)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-cf]pyrimidin-4-amine and 75 mg (0.24 mmol) of /V-(3-hydroxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide following the experimental procedure described in Example 45. After 16 hours of reaction at 100 °C, the reaction mixture was filtered through Celite®, the solvent was removed and after extractions a crude product was obtained, which was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by a second reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium hydroxide buffered] 0% to 100%) to obtain 7 mg (13% yield) of the title compound as a white solid. Purity: 97%.
LRMS (m/z): 578 (M+1 )+.
EXAMPLE 89
4-Amino-6-(((S)-1 -(4-((3R,5S)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1 -yl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2, 1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 21 mg (0.1 1 mmol) of (2S,6R)-2,6-dimethyl-1- (methylsulfonyl)piperazine hydrochloride and 64 μΙ (0.37 mmol) of DIEA were stirred in 3 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 16% DCM/MeOH) to obtain 9 mg (20% yield) of the title compound. Purity: 100%.
LRMS (m/z): 485 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.56 (d, 1 H), 6.58 (d, 1 H), 6.50 (d, 1 H), 5.35 (s, 2H), 5.29 - 5.18 (m, 1 H), 4.25 (dtd, 2H), 4.13 - 3.97 (m, 2H), 3.61 (ddd, 2H), 2.87 (s, 3H), 2.46 (s, 3H), 1.57 (d, 3H), 1.46 (dd, 6H). EXAMPLE 90
5-(4-Amino-1-((4-((3S,5 ?)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d|pyrimidin-3-yl)pyridin-3-ol
The title compound was prepared from 50 mg (0.10 mmol) of 1 -((4-((3S,5f?)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-o]pyrimidin-4-amine and 43 mg (0.19 mmol) of 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-3-ol following the experimental procedure described in Example 45. After 16 hours of reaction at 100 °C, the reaction mixture was filtered through Celite®, the solvent was removed and after extractions a crude product was obtained, which was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 : 1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%), then by a second reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium hydroxide buffered] 0% to 100%) and finally by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A B from 5% B to 35% B, in a 15 min. gradient) to obtain 8 mg (17% yield) of the title compound as a white solid. Purity: 99%.
LRMS (m/z): 486 (M+1 )+.
1H NMR (400 MHz, CD30D) d 8.50 (s, 1 H), 8.34 (s, 1 H), 8.31 (s, 1 H), 8.21 (d, 1 H), 7.56 (d, 1 H), 7.53 (dd, 1 H), 6.55 (d, 1 H), 5.55 (s, 2H), 3.96 (dd, 2H), 3.14 (ddd, 2H), 2.87 (dd, 2H), 2.42 (s, 3H), 1.14 (d, 6H).
EXAMPLE 91
4-(((S)-1 -(4-((3/?,5S)-4-Acetyl-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - ][1,2,4]triazin-2-yl)ethyl)amino)-6-aminopyrimidine-5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2, 1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 29 mg (0.18 mmol) of 1-((2S,6ft)-2,6- dimethylpiperazin-1-yl)ethanone hydrochloride and 64 μΙ (0.37 mmol) of DIEA were stirred in 2 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to obtain 36 mg (88% yield) of the title compound. Purity: 98%.
LRMS (m/z): 449 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.56 (d, 1 H), 6.60 (d, 1 H), 6.49 (dd, 1 H), 5.33 - 5.20 (m, 3H), 4.61 - 4.33 (m, 2H), 4.19 (dd, 2H), 3.47 (ddd, 2H), 2.47 (s, 3H), 2.16 (s, 3H), 1.57 (d, 3H), 1.36 (dd, 6H).
EXAMPLE 92
(S)-4-Amino-6-((1-(4-((3-aminopropyl)(methyl)amino)-5-methylpyrrolo[2,1- fl[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
The title compound was prepared following the experimental procedure described in Example 71 from 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile and 12 μΙ (0.11 mmol) of /V1-methylpropane-1 ,3-diamine. The reaction mixture was stirred at room temperature overnight and the crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) then by flash chromatography (100% DCM to 100% DCM/MeOH/NHs, 100:8:1 ) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 45% B, in a 15 min. gradient) to obtain 3 mg (10% yield) of the title compound. Purity: 100%.
LRMS (m/z): 381 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.22 (s, 1 H), 7.37 (d, 1 H), 6.75 (d, 1 H), 6.37 (s, 1 H), 5.32 (s, 2H), 5.23 - 5.12 (m, 1 H), 3.92 - 3.62 (m, 2H), 3.08 - 2.85 (m, 2H), 2.52 (s, 3H), 2.19 - 2.00 (m, 2H), 1.56 (d, 3H), 1.25 (s, 3H).
EXAMPLE 93
(S)-4-Amino-6-((1-(5-methyl-4-((3-(methylamino)propyl)amino)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 3 mg of the title compound were obtained and isolated as a side product of the experimental procedure described in Example 92. Purity: 100%.
LRMS (m/z): 381 (M+1)+. 1H NMR (400 MHz, cdcl3) δ 8.57 (s, 1 H), 8.19 (s, 1 H), 7.36 (d, 1 H), 6.78 (d, 1 H), 6.69 (s, 1 H), 6.36 (d, 1 H), 5.53 (s, 2H), 5.27 - 5.05 (m, 1 H), 3.96 - 3.61 (m, 2H), 3.01 (t, 2H), 2.62 (s, 3H), 2.53 (s, 3H), 2.16 (s, 2H), 1.55 (d, 3H). EXAMPLE 94
4-Amino-6-(((S)-1-(4-((2S,6 ?)-2,6-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
8 mg (0.016 mmol) of (3S,5ft)-terf-butyl 4-(2-((S)-1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-3,5-dimethylpiperazine-1- carboxylate were dissolved in 0.2 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 5 mg (78% yield) of the title compound were obtained. Purity: 100%.
LRMS (m/z): 407 (M+1)+.
1H NMR (400 MHz, cd3od) δ 8.17 (s, 1 H), 7.72 (d, 1 H), 6.69 (s, 1 H), 5.51 - 5.33 (m, 1 H), 3.59 (t, 2H), 3.36 (d, 2H), 2.98 (t, 2H), 2.55 (s, 3H), 1.60 (d, 3H), 0.85 (t, 6H).
EXAMPLE 95
3-(4-Amino-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1-/l[1,2,4]triazin-2-yl)methyl)- 1H-pyrazolo[3,4-cf]pyrimidin-3-yl)-5-fluorophenol The title compound was prepared from 130 mg (0.27 mmol) of 3-iodo-1-((5-methyl-4- (piperazin-1-yl)pyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine and 82 mg (0.52 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. After 20 hours of reaction at 80 °C, the reaction mixture was filtered through Celite®, the filter washed with ethyl acetate, the solution dried over sodium sulphate and the solvent was removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) and then after a second reverse phase chromatography in the same conditions, 6 mg (6% yield) of the title compound were obtained as a white solid (formate salt). Purity: 98%.
LRMS (m/z): 475 (M+1)+. 1H RMN: (dmso-d6, 400 MHZ) δ 8.24 (1 H , s), 8.19 (1 H, s), 7.60 (1 H, d); 6.89 - 6.88 (1 H, m), 6.82 (1 H, ddd), 6.64 (1 H, dt), 6.53 (1 H, dd), 5.41 (2H, s), 3.35 - 3.33 (4H, m), 2.70 - 2.68 (4H, m), 2.34 (3H, s). EXAMPLE 96
3-(4-Amino-1-((5-methyl-4-thiomorpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
The title compound was prepared from 118 mg (0.23 mmol) of 3-iodo-1-((5-methyl-4- thiomorpholinopyrrolo[2 -/][1 ,2,4]triazin-2-yl)methyl)-1 /- -pyrazolo[3,4-c/]pyrimidin-4- amine and 85 mg (0.55 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. After 20 hours of reaction at 80 °C, the reaction mixture was filtered through Celite®, the filter washed with ethyl acetate, the solution dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) and after a second reverse phase chromatography in the same conditions, 9 mg (7% yield) of the title compound were obtained as a white solid (formate salt). Purity: 97%.
LRMS (m/z): 492 (M+1)+.
1H RMN (dmso-d6, 500 MHZ) δ 10.15 (1 H, brs), 8.25 (1 H, s), 7.63 (1 H, d), 6.89 - 6.88 (1 H, m), 6.83 (1 H, ddd), 6.64 (1 H, dt), 6.53 (1 H, dd), 5.43 (2H, s), 3.64 - 3.61 (4H, m), 2.53 - 2.51 (4H, m), 2.34 (3H, s). EXAMPLE 97
3-(4-Amino-1-((5-methyl-4-((2-(pyrrolidin-1-yl)ethyl)amino)pyrrolo[2,1- f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
The title compound was prepared from 90 mg (0.17 mmol) of 3-iodo-1-((5-methyl-4-((2- (pyrrolidin-1-yl)ethyl)amino)pyrrolo[2,1-r][1 ,2,4]triazin-2-yl)methyl)-1 /-/-pyrazolo[3,4- d]pyrimidin-4-amine and 40 mg (0.26 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid following the experimental procedure described in Example 45. After 20 hours of reaction at 80 °C, excess of the boronic acid and the catalyst were added and the reaction was heated at 80 °C for 60 hours more. Then the reaction mixture was filtered through Celite®, the filter washed with ethyl acetate, the solution dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 5 mg (6% yield) of the title compound as a white solid (formate salt). Purity: 99%.
LRMS (m/z): 503 (M+1)+.
H RMN: (dmso-d6, 500 MHZ) δ 10.16 (1 H, brs), 8.24 (1 H, s), 8.14 (1 H, s), 7.46 (1 H, d), 6.97 (1 H, t), 6.89 - 6.88 (1 H, dd), 6.82 (1 H, ddd), 6.64 (1 H, dt), 6.37
(1 H, dd), 5.34 (2H, s), 3.36 - 3.33 (2H, m), 2.40 (3H, s), 2.39 - 2.35 (2H, m), 2.29 (4H, brs), 1.58 - 1.56 (4H, m).
EXAMPLE 98
(S)-4-Amino-6-((1 -(4-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-5-methylpyrrolo[2,1 - f|[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
40 mg (0.12 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 32 mg (0.14 mmol) of 1 ,3-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (purchased from Combi-blocks® cat. no. PN-6021), 20 mg (0.02 mmol) of PdCI2dppf DCM and 183 μΙ (0.37 mmol) of a 2 M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 90 °C for 4 hours. After cooling, the reaction mixture was filtered through a layer of Celite® and the volatiles were removed under reduced pressure. The crude product was directly purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 35 mg (74% yield) of the title compound as a solid. Purity: 100%.
LRMS (m/z): 389 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.82 (s, 1 H), 6.77 (s, 1 H), 6.47 - 6.22 (m, 2H), 5.63 - 5.43 (m, 1 H), 5.32 (s, 2H), 3.94 (s, 3H), 2.36 (s, 3H), 2.23 (s,
3H), 1.65 (d, 3H).
EXAMPLE 99
(S)-Methyl 4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -fj[1 ,2,4]triazin-4-yl)-2,6-dimethylbenzoate
250 mg (0.76 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 316 mg (1.52 mmol) of (4- (methoxycarbonyl)-3,5-dimethylphenyl)boronic acid (purchased from Combi-blocks® cat. no. FA-1919), 62 mg (0.08 mmol) of PdCI2dppf DCM and 1.14 ml (2.3 mmol) of a 2 M aqueous solution of caesium carbonate were dissolved in 8.5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the two layers separated and the organic solution was washed with water and brine, dried over sodium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was directly purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 223 mg (64% yield) of the title compound. Purity: 100%.
LRMS (m/z): 348 (M+1)+. EXAMPLE 100
3-(1 -((4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4-cflpyrimidin-3-yl)-5- fluorophenol 16 mg (27 mmol) of (1 S,4S)-ierf-butyl 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -f \ ,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate were stirred in 0.5 ml of a 4M solution of hydrochloric acid in dioxane at room temperature for 2 hours. The resulting suspension was diluted with diethylether and the solid filtered, washed with ether and dried under reduced pressure at 40 °C to give 15 mg of the title compound (hydrochloride) as a pale brown solid. Purity: 99%.
LRMS (m/z): 487 (M+1)+.
1H RMN: (dmso-d6, 400 MHZ) δ 10.29 (1 H, brs), 9.43 (1 H, brs), 8.58 (1 H, brs), 8.46 (1 H , s), 7.65 (1 H,d), 6.91 - 6.89 (1 H, m), 6.69 (1 H, dt), 6.54 (1 H, d), 5.50 (1 H, d), 5.38 (1 H, d), 4.54 (1 H, s), 4.33 (1 H, s), 3.95 (1 H, d), 3.69 (1 H, d), 3.10
(1 H, m), 2.92 (1 H, m), 2.35 (3H, s), 2.07 (1 H, d), 1.82 (1 H, d).
EXAMPLE 101
3-(4-Amino-1-((4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1 - ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-f luorophenol
66 mg (0.13 mmol) of 3-((2-((4-amino-3-iodo-1/-/-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)- 5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)(methyl)amino)propan-1-ol, 31 mg (0.20 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 11 mg (0.013 mmol) of PdCI2dppf DCM and 133 μΙ (0.26 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the two layers separated and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 8 mg (13% yield) of the title compound. Purity: 99%.
LRMS (m/z): 478 (M+1)+.
H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1 H), 8.25 (s, 1 H), 7.57 (d, 1 H), 6.90 - 6.88 (m, 1 H), 6.85 - 6.81 (m, 1 H), 6.64 (dt, 1 H), 6.48 (d, 1 H), 5.37 (s, 1 H), 4.37 (t, 1 H), 3.17 (q, 2H), 3.06 (s, 3H), 2.38 (s, 3H), 1.49 - 1.38 (m, 2H).
EXAMPLE 102
3-(4-Amino-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholino)pyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-c(lpyrimidin-3-yl)-5-fluorophenol 63 mg (0.12 mmol) 3-iodo-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholino)pyrrolo[2,1- /][1 ,2,4]triazin-2-yl)methyl)-1/- -pyrazolo[3,4-d]pyrimidin-4-amine, 35 mg (0.22 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 12 mg (0.015 mmol) of PdCI2dppf DCM and 150 μΙ (0.29 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the two layers separated and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/ acetonitrile (1 : 1 ) as eluents [0.1 % v/v formic acid buffered] 15% to 50%) to obtain 9 mg (15% yield) of the title compound. Purity: 99%.
LRMS (m/z): 532 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1 H), 8.25 (s, 1 H), 7.65 (d, 1 H), 6.88 - 6.84 (m, 1 H), 6.81 - 6.75 (m, 1 H), 6.64 (dt, 1 H), 6.53 (d, 1 H), 5.38 (s, 2H), 3.37
(s, 3H), 2.38 (s, 3H), 0.91 (s, 12H).
EXAMPLE 103
(S)-Methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -fl[1 ,2,4]triazin-4-yl)-5-methylbenzoate 440 mg (1.3 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 739 mg (2.7 mmol) of methyl 3-methyl-5- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (purchased from Combi-blocks®, cat. no. PN-5549), 84 mg (0.10 mmol) of PdCI2dppf DCM and 2 ml (2.0 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 15 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the crude product was purified directly by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 372 mg (63% yield) of the title compound. Purity: 99%.
LRMS (m/z): 443 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, 1 H), 8.04 - 7.97 (m, 3H), 7.78 (s, 1 H), 7.43 (d, 1 H), 7.29 (s, 2H), 6.90 - 6.84 (m, 1 H), 5.37 (q, 1 H), 3.89 (s, 3H), 2.49 (s, 3H), 2.02 (s, 3H), 1.59 (d, 3H).
EXAMPLE 104
(S)-4-Amino-6-((1-(4-(3-cyano-5-hydroxyphenyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 157 mg (0.47 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 234 mg (0.95 mmol) of 3-hydroxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (purchased from Milestone®, cat. no. 8C-0165), 40 mg (0.049 mmol) of PdCI2dppf DCM and 720 μΙ (1.4 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the crude product was purified directly by flash chromatography (0% to 10% DCM/MeOH) to obtain 180 mg (91% yield) of the title compound. Purity: 96%.
LRMS (m/z): 412 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1 H), 8.00 (s, 1 H), 7.54 (s, 1 H), 7.43 (d, 1 H), 7.37 - 7.32 (m, 2H), 7.29 (s, 1 H), 6.88 (d, 1 H), 5.37 (p, 1 H), 2.54 (s, 3H),
2.04 (s, 3H), 1.58 (d, 3H).
EXAMPLE 105
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-5-methylbenzoic acid 480 mg (1.1 mmol) of (S)-methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)- 5-methylpyrrolo[2, 1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoate was dissolved in 20 ml of THF. 4.4 ml (0.44 mmol) of a 1 aqueous solution of lithium hydroxide were added and the resulting solution was stirred at room temperature overnight. The volatiles were evaporated and the crude product was directly purified by reverse phase chromatography (C-18 silica from Waters®, water/ acetonitrile (1 : 1 ) as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 350 mg (75% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 427 (M-1 )\
1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, 1 H), 8.01 (s, 1 H), 7.98 (s, 2H), 7.73 (s,
1 H), 7.43 (d, 1 H), 7.28 (s, 2H), 6.87 (d, 1 H), 5.38 (p, 1 H), 2.48 (s, 3H), 2.02 (s,
3H), 1.59 (d, 3H).
EXAMPLE 106
1 -(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1 -/][1,2,4]triazin-4-yl)piperidin-4-ol
86 mg (0.17 mmol) 1-(2-((4-amino-3-iodo-1 /-/-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- methylpyrrolo[2, 1-/][1 ,2,4]triazin-4-yl)piperidin-4-ol, 40 mg (0.25 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid, 13 mg (0.016 mmol) of PdCI2dppf DCM and 250 μΙ (0.48 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, the two layers separated and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 19 mg (23% yield) of the title compound. Purity: 98%.
LRMS (m/z): 490 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.25 (s, 1 H), 7.59 (d, 1 H), 6.93 -
6.85 (m, 1 H), 6.87 - 6.80 (m, 1 H), 6.65 (dt, 1 H), 6.51 (d, 1 H), 5.41 (s, 2H), 4.71 (d, 1 H), 3.75 - 3.58 (m, 2H), 3.22 - 3.01 (m, 2H), 2.35 (s, 3H), 1.78 - 1.56 (m, 2H), 1.41 - 1.23 (m, 2H).
EXAMPLE 107
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)-/V-(2-(dimethylamino)ethyl)-5-methylbenzamide 50 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 16 μΙ (0.14 mmol) of Λ/1,Λ/1- dimethylethane-1 ,2-diamine, 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 2 ml of anhydrous methylene chloride at room temperature for 2.5 hours. The reaction mixture was diluted with methylene chloride and washed with water, saturated solution of sodium hydrogencarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to afford 37 mg (63% yield) of the title compound. Purity: 96%.
LRMS (m/z): 499 (M+1)+.
H NMR (400 MHz, DMSO-d6) δ 8.47 (t, 1 H), 8.06 (d, 1 H), 8.01 (s, 1 H), 7.91 (d, 2H), 7.63 (s, 1 H), 7.41 (d, 1 H), 7.28 (s, 2H), 6.87 (dd, 1 H), 5.38 (p, 1 H), 3.38 (q, 2H), 2.48 - 2.41 (m, 5H), 2.20 (s, 6H), 2.00 (s, 3H), 1.59 (d, 3H).
EXAMPLE 108
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-/V-(2-hydroxyethyl)-5-methylbenzamide 50 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 9 μΙ (0.14 mmol) of 2- aminoethanol, 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 2 ml of anhydrous methylene chloride at room temperature for 2.5 hours. The reaction mixture was diluted with methylene chloride and washed with water, saturated solution of sodium hydrogencarbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to afford 35 mg (63% yield) of the title compound. Purity: 95%.
LRMS (m/z): 472 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.43 (m, 1 H), 8.06 (d, 1 H), 8.01 (d, 1 H), 7.97 - 7.88 (m, 2H), 7.63 (dt, 1 H), 7.44 - 7.37 (m, 1 H), 7.28 (s, 2H), 6.87 (dd,
1 H), 5.38 (p, 1 H), 4.69 (t, 1 H), 3.51 (q, 2H), 3.35 (t, 2H), 2.47 (s, 3H), 2.00 (s, 3H), 1.59 (d, 3H).
EXAMPLE 109
4-Amino-6-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1 - f|[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 32 mg (0.27 mmol) of (2f?,6S)-2,6- dimethylmorpholine were stirred in 1 ml of acetone at 55 °C overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. 29 mg (78% yield) of the title compound were obtained without need of any purification. Purity: 100%.
LRMS (m/z): 408 (M+1)+.
1H N R (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.53 (d, 1 H), 6.66 (d, 1 H), 6.48 (d,
1 H), 5.36 - 5.10 (m, 3H), 4.08 - 3.91 (m, 2H), 3.90 - 3.71 (m, 2H), 2.97 - 2.75
(m, 2H), 2.43 (s, 3H), 1.56 (d, 3H), 1.26 (d, 6H).
EXAMPLE 110
W-(3-(4-(((S)-1 -(4-((3S,5f?)-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 - f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-oqpyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide
34 mg (0.05 mmol) of A/-(3-(4-(((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f\[\ ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide were treated with 1.0 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure and the residue was dissolved in 1 ml of methanol and 1.5 ml of a 7 M solution of ammonia in methanol was added. The solution was stirred at room temperature for 1 hour, the volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium hydroxide buffered] 0% to 100%) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 20% B to 60% B, in a 20 min. gradient) to obtain 3 mg (11 % yield) of the title compound. Purity: 98%.
LRMS (m/z): 592 (M+1)+.
EXAMPLE 111 4- (2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1W-pyrazolo[3,4-dlpyrimidin-1- yl)methyl)-5-methylpyrro!o[2,1-^[1,2,4]triaz!n-4-y!)piperazin-2-one
100 mg (0.20 mmol) of 4-(2-((4-amino-3-iodo-1H-pyrazolo[3,4-c/]pynmidin-1-yl)methyl)- 5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)piperazin-2-one, 62 mg (0.40 mmol) of (3-fluoro-
5- hydroxyphenyl)boronic acid, 16 mg (0.020 mmol) of PdCI2dppf DCM and 300 μΙ (0.60 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 26 mg (27% yield) of the title compound. Purity: 99%.
LRMS (m/z): 489 (M+1 )\
1H NMR (400 MHz, DMSO-d6) δ 10.15 (1 H, s), 8.23 (1 H, s), 7.98 (1 H, s), 7.65 (1 H, d), 6.88 (1 H, t,), 6.85 - 6.82 (1 H, m), 6.65 - 6.61 (1 H, m), 6.54 (1 H, d), 5.42 (2H, s), 3.95 (2H,s), 3.60 (2H, d), 3.11 (2H, brs), 2.36 (3H, s).
EXAMPLE 112
1-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-r][1,2,4]triazin-4-yl)piperidine-4-carboxamide
110 mg (0.21 mmol) of 1-(2-((4-amino-3-iodo-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)methyl)- 5-methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)piperidine-4-carboxamide, 62 mg (0.40 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 16 mg (0.020 mmol) of PdCI2dppf DCM and 300 μΙ (0.60 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 16 mg (15% yield) of the title compound. Purity: 99%.
LRMS (m/z): 517 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.13 (1 H , s), 8.23 (1 H, s), 7.58 (1 H, d), 7.26
(1 H, s), 6.88 (1 H, s), 6.82 (1 H,d), 6.77 (1 H, s), 6.63 (1 H, dd), 6.50 (1 H, d), 5.40
(2H, s), 3.86 (2H, d), 2.92 - 2.87 (2H, m), 2.34 (3H, s), 2.33 - 2.28 (1 H, m), 1.70
- 1.67 (2H, m), 1.56 - 1.47 (2H, m). EXAMPLE 113
3-(4-Amino-1 -((5-methyl-4-(2-(pyrrolidin-1 -yl)ethoxy)pyrrolo[2,1 -f [\ ,2,4]triazin-2- yl)methyl)-1W-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol 50 mg (0.10 mmol) of 3-iodo-1-((5-methyl-4-(2-(pyrrolidin-1 -yl)ethoxy)pyrrolo[2, 1- f][1 ,2,4]triazin-2-yl)methyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-amine, 31 mg (0.20 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 5 mg (0.010 mmol) of PdCI2dppf DCM and 150 μΙ (0.30 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was purified first by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8: 1 ) and then by reverse phase chromatography (C-18 silica from Waters®, water/ acetonitrile (1 : 1 ) as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 23 mg (45% yield) of the title compound. Purity: 99%.
LRMS (m/z): 504 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 8.24 (1 H, s), 7.73 (1 H, d), 6.88 (1 H, s), 6.81 (1 H, d), 6.63 (1 H, d), 6.57 (1 H, d), 5.49 (2H, s), 4.35 (2H, t), 2.83 - 2.77 (1 H, q), 2.59 (2H, d), 2.36 (3H, s), 2.31 (4H, brs), 1.55 (4H, brs), 1.06 (1 H, t).
EXAMPLE 1 14
4-(2-((4-Amino-3-(3-fIuoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- /lpyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4-yl)thiomorpholine 1 ,1 -dioxide
164 mg of the crude product obtained in Preparation 77, containing impure 4-(2-((4- amino-3-iodo-1 /- -pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2, 1-][1 ,2,4]triazin-4-yl)thiomorpholine 1 ,1 -dioxide, 93 mg (0.60 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid, 24 mg (0.03 mmol) of PdCI2dppf DCM and 450 μΙ (0.90 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 27 mg (23% yield in two steps) of the title compound. Purity: 97%.
LRMS (m/z): 524 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 10.14 (1 H, s), 8.24 (1 H, s), 7.70 (1 H, d), 6.89 - 6.87 (1 H, m), 6.84 (1 H, dd), 6.63 (1 H, dt), 6.57 (1 H, d), 5.46 (2H, s), 3.80 (4H, brs), 3.07 (4H, brs), 2.37 (3H, s). EXAMPLE 1 15
3-(1 -((4-(1 ,4-Diazepan-1 -yl)-5-methylpyrrolo[2,1 -ί [Λ ,2,4]triazin-2-yl)methyl)-4- amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol 70 mg (0.14 mmol) of 1-((4-(1 ,4-diazepan-1-yl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)methyl)-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 43 mg (0.27 mmol) of (3-fluoro- 5-hydroxyphenyl)boronic acid, 1 1 mg (0.013 mmol) of PdCI2dppf DCM and 210 μΙ (0.42 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was purified first by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8:1) and then by crystallisation in acetonitrile to obtain 23 mg (34% yield) of the title compound. Purity: 95%.
LRMS (m/z): 489 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.27 (1 H, brs), 8.25 (1 H, s), 7.62 (1 H, s), 6.92 (1 H, s), 6.82 (1 H, d), 6.64 (1 H, d), 6.50 (1 H, s), 5.38 (2H, s), 3.69 - 3.66 (4H, m), 3.02 - 2.96 (4H, m), 2.31 (3H, s), 1.86 (2H, brs).
EXAMPLE 116
(S)-4-Amino-6-((1-(4-(3-hydroxy-5-methylphenyl)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 30 mg (0.09 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 26 mg (0.1 1 mmol) of 3-methyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (purchased from Combi-blocks®, cat. no. PN-5985), 15 mg (0.02 mmol) of PdCI2dppf DCM and 137 μΙ (0.27 mmol) of a 2M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 80 °C for 4 hours. After cooling, the reaction mixture was diluted with dioxane and filtered through Celite®, the solvents were removed and the crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 5 mg (14% yield) of the title compound as a yellowish solid. Purity: 96%.
LRMS (m/z): 401 (M+1 )+. EXAMPLE 117
3-(1 -((4-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)methyl)-4-amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol 100 mg (0.17 mmol) of terf-butyl 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H- pyrazolo[3,4-cf]pyrimidin-1 -y!)methy!)-5-methylpyrrolo[2, 1 -f [\ ,2,4]triazin-4-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate were suspended in 5 ml of a 4M solution of hydrochloric acid in dioxane. The resulting mixture was stirred at room temperature for 1 hour. The suspension was filtered and the solid was washed with dioxane and hexanes and then dried under vacuum at 35 °C to obtain 80 mg (89% yield) of the title compound (hydrochloride)
LRMS (m/z): 501 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.30 (1 H, brs), 9.35 (1 H, brs), 9.13 (1 H, brs), 8.47 (1 H, s), 7.65 (1 H,d), 6.89 - 6.87 (1 H, m), 6.84 (1 H, dt), 6.69 (1 H, dt), 6.54 (1 H, d), 5.44 (2H, s), 4.20 (1 H, brs), 4.02 (1 H, d), 3.76 (1 H, d), 3.72 (1 H, brs), 3.28 (1 H, m), 3.13 (1 H, m), 2.34 (3H, s), 1.99 - 1.87 (2H, m), 1.75 - 1.64 (2H, m). EXAMPLE 118
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- j[1,2,4]triazin-4-yl)-A/-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5- methylbenzamide
50 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 25 mg (0.15 mmol) of 2- ((5-aminopentyl)(methyl)amino)ethanol (prepared according to the experimental procedure described in PCT Int. Appl. WO2010069504), 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 2 ml of anhydrous methylene chloride at room temperature overnight. The reaction mixture was treated with water and the organic layer was separated and washed with water, a saturated solution of sodium hydrogencarbonate, a saturated solution of sodium carbonate and brine, then it was dried over magnesium sulphate, filtered and the solvents removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/ acetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%) to affordl 0 mg (15% yield) of the title compound.
LRMS (m/z): 501 (M+1)+.
1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, 1 H), 7.97 (s, 1 H), 7.88 (s, 1 H), 7.81 (d, 1 H), 7.57 (d, 1 H), 7.14 (d, 1 H), 7.06 (t, 1 H), 6.76 (dd, 1 H), 5.47 - 5.35 (m, 1 H), 3.76 - 3.63 (m, 2H), 3.47 (qd, 2H), 2.74 - 2.67 (m, 2H), 2.66 - 2.57 (m, 2H), 2.55 - 2.45 (m, 3H), 2.41 (s, 3H), 2.13 (s, 3H), 1.77 - 1.59 (m, 6H), 1.55 -
1.40 (m, 3H). EXAMPLE 119
(S)-4-Amino-6-({1 -(5-methyl-4-(2-(4=methyIpiperazin-1 -yl)pyridin-4-yl)pyrrolo[2,1 - ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 30 mg (0.09 mmol) (S)-4-amino-6-((1-(4-chloro-5-rnethylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 55 mg (0.18 mmol) of 1-methyl-4-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (purchased from Combi- blocks®, cat. no. PN-8651 ), 5 mg (0.004 mmol) of Pd(PPh3)4 and 137 μΙ (0.27 mmol) of a 2M aqueous solution of sodium carbonate were dissolved in 1 ml of dioxane. The mixture was stirred under argon atmosphere at 90 °C overnight. An excess of all the reagents in the same amount was added and the reaction proceeded at 90 °C for 24 hours more. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 53% B, in a 16 min. isocratic gradient) to obtain 14 mg (11% yield) of the title compound as a yellowish solid. Purity: 100%.
LRMS (m/z): 470 (M+1)+.
H NMR (400 MHz, cdcl3) δ 8.33 (d, 1 H), 8.20 (s, 1 H), 7.81 (d, 1 H), 6.88 (s, 1 H), 6.83 (d, 1 H), 6.75 (s, 1 H), 6.50 (d, 1 H), 5.60 - 5.43 (m, 1 H), 5.31 (s, 2H), 3.72 (br s, 4H), 2.66 (br s, 4H), 2.43 (s, 3H), 2.13 (s, 3H), 1.65 (d, 3H). EXAMPLE 120
(S)-4-Amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
156 mg (0.37 mmol) of (S)-4-amino-6-((1-(4-(4-formyl-3,5-dimethylphenyl)-5- methylpyrrolo[2,1- [1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were suspended in 4 ml of methanol. Then 1 1 mg (0.29 mmol) of sodium borohydride were added and the resulting suspension was stirred at room temperature overnight. Successive additions of sodium borohydride were made until the reaction was completed. An aqueous saturated sodium carbonate solution was added and the product was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 25% DCM/EtOAc) to obtain 97 mg (62% yield) of the title compound as a yellow solid. Purity: 100%.
LRMS (m/z): 429 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.78 (d, 1 H), 7.36 (s, 2H), 6.72 (d, 1 H), 6.63 (d, 1 H), 5.60 - 5.42 (m, 1 H), 5.28 (s, 2H), 4.83 (s, 2H), 2.53 (s, 6H),
2.13 (s, 3H), 1.65 (d, 3H).
EXAMPLE 121
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-5-methyl-W-(4-sulfamoylbenzyl)benzamide
52 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 35 mg (0.19 mmol) of 4- (aminomethyl)benzenesulfonamide hydrochloride (purchased from Sigma® cat. no. A- 2134), 28 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 42 μΙ (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride at room temperature overnight. The volatiles were removed under reduced pressure and the residue was washed with water and hexane. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 50 mg (69% yield) of the title compound. Purity: 95%.
LRMS (m/z): 598 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 9.21 (t, 1 H), 8.07 (d, 1 H), 8.03 - 7.95 (m, 3H), 7.85 - 7.75 (m, 2H), 7.67 (td, 1 H), 7.56 - 7.47 (m, 2H), 7.43 (d, 1 H), 7.30 (s, 4H), 6.87 (dd, 1 H), 5.38 (p, 1 H), 4.55 (d, 2H), 2.48 (s, 3H), 2.02 (s, 3H), 1.59 (d, 3H).
EXAMPLE 122
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f|[1,2,4]triazin-4-yl)-/V-(3-hydroxybenzyl)-5-methylbenzamide
50 mg (0.12 mmol) of (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 19 mg (0.15 mmol) of 3- (aminomethyl)phenol (purchased from Apollo Scientific® cat. no. OR14753), 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride at room temperature overnight. The volatiles were removed under reduced pressure and the residue was washed with water and hexane. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 30 mg (48% yield) of the title compound. Purity: 98%.
LRMS (m/z): 535 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1 H), 9.08 (t, 1 H), 8.06 (d, 1 H), 8.03 - 7.92 (m, 3H), 7.66 (s, 1H), 7.43 (d, 1 H), 7.29 (s, 1 H), 7.10 (t, 1 H), 6.87 (d, 1 H),
6.76 - 6.68 (m, 2H), 6.62 (dt, 1 H), 5.37 (p, 1 H), 4.41 (d, 2H), 2.48 (s, 3H), 2.01 (s, 3H), 1.59 (d, 3H).
EXAMPLE 123
3-(4-Amino-1 -((5-methyl-4-((1 S,4S)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.2]octan-2-yl)pyrrolo[2,1 ,2,4]triazin-2-yl)methyl)-1 H- pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
To a solution of 25 mg (0.05 mmol) of 3-(1-((4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4- ]pyrimidin-3- yl)-5-fluorophenol hydrochloride in 6 ml of a 1 :1 mixture of THF and methylene chloride was added a solution of 4 μΙ (0.05 mmol) of methanesulfonyl chloride and 10 μΙ (0.06 mmol) of DIEA in 1 ml of methylene chloride at 0°C. The mixture was stirred at 0 °C for 5 hours and then a second addition of both reagents was needed. Then the reaction was stirred at room temperature for 36 hours. Methanol was added to quench the reaction and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 11 mg (38% yield) of the title compound. Purity: 98%.
LRMS (m/z): 580 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.15 (1 H, s), 8.23 (1 H, s), 7.61 (1 H, d), 6.89
- 6.87 (1 H, m), 6.82 (1 H, ddd), 6.63 (1 H, dt), 6.50 (1 H, d), 5.38 (2H, d), 4.26 (1 H, brs), 3.94 - 3.88 (2H, m), 3.67 (1 H, dd), 3.45 (1 H, d), 3.24 (1 H, dd), 2.85 (3H, s), 2.38 (3H, s), 1.90 - 1.80 (2H, m), 1.64 - 1.55 (2H, m). EXAMPLE 124
/V-((S)-1 -(4-((2S,6/?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1 ,2,4]triazin- 2-yl)ethyl)-5-(1-methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
35 mg (0.057 mmol) of A/-((S)-1-(4-((2S,6ft)-2,6-dimethylmorpholino)-5- methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7-((2-
(trimethylsilyl)ethoxy)methyl)-7 -/-pyrrolo[2,3-d]pyrimidin-4-amine were treated with 1.0 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure and the residue was dissolved 1 ml of a 7 M solution of ammonia in methanol. The solution was stirred at room temperature for 6 hours and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 15 mg (72% yield) of the title compound. Purity: 96%.
LRMS (m/z): 488 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 1 1.71 (s, 1 H), 8.17 (s, 1 H), 7.86 (s, 1 H), 7.67 (d, 1 H), 7.61 (s, 1 H), 7.10 (d, 1 H), 6.58 (d, 1 H), 6.21 (d, 1 H), 5.20 (p, 1 H), 3.91 (s, 3H), 3.88 - 3.76 (m, 2H), 3.74 - 3.59 (m, 2H), 2.76-2.60 (m, 2H), 2.39 (s, 3H), 1.48 (d, 3H), 1.12 (t, 6H).
EXAMPLE 125
3-(4-Amino-1-((4-((2-(dimethylamino)ethyl)(tetrahydro-2H-pyran-4-yl)amino)-5- methylpyrrolo[2,1-fl[1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-c/lpyrimidin-3-yl)-5- fluorophenol
90 mg (0.16 mmol) of A/1-(2-((4-amino-3-iodo-1 /-/-pyrazolo[3,4-cf]pyrimidin-1-yl)methyl)- 5-methylpyrrolo[2, 1 -r][1 ,2,4]triazin-4-yl)-/\/2,A/2-dimethyl-A/1-(tetrahydro-2H-pyran-4- yl)ethane-1 ,2-diamine, 47 mg (0.30 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 13 mg (0.016 mmol) of PdCI2dppf DCM and 225 μΙ (0.45 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C for 24 hours. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 20% DCM/MeOH) to obtain 11 mg (13% yield) of the title compound. Purity: 98%.
LRMS (m/z): 561 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.16 (1 H, brs), 8.23 (1 H, s), 7.81 (1 H, brs), 7.67 (1 H, d), 6.87 - 6.85 (1 H, m), 6.79 (1 H, dd), 6.62 (1 H, dt), 6.57 (1 H, d), 5.40 (2H, s), 3.97 - 3.90 (1 H, m), 3.80 (2H, dd), 3.34 - 3.13 (6H, m), 2.37 (3H, s), 2.30 (3H, brs), 2.00 (3H, brs), 1.78 - 1.71 (2H, m), 1.48 - 1.52 (2H, m).
EXAMPLE 126
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f|[1,2,4]triazin-4-yl)-5-methyl-W-((1-(methylsulfonyl)piperidin-4- yl)methyl)benzamide To a solution of 43 mg (0.08 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)-5-methylpyrro!o[2,1-/][1 ,2,4]triazin-4-yl)-5-methyl-/\/-(piperidin-4- ylmethyl)benzamide hydrochloride and 32 μΙ (0.18 mmol) of DIEA in 5 ml of THF at 0 °C were added 8 μΙ (0.1 1 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at 0 °C for 1 hour and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 10 mg (20% yield) of the title compound.
LRMS (m/z): 604 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.61 (t, 1 H), 8.07 (d, 1 H), 8.01 (s, 1 H), 7.93 (d, 2H), 7.64 (d, 1 H), 7.47 - 7.37 (m, 1 H), 7.29 (s, 1 H), 6.91 - 6.82 (m, 1 H), 5.37
(p, 1 H), 3.55 (d, 2H), 3.20 (t, 2H), 2.83 (s, 3H), 2.66 (td, 2H), 2.47 (s, 3H), 2.01 (s, 3H), 1.78-1.65 (m, 3H), 1.59 (d, 3H), 1.23 (td, 2H).
EXAMPLE 127
3-(4-Amino-1 -((5-methyl-4-((1 ?,4/?)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2,1- ][1,2,4]triazin-2-yl)methyl)-1H- pyrazolo[3,4-cdpyrimidin-3-yl)-5-fluorophenol
The crude obtained from Preparation 88, containing 3-iodo-1-((5-methyl-4-((1 f?,4R)-5- (methylsulfonyl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)pyrrolo[2, 1 -/][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-Q]pyrimidin-4-amine as the main component, 100 mg (0.64 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 25 mg (0.031 mmol) of PdCI2dppf DCM and 500 μΙ (1.0 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C for 20 hours. After cooling, the volatiles were removed under reduced pressure and the crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 23 mg (16% yield in two steps) of the title compound. Purity: 97%.
LRMS (m/z): 566 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 10.15 (1 H, brs), 8.26 (1 H, s), 7.62 (1 H, d), 6.91 - 6.89 (1 H, m), 6.87 - 6.83 (1 H, m), 6.66 - 6.62 (1 H, m), 6.51 (1 H, d), 5.39 (2H, dd), 4.56 (1 H, s), 4.40 (1 H, s), 3.93 (1 H, dd), 3.45 (1 H, d), 3.17 (1 H, d), 3.09 (1 H, dd), 2.89 (3H, s), 2.37 (3H, s), 1.89 (1 H, d), 1.79 (1 H, d).
EXAMPLE 128 (S)-2-((2-((S)-1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- fj[1,2,4]triazin-4-yl)amino)-3-(4-hydroxypheny!)propanamide
30 mg (0.19 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2, 1-^[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile and 49 mg (0.27 mmol) of (S)-2-amino-3-(4- hydroxyphenyl)propanamide (purchased from Aldrich® cat. no. T3879) were stirred in 2 ml of acetone at 50 °C for 16 hours. Then 2 ml of THF were added and the mixture was stirred at 50 °C for 16 hours more. Finally, 3 ml of DMSO were added and the resulting solution was stirred at 70 °C for 20 hours and at room temperature for 60 hours more. The volatiles were removed under reduced pressure and the residue was treated with water. The solid that formed was filtered and washed with water. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 20 mg (46% yield) of the title compound as a white solid. Purity: 96%.
LRMS (m/z): 473 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.09 (s, 1 H), 7.32 (d, 1 H), 7.00 (d, 2H), 6.67 (d,
2H), 6.31 (d, 1H), 5.14 - 5.02 (m, 1H), 5.02 - 4.94 (m, 1H), 2.35 (s, 3H), 1.50 (d, 3H), 1.34 - 1.14 (m, 2H).
EXAMPLE 129
W-(3-(4-(((S)-1-(4-((2S,6 ?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- J[1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-c0pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide
The title compound was prepared from 60 mg (0.08 mmol) of A/-(3-(4-(((S)-1-(4- ((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c/]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide following the experimental procedure described in Example 124. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%)to obtain 12 mg (26% yield) of the title compound as a pale solid. Purity: 95%.
LRMS (m/z): 593 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 11.81 (d, 1 H), 8.17 (s, 1 H), 7.53 (d, 1 H), 7.18 (d, 1 H), 6.88 - 6.68 (m, 2H), 6.60 (t, 1 H), 6.53 (d, 1 H), 6.16 (d, 1 H), 5.28 - 5.06 (m, 1 H), 3.85 - 3.71 (m, 2H), 3.65 - 3.51 (m, 2H), 2.91 (s, 3H), 2.76 - 2.61 (m,
1 H), 2.61 - 2.50 (m, 1 H), 2.35 (s, 3H), 1.45 (d, 3H), 1.06 (t, 6H). EXAMPLE 130
(S)-4-(2-{1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethy!)-5-methylpyrrolo[2,1- |[1,2,4]triazin-4-yl)-W-(2-hydroxyethyl)-2,6-dimethylbenzamide 30 mg (0.09 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 58 mg (0.18 mmol) of /V-(2-hydroxyethyl)-2,6- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide, 7.5 mg (0.001 mmol) of PdCI2dppf DCM and 137 μΙ (0.27 mmol) of a 2M aqueous solution of sodium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. The reaction mixture was filtered through Celite® and the filtrate was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 15 mg (34% yield) of the title compound as a yellowish solid. Purity: 96%.
LRMS (m/z): 486 (M+1)+.
H NMR (400 MHz, cdcl3) δ 8.22 (s, 1 H), 7.79 (d, 1 H), 7.29 (s, 2H), 6.65 - 6.75 (m, 3H), 5.62 - 5.30 (m, 3H), 3.81 (t, 2H), 3.67 - 3.41 (m, 2H), 2.39 (s, 6H), 2.09 (s, 3H), 1.64 (d, 3H).
EXAMPLE 131
W-(5-(4-(((S)-1-(4-((2S,6R)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)amino)-7H^yrrolo[2,3-d]pyrimidin-5-yl)-2- methoxypyridin-3-yl)methanesulfonamide
The title compound was prepared from 85 mg (0.12 mmol) of A/-(5-(4-(((S)-1-(4- ((2 ,6S)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c |pyrimidin-5-yl)-2-methoxypyridin-3- yl)methanesulfonamide following the experimental procedure described in Example 124. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to give 59 mg (84% yield) of the title compound as a solid. Purity: 99%.
LRMS (m/z): 608 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 11.97 - 11.92 (m, 1 H), 8.21 (s, 1 H), 8.11 (d, 1 H), 7.75 (d, 1 H), 7.55 (d, 1 H), 7.30 (d, 1 H), 6.55 (d, 1 H), 5.98 (d, 1 H), 5.17 (p,
1 H), 3.98 (s, 3H), 3.85 - 3.71 (m, 2H), 3.68 - 3.54 (m, 2H), 2.98 (s, 3H), 2.64 (dd, 1 H), 2.61 - 2.53 (m, 1 H), 2.37 (s, 3H), 1.48 (d, 3H), 1.08 (dd, 6H). EXAMPLE 132
3-(4-Amino-1 -((5-methyl-4-(2-morpholinoethoxy)pyrrolo[2,1 -f][i ,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
The crude product of Preparation 92, containing 3-iodo-1-((5-methyl-4-(2- morpholinoethoxy)pyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- amine as the main component, 82 mg (0.53 mmol) of (3-fluoro-5- hydroxyphenyl)boronic acid, 29 mg (0.036 mmol) of PdCI2dppf DCM and 524 μΙ (1.10 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of ethanol. The mixture was stirred under argon atmosphere at 80 °C for 16 hours. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 20 mg (17% yield in two steps) of the title compound. Purity: 98%.
LRMS (m/z): 520 (M+1)+.
H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.26 (s, 1 H), 7.75 (d, 1 H), 6.93 -
6.87 (m, 1 H), 6.87 - 6.80 (m, 1 H), 6.65 (dt, 1 H), 6.59 (d, 1 H), 5.50 (s, 2H), 4.37 (t, 2H), 3.48 - 3.42 (m, 4H), 2.38 (s, 3H), 2.31 - 2.24 (m, 4H). EXAMPLE 133
1-(2-((2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H^yrazolo[3,4-i/lpyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one
100 mg (0.19 mmol) of 1-(2-((2-((4-Amino-3-iodo-1 /-/-pyrazolo[3,4-cf]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one, 44 mg (0.28 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 15 mg (0.018 mmol) of PdCI2dppf DCM and 281 μΙ (0.56 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of ethanol. The mixture was stirred under argon atmosphere at 80 °C for 16 hours. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 15 mg (15% yield) of the title compound. Purity: 98%.
LRMS (m/z): 518 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.27 (s, 1 H), 7.74 (d, 1 H), 6.92 -
6.88 (m, 1 H), 6.87 - 6.81 (m, 1 H), 6.65 (dt, 1 H), 6.58 (dd, 1 H), 5.51 (s, 2H), 4.40 (t, 2H), 3.48 (t, 2H), 3.25 (t, 2H), 2.36 (s, 3H), 2.13 (t, 2H), 1.87 - 1.72 (m,
2H). EXAMPLE 134
(S)-4-Amino-6-((1-(4-(3-cyano-5-(3-hydroxypropoxy)phenyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 60 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-(3-cyano-5-hydroxyphenyl)-5- methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2 ml of acetone and 15 μΙ (0.17 mmol) of 3-bromopropan-1-ol, 30 mg (0.22 mmol) of potassium carbonate and 7 mg (0.04 mmol) of potassium iodide were added. The resulting mixture was stirred at 50 °C for 5 hours. Then a second addition of all the reagents was done and the mixture was heated at 50 °C overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with a 1 M aqueous solution of sodium hydroxide, brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) and the solid that was obtained was treated with acetonitrile and filtered to give 26 mg (38% yield) of the title compound. Purity: 99%.
LRMS (m/z): 470 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.07 (1 H, d), 7.98 (1 H, s), 7.67 - 7.64 (2H, m), 7.51 - 7.50 (1 H, m), 7.39 (1 H, d), 7.27 (2H, brs), 6.87 (1 H, d), 5.36 (1 H, q), 4.54 (1 H, t), 4.16 (2H, t), 3.54 (2H, dd), 2.00 (3H, s), 1.90 - 1.85 (2H, m), 1.55 (4H, brs), 1.56 (3H,d).
EXAMPLE 135
5-(5-Amino-6-methoxypyridin-3-yl)-/V-((S)-1-(4-((2S,6 ?)-2,6-dimethylmorpholino)- 5-methylpyrrolo[2,1 - |[1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
The title compound was prepared from 43 mg (0.07 mmol) of 5-(5-amino-6- methoxypyridin-3-yl)-A/-((S)-1-(4-((2R,6S)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1-][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine following the experimental procedure described in Example 124. The crude product was purified first by flash chromatography (0% to 5% DCM/MeOH), then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1 % v/v formic acid buffered] 0% to 100%) and finally by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 40% B to 80% B, in a 20 min. gradient) to give 8 mg (23% yield) of the title compound as a solid. Purity: 100%.
LRMS (m/z): 530 (M+1 )+. 1H NMR (400 MHz, cdcl3) δ 8.25 (s, 1 H), 7.70 (d, 1 H), 7.46 (d, 1 H), 7.40 (d, 1 H), 7.08 (d, 1 H), 7.00 (d, 1 H), 6.48 (s, 1 H), 5.29 - 5.18 (m, 1 H), 3.93 - 3.60 (m, 4H), 3.36 (s, 2H), 2.85 - 2.53 (m, 2H), 2.42 (d, 3H), 1 .56 (t, 3H), 1.19 (s, 6H). EXAMPLE 136
A/-(3-(4-Amino-1 -((4-((2S,6/?)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1-
^[1,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4- /|pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide The title compound was prepared from 65 mg (0.1 1 mmol) of 1 -((4-((2S,6ft)-2,6- dimethylmorpholino)-5-methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-d]pyrimidin-4-amine and 71 mg (0.23 mmol) of A/-(3-hydroxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide following the experimental procedure described in Example 45. After 1 hour of reaction at 100 °C, the reaction mixture was filtered through Celite®, the solvent was removed and after extractions a crude product was obtained, which was purified by flash chromatography (0% to 25% DCM/MeOH) to obtain 23 mg (32% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 580 (M+1 )+.
1H NMR (400 MHz, dmso) δ 9.87 (s, 1 H), 9.81 (s, 1 H), 8.26 (s, 1 H), 7.66 (d,
1 H), 6.94 (s, 1 H), 6.77 (s, 2H), 6.54 (d, 1 H), 5.43 (s, 2H), 3.68 (d, 2H), 3.17 (d, 2H), 2.71 - 2.59 (m, 2H), 2.34 (s, 3H), 0.95 (d, 6H).
EXAMPLE 137
(S)-4-Amino-6-((1-(4-(3-cyano-5-((4-(methylsulfonyl)benzyl)oxy)phenyl)-5- methylpyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
28 mg (0.7 mmol) of (S)-4-amino-6-((1-(4-(3-cyano-5-hydroxyphenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile were dissolved in 2 ml of acetone and 26 mg (0.10 mmol) of 1 -(bromomethyl)-4- (methylsulfonyl)benzene (purchased from Acros® cat. no. 357580025), 19 mg (0.14 mmol) of potassium carbonate and 3.4 mg (0.02 mmol) of potassium iodide were added. The resulting mixture was stirred at 50 °C for 5 hours. Then a second addition of all the reagents was done and the mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography (0% to 15% DCM/MeOH). The solid that was obtained was triturated in hexane to give 20 mg (35% yield) of the pure title compound. Purity: 98%.
LRMS (m/z): 581 (M+1 )+.
1H NMR (400 MHz, dmso) δ 8.07 (1 H, d), 8.00 (1 H, s), 7.95 (2H, d), 7.81 (1 H, s), 7.76 - 7.74 (3H, m), 7.64 - 7.62 (1 H, m), 7.39 (1 H, d), 7.27 (1 H, brs), 6.86
(1 H, d), 5.39 (2H, s), 5.38 - 5.35 (1 H, m), 3.90 (1 H, s), 3.20 (3H, s), 1.94 (3H, s), 1.56 (3H, d).
EXAMPLE 138
(S)-3-(2-(1 -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 - ][1,2,4]triazin-4-yl)-5-methyl-/V-(4-(methylsulfonamido)benzyl)benzamide
50 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 28 mg (0.14 mmol) of N-(4- (aminomethyl)phenyl)methanesulfonamide hydrochloride (purchased from ABCR® cat. no. AB233719), 27 mg (0.14 mmol) of EDC HCI, 22 mg (0.14 mmol) of HOBt and 41 μΙ (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride and some drops of DMF at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to obtain 57 mg (79% yield) of the title compound. Purity: 99%.
LRMS (m/z): 612 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1 H), 9.09 (t, 1 H), 8.06 (d, 1 H), 8.00 (s, 1 H), 7.99 - 7.92 (m, 2H), 7.67 - 7.62 (m, 1 H), 7.43 (d, 1 H), 7.33 - 7.25 (m, 3H),
7.20 - 7.1 1 (m, 2H), 6.87 (dd, 2H), 5.37 (p, 1 H), 4.44 (d, 2H), 2.94 (s, 3H), 2.47 (s, 3H), 2.01 (s, 3H), 1.59 (d, 3H).
EXAMPLE 139
(S)-Methyl 4-((3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-fJ[1 ,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoate
150 mg (0.35 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -r][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 85 mg (0.42 mmol) of methyl 4-(aminomethyl)benzoate hydrochloride (purchased from Aldrich® cat. no. 47,999-3), 81 mg (0.42 mmol) of EDC HCI, 65 mg (0.42 mmol) of HOBt and 122 μΙ (0.87 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride and some drops of DMF at room temperature for 4 hours. The reaction mixture was diluted with methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to obtain 150 mg (75% yield) of the pure title compound. Purity: 98%.
LRMS (m/z): 677 (M+1)+.
H NMR (400 MHz, DMSO-d6) δ 9.22 (t, 1 H), 8.06 (d, 1 H), 8.00 (s, 1H), 8.00 - 7.96 (m, 2H), 7.95 - 7.93 (m, 1 H), 7.93 - 7.91 (m, 1 H), 7.68 - 7.66 (m, 1 H), 7.48 - 7.44 (m, 2H), 7.43 (d, 1 H), 7.29 (bs, 1 H), 6.87 (dd, 1 H), 5.37 (p, 1 H), 4.57 (d, 1 H), 3.84 (d, 3H), 2.48 (s, 3H), 2.02 (s, 3H), 1.59 (d, 3H).
EXAMPLE 140
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ^[1,2,4]triazin-4-yl)-/V-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4- yl)methyl)-5-methylbenzamide
30 mg (0.07 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 17 mg (0.07 mmol) of 4- (aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol dihydrochloride hydrate
(purchased from Aldrich® cat. no. 28,709-1 ), 16 mg (0.08 mmol) of EDC HCI, 13 mg (0.42 mmol) of HOBt and 24 μΙ (0.40 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride and some drops of DMF at room temperature for 5 hours. The reaction mixture was diluted with methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to obtain 32 mg (78% yield) of the pure title compound. Purity: 98%.
LRMS (m/z): 580 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1 H), 9.33 (t, 1 H), 8.06 (d, 1 H), 8.00 (s, 1 H), 7.99 - 7.94 (m, 2H), 7.93 (s, 1 H), 7.68 - 7.66 (m, 1 H), 7.42 (d, 1 H), 7.28 (bs, 1 H), 6.87 (dd, 1 H), 5.37 (p, 1 H), 5.19 (t, 1 H), 4.64 (d, 2H), 4.53 (d, 2H),
2.46 (s, 3H), 2.35 (s, 3H), 1.97 (s, 3H), 1.58 (d, 3H).
EXAMPLE 141
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-4-yl)-/V-(3-hydroxyphenyl)-5-methylbenzamide 60 mg (0.14 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methy!pyrro!o[2,1-r [1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 18 mg (0.16 mmol) of 3- aminophenol, 64 mg (0.17 mmol) of HATU and 29 μΙ (0.17 mmol) of triethylamine were stirred in 4 ml of anhydrous methylene chloride and some drops of DMF at room temperature for 4 hours. Another 12 mg of 3-aminophenol were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 43 mg (58% yield) of the title compound. Purity: 97%.
LRMS (m/z): 520 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 9.43 (s, 1 H), 8.08 (d, 1 H), 8.04 - 8.02 (m, 1 H), 8.01 (s, 1H), 8.01 - 7.99 (m, 1 H), 7.70 - 7.68 (m, 1 H), 7.44 (d, 1 H), 7.36 (t, 1 H), 7.29 (bs, 2H), 7.15 (dt, 1 H), 7.11 (t, 1 H), 6.88 (dd, 1 H), 6.51
(ddd, 1 H), 5.39 (p, 1 H), 2.03 (s, 3H), 1.60 (d, 3H).
EXAMPLE 142
(S)-4-((3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoic acid
114 mg (0.20 mmol) of (S)-methyl 4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-4-yl)-5- methylbenzamido)methyl)benzoate were dissolved in 5 ml of THF and 800 μΙ (0.8 mmol) of a 1 M aqueous solution of lithium hydroxide were added. The resulting solution was stirred at room temperature overnight and the volatiles were then removed under reduced pressure. The residue was dissolved in water and the solution was acidified with 2M hydrochloric acid until a precipitate appeared. The solid was filtered, washed with water and dried in a vacuum oven at 45 °C overnight. 105 mg (93% yield) of the title compound were obtained. Purity: 96%.
LRMS (m/z): 560 (M-1)\
1H NMR (400 MHz, DMSO-d6) δ 9.18 (1 H, brs), 8.04 (1 H, d), 7.98 - 7.95 (3H, m), 7.88 (2H, d), 7.65 (1 H, s), 7.41 (3H, d), 7.27 (1 H, brs), 6.86 (1 H, s), 5.35 (1 H, q), 4.54 (2H, d), 2.46 (3H, s), 2.00 (3H, s), 1.57 (3H, d).
EXAMPLE 143 Ethyl 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-
^pyrimidin-1-yl)methyl)-5-methylpyrroIo[2,1- |[1,2,4]triazin-4- yl)oxy)ethyl)piperidine-4-carboxylate 120 mg (0.20 mmol) of ethyl 1-(2-((2-((4-amino-3-iodo-1/- -pyrazolo[3,4-c/]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylate, 62 mg (0.40 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 16 mg (0.02 mmol) of PdCI2dppf DCM and 300 μΙ (0.60 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C for 16 hours. After cooling, the volatiles were removed under reduced pressure and the crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to obtain 17 mg (15% yield) of the title compound. Purity: 99%.
LRMS (m/z): 591 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 10.16 (1 H, s), 8.24 (1 H, s), 7.73 (1 H, s), 6.87 (1H, s), 6.81 (2H, d), 6.63 (1 H, d), 6.57 (1 H, s), 5.48 (2H, s), 4.32 (2H, s), 4.01
(2H, d), 2.64 (2H, s), 2.36 (3H, s), 2.16 (1 H, brs), 1.90 (2H, t), 1.67 (2H, d), 1.45 - 1.59 (2H, m), 1.16 - 1.12 (3H, m).
EXAMPLE 144
W-(4-(4-(((S)-1-(4-((2S,6/?)-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- n[1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide
The title compound was prepared from 73 mg of the crude product obtained in Preparation 98, which contained A/-(4-(4-(((S)-1-(4-((2S,6/:?)-2,6-dimethylmorpholino)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide as the main component, following the experimental procedure described in Example 124. The crude product was purified first by flash chromatography (0% to 15% DCM/iPrOH), then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%) and finally by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 40% B to 80% B, in a 20 min. gradient) to give 1 mg (23% yield) of the title compound as a solid. Purity: 97%.
LRMS (m/z): 577 (M+1)+.
EXAMPLE 145 (S)-A/-(3-(4-((1-(4-(2,6-Dimethy^
yl)ethyl)amino)-7H-pyrrolo[2,3-c |pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide
The title compound was prepared from 42 mg (0.06 mmol) of (S)-/V-(3-(4-((1-(4-(2,6- dimethylpyridin-4-yl)-5-methylpyrrolo[2, 1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7 -/-pyrrolo[2,3-cdpyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide following the experimental procedure described in Example 124. The crude product was purified first by flash chromatography (0% to 15% DCM/iPrOH), then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%) and finally by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 95% B, in a 12 min. gradient) to give 10 mg (29% yield) of the title compound as a solid. Purity: 98%.
LRMS (m/z): 585 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 9.40 (s, 2H), 8.36 (s, 1 H), 7.80 (d, 1 H), 7.13 (s, 1 H), 7.01 (d, 1H), 6.82 (d, 2H), 6.73 (d, 1 H), 6.63 (s, 1 H), 6.41 (d, 1 H), 5.65 - 5.46 (m, 2H), 2.96 (s, 3H), 2.62 (d, 3H), 2.02 (s, 3H), 1.25 (s, 6H).
EXAMPLE 146
(S)-3-Aminophenyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzoate
6 mg (9% yield) of the title compound were obtained and isolated as a side product of the experimental procedure described in Example 141. Purity: 95%.
LRMS (m/z): 520 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 2H), 8.08 (d, 1 H), 8.01 (s, 1 H), 7.86 (s, 1 H), 7.45 (d, 1 H), 7.29 (bs, 2H), 7.07 (t, 1 H), 6.89 (d, 1 H), 6.49 (dd, 1 H), 6.44 (t, 1 H), 6.37 (dd, 1 H), 5.39 (p, 1 H), 5.31 (s, 2H), 2.53 (s, 3H), 2.06 (s, 3H), 1.60 (d, 3H).
EXAMPLE 147
(S)-3-(2-(1-((5-(5-Amino-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)- V-(2-hydroxyethyl)-5- methylbenzamide The title compound was prepared from 31 mg (0.043 mmol) of (S)-3-(2-(1-((5-(5-amino- 6-methoxypyridin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c(]pyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2, 1 -/][1 ,2,4]triazin-4-yl)-A/-(2-hydroxyethyl)-5- methylbenzamide following the experimental procedure described in Example 124. The crude product was purified by flash chromatography (0% to 15% DCM/MeOH) to give 10 mg (37% yield) of the title compound as a solid. Purity: 95%.
LRMS (m/z): 593 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 1 1.83 (s, 1 H), 8.51 (t, 1 H), 8.20 (s, 1 H), 7.94 (d, 1 H), 7.92 - 7.87 (m, 2H), 7.59 - 7.52 (m, 3H), 7.19 (d, 1 H), 7.04 (d, 1 H), 6.91 - 6.85 (m, 1 H), 6.24 (d, 1 H), 5.40 (q, 1 H), 5.08 (s, 2H), 4.70 (t, 1 H), 3.88
(s, 3H), 3.57 - 3.44 (m, 2H), 3.42 - 3.32 (m, 1 H), 2.46 (s, 3H), 1.98 (s, 3H), 1.56 (d, 3H).
EXAMPLE 148
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-][1,2,4]triazin-4-yl)-/V-(3-hydroxybenzyl)-A ,5-dimethylbenzamide
30 mg (0.07 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-r][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 15 mg (0.11 mmol) of 3- ((methylamino)methyl)phenol, 16 mg (0.08 mmol) of EDC HCI, 13 mg (0.42 mmol) of HOBt and 24 μΙ (0.40 mmol) of triethylamine were stirred in 2 ml of a 1 :1 mixture of anhydrous methylene chloride and DMF at room temperature overnight. The solvents were removed under reduced pressure and the residue was redissolved in methylene chloride. This solution was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 24 mg (63% yield) of the title compound. Purity: 97%.
LRMS (m/z): 548 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 8.05 (bs, 1 H), 8.00 (s, 1 H), 7.61 -
7.51 (m, 1 H), 7.48 (s, 1 H), 7.46 - 7.37 (m, 2H), 7.29 (bs, 2H), 7.20 - 7.07 (m, 1 H), 6.86 (bs, 1 H), 6.77 - 6.72 (m, 1 H), 6.69 - 6.55 (m, 2H), 5.41 - 5.27 (m, 1 H), 4.60 (bs, 1 H), 4.44 (bs, 1 H), 2.87 (bs, 3H), 2.01 (bs 3H), 1.58 (d, 3H). EXAMPLE 149
3-(4-Amino-1-(( ?)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-2-yl)ethyl)-1H-pyrazolo[3,4-cGpyrimidin-3-yl)-5-fluorophenol 52 mg (0.10 mmol) of racemic 1-(1-(4-((3S,5ft)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -r][1 ,2,4]triazin-2-yl)ethyl)-3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine, 31 mg (0.20 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 8 mg (0.01 mmol) of PdCI2dppf DCM and 147 μΙ (0.30 mmol) of a 2M aqueous solution of sodium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 80 °C for 16 hours. Excess of reagents and catalyst was added and the reaction was stirred for another 24 hours at 80 °C. Then the reaction mixture was filtered through Celite®, the filter washed with ethyl acetate and the filtered organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3, 90:8:1) to obtain 34 mg (67% yield) of the racemic mixture. The two enantiomers were separated by chiral preparative HPLC (Daicel Chiralpack IC® Ci8 column, isocratic gradient of heptanol/ethanol/diethylamine (93:7:0.5), in a 40 min. run) to obtain 15 mg of the title compound (first peak to elute) as a white solid. Purity: 100%.
LRMS (m/z): 517 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.45 (s, 1 H), 7.52 (d, 1 H), 6.98 - 6.80 (m, 2H), 6.63 (d, 1 H), 6.44 (d, 1 H), 6.13 (q, 1 H), 5.56 (s, 2H), 4.18 (d, 1 H), 4.01 (br s, 1 H), 3.85 (d, 1 H), 3.53 - 3.42 (m, 1 H), 2.94 - 2.81 (m, 1 H), 2.81 - 2.70 (m, 1 H), 2.70
- 2.56 (m, 1 H), 2.40 (s, 3H), 2.01 (d, 3H), 1.11 (d, 3H), 1.00 (d, 3H).
EXAMPLE 150
3-(4-Amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f\[\ ,2,4]triazin-2-yl)ethyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
15 mg of the title compound were obtained from the chiral preparative HPLC separation described in Example 149 (second peak to elute) as a white solid. Purity: 100%.
LRMS (m/z): 517 (M+1 )+.
EXAMPLE 151
1-(2-((2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)oxy)ethyl)piperidine-4- carboxylic acid 15 mg (0.025 mmol) of ethyl 1-(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H- pyrazolo[3,4-cflpyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -r][1 ,2,4]triazin-4- yl)oxy)ethyl)piperidine-4-carboxylate were dissolved in 1 ml of THF and 100 μΙ (0.1 mmol) of a 1 M aqueous solution of lithium hydroxide were added. The resulting solution was stirred at room temperature overnight and then additional 100 μΙ of the lithium hydroxide solution were added and the resulting reaction mixture was heated at 50 °C for 3 hours. The volatiles were then removed under reduced pressure. The residue was dissolved in water and the solution was washed with ether and acidified with 1 M hydrochloric acid until a precipitate appeared. The solid was filtered, washed with water and dried. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 2.3 mg (64% yield) of the title compound. Purity: 98%.
LRMS (m/z): 560 (M-1)\
1H NMR (400 MHz, DMSO-d6) δ 11.5 (1 H, brs), 8.25 (1 H, s), 8.23 (1 H, brs),
7.73 (1H, d), 6.90 - 6.89 (1H, m), 6.81 (1 H, dt), 6.62 (1 H, dt), 6.57 (1H, dd), 5.49 (2H, s), 4.38 (2H, t), 2.65 - 2.61 (3H, m), 2.48 (2H, t), 2.37 (3H, s), 2.36 - 2.34 (1 H, m), 2.09 - 2.04 (2H, m), 1.93 - 1.88 (2H, m), 1.68 - 1.65 (2H, m), 1.45 - 1.37 (2H, m).
EXAMPLE 152
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-][1,2,4]triazin-4-yl)-A/-(4-((2-hydroxyethyl)carbamoyl)benzyl)-5-methylbenzamide 50 mg (0.09 mmol) of (S)-4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoic acid, 8.2 μΙ (0.13 mmol) of 2-aminoethanol, 21 mg (0.11 mmol) of EDC HCI, 16 mg (0.12 mmol) of HOBt and 31 μΙ (0.22 mmol) of triethylamine were stirred in 5 ml of methylene chloride at room temperature overnight. A second addition of the reagents was done and then the solution was stirred at 50 °C for 3 hours. The reaction mixture was diluted with methylene chloride and was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product stirred in acetonitrile and the insoluble solid was filtered and dried under air steam and in the vacuum oven at 45 °C. 20 mg (37% yield) of the title compound were obtained. Purity: 95%.
LRMS (m/z): 605 (M+1)+. H NMR (400 MHz, DMSO-d6) δ 9.16 (1 H, br s), 8.34 (1 H, t), 8.05 (1 H, d), 7.98 (2H, d), 7.95 (1 H, s), 7.79 (2H, d), 7.65 (1 H, s), 7.40 (1 H, d), 7.36 (2H, d), 7.27 (1 H, br s), 6.85 (1 H, d), 5.36 (1 H, q), 4.68 (1 H, t), 4.52 (2H, d), 3.48 (2H, q), 3.31 - 3.27 (2H, m), 2.46 (3H, s), 2.00 (3H, s), 1.57 (3H, d).
EXAMPLE 153
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- ^[1,2,4]triazin-4-yl)-5-methyl-A/-(4-(sulfamoylamino)benzyl)benzamide 60 mg (0.14 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 33 mg (0.17 mmol) of EDC HCI and 26 mg (0.17 mmol) of HOBt were stirred in 2 ml of DMF at room temperature for 90 minutes. Then 88 μΙ (0.63 mmol) of triethylamine and a solution of 4-(sulfamoylamino)benzylamine hydrochloride in 2 ml of DMF were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 18 mg (21% yield) of the title compound. Purity: 95%.
LRMS (m/z): 612 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1 H), 9.07 (t, 1 H), 8.06 (d, 1 H), 8.00 (s, 1 H), 7.96 (d, 2H), 7.65 (s, 1 H), 7.43 (d, 1 H), 7.29 (s, 2H), 7.22 (d, 2H), 7.11 (d, 2H), 7.02 (s, 2H), 6.89 - 6.85 (m, 1 H), 5.36 (q, 1 H), 4.41 (d, 2H), 2.47 (s, 3H), 2.01 (s, 3H), 1.58 (d, 3H).
EXAMPLE 154
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-4-yl)-W-(3-methoxy-5-(methylsulfonamido)benzyl)-5- methylbenzamide
37 mg (0.09 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 30 mg (0.13 mmol) of Λ/-(3- (aminomethyl)-5-methoxyphenyl)methanesulfonamide, 21 mg (0.11 mmol) of EDC HCI, 16 mg (0.12 mmol) of HOBt and 31 μΙ (0.22 mmol) of triethylamine were stirred in 2 ml of DMF at room temperature overnight. A second addition of the reagents was done and then the solution was stirred at room temperature for 90 hours more. The reaction mixture was diluted with ethyl acetate and was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified first by flash chromatography (0% to 15% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/ cetonitrile (1 :1) as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 13 mg (24% yield) of the title compound. Purity: 99%.
LRMS (m/z): 640 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.12 (1 H, brs), 8.06 (1 H, d), 8.00 (1 H, s), 7.96 (2H, d), 7.66 (1 H, s), 7.42 (1 H, d), 7.29 (2H, brs), 6.87 ( 1 H, d), 6.76 (1 H, s),
6.64 (2H, dd), 5.35 (1 H, q), 4.40 (2H, d), 3.71 (3H, s), 2.96 (3H, s), 2.47 (3H, s), 2.01 (3H, s), 1.59 (3H, d).
EXAMPLE 155
(S)-Methyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1,2,4]triazin-4-yl)-5-cyanobenzoate
572 mg (1.7 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 549 mg (1.9 mmol) of methyl 3-cyano-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (purchased from Combi-blocks®, cat. no. PN-5521), 100 mg (0.09 mmol) of Pd(PPh3)4 and 553 mg (5.2 mmol) of sodium carbonate were suspended in 11.5 ml of dioxane. The mixture was stirred under argon atmosphere at 90 °C overnight. Additions of 200 mg of the catalyst were done every 24 hours until no starting material was detected (two extra additions, 64 hours of reaction). After cooling, the mixture was filtered through Celite® and the filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) to obtain 116 mg (15% yield) of the title compound. Purity: 100%.
LRMS (m/z): 454 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.56 (s, 1 H), 8.50 (s, 1 H), 8.20 (s, 1 H), 8.17 (s, 1 H), 7.87 (d, 1 H), 6.80 (d, 1 H), 6.37 (d, 1 H), 5.63 - 5.47 (m, 1 H), 5.37 (s, 2H), 4.00 (s, 3H), 2.10 (s, 3H), 1.67 (d, 3H).
EXAMPLE 156 (S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- j[1 ,2,4]triazin-4-yl)-5-cyanobenzoic acid
100 mg (0.22 mmol) of (S)-methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-cyanobenzoate was dissolved in 2.7 ml of THF. 1.10 ml (1.1 mmol) of a 1 M aqueous solution of lithium hydroxide were added and the resulting solution was stirred at room temperature overnight. Another addition of 1.10 ml of lithium hydroxide was done and the resulting mixture was stirred at room temperature for 3 hours and at 50 °C for another 2 hours. The volatiles were then evaporated, the residue was acidified with diluted hydrochloric acid and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed to give 61 mg (52% yield) of the title compound. Purity: 94%.
LRMS (m/z): 438 (M-1)".
1H NMR (400 MHz, dmso) δ 8.49 (s, 1 H), 8.44 (s, 1 H), 8.42 (s, 1 H), 8.1 1 (d,
1 H), 7.99 (s, 1 H), 7.50 (d, 1 H), 7.30 (s, 2H), 6.90 (s, 1 H), 5.48 - 5.28 (m, 1 H), 2.00 (s, 3H), 1.58 (d, 3H).
EXAMPLE 157
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-][1 ,2,4]triazin-4-yl)-/V-(3-methoxy-4-(methylsulfonamido)benzyl)-5- methylbenzamide
69 mg (0.16 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1- ][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 56 mg (0.24 mmol) of Λ/-(4- (aminomethyl)-2-methoxyphenyl)methanesulfonamide, 37 mg (0.19 mmol) of EDC HCI, 30 mg (0.19 mmol) of HOBt and 56 μΙ (0.4 mmol) of triethylamine were stirred in 3 ml of DMF at room temperature overnight. The reaction mixture was diluted with ethyl acetate and was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 29 mg (28% yield) of the title compound. Purity: 95%.
LRMS (m/z): 641 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 9.11 (1 H, m), 8.83 (1 H, brs), 8.06 (1 H, s), 8.00 (1 H, s), 7.99 (1 H, m), 7.96 (1 H, m), 7.66 (1 H, s), 7.42 (1 H, d), 7.28 (1 H, brs),
7.19 (1 H, d), 7.04 (1 H, s), 6.88 (2H, d), 5.37 (1 H, q), 4.47 (2H, d), 3.80 (3H, s), 2.91 (3H, s), 2.47 (3H, s), 2.01 (3H, s), 1.59 (3H, d). EXAMPLE 158
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)-5-cyano-A/-(4-sulfamoylbenzyl)benzamide
54 mg (0.12 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1-/][1 ,2,4]triazin-4-yl)-5-cyanobenzoic acid, 35 mg (0.16 mmol) of 4- (aminomethyl)benzenesulfonamide, 28 mg (0.15 mmol) of EDC HCI, 20 mg (0.15 mmol) of HOBt and 54 μΙ (0.31 mmol) of DIEA were stirred in 4 ml of methylene chloride at room temperature overnight. The reaction mixture was diluted with ethyl acetate and was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (0% to 5% DCM/MeOH) to obtain 13 mg (17% yield) of the title compound as a yellowish solid. Purity: 95%.
LRMS (m/z): 608 (M+1 )+.
1H NMR (400 MHz, dmso) δ 9.43 (t, 1 H), 8.54 (s, 1 H), 8.45 (s, 1 H), 8.37 (s, 1 H), 8.1 1 (d, 1 H), 7.98 (s, 1 H), 7.76 (d, 2H), 7.50 (d, 2H), 7.45 (d, 1 H), 7.37 - 7.19 (m, 4H), 6.90 (d, 1 H), 5.48 - 5.29 (m, 1 H), 4.56 (d, 2H), 1.99 (s, 3H), 1.58 (d, 3H).
EXAMPLE 159
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-4-yl)-/V-(3-hydroxy-5-(methylsulfonamido)benzyl)-5- methylbenzamide
33 mg (0.08 mmol) of (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1- ][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 18 mg (0.09 mmol) of EDC HCI and 14 mg (0.09 mmol) of HOBt were stirred in 2 ml of methylene chloride at room temperature for 1 hour. Then a solution of 25 mg (0.12 mmol) of N-(3- (aminomethyl)-5-hydroxyphenyl)methanesulfonamide in a mixture of 2 ml of methylene chloride and 1 ml of DMF was added. The resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the crude product was directly purified first by flash chromatography (0% to 10% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 22 mg (45% yield) of the title compound. Purity: 99%. LRMS (m/z): 627 (M+1)+.
1H NMR (400 MHz, dmso) δ 9.57 (1 H, s), 9.47 (1 H, s), 9.08 (1 H, m), 8.05 (1 H, d), 8.0 (1 H, s), 7.97 (2H, d), 7.65 (1 H, s), 7.42 (1 H, d), 7.28 (1 H, s), 6.87 (1 H, d), 6.60 (1 H, s), 6.56 (1 H, s), 6.46 (1 H, s), 5.37 (1 H, m), 4.36 (2H, d), 2.94 (3H, s), 2.47 (3H, s), 2.01 (3H, s), 1.59 (3H, d).
EXAMPLE 160
(S)-4-Amino-6-((1-(5-methyM-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)pyrrolo[2,1- |[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
108 mg (0.15 mmol) of 2-methyl-4-(4-methylpiperazin-1-yl)-6- (trimethylstannyl)pyrimidine (crude product obtained in Preparation 1 14b), 50 mg (0.15 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-^[1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 18 mg (0.02 mmol) of Pd(PPh3)4 and 15 mg (0.08 mmol) of copper (I) iodide were suspended in 2 ml of DMF and heated at 100 °C in a sealed tube overnight. After cooling, the mixture was filtered through Celite® and the filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 28 mg (38% yield) of the title compound as a solid. Purity: 100%.
LRMS (m/z): 485 (M+1)+.
1H NMR (400 MHz, dmso) δ 8.04 (d, 1 H), 7.98 (s, 1 H), 7.42 (d, 1 H), 7.28 (s, 2H), 6.95 (s, 1 H), 6.84 (d, 1 H), 5.40 - 5.27 (m, 1 H), 2.44 (s, 3H), 2.41 - 2.34 (m, 4H), 2.21 (s, 3H), 2.13 (s, 3H), 1.56 (d, 3H).
EXAMPLE 161
(S)-2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-4-yl)-6-methyl-A/-(4-sulfamoylbenzyl)pyrimidine-4-carboxamide
10 mg (0.02 mmol) of (S)-2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid, 5 mg (0.03 mmol) of EDC HCI, 4 mg (0.03 mmol) of HOBt and 10 μΙ (0.06 mmol) of DIEA were stirred in 2 ml of methylene chloride at room temperature for 30 minutes. Then 7 mg (0.03 mmol) of 4-(aminomethyl)benzenesulfonamide hydrochloride were added and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10% DCM/MeOH) to obtain 4 mg (29% yield) of the title compound. Purity: 96%.
LRMS (m/z): 599 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.64 (t, 1 H), 8.17 (s, 1 H), 8.10 (s, 1 H), 7.86 (d, 3H),
7.49 (d, 2H), 6.79 (s, 1 H), 6.48 (d, 1 H), 5.54 - 5.46 (m, 1 H), 5.42 (s, 2H), 5.12 (s, 2H), 4.73 (dd, 2H), 2.77 (s, 3H), 2.01 (s, 3H), 1.63 (d, 3H).
EXAMPLE 162
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-][1,2,4]triazin-4-yl)-/V-(3-hydroxybenzyl)-5-methylbenzenesulfonamide
50 mg (0.15 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 74 mg (0.18 mmol) of /V-(3-hydroxybenzyl)-3- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide, 12 mg (0.01 mmol) of PdCI2dppf-DCM and 228 mg (0.46 mmol) of a 2M aqueous solution of caesium carbonate were suspended in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C overnight. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite® and the filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed. The crude product was purified first by flash chromatography (0% to 15% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile- methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 34 mg (39% yield) of the title compound. Purity: 95%.
LRMS (m/z): 570 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.92 (s, 1 H), 7.86 (d, 1 H), 7.62 (s, 1 H), 7.53 (s, 1 H), 7.05 (t, 1 H), 6.89 (br s, 1 H), 6.79 (s, 1 H), 6.76 - 6.65 (m, 2H), 6.60 (d, 1 H), 6.35 (s, 1 H), 5.57 - 5.42 (m, 2H), 5.33 (s, 2H), 4.19 (d, 2H), 2.37 (s, 3H), 2.07 (s, 3H), 1.70 (d, 3H).
EXAMPLE 163
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(4-(4-methylpiperazin-1- yl)benzyl)amino)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-
5-carbonitrile
30 mg (0.09 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 38 mg (0.14 mmol) of /V1,/V1-dimethyl-/\/2-(4-(4- methylpiperazin-1-yl)benzyl)ethane-1 ,2-diamine and 48 μΙ (0.28 mmol) of DIEA were stirred in 2 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and methylene chloride. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3) to obtain 20 mg (39% yield) of the title compound as a white solid. Purity: 100%.
LRMS (m/z): 569 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.52 (d, 1 H), 7.10 (d, 2H), 6.87 (d, 2H), 6.65 (d, 1 H), 6.45 (d, 1 H), 5.33 - 5.13 (m, 3H), 4.87 - 4.71 (m, 2H), 3.69 -
3.53 (m, 2H), 3.26 - 3.12 (m, 4H), 2.60 - 2.48 (m, 6H), 2.44 (s, 3H), 2.34 (s, 3H), 2.16 (s, 6H), 1.54 (d, 3H).
EXAMPLE 164
3-(2-((S)-1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- /][1,2,4]triazin-4-yl)- V-((S)-1 -(3-hydroxyphenyl)ethyl)-5-methylbenzamide
35 mg (0.08 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 18 mg (0.09 mmol) of EDC HCI and 15 mg (0.10 mmol) of HOBt were stirred in 2 ml of DMF at room temperature for 1 hour. Then a solution of 44 mg (0.33 mmol) of (S)-3-(1- aminoethyl)phenol in 2 ml of DMF was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 22 mg (49% yield) of the title compound. Purity: 97%.
LRMS (m/z): 548 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1 H), 8.83 (d, 1 H), 8.06 (d, 1 H), 8.04 - 7.89 (m, 3H), 7.64 (s, 1 H), 7.42 (d, 1 H), 7.29 (s, 2H), 7.10 (t, 1 H), 6.87 (d, 1 H),
6.84 - 6.74 (m, 2H), 6.66 - 6.57 (m, 1 H), 5.38 (q, 1 H), 5.10 (q, 1 H), 2.47 (s, 3H), 2.00 (s, 3H), 1.59 (d, 3H), 1.44 (d, 3H).
EXAMPLE 165
(S)-4-Sulfamoylbenzyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1 ,2,4]triazin-4-yl)-5-methylbenzoate 40 mg (0.09 mmol) of (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-r [1 ,2,4]triazin-4-yl)-5-methylbenzoic acid, 22 mg (0.11 mmol) of EDC HCI and 17 mg (0.13 mmol) of HOBt were stirred in 4 ml of DMF at room temperature for 1 hour. Then a solution of 52 mg (0.27 mmol) of 4- (hydroxymethyl)benzenesulfonamide and 13 μΙ (0.09 mmol) of triethylamine in 2 ml of DMF was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified by flash chromatography (0% to 100% hexane/EtOAc) to obtain 20 mg (35% yield) of the title compound as a solid. Purity: 96%.
LRMS (m/z): 598 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.11 - 8.02 (m, 3H), 8.00 (s, 1 H), 7.85 (s, 1 H), 7.83 (s, 1 H), 7.81 (s, 1 H), 7.69 - 7.62 (m, 2H), 7.43 (d, 1 H), 7.37 (s, 2H), 7.33 - 7.25 (m, 1 H), 6.88 (dd, 1H), 5.46 (s, 2H), 5.42 - 5.30 (m, 1 H), 2.49 (s, 3H), 2.02
(s, 3H), 1.59 (d, 3H).
EXAMPLE 166
(S)-4-Amino-6-((1-(4-(2-(4-(dimethylamino)piperidin-1-yl)pyridin-4-yl)-5- methylpyrrolo[2,1 -f \ ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
100 mg (0.30 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile, 112 mg (0.30 mmol) of A/,/V-dimethyl-1-(4- (trimethylstannyl)pyridin-2-yl)piperidin-4-amine, 35 mg (0.03 mmol) of Pd(PPh3)4 and 29 mg (0.15 mmol) of copper (I) iodide were suspended in 4 ml of dioxane and heated at 100 °C in a sealed tube overnight under argon atmosphere. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite® and the filtrates were washed with water and brine, dried over magnesium sulphate, filtered and the solvents removed. The crude product was purified by flash chromatography (0% to 20% DCM/MeOH) to obtain 42 mg (28% yield) of the title compound as a pale solid. Purity: 100%.
LRMS (m/z): 498 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.32 (d, 1 H), 8.21 (s, 1 H), 7.80 (d, 1 H), 6.87 (s, 1 H), 6.78 (d, 1 H), 6.74 (d, 1 H), 6.48 (d, 1 H), 5.58 - 5.44 (m, 1 H), 5.29 (s, 2H), 4.43 (d, 2H), 2.92 (t, 2H), 2.50 - 2.37 (m, 1 H), 2.33 (s, 6H), 2.13 (s, 3H), 1.95 (d,
2H), 1.65 (d, 3H). EXAMPLE 167
(S)-4-Amino-6-((1-(4-(2-(4-(4-(dimethy!amino)-6-methylpyridin-2-y!)piperidin yl)pyridin-4-yl)-5-methylpyrrolo[2,1-^[1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile
30 mg (0.09 mmol) (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 77 mg (0.18 mmol) of A/,/V,2-trimethyl-6-(1-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-yl)pyridin-4-amine, 22 mg (0.03 mmol) of PdCI2dppf DCM and 137 mg (0.27 mmol) of a 2M aqueous solution of sodium carbonate were suspended in 4 ml of dioxane. The mixture was stirred under nitrogen atmosphere at 100 °C overnight. After cooling, the mixture was filtered through Celite® and the solvents were removed. The crude product was purified by flash chromatography (0% to 20% DCM/MeOH) to obtain 14 mg (26% yield) of the title compound as a pale solid. Purity: 100%.
LRMS (m/z): 589 (M+1)+.
H NMR (400 MHz, cdcl3) δ 8.33 (d, 1 H), 8.20 (s, 1H), 7.80 (d, 1 H), 6.88 (s, 1 H), 6.77 (d, 1 H), 6.74 (s, 1 H), 6.47 (d, 1 H), 6.25 (s, 1 H), 6.22 (s, 1 H), 5.60 - 5.43 (m, 1 H), 5.34 (s, 2H), 4.53 (d, 2H), 3.10 - 2.84 (m, 9H), 2.44 (s, 3H), 2.14 (s, 3H), 2.08 (d, 2H), 1.66 (d, 3H).
EXAMPLE 168
(S)-4-Amino-6-((1-(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4- yl)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 40 mg (0.12 mmol) of (S)-4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- ][1 >2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 43 mg (0.12 mmol) of 1 -methyl-4-(6-methyl-4- (trimethylstannyl)pyridin-2-yl)piperazine, 14 mg (0.01 mmol) of Pd(PPh3)4 and 12 mg (0.06 mmol) of copper (I) iodide were suspended in 4 ml of dioxane and heated at 100 °C in a sealed tube overnight under nitrogen atmosphere. After cooling, the mixture was filtered through Celite® and the solvents were removed under reduced pressure. The crude product was purified first by flash chromatography (0% to 15% DCM/MeOH) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to obtain 8 mg (14% yield) of the title compound as a yellowish solid. Purity: 99%.
LRMS (m/z): 484 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1 H), 7.79 (d, 1 H), 6.73 (d, 1 H), 6.69 (s, 1 H), 6.65 (s, 1 H), 6.51 (d, 1 H), 5.60 - 5.43 (m, 1 H), 5.32 (s, 2H), 3.69 - 3.60 (m, 4H), 2.58 - 2.51 (m, 4H), 2.49 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H), 1.65 (d, 6H).
EXAMPLE 169
5-(2-Aminopyridin-4-yl)-A/-((S)-1-(4-((3S,5 ?)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-fl[1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
The title compound was prepared from 70 mg (0.11 mmol) of 5-(2-aminopyridin-4-yl)-/\/- ((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyrimidin-4-amine following the experimental procedure described in Example 124. The crude product was redissolved in ethyl acetate and the solution was washed with an aqueous saturated solution of sodium carbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to give 39 mg (70% yield) of the pure title compound as a pale solid. Purity: 95%.
LRMS (m/z): 499 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 11.93 (1 H, s), 8.18 (1 H, s), 7.95 (1 H, d), 7.53 (1 H, d), 7.31 (1 H, d), 6.62 (1 H, dd), 6.53 - 6.50 (1 H, m), 6.22 (1 H, d), 5.97 (1 H, s), 5.15 (1 H, q), 3.78 (2H, t), 2.81 - 2.71 (2H, m), 2.47 - 2.37 (2H, m), 2.35 (3H, s), 1.46 (3H, d), 0.95 (6H, t).
EXAMPLE 170
5-(6-Aminopyridin-3-yl)- V-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl)-7W-pyrrolo[2,3-cGpyrimidin-4-amine
The title compound was prepared from 70 mg (0.1 1 mmol) of 5-(6-aminopyridin-3-yl)-/V- ((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-r][1 ,2,4]triazin-2- yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 -/-pyrrolo[2,3-c/]pyrimidin-4-amine following the experimental procedure described in Example 124. The crude product was redissolved in ethyl acetate and the solution was washed with an aqueous saturated solution of sodium carbonate and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 5% B to 25% B, in a 8 min. gradient) to give 3 mg (5% yield) of the title compound. Purity: 99%.
LRMS (m/z): 499 (M+1)+. 1H NMR (400 MHz, cdcl3) δ 9.68 (s, 1 H), 8.38 (s, 1 H), 8.31 (s, 1 H), 7.63 (dd, 1 H), 7.47 (d, 1 H), 6.96 (s, 1 H), 6.61 (d, 1 H), 6.44 (d, 1 H), 6.20 (d, 1 H), 5.42 - 5.23 (m, 1 H), 4.64 (s, 2H), 3.92 (d, 2H), 3.09 - 2.85 (m, 2H), 2.72 - 2.47 (m, 2H), 2.41 (s, 3H), 1.56 (d, 3H), 1.09 (t, 6H).
EXAMPLE 171
Ethyl 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-cqpyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-/][1,2,4]triazin-4-yl)-5-methylbenzoate 25 mg (26% yield) of the title compound were obtained as a side product in the experimental procedure described in Preparation 129. The product was isolated after purification of the crude material by flash chromatography (0% to 20% DCM/MeOH) as a white solid. Purity: 97%.
LRMS (m/z): 553 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1 H), 8.05 (d, 1 H), 7.99 - 7.95 (m, 1 H),
7.95 - 7.91 (m, 1 H), 7.72 - 7.67 (m, 1 H), 6.92 - 6.90 (m, 2H), 6.90 - 6.87 (m, 2H), 6.88 - 6.81 (m, 1 H), 6.65 (m, 1 H), 5.68 (s, 2H), 4.33 (q, 2H), 2.45 (s, 3H), 2.00 (s, 3H), 1.31 (t, 3H). EXAMPLE 172
3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-c/lpyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1- |[1,2,4]triazin-4-yl)- V-(2-hydroxyethyl)-5- methylbenzamide To a solution of 52 mg (0.01 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H- pyrazolo[3,4-c]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -r][1 ,2,4]triazin-4-yl)-5- methylbenzoic acid in DCM, 0.07 ml (0.01 mmol) of 2-aminoethanol, 23 mg (0.01 mmol) of EDC-HCI, 16 mg (0.01 mmol) of HOBt and 0.4 ml (0.03 mmol) of triethylamine were added. The reaction mixture was stirred for 3 hours at room temperature and then additional amounts of reagents were added. The solution was stirred at room temperature overnight and then it was transferred to a separation funnel and it was washed with a saturated aqueous solution of sodium bicarbonate and then with a 5% citric acid solution. The organic phase was dried over magnesium sulphate, filtered and the solvents were removed to give 5 mg (9% yield) of the title compound as a yellow solid. Purity: 98%.
LRMS (m/z): 568 (M+1)+. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (s, 1 H), 7.92 - 7.90 (m, 2H), 7.82 (d, 1 H), 7.64 - 7.59 (m, 1 H), 6.99 - 6.98 (m, 1 H), 6.93 (ddd, 1 H), 6.84 - 6.78 (m, 1 H), 6.67 (dt, 1 H), 5.76 (s, 2H), 5.51 (s, 1 H), 3.73 (t, 2H), 3.53 (t, 2H), 2.52 (s, 3H), 2.06 (s, 3H).
EXAMPLE 173
2-(Dimethylamino)-A/-(3-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-^[1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-cGpyrimidin-5- yl)-5-hydroxyphenyl)ethanesulfonamide
The title compound was prepared from 18 mg (0.02 mmol) of 2-(dimethylamino)-/V-(3- (4-(((S)-1 -(4-((3S,5ft)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-5- hydroxyphenyl)ethanesulfonamide following the experimental procedure described in Example 124. The crude product was directly purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to give 4 mg (25% yield) of the title compound. Purity: 96%.
LRMS (m/z): 648 (M+1 )+.
1H NMR (400 MHz, Methanol-d4) δ 8.20 (1 H, s), 7.56 (1 H, d), 7.13 (1 H, s), 6.87
- 6.85 (1 H, m), 6.76 - 6.75 (1 H, m), 6.73 - 6.72 (1 H, m), 6.58 (1 H, d), 5.25 (1 H, q), 4.12 - 4.01 (2H, m), 3.48 - 3.45 (2H, m), 3.30 (2H, m), 3.02 - 2.89 (2H, m), 2.87 - 2.76 (2H, m), 2.48 (3H, s), 2.19 (6H, s), 1.57 (3H, d), 1.29 (6H, s). EXAMPLE 174
(S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(4-(4-(dimethylamino)piperidin- yl)benzyl)amino)-5-methylpyrrolo[2,1-fl[1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-
5-carbonitrile 40 mg (0.12 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 56 mg (0.18 mmol) of Λ/1-(4-(4- (dimethylamino)piperidin-1-yl)benzyl)-/\/2,/\/2-dimethylethane-1 ,2-diamine and 64 μΙ (0.37 mmol) of DIEA were stirred in 3 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and methylene chloride. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NHs) to obtain 38 mg (52% yield) of the title compound as a white solid. Purity: 99%.
LRMS (m/z): 597 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1 H), 7.52 (d, 1 H), 7.08 (d, 2H), 6.87 (d, 2H), 6.66 (d, 1 H), 6.45 (d, 1 H), 5.30 (s, 2H), 5.27 - 5.16 (m, 1 H), 4.78 (q, 2H),
3.71 (d, 2H), 3.61 (dq, 2H), 2.69 (t, 2H), 2.53 (t, 2H), 2.44 (s, 3H), 2.30 (s, 6H), 2.27 - 2.23 (m, 1 H), 2.16 (s, 6H), 1 .92 (d, 2H), 1.55 (t, 3H).
EXAMPLE 175
/V-((S)-1-(4-((3S,5 ?)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 - ^[1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-o(]pyrimidin-4-amine
The title compound was prepared from 47 mg (0.06 mmol) of A/-((S)-1 -(4-((3S,5ft)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d)pyrimidin-4-amine following the experimental procedure described in Example 124. The crude product was directly purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%.) to give 15 mg (61 % yield) of the title compound. Purity: 99%.
LRMS (m/z): 406 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 1 1.46 (1 H, s), 8.17 (1 H, s), 8.03 (1 H, s), 7.62 (1 H, d), 7.47 (1 H, d), 7.07 (1 H, dd), 6.68 (1 H, dd), 6.52 (1 H, d), 5.31 (1 H, q), 3.97 - 3.90 (2H, m), 2.99 - 2.92 (2H, m), 2.68 - 2.61 (2H, m), 2.37 (3H, s), 1.55 (3H, d), 1.03 - 1.01 (6H, m).
EXAMPLE 176
3-(4-Amino-1 -((4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5-methylpyrrolo[2,1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol 67 mg (0.1 1 mmol) of 1-((4-(2-(4-(dimethylamino)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)methyl)-3-iodo-1 /-/-pyrazolo[3,4-d]pyrimidin-4- amine, 40 mg (0.26 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 10 mg (0.01 mmol) of PdCI2dppf DCM and 200 μΙ (0.40 mmol) of a 2M aqueous solution of caesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred under argon atmosphere at 100 °C for 16 hours. Then the reaction mixture was filtered through Celite®, the filter washed with ethyl acetate and the solvents were removed from the organic solution. The crude product was purified by reverse phase chromatography (C- 18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 18 mg of an oil that was treated with hexane and sonicated until a solid formed. The solid was filtered and dried in the vacuum oven to give 13 mg (20% yield) of the title compound as a colourless solid. Purity: 98%.
LRMS (m/z): 562 (M+1 )+.
1H NMR (400 MHz, DMSO-d6) δ 8.24 (1 H, s), 8.20 (1 H, s), 7.73 (1 H, d), 6.88 (1 H, s), 6.81 (1 H, d), 6.63 (1 H, d), 6.57 (1 H, d), 5.48 (2H, s), 4.33 (2H, t), 2.71 (1 H, d), 2.48 - 2.43 (2H, m), 2.36 (3H, s), 2.19 (6H, s), 2.1 1 - 2.06 (1 H, m), 1.80 (2H, t), 1.61 (2H, t), 1.26 - 1.18 (2H, m).
EXAMPLE 177
(S)-4-Amino-6-((1-(5-methyl-4-((4-(4-methylpiperazin-1-yl)benzyl)(2-(pyrrolidin-1- yl)ethyl)amino)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile
40 mg (0.12 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2,1 - ][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 55 mg (0.18 mmol) of A/-(4-(4-methylpiperazin- 1-yl)benzyl)-2-(pyrrolidin-1-yl)ethanamine and 64 μΙ (0.37 mmol) of DIEA were stirred in 3 ml of acetone at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM/MeOH/NH3) to obtain 57 mg (79% yield) of the title compound as a pale solid. Purity: 100%.
LRMS (m/z): 595 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.45 (s, 1 H), 8.19 (s, 1 H), 7.58 (d, 1 H), 6.98 (d, 2H), 6.82 (d, 2H), 6.54 (d, 1 H), 6.51 (d, 1 H), 5.50 (s, 2H), 5.33 - 5.21 (m, 1 H), 4.81 (s, 2H), 3.83 - 3.63 (m, 2H), 3.25 (br s, 4H), 3.17 (ddd, 2H), 3.07 (br s, 4H), 2.78 - 2.71 (m, 4H), 2.47 (d, 6H), 1.94 (br s, 4H), 1.55 (d, 3H).
EXAMPLE 178
(S)-4-Amino-6-((1-(4-(2-(4-(dimethylamino)piper^
methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 50 mg (0.15 mmol) of (S)-4-amino-6-((1 -(4-chloro-5-methylpyrrolo[2, 1-r][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile, 73 mg (0.15 mmol) of N, N-d methyl- 1 -(6- methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine, 18 mg (0.02 mmol) of Pd(PPh3)4 and 15 mg (0.08 mmol) of copper (I) iodide were stirred in 2 ml of dioxane at 100 °C overnight. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The crude product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1 % v/v ammonium formate buffered] 0% to 100%) and then by preparative HPLC (Symmetry Prep® C18 column, mixture of eluents A/B from 15% B to 95% B, in a 20 min. gradient) to obtain 4 mg (5% yield) of the title compound as a pale solid. Purity: 99%.
LRMS (m/z): 512 (M+1)+.
EXAMPLE 179
5-(2-Aminopyridin-4-yl)-W-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)pyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
A solution of trifluoroacetic acid (2 ml) and 5-(2-aminopyridin-4-yl)-/\/-((S)-1-(4- ((2S,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7 -/-pyrrolo[2,3-cdpyrimidin-4-amine (53 mg, 0.08 mmol) was stirred at room temperature for 1.5 hours. Trifluoroacetic acid was then removed under reduced pressure. The obtained residue was then dissolved in 0.5 ml of methanol and 2 ml of a 7M solution of ammonia in methanol was added. The mixture was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue was partitioned between ethyl acetate (30 ml) and water (60 ml). The aqueous phase was re-extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine, dried with sodium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 5% DCM/MeOH) to give 20 mg (48% yield) of the title compound as a pale brown solid. Purity: 97%.
LRMS (m/z): 485 (M+1 )+.
1H NMR (500MHz, CDCI3) δ 1.30 (6H, m), 1.66 (3H, d), 2.82 (1 H, m), 2.92 (1 H, m), 3.72 (2H, m), 4.63 (2H, m), 4.73 (2H, br s), 5.40 (1 H, m), 6.52 (1 H, d), 6.69
(2H, m), 6.77 (1 H, s), 6.93 (1 H, d), 7.22 (1 H, s), 7.59 (1 H, s), 8.18 (1 H, d), 8.47 (1 H, s), 10.60 (1 H, br s).
EXAMPLE 180
(1 -(2-((2-((4-Amino-3-(3-f luoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)oxy)ethyl)piperidin-4-yl)(4- methylpiperazin-1 -yl)methanone 10 mg (0.017 mmol) of 1-(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4- yl)oxy)ethyl)piperidine-4-carboxylic acid, 3 μΙ (0.03 mmol) of 1-methylpiperazine and 7 mg (0.018 mmol) of HATU were suspended in 2 ml of methylene chloride. 6 μΙ (0.03 mmol) of DIEA were added and the resulting solution was stirred at room temperature for 4 hours. A further equivalent of all reagents was added and the stirring continued for 72 hours more. Then the reaction mixture was diluted with DCM and washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 3 mg (26% yield) of the title compound as its diformiate salt.
LRMS (m/z): 644 (M+1)+.
1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 2H), 7.63 (d, 1 H), 7.06 - 7.03 (m,
1 H), 6.99 (ddd, 1 H), 6.75 (dt, 1 H), 6.61 (dd, 1 H), 5.67 (s, 2H), 4.64 (t, 2H), 3.71
(s, 4H), 3.21 (d, 2H), 2.99 (dd, 2H), 2.82 - 2.72 (m, 1 H), 2.68 - 2.56 (m, 4H),
2.54 (s, 3H), 2.48 (s, 3H), 1.98 - 1.77 (m, 4H). EXAMPLE 181
5-(2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl)-W-((S)-1-(4-((3S,5/?)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-2-yl)ethyl)-7H- pyrrolo[2,3-cdpyrimidin-4-amine The title compound was prepared from 45 mg (0.06 mmol) of 5-(2-(4- (dimethylamino)piperidin-1-yl)pyridin-4-yl)-/\/-((S)-1-(4-((3S,5f?)-3,5-dimethylpiperazin- 1 -yl)-5-methylpyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-c/]pyrimidin-4-amine following the experimental procedure described in Example 124. 27 mg (73% yield) of the title compound were obtained. Purity: 100%.
LRMS (m/z): 610 (M+1)+.
H NMR (400 MHz, CD30D) δ 8.25 (s, 1 H), 8.16 (d, 1 H), 7.45 (d, 1 H), 7.33 (s, 1 H), 6.88 (dd, 1 H), 6.82 (s, 1 H), 6.55 (d, 1 H), 5.18 (q, 1 H), 4.33 (d, 1 H), 4.11 (d, 1 H), 3.86 (d, 1 H), 3.77 (d, 1 H), 3.01 - 2.91 (m, 1 H), 2.90 - 2.76 (m, 1 H), 2.68 - 2.56 (m, 2H), 2.46 (s, 3H), 2.44 - 2.29 (m, 2H), 2.16 (s, 6H), 1.70 (dd, 2H), 1.57 (d, 3H), 1.31 - 1.10 (m, 2H), 1.06 (d, 6H).
EXAMPLE 182 5-(2-(Dimethylamino)pyridin-4-yl)-W-((S)-1-(4-((3S,5 ?)-3,5-dimethylpiperazin- 5-methylpyrro!o[2,1- }[1,2,4]triazin-2-yl)et yl)-7H-pyrrolo[2,3-cqpyrimid!n-4-amine
The title compound was prepared from 43 mg (0.07 mmol) of 5-(2- (dimethylamino)pyridin-4-yl)-A/-((S)-1-(4-((3S,5 )-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2, 1-/][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 - - pyrrolo[2,3-cdpyrimidin-4-amine following the experimental procedure described in Example 124. 25 mg (72% yield) of the title compound were obtained. Purity: 99%.
LRMS (m/z): 526 (M+1 )+.
1H NMR (400 MHz, CD30D) δ 8.24 (s, 1 H), 8.1 1 (d, 1 H), 7.42 (d, 1 H), 7.31 (s,
1 H), 6.82 - 6.79 (m, 1 H), 6.62 (s, 1 H), 6.55 (s, 1 H), 5.20 (q, 1 H), 3.89 - 3.84
(m, 1 H), 3.70 (d, 1 H), 3.06 - 2.92 (m, 1 H), 2.92 - 2.78 (m, 7H), 2.67 - 2.54 (m,
1 H), 2.53 - 2.39 (m, 4H), 1.56 (d, 3H), 1.07 (d, 6H). EXAMPLE 183
3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1 ,2,4]triazin-4-yl)-W-(3-(4- (dimethylamino)piperidin-1-yl)propyl)-5-methylbenzamide To a solution of 50 mg (0.10 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H- pyrazolo[3,4-c(]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 - ][1 ,2,4]triazin-4-yl)-5- methylbenzoic acid in 5 ml of DCM, 27 mg (0.14 mmol) of 1-(3-aminopropyl)-/\/,/\/- dimethylpiperidin-4-amine, 27 mg (0.14 mmol) of EDC HCI, 19 mg (0.14 mmol) of HOBt and 40 μΙ (0.3 mmol) of triethylamine were added. The reaction mixture was stirred at room temperature overnight and then at 50 °C for 3 hours. Then the volatiles were removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to give 9 mg (14% yield) of the title compound (diformate salt) as a solid. Purity: 98%.
LRMS (m/z): 693 (M+1 )+.
1H NMR (400 MHz, cdcl3) δ 8.43 (s, 1 H), 8.40 (s, 1 H), 7.90 (s, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H), 7.78 (d, 1 H), 7.55 (s, 1 H), 7.20 (s, 1 H), 6.88 - 6.78 (m, 1 H), 6.73 (d, 1 H), 6.72 - 6.64 (m, 1 H), 5.77 (s, 2H), 3.61 - 3.51 (m, 2H), 3.15 (d, 2H),
2.89 - 2.74 (m, 1 H), 2.72 - 2.56 (m, 2H), 2.47 (s, 3H), 2.39 (s, 6H), 2.22 - 2.1 1 (m, 2H), 2.08 (s, 3H), 1.92 - 1.77 (m, 4H), 1.62 - 1.47 (m, 2H). EXAMPLE 184
3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 y-pyrazolo[3,4-djpyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-A -(3-((3- (dimethylamino)propyl)(methyl)amino)propyl)-5-methylbenzamide
To a solution of 50 mg (0.10 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1AY- pyrazolo[3,4-c]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -r][1 ,2,4]triazin-4-yl)-5- methylbenzoic acid in 5 ml of DCM, 25 mg (0.14 mmol) of ^-(S-aminopropy -A/1,^3,/^- trimethylpropane-1 ,3-diamine, 27 mg (0.14 mmol) of EDC HCI, 19 mg (0.14 mmol) of HOBt and 40 μΙ (0.3 mmol) of triethylamine were added. The reaction mixture was stirred at room temperature overnight and then at 50 °C for 3 hours. Then the volatiles were removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/acetonitrile as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 8 mg (12% yield) of the title compound (diformate salt) as a solid. Purity: 96%.
LRMS (m/z): 681 (M+1)+.
1H NMR (400 MHz, cdcl3) δ 8.43 - 8.35 (m, 2H), 8.29 (s, 1 H), 7.90 (s, 1 H), 7.84
(s, 1 H), 7.76 (d, 1 H), 7.48 (s, 1 H), 7.17 - 7.15 (m, 1 H), 6.85 - 6.79 (m, 1 H), 6.69 (dd, 1 H), 6.64 (dt, 1 H), 5.72 (s, 2H), 3.60 - 3.45 (m, 2H), 2.63 (d, 4H), 2.55 (d, 2H), 2.44 (s, 3H), 2.35 (s, 6H), 2.34 (s, 3H), 2.04 (s, 3H), 1.91 - 1.74 (m, 4H).
EXAMPLE 185
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- |[1 ,2,4]triazin-4-yl)-5-methylbenzoic acid A 2M aqueous solution of lithium hydroxide (4 ml, 8 mmol) was added to a stirred suspension of (S)-methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)pyrrolo[2,1-r][1 ,2,4]triazin-4-yl)-5-methylbenzoate (85 mg, 0.2 mmol) in tetrahydrofurane and the reaction mixture was stirred at room temperature for 15 hours. The solvent was removed in vacuo and then water (15 ml) was added to the residue and the solution was acidified to pH 6 with acetic acid. The resulting yellow solid was filtered off, washed with water and purified by preparative HPLC to give 50 mg (61 % yield) of the title compound. Purity: 100%. LRMS (m/z): 415 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1 H), 8.18 (m, 1 H), 8.12 (s, 1 H), 8.01 (s, 1 H), 8.0 (s, 1 H), 7.57 (d, 1 H), 7.32 (br s, 2H), 7.16 (m, 1 H), 7.10 (m, 1 H), 5.46 (m, 1 H), 2.54 - 2.49 (Methyl peak obscured by DMSO, 3H), 1.64 (d, 3H).
EXAMPLE 186
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- /][1,2,4]triazin-4-yl)-/V-(2-hydroxyethyl)-5-methylbenzamide Triethylamine (130 μΙ, 0.93 mmol) was added to a stirred mixture of (S)-3-(2-(1-((6- amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2, 1 -][1 ,2,4]triazin-4-yl)-5- methylbenzoic acid (200 mg, 0.48 mmol), N-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (98 mg, 0.72 mmol) in dimethylformamide at 0 - 5 °C. The reaction mixture was stirred at 0 - 5 °C for 1 hour and then ethanolamine (31 mg, 0.5 mmol) was added and the reaction mixture was allowed to warm up to room temperature and stirred for 3 days, giving a yellow solution. The solvent was removed under reduced pressure. The residue was redissolved in methylene chloride and washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and a yellow gum was obtained and purified by flash chromatography (0% to 4% DCM/MeOH) to yield 89 mg (40% yield) of the title compound as a yellow foam. Purity: 100%.
LRMS (m/z): 458 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.64 (t, 1 H), 8.35 (s, 1 H), 8.19 (m, 1 H), 8.06 (s, 1 H), 8.01 (s,1 H), 7.95 (s, 1 H), 7.56 (d, 1 H), 7.34 (br s, 2H), 7.24 (dd, 1 H), 7.11 (m, 1 H), 5.49 - 5.42 (m, 1 H), 4.79 (t, 1 H), 3.57 (m, 2H), 3.39 (m, 2H, obscured by WATER peak), 2.52 (s, 3H, obscured by DMSO peak), 1.66 (d, 3H).
EXAMPLE 187
(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide
The title compound was prepared following the experimental procedure described in Example 186 from (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1-][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid (200 mg, 0.48 mmol) and 4- (aminomethyl)benzenesulfonamide (96 mg, 1.97 mmol). The crude product was purified by flash chromatography (0% to 4% DCM/MeOH) to give 90 mg (32% yield) of the title compound as a yellow solid. Purity: 100%. LRMS (m/z): 583 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, 1 H), 8.41 (s, 1 H), 8.19 (s, 1 H), 8.09 (s, 1 H), 8.02 (m, 2H), 7.81 (m, 2H), 7.54 (m, 3H), 7.32-724 (m, 5H), 7.11 (m, 1 H), 5.50 (m, 1 H), 4.60 (d, 2H), 2.5 (s, 3H, obscured by the DMSO peak), 1.66 (d, 3H).
EXAMPLE 188
(S)-4-Amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)pyrrolo[2,1- l[1,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
(S)-4-Amino-6-((1-(4-chloropyrrolo[2,1-r][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin carbonitrile (200 mg, 0.63 mmol) was dissolved in dioxane (4 ml). 2,6-Dimethylpyridin- 4-yl)boronic acid (140 mg, 0.93 mmol), bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane complex (52 mg, 0.06 mmol) and a 2M solution of caesium carbonate (0.64 ml, 1.28 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 flash chromatography (80% light- petrol/EtOAc) to give a yellow solid. The solid was shown by LCMS to be a mixture of the desired product and triphenylphosphine oxide. The solid was triturated with methyl tert-butyl ether (2 x 4ml) to give a yellow solid, which was dried in a vacuum oven at 50°C to give 51 mg (21 % yield) of the title compound. Purity: 98%.
LRMS (m/z): 386 (M+1)+.
1H-NMR (400 MHz, CDCI3) δ 8.24 (s, 1 H), 7.98 (s, 1 H), 7.77 (br s, 2H), 7.11-
7.06 (m, 2H), 6.59 (d, 1H), 5.64 - 5.57 (m, 1 H), 5.41 (br s, 2H), 2.82 (s, 6H), 1.74 (d, 3H).
EXAMPLE 189
(S)-4-Amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
Sodium borohydride (9 mg, 0.23 mmol) was added to a stirred solution of (S)-4-amino- 6-((l-(4-(4-formyl-3,5-dimethylphenyl)pyrrolo[2,1-/][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile (100 mg, 0.24 mmol) in THF (4 ml) and methanol (2 ml) and was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml), acidified with 1M hydrochloric acid and then basified with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 25ml) and the extracts were washed with water and brine and dried over sodium sulphate. The solvent was removed in vacuo to leave a yellow solid that was purified by flash chromatography (0% to 100% petrol/AcOEt) to give 60 mg (60% yield) of the title compound as a yellow solid. Purity: 99%.
LRMS (m/z): 415 (M+1)+.
H-NMR (400 MHz, CDCI3 + few drops of CD30D) δ 8.11 (s, 1 H), 7.81 (m, 1 H), 7.71 (s, 2H), 7.02 (dd, 1 H), 6.91 (m, 1 H), 5.49 (m, 1 H), 4.73 (s, 2H), 2.49 (s, 6H), 1.63 (d, 3H).
EXAMPLE 190
(S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f)[1,2,4]triazin-4-yl)- V-(2-hydroxyethyl)-2,6-dimethylbenzamide (S)-4-Amino-6-((1-(4-chloropyrrolo[2,1-/][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile (120 mg, 0.38 mmol) was dissolved in dioxane (4 ml). A/-(2-Hydroxyethyl)- 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (150 mg, 0.47 mmol), bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (31 mg, 0.038 mmol) and a 2M solution of caesium carbonate (0.38 ml, 0.76 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 and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC to give 49 mg (27% yield) of the title compound. Purity: 98%.
LRMS (m/z): 472 (M+1)+.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (t, 1 H), 8.17 (m, 1 H), 8.02 (s, 1 H), 7.81 (s, 2H), 7.50 (d, 1 H), 7.35 (br s, 2H), 7.23 (dd, 1 H), 7.09 (m, 1 H), 5.47 - 5.40 (m, 1 H), 4.74 (t, 1 H), 3.56 (m, 2H), 3.3 (m, 2H, obscured by the water peak), 2.35 (s, 6H), 1.65 (d, 3H).
EXAMPLE 191
/V-(3-(4-(((S)-1 -(4-((2S,6/?)-2,6-Dimethylmorpholino)pyrrolo[2,1 ,2,4]triazin-2- yl)ethyl)amino)-7AY-pyrrolo[2,3- |pyrimidin-5-yl)phenyl)methanesulfonamide A solution of trifluoroacetic acid (2 ml) and A/-(3-(4-(((S)-1-(4-((2S,6f?)-2,6- dimethylmorpholino)pyrrolo[2, 1 -f [\ ,2,4]triazin-2-yl)ethyl)amino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7 -/-pyrrolo[2,3-c pyrimidin-5- yl)phenyl)methanesulfonamide (200 mg, 0.28 mmol) was stirred at room temperature for 1.5 hours. Trifluoroacetic acid was then removed under reduced pressure. The obtained mixture was then diluted in 5 ml of methanol and 2.6 ml of a 7M solution of ammonia in methanol were added. The mixture was stirred at room temperature overnight. The solvent was then evaporated and the resulting residue was partitioned between ethyl acetate (30 ml) and water (60 ml). The aqueous phase was re-extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine, dried with sodium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 5% DCM/MeOH) to give 73 mg (43% yield) of the title compound as a pale yellow solid. Purity: 95%.
LRMS (m/z): 562 (M+1 )+.
1H NMR (500MHz, CDCI3) δ 1.26 (6H, dd), 1.61 (3H, d), 2.76 (1 H, m), 2.87 (1 H, m), 3.02 (3H, s), 3.67 (2H, m), 4.58 (2H, m), 5.34 (1 H, m), 6.49 (1 H, d), 6.62 (1 H, dd), 6.66 (1 H, dd), 7.10 (1 H, s), 7.37 -7.56 (4H, m), 7.86 (1 H, br s), 8.43 (1 H, s), 10.81 (1 H, br s).
Following the methods and procedures described above, including the methodologies described in Schemes 1 to 6 and the above examples, the following compounds can be obtained.
EXAMPLE 192
/V-(4-(4-(((S)-1 -(4-((3S,5 ?)-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1- ][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrro!o[2,3-cflpyrimidin-5-yl)-1 H-indol-6- yl)methanesulfamide
EXAMPLE 193
(S)-A/-(4-(4-((1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1 -^[1,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-c(|pyrimidin-5-yl)-1 H-indol-6-yl)methanesulfamide
EXAMPLE 194
(S)-W-(4-(4-((1-(5-Methyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1 - l[1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-c(lpyrimidin-5-yl)-1W-indol-6-yl)methanesulfamide EXAMPLE 195
(S)-5-(2-Aminopyridin-4-yl)-/V-(1 -(4-(2-(4-(dimethylamino)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2,1 - ][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-cqpyrimidin-4-amine EXAMPLE 196
(S)-3-(4-(4-((1-(4-(2-(4-(Dimethylamm^
^[1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-<^pyrimidin-5-yl)-1H-pyrazol-1- yl)propan-1-ol
EXAMPLE 197
(S)-1-(5-(4-((1-(4-(2-(4-(Dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxypyridin-3-yl)urea
EXAMPLE 198
W1-(4-(4-(((S)-1-(4-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl)amino)-7W-pyrrolo[2,3-cqpyrimidin-5-yl)pyridin-2-yl)-
A 2,yV2-dimethylethane-1,2-diamine
EXAMPLE 199
/V-((S)-1 -(4-((3S,5 )-3,5-Dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 -
/][1,2,4]triazin-2-yl)ethyl)-5-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
EXAMPLE 200
3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2,1- ][1,2,4]triazin-4-yl)-A -(1-(3-
(dimethylamino)propyl)piperidin-4-yl)-5-methylbenzamide
EXAMPLE 201
3-(4-Amino-1-((4-(2-((3-(dimethylamino)propyl)(methyl)amino)ethoxy)-5- methylpyrrolo[2,1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol
EXAMPLE 202
3-(4-Amino-1-((4-(2-(4-((dimethylamino)methyl)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2,1-/][1 ,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-cflpyrimidin-3-yl)-5- fluorophenol
EXAMPLE 203 3-(4-Amino-1-((4-(3-(4-(dimethylamino)piperidin-1-yl)propoxy)-5- methylpyrrolo[2,1-n[1,2,4]triazin-2-yl)methyl)-1H-pyra2olo[3,4-d]pyrimidin-3-yl)-5- fluorophenol
EXAMPLE 204
3-(4-Amino-1-((4-(2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)ethoxy)-5- methylpyrrolo[2,1-/][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-onpyrimidin-3-yl)-5- fluorophenol
EXAMPLE 205
3-(4-Amino-1 -((5-methyl-4-((1 -(3-(piperidin-1 -yl)propyl)piperidin-4- yl)oxy)pyrrolo[2,1- l[1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-cflpyrimidin-3-yl)-5- fluorophenol
EXAMPLE 206
3-(4-amino-1 -((5-methyl-4-(methyl(2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2,1 - f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
EXAMPLE 207
3- (4-amino-1-((4-(2-(dimethylamino)ethoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2- yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol
EXAMPLE 208
4- amino-6-(((S)-1-(4-((3S,5R)-4-(4-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
EXAMPLE 209
4-amino-6-(((S)-1 -(4-((3S,5R)-4-(3-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
EXAMPLE 210
4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1 -yl)-5-methylpyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile
REFERENCES 1 Prepared following the experimental procedure described in: Simmen, Kenneth Alan; Lin, Tse-I.; Lenz, Oliver; Surleraux, Dominique Louis Nestor Ghislain; Raboisson, Pierre Jean-Marie Bernard, PCT Int. Appl. (2006) WO2006035061 2 Prepared according to the procedure described in PCT Int. Appl., 2010151735.
3 Prepared following the experimental procedure described in: Ohta, T.; Fukuda, T.; Ishibashi, F., Iwao, M. J. Org. Chem., 2009, 74, 8143-8153 4 Prepared following the experimental procedure described in: Mazaro, G. et al., Green Chem., 2009, 11 , 774-776
5 Prepared following the experimental procedure described in: Wu, Y.-C, J. Am. Chem. Soc, 2008, 130 (22), 7148-7152
6 Prepared according to the procedure described in PCT Int. Appl., 2012064973.
PHARMACOLOGICAL ACTIVITY
PI3K , β, δ and γ Enzymatic Inhibition Assays
Compounds were screened for their ability to inhibit PI3Koc (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 Reaction [Enz] [ATP] [PIP2] Preincubation Reading
PI3K
Time (min) (nM) (μΜ) (μΜ) Time (min) (hours)
ALPHA 6 0.30 15 2 30 1 - 18
BETA 6 0.75 15 5 30 1 - 18
DELTA 8 0.35 15 2 30 1 - 18
GAMMA 8 2.5 15 10 30 1 - 18
Reaction time and enzyme concentration in the assay will depend of each batch.
All experiments were analysed using Activity Base software from I DBS and the four- parameter log equation.
The results are shown in Table 1.
Example ICso PI3Kd HTRF (nM)
2 27
6 62
7 6
8 31
17 6
19 62
22 7
32 1
34 7
38 10
45 2
48 1
49 0.3
50 2
52 13
54 1
55 0.1 Example ICso PI3Kd HTRF (nM)
57 8
59 10
61 19
66 0.5
68 6.2
69 1.0
70 1.9
76 8.8
77 3.6
78 10.6
83 6.1
85 2.0
88 0.5
90 0.9
91 45.4
96 2.7
97 1 .1
98 9.9
100 1.0
104 1.3
105 0.4
112 2.8
114 2.5
115 6.1
118 3.1
123 5.9
128 14.6
131 0.5
132 0.8
133 2.5
143 1.2
148 1.7
151 0.6
152 2.6 Example ICso PI3Kd HTRF (nM)
163 2.9
166 5.9
167 2.8
173 6.2
174 6.4
187 76.7
190 11.4
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 compounds of formula (I) 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.
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.
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 betamethasone;
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 (IMPDH) 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 AZA 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;
qq) Phosphosdiesterase (PDE) IV inhibitors such as roflumilast or
GRC-4039;
rr) Dual Phosphodiestearase (PDE) lll/IV inhibitors;
ss) Xanthine derivatives, such as theophylline or theobromine;
tt) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797;
uu) Mitogen-activated extracellular signal regulated kinase kinase
(MEK) inhibitor, such as ARRY-142886 or ARRY-438162;
vv) Janus kinase (JAK) inhibitors, such as tofacitinib (previously known as tasocitinib or CP-690,550) from Pfizer and INCB-18424, from
Incyte;
ww) 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;
xx) Interferon alpha such as Sumiferon MP;
yy) Epidermal Growth Factor Receptor (EGFR) inhibitors such as
erlotinib, Trastuzumab, Herceptin, Avastin, Platins (cisplatin, carboplatin) or Temazolamide;
zz) 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 furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541 , deprodone propionate, fluticasone propionate, fluticasone furoate, 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-1 12 (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)- Cyc!openty!-2-hydroxy-N-[1-[4(S)-methy!hexyl]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 ( 2-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- propylaminojethanol, KUL-1248, HOKU-81 , SM-110444, 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-11294A), 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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. 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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. 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 compounds of formula (I) 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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.
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 and pain;
cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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. 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 inhibitor) 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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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.
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 and pain; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 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. 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, 21st 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, 21st 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 disinteg rants 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 t% 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 cannot 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 μηι, preferably 2-5 μΐτι. Particles having a size above 20 μηη 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, intra urethra I, 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. viii) 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) 11 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 imgf000307_0001
Formulation Example 3 (Gelatin cartridge for inhalation)
Figure imgf000307_0002
Formulation Example 4 (Formulation for inhalation with a DPI)
Figure imgf000307_0003
Formulation Example 5 (Formulation for a MDI)
Figure imgf000307_0004
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, isotopically-labeled derivate thereof:
Figure imgf000308_0001
Formula (I) wherein,
W represents a direct bond or a linker selected from a -0-(CH2)o-3- group, a -S-(CH2)o-3- group, a -(CH2)1-4- group, a -(CH2)0-3-NRa-(CH2)o-3- group, a -(CH2)0-3-NRa-C(0)-(CH2)o- 3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2-4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2]-(CH2)0-3-C(O)-N(Ra)Rb group, a -(CH2)o-3-N[C(*)H2]-(CH2)2.4N(Ra)R group, a -(CH2)0-3-NO-(CH2)0.3-Rc group or a -(CH2)0.3-N[C(*)H2]-(CH2)o-3-Rc group; wherein Ra and R each independently represents hydrogen, a linear or branched Ci- C4 alkyl group or a -(CH2)0-3-O-(linear or branched Ci-C4 alkyl) group; and wherein (*) represents the point of attachment to R^
Rc represents a C3-C 0 cycloalkyi group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyi, phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched CrC4 alkyl group;
X represents a nitrogen atom or a -CR6 group; Ri represents a linear or branched C^Ce alkyl group, a linear or branched C C6 hydroxyalkyl group, a -(CH2)0-3N(Rd)Regroup, a linear or branched C^Ce haloalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C C alkyl group; and
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a CTC4 haloalkyl group, a linear or branched CVC4 hydroxyalkyl group, a C3-C cycloalkyl group, a -(CH2)i.3CN group, a -(CH2)o-3-0-(CH2)o-3-0-R7 group, a -(CH2)0-3-O-(linear or branched CTC alkyl) group, a -(CH2)0.3-O-(CH2)2.4- NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)o-3NH-(CH2) 2.4NR7R8 group, a - C(0)-(CH2)1-3CN group, a -C(0)-0-(linear or branched Ci-C4 alkyl) group, a - C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0-3-(linear or branched d-C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a -C(O)-O-(CH2)0-3-(phenyl) group, a - C(O)-(CH2)0.3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)0.3-(5- to 7- membered heteroaryl group containing at least one
heteroatom selected from O, S and N) group, a
Figure imgf000309_0001
alkyl)]o-3-(phenyl) group, a -C(0)-(CH2)0-3-NR7(CH2)o-3-(phenyl) group, a -C(O)- (CH2)o-3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)0-3-NR7(CH2)o-3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0-3-NR7R8 group, a -C(O)-(CH2)0.3-NR7-(CH2)2.6-NR7R8 group, a -CiOMCHzJo-s-N y-iCHa),. 6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0.3R8 group, a -S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0-3NR7R8 group, a -S(0)2CH2)o-3-NR7(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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0.3-(phenyl) group or a -(CH2)0.3-O- (CH2)o-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched CTC4 alkyl group, a linear or branched C C4 hydroxyalkyi group, a -(CH2)0-3-O-(linear or branched d C4 alkyl) group, a -C(0)-0-(linear or branched CrC4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0.3NRfR9 group, a -(CH2)0-3N(Rf)R9group, a -S(O)2(CH2)0. 3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(O)2(CH2)0.3NRfR9 group, a -NRf-S(O)2(CH2)0.3R9 group, a -(CH2)0-3 0-(CH2)2-4-NRfR9 group or a -(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C^Cs alkyl group or a -(CH2)0-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C^C4 alkyl group or a linear or branched C C4 hydroxyalkyi group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched (VC alkyl group, a (-VC haloalkyi group, a linear or branched C1-C4 hydroxyalkyi group, a C3-C4 cycloalkyi group, a C 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 Ci-C4 haloalkyi group, a linear or branched C1-C4 hydroxyalkyi group, a C3-C7 cycloalkyi 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), 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), 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),
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 C C haloalkyi group, a linear or branched C C4 hydroxyalkyi group or a C C4 alkoxy group;
R6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C4 alkyl group; a C C alkoxy group; a ( C4 haloalkyi group; a linear or branched C C hydroxyalkyi group; a C3-C7 cycloalkyi group; a -(CH2)0- 3NR7R8 group; a -(CH2)1-3-0-(linear or branched C C4 alkyl group); a -(CH2)0.3-OC(O)-( linear or branched C^CA alkyi group); a -(CH2)0-3-C(O)O-(linear or branched C C4 alkyi group); a -C(O)-(CH2)0-3-NR7R8 group; or a -(CH2)0.3-C(O)OH group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched Ci-C alkyi group, a d-C4 haloalkyi group, a linear or branched C C hydroxyalkyi group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C^C4 alkyi group, a C!-C4 haloalkyi group, a linear or branched Ci-C4 hydroxyalkyi group or a C C4 alkoxy group;
R5 rep -6) or (II-7)
Figure imgf000311_0001
formula (11-1 ) formula (II-2) formula (II-3) formula (I l-4)
Figure imgf000311_0002
formula (II-5) formula (II-6) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group;
Rs>, Rii, i3, Ri and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyi group; R10 and Rs each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched ( C4 alkyi group, a C!-C haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a -0-(linear or branched ( C3 alkyl) group, a -(CH2)0-3- C(0)-(CH2) o.3-NR'R"group, a -(CH2) o-3NR'R" group, a -(CH2)0.3- NR'-(CH2)i.6-NR'R" group, a -(CH2) 0.3-C(O)OH group, or a - (CH2)o.3NR'-S(0)2(CH2)o-3R" group, a -(CH2)0-3NR'-S(O)2(CH2)0-3 NR'R" group, a -(CH2)0-3NR'-C(O)(CH2)0.3 NR'R" group, a -
(CH2)o-3-(piperidinyl) group or a -(CH2)0.3-(piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched
(VC3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
• L represents a direct bond or a linker selected from -O-(CH2)0.3-, -S-
(CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH2)1-4 group. 2. A compound according to claim 1 , wherein
W represents a direct bond or a linker selected from a -O-(CH2)0.3- group, a -S-(CH2)0-3- group, a -(CH2)1-4- group, a -(CH2)0.3-NRa-(CH2)0.3- group, a -(CH2)0-3-NRa-C(O)-(CH2)0. 3- group, a -0-(CH2)2-4-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2.4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2]-(CH2)0-3-C(O)-N(Ra)R group, a -(CH2)0-3-N[C(*)H2]-(CH2)2.4N(Ra)Rb group, a -(CH2)0-3-N(*)-(CH2)0.3-Rc group or a -(CH2)0-3-N[C(*)H2]-(CH2)o.3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0.3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment to R^
Rc represents a C3-C10 cycloalkyi group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyi, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched Ci-C4 alkyl group; X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched C^Ce alkyl group, a linear or branched C C6 hydroxyalkyl group, a -(CH2)o-3N(Rd)Regroup, a linear or branched C^Ce haloalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C1-C4 alkyl group; and
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C^-C4 alkyl group, a Ci-C haloalkyl group, a linear or branched CrC4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)i-3CN group, a -(CH2)o-3-0-(CH2)o-3-0-R7 group, a -(CH2)o-3-0-(linear or branched C C4 alkyl) group, a -(CH2)0-3-O-(CH2)2.4- NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)0-3NH-(CH2) 2.4NR7R8 group, a - C(0)-(CH2)1-3CN group, a -C(0)-0-(linear or branched C C4 alkyl) group, a - C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0-3-(linear or branched d-C4 alkyl) group, a -C(0)-(CH2)o-3-(phenyl) group, a -C(O)-O-(CH2)0-3-(phenyl) group, a -
C(0)-(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-(5- to 7- membered heteroaryl group containing at least one
heteroatom selected from O, S and N) group, a -C(O)-(CH2)0-3-NR7[CH(C1-C2 alkyl)]o-3-(phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0-3-(phenyl) group, a -C(O)-
(CH2)o-3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o-3-NR7(CH2)o-3- (monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-NR7R8 group, a -C(O)-(CH2)0.3-NR7-(CH2)2-6-NR7R8 group, a -C(0)-(CH2)o.3-NR7-(CH2)i.
6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0.3R8 group, a -S(O)2(CH2)0-3R8 group, a -S(O)2(CH2)0-3NR7R8 group, a -S(0)2CH2)o-3-NR7(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)0-3-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0-3-(phenyl) group or a -(CH2)0.3-O- (CH2)o-3-(phenyl) group; wherein each phenyl, heteroaryl, and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched Ci-C4 alkyl group, a linear or branched C C4 hydroxyalkyi group, a -(CH2)0-3-O-(linear or branched CV C4 alkyl) group, a -C(0)-0-(linear or branched C C alkyl) group, a -
C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0-3NRfR9 group, a -(CH2)0-3N(Rf)R9group, a -S(O)2(CH2)0. 3(linear or branched C C4 alkyl) group, a -S(0)2(CH2)o-3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(O)2(CH2)0-3R9 group, a -(CH2)0.3- 0-(CH2)2.4-NRfR9 group or a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C^-C3 alkyl group or a -(CH2)0.3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C -C4 alkyl group or a linear or branched C C4 hydroxyalkyi group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C4 cycloalkyi group, a CrC4 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 Ci-C4 alkyl group, a Ci-C4 haloalkyi group, a linear or branched Ci-C4 hydroxyalkyi group, a C3-C7 cycloalkyi 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), a - (CH2)o.3-0-(CH2)o-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), 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),
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 C alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group or a C C4 alkoxy group;
R6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C4 alkyl group; a C C4 alkoxy group; a CVC haloalkyi group; a linear or branched C C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a -(CH2)0.
3NR7R8 group; a -(CH2)i.3-0-(linear or branched C1-C4 alkyl group); a -(CH2)0-3-OC(O)-( linear or branched C C4 alkyl group); a -(CH2)o-3-C(0)0-(linear or branched C1-C4 alkyl group); a -C(O)-(CH2)0-3-NR7R8 group; or a -(CH2)0-3-C(O)OH group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C-,-C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched (- C4 alkyl group, a C^C^ haloalkyi group, a linear or branched CVC4 hydroxyalkyl group or a C!-C4 alkoxy group;
R5 represents a m
Figure imgf000315_0001
formula (11-1) formula (II-2) formula (II-5)
Figure imgf000315_0002
formula (II-6) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R and to the pyrrolotriazine group;
R9, R10, ii, Ri2, i3, i4, Ri5, Z and L are as defined in claim 1.
3. A compound according to claim 1 , wherein
W represents a direct bond or a linker selected from a -O-(CH2)0-3- group, a -S- (CH2)0. 3- group, a -(CH2)1-4- group, a -(CH2)0.3-NRa-(CH2)o-3- group, a -(CH2)0.3-NRa-C(O)- (CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2-4.N(Ra)R group or a -(CH2)o-3-N(*)-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C alkyl group or a -(CH2)0-3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen
Rc represents a C3-C10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C C alkyl group;
X represents a nitrogen atom or a -CR6 group;
R-i represents a linear or branched C^-Ce alkyl group, a linear or branched C C6 hydroxyalkyl group, a linear or branched C^C6 haloalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group; a cyano group; a linear or branched Ci-C4 alkyl group; a Ci-C4 haloalkyl group; a linear or branched C C4 hydroxyalkyl group; a C3-C4 cycloalkyl group; a -(CH2)1-3CN group; a -(CH2)o-3-0-(linear or branched Ci-C4 alkyl) group; a -(CH2)o-3-0-(CH2)2. -NR7R8 group; a -(CH2)0.3NR7R8 group; a -(CH2)o-3NH-(CH2) 2.4NR7R8 group; a -C(0)-(CH2)1-3-CN group; a -C(0)-0- (linear or branched C C4 alkyl) group; a -C(O)-(CH2)0-3-NR7R8 group; a -C(O)- (CH2)o-3-NR7-(CH2)2.4-NR7R8 group; a -NR7-S(0)2(CH2)o-3R8 group; a - S(0)2(CH2)o.3R8 group; a -S(O)2(CH2)0-3NR7R8 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-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; a -(CH2)0.3-(phenyl) group or a -(CH2)o-3-0-(CH2)0-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group or a - (CH2)o-3-0-(CH2)2-4- R7R8 group;
R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched ( C4 hydroxyalkyi group, a C3-C4 cycloalkyi group, a ( 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 C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C7 cycloalkyi 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), a - (CH2)o.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), 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),
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 C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group or a (- C4 alkoxy group;
R6 represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C4 alkyl group; a ( C4 alkoxy group; a C C4 haloalkyi group; a linear or branched C C4 hydroxyalkyi group; a C3-C cycloalkyi group; a -(CH2)0.
3NR7R8 group; a -(CH2)1-3-0(linear or branched C C4 alkyl group); a -(CH2)0.3-OC(O)-( linear or branched C C4 alkyl group); a -(CH2)o-3-C(0)0-(linear or branched C^C4 alkyl group); a -C(O)-(CH2)0.3-NR7R8 group; or a -(CH2)o-3-C(0)OH group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C^C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group, a C3-C7 cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group or a C CA alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-2), (II-3), (II-4), (II-5), (II-6) or (II-7)
Figure imgf000318_0001
formula (11-1) formula (II-2) formula (II-3) formula (II-4)
Figure imgf000318_0002
formula (II-5) formula (II-6) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group;
Rg, Rii, Ri3, Ri4 and R15each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C C4 alkyl group; Rio and R 2 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C1-C4 alkyl group, a Ci-C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a -0-(linear or branched C!-C3 alkyl group) group, a - (CH2)0.3-C(0)-(CH2) o-3-NR'R"group, a -NH2 group, a -(CH2) <M- C(0)OH group, or a -(CH2)o-3NR'-S(0)2R" group; wherein R' represents a hydrogen atom or a linear or branched ( C3 and wherein R" represents a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
L represents a direct bond or a linker selected from -O-(CH2)0-3-, -S- (CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH2)1- group.
4. A compound according to claim 3, wherein
W represents a direct bond or a linker selected from a -0-(CH2)o-3- group, a -S- (CH2)0- a- group, a -(CH2)i-4- group, a -(CH2)o-3-NRa-(CH2)o-3- group, a -(CH2)0-3-NRa-C(O)-
(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)-(CH2) 2.4.N(Ra)Rb group or a -(CH2)o.3-N(*)-(CH2)o.3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R^
R° represents a C3-C10 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched CTC4 alkyl group; X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched C C6 alkyl group; a linear or branched Ci-C6 hydroxyalkyl group, a linear or branched C^-Ce haloalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a hydroxyl group; a cyano group; a linear or branched C C4 alkyl group; a C C4 haloalkyl group; a linear or branched C1-C4 hydroxyalkyl group; a C3-C4 cycloalkyl group; a -(CH2)1-3CN group; a -(CH2)0-3-O-(linear or branched C C4 alkyl) group; a -(CH2)o-3-0-(CH2)2.4-NR7R8 group; a -(CH2)o-3NR7R8 group; a -(CH2)o-3NH-(CH2) 2.4NR7R8 group; a -CiOMCHz s-CN group; a -C(0)-0- (linear or branched d-C alkyl) group; a -C(O)-(CH2)0-3-NR7R8 group; a -C(O)-
(CH2)0.3-NR7-(CH2)2.4-NR7R8 group; a -NR7-S(O)2(CH2)0-3R8 group; a - S(O)2(CH2)0.3R8 group; a -S(O)2(CH2)0-3NR7R8 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)o-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; a -(CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)o-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group or a - (CH2)o.3-0-(CH2)2.4-NR7R8 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, or a linear or branched C C4 hydroxyalkyl group;
R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)0-3-S-(CH2)o-3-(phenyl group), a -(CH2)0-3-O-(CH2)0-3-(phenyl group), or a -(CH2)0-3-(phenyl group);
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C1-C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group or a C C4 alkoxy group;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C!-C4 alkyl group, a C C4 haloalkyi group, or a linear or branched C C4 hydroxyalkyl group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group, a C^-C haloalkyi group, a linear or branched C C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyl group or a C 4 alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
Figure imgf000321_0001
formula (11-1) formula (II-5) formula (II-7)
wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9, R10, Ri i, Ri2, Ri3, Ri4, Ri5, Z and L are as defined in claim 1.
5. A compound according claim 1 or claim 2, wherein Ri represents a linear or branched C C6 alkyl group, a linear or branched C Ce hydroxyalkyi group, a -(CH2)0. 3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicydic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched C^C alkyl group; and
wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, a linear or branched Ci-C4 hydroxyalkyi group, a C3-C cycloalkyl group, a -(CH2)o-3-0-(CH2)o-3-0-R7 group, a -(CH2)o-3-0-(linear or branched C C4 alkyl) group, a -(CH2)o-3-0-(CH2)2.4-NR7R8 group, a -(CH2)0. 3NR7R8 group, a -(CH2)o-3NH-(CH2) 2.4NR7R8 group, a -C(0)-0-(linear or branched C C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0. 3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a - C(0)-0-(CH2)o-3-(phenyl) group, a -C(O)-(CH2)0-3-(monocyclic or bicydic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(O)-(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-NR7[CH(C1-C2 alkyl)]o.3-(phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0.3- (phenyl) group, a -C(0)-(CH2)0.3-NR7(CH2)o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a - C(0)-(CH2)0-3-NR7(CH2)o-3-(monocyclic or bicydic 5- to 9- membered
heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o.3-NR7R8 group, a -C(OHCH2)o-3-NR7-(CH2)2-6-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)1-6-NR7-(CH2)1.6-NR7R8 group, a -NR7- S(0)2(CH2)o-3R8 group, a -S(0)2(CH2)o-3R8 group, a -S(0)2(CH2)o-3NR7R8 group, a -S(0)2CH2)0-3-NR7(CH2)o-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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0- 3-(phenyl) group or a -(CH2)o-3-0-(CH2)o-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched C^C4 alkyl group, a linear or branched C C4 hydroxyalkyl group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -C(0)-0-(linear or branched C C alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched C C4 alkyl) group, a -C(O)-(CH2)0.3NRfR9 group, a -(CH2)0.3N(Rf)R9group, a -S(O)2(CH2)0.
3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(O)2(CH2)0.3R9 group, a -(CH2)0.3- 0-(CH2)2.4-NRfR9 group or a -(CH2)0.3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-C3 alkyl group or a -(CH2)0-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched CrC4 alkyl group or a linear or branched C C4 hydroxyalkyl group.
6. A compound according to any one of the preceding claims, wherein R2 represents a hydrogen atom, a halogen atom or a linear or branched CVC4 alkyl group.
7. A compound according to any one of the preceding claims, wherein R3 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched CVC4 alkyl group, a C C4 haloalkyl group, or a linear or branched C C4 hydroxyalkyl group.
8. A compound according to any one of claims 1 to 5 wherein R represents a hydrogen atom, a linear or branched C^C4 alkyl group, a -(CH2)0-3-S-(CH2)0.3-(phenyl group), a -(CH2)o-3-0-(CH2)0-3-(phenyl group), or a -(CH2)0-3-(phenyl group);
wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched ( C4 alkyl group, a C1-C4 haloalkyl group, a linear or branched CrC4 hydroxyalkyl group or a C!-C4 alkoxy group.
9. A compound according to any one of the preceding claims, wherein R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, or a linear or branched C1-C4 hydroxyalkyl group.
10. A compound according to any one of claims 1 to 3 and 5 to 9, wherein R5 represents a moiety of formula (11-1), (II-2), (II-5), (II-6)
Figure imgf000323_0001
formula (11-1 ) formula (II-2) formula (II-5)
Figure imgf000323_0002
wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• R9i R10, Rii, Ri2, i3, Ri4, Ri5, Z and L are as defined in claim 1.
1 1. A compound of according to claim 1 , wherein W represents a direct bond or a linker selected from a-0-(CH2)o-3- group, a -S- (CH2)0-3- group, a -(CH2)i-4- group, a -(CH2)0-3-NRa-(CH2)o-3- group, a -(CH2)0-3-NRa-C(0)-(CH2)o- 3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)o.3-N(*)-(CH2) 2-4-N(Ra)Rb group, a -(CH2)0. 3-NRa-CH[C(*)H2]-(CH2)o-3-C(0)-N(Ra)R group, a -(CH2)o-3-N[C(*)H2]-(CH2)2.4N(Ra)R group, a -(CH2)0.3-N(*)-(CH2)o-3-Rc group or a -(CH2)o-3-N[C(*)H2]-(CH2)0.3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched C^C4 alkyl) group; and wherein (*) represents the point of attachment to F^;
Rc represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
wherein the phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C^-CA alkyl group;
X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched C -C6 alkyl group, a linear or branched C C6 hydroxyalkyl group, a -(CH2)o-3N(Rd)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein Rd and Re each independently represents hydrogen or a linear or branched Ci-C alkyl group; and
wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched ( C4 alkyl group, a C1-C4 haloalkyl group, a linear or branched Ci-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3-O-(CH2)0.3-O-R7 group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -(CH2)0-3-O-(CH2)2.4-NR7R8 group, a -(CH2)0-
3NR7R8 group, a -(CH2)0.3NH-(CH2) 2.4NR7R8 group, a -C(0)-0-(linear or branched C C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0. 3-(linear or branched (- C4 alkyl) group, a -C(O)-(CH2)0-3-(phenyl) group, a - C(0)-0-(CH2)o-3-(phenyl) group, a -C(O)-(CH2)0.3-(monocyclic or bicyclic 5- to 9- membered heterocyclyl group containing at least one heteroatom selected from
O, S and N) group, a -C(O)-(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -C(O)- (CH2)o-3-NR7[CH(C1-C2 alkyl)]o-3-(phenyl) group, a -C(0)-(CH2)o-3-NR7(CH2)o-3- (phenyl) group, a -C(O)-(CH2)0.3-NR7(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -
C(0)-(CH2)0.3-NR7(CH2)o-3-(monocyclic or bicyclic 5- to 9- membered
heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -C(0)-(CH2)o.3-NR7R8 group, a -C(0)-(CH2)o-3-NR7-(CH2)2-6-NR7R8 group, a -C(O)-(CH2)0-3-NR7-(CH2)1-6-NR7-(CH2)1.6-NR7R8 group, a -NR7- S(O)2(CH2)0.3R8 group, a -S(0)2(CH2)o-3R8 group, a -S(O)2(CH2)0.3NR7R8 group, a -S(0)2CH2)o-3-NR7(CH2)o-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-(monocyclic or bicyclic 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a -(CH2)0- 3-(phenyl) group or a -(CH2)0-3-O-(CH2)0-3-(phenyl) group;
wherein each phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched CVC4 alkyl group, a linear or branched CrC hydroxyalkyl group, a -(CH2)0-3-O-(linear or branched C C4 alkyl) group, a -C(0)-0-(linear or branched C C4 alkyl) group, a - C(0)-OH group, a -C(O)-(CH2)0-3-(linear or branched C^CA alkyl) group, a -C(0)-(CH2)o-3NRfR9 group, a -(CH2)0.3N(Rf)R9group, a -S(O)2(CH2)0. 3(linear or branched C C4 alkyl) group, a -S(O)2(CH2)0-3NRfR9 group, a - NRf-S(0)2(CH2)o.3NRfR9 group, a -NRf-S(O)2(CH2)0-3R9 group, a -(CH2)0.3- 0-(CH2)2.4-NRfR9 group or a -(CH2)0-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; which heteroaryl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C C3 alkyl group or a -(CH2)o-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C1-C4 alkyl group or a linear or branched Ci-C4 hydroxyalkyl group;
R2 represents a hydrogen atom or a linear or branched C1-C4 alkyl group;
R3 represents a hydrogen atom or a linear or branched C^-C^ alkyl group;
R4 represents a hydrogen atom, a linear or branched C C alkyl group, or a -(CH2)0.3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C4 alkyl group;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a C C4 haloalkyi group, or a linear or branched C C4 hydroxyalkyl group; R7 and R8 each independently represent a hydrogen atom, a linear or branched ( C alkyl group, a linear or branched C C3 hydroxyalkyi group, a C3-C7 cycloalkyl group, a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C1-C4 alkyl group, a C C4 haloalkyi group, a linear or branched C C4 hydroxyalkyi group or a C C4 alkoxy group;
R5 represents a m
Figure imgf000326_0001
formula (11-1 ) formula (II-2) formula (II-5)
Figure imgf000326_0002
formula (II-6) formula (I I-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
· Z represents a nitrogen atom or a -CH group;
• R9 R-i ,, R13i R1 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C^C4 alkyl group;
• R10 and R 2 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched Ci-C4 alkyl group, a Ci-C4 haloalkyi group, a linear or branched Ci-C4 hydroxyalkyi group, a -0-(linear or branched ( C3 alkyl) group, a -(CH2)o-3-
C(0)-(CH2) o-3-NR'R"group, a -(CH2) 0.3NR'R" group, a -(CH2)0-3- NR'-(CH2)i-6-NR'R" group, a -(CH2) 0-3-C(O)OH group, or a - (CH2)o.3NR'-S(0)2(CH2)0.3R" group, a -(CH2)0-3NR'-S(0)2(CH2)o-3 NR'R" group, a -(CH2)MNR,-C(0)(CH2)M NR'R" group, a - (CH2)o-3-(piperidinyl) group or a -(CH2)0-3-(piperazinyl) group; wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched C C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
• L represents a direct bond or a linker selected from -O-(CH2)0-3-, -S- (CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a -
C(0)-0- group or a -(CH2)1-4 group.
12. A compound according to claim 11 , wherein: W represents a direct bond or a linker selected from a-O-(CH2)0-3- group, a -(CH2)1^- group, a -(CH2)0.3-NRA-(CH2)0-3- group, a -0-(CH2)2.4-N(*)RA group, a -(CH2)0.3-N(*)- (CH2) 2.4.N(RA)RB group, a -(CH2)o.3-NRA-CH[C(*)H2]-(CH2)o.3-C(0)-N(RA)RB group, a - (CH2)o.3-N[C(*)H2]-(CH2)2^N(RA)RB group, a -(CH2)0-3-N(*)-(CH2)0-3-RC group or a - (CH2)o-3-N[C(*)H2]-(CH2)o-3-RC group; wherein RA and RB each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0.3-O-(linear or branched C C4 alkyl) group; and wherein (*) represents the point of attachment to R^
RC represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
X represents a -CR6 group;
RT represents a linear or branched C C6 alkyl group, a linear or branched Ci-C6 hydroxyalkyl group, a -(CH2)0.3N(RD)Regroup, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, a 1 ,4-azathianyl group, a thiomorpholinyl 1 ,1 -dioxide group, a 2,5-diazabicyclo[2.2.1]heptan-2-yl group, a 2,5-diazabicyclo[2.2.1 ]octan-2-yl group, a pyrrolidinyl-2-one group, or a pyrrolidinyl group; wherein Rd and Re each independently represents hydrogen or a linear or branched C C4 alkyl group; and
wherein the cycloalkyl, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1 ,4-azathianyl, thiomorpholinyl 1 , 1 - dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1]octan-2-yl, pyrrolidinyl-2-one or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched Ci-C4 alkyl group, a C†-C4 haloalkyl group, a linear or branched C C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0.3-O- (CH2)o-3-0-R7 group, a -(CH2)o-3-0-(linear or branched CVC alkyl) group, a - (CH2)o-3-0-(CH2)2-4-NR7R8 group, a -(CH2)0-3NR7R8 group, a -(CH2)0-3NH-(CH2) 2. 4NR7R8 group, a -C(0)-0-(linear or branched d-C4 alkyl) group, a -C(0)-OH group, a -C(O) group, a -C(O)-(CH2)0-3-(linear or branched d-d alkyl) group, a -C(0)-(CH2)o-3-(phenyl) group, a -C(0)-0-(CH2)o-3-(phenyl) group, a -C(O)- (CH2)o-3-(piperazinyl) group, a -C(O)-(CH2)0-3-NR7[CH(d-d alkyl)]0.3-(phenyl) group, a -C(0)-(CH2)0.3-NR7(CH2)o-3-(phenyl) group, a -C(O)-(CH2)0-3-NR7(CH2)0- 3-(piperidinyl) group, a -C(O)-(CH2)0-3-NR7(CH2)0-3-(pyridinyl) group, a -C(O)- (CH2)o-3-NR7R8 group, a -C(O)-(CH2)0-3-NR7-(CH2)2.6-NR7R8 group, a -C(O)- (CH2)o-3-NR7-(CH2)1.6-NR7-(CH2)1.6-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(0)2(CH2)o-3R8 group, a -S(O)2(CH2)0-3NR7R8 group, a -S(O)2CH2)0.3- NR7(CH2)o-3-(phenyl) group, a -(CH2)0-3-(pyrrolidinyl) group, a -(CH2)0-3- (piperazinyl) group, a -(CH2)0.3-(piperidinyl) group, a -(CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)o.3-(phenyl) group;
wherein each phenyl, pyridinyl, pyrrolidinyl, piperazinyl or piperidinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched d-d alkyl group, a linear or branched d-d hydroxyalkyl group, a -(CH2)0.3-O-(linear or branched d-d alkyl) group, a -C(0)-0-(linear or branched d-d alkyl) group, a -C(0)-OH group, a -C(O)-(CH2)0.3-(linear or branched d-d alkyl) group, a -C(O)-(CH2)0-3NRfR9 group, a -(CH2)0-3N(Rf)R9group, a - S(0)2(CH2)o-3(linear or branched d-d alkyl) group, a -S(O)2(CH2)0- 3NRfR9 group, a -NRf-S(O)2(CH2)0.3NRfR9 group, a -NRf-S(O)2(CH2)0.3R9 group, a -(CH2)0.3-O-(CH2)2.4-NRfR9 group or a -(CH2)0-3-(pyridinyl) group; which pyridinyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-C3 alkyl group or a - (CH2)o-3NRfR9 group; and wherein Rf and R9 each independently represents hydrogen, a linear or branched C C4 alkyl group or a linear or branched C C4 hydroxyalkyi group;
R2 represents a hydrogen atom;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, or a -(CH2)0-3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched C^-C3 alkyl group; R7 and R8 each independently represent a hydrogen atom, a linear or branched C C3 alkyl group, a linear or branched C^C3 hydroxyalkyi group, a C3-C cycloalkyi group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C C4 alkoxy groups; R5 represents a moiety of formula (11-1 ), (II-2), (II-5), (II-6) or (II-7);
Figure imgf000329_0001
formula (11-1) formula (II-2) formula (II-5)
Figure imgf000329_0002
formula (11-6} formula (11-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group; • Z represents a nitrogen atom;
β R9 R R13 R14 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C -C3 alkyl group;
• R 0 and R12 each independently represent a phenyl group, a pyridinyl group, a pyrazolyl group or an indolyl group;
wherein the phenyl, pyridinyl, pyrazolyl, or indolyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C hydroxyalkyi group, a -0-(linear or branched C C3 alkyl) group, a
-(CH2)o.3-C(0)-(CH2) o-3-NR'R"group, a -(CH2) o-3NR'R" group, a - (CH2)o-3-NR'-(CH2)1-6-NR'R" group, a -(CH2) 0-3-C(O)OH group, a - (CH2)o-3NR'-S(0)2(CH2)o.3R" group, a -(CH2)0-3NR'-S(0)2(CH2)o.3 NR'R" group, a -(CH2)o.3NR'-C(0)(CH2)o-3 NR'R" group, a - (CH2)o-3-(piperidinyl) group or a -(CH2)0-3-(piperazinyl) group, wherein said piperidinyl or piperazinyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C C4 alkyl group or a -(CH2) 0-3NR'R" group; and wherein R' represents a hydrogen atom or a linear or branched ( C3 alkyl group and wherein R" represents a hydrogen atom, a linear or branched C^C3 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C4 alkyl group;
· L represents a direct bond.
13. A compound of according to claim 3, wherein
W represents a direct bond or a linker selected from a -O-(CH2)0-3- group, a -S- (CH2)0. 3- group, a -(CH2)i-4- group, a -(CH2)0-3-NRa-(CH2)o-3- group, a -(CH2)0-3-NRa-C(O)-
(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0.3-N(*)-(CH2) 2-4.N(Ra)Rb group or a -(CH2)o-3-N(*)-(CH2)0.3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C4 alkyl group or a -(CH2)0-3-O-(linear or branched C -C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R^ c represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -NH2 group, a -CHF2 group, a -CF3 group or a linear or branched C C alkyl group;
X represents a nitrogen atom or a -CR6 group;
Ri represents a linear or branched C^C& alkyl group, a linear or branched C C6 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N,
wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched <-VC hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0.3-O-(linear or branched C C4 alkyl) group, a -(CH2)o. 3-0-(CH2)2.4-NR7R8 group, a -(CH2)0.3NR7R8 group, a -(CH2)0.3NH-(CH2) 2.4NR7R8 group, a -C(0)-0-(linear or branched C C alkyl) group, a -C(O)-(CH2)0-3-NR7R8 group, a -C(O)-(CH2)0-3-NR7-(CH2)2- -NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a -S(0)2(CH2)o-3R8 group, a -(CH2)0.3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group, a - (CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)0-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C^C4 alkyl group or a -(CH2)0.3-O-(CH2)2.4-NR7R8 group; R2 represents a hydrogen atom or a linear or branched CrC alkyl group;
R3 represents a hydrogen atom or a linear or branched C C4 alkyl group;
R4 represents a hydrogen atom, a linear or branched CVC4 alkyl group, or a -(CH2)0.3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C C4 alkyl group; R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C4 alkyl group, a Ci-C4 haloalkyl group, or a linear or branched C C hydroxyalkyl group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C C4 alkyl group, a C3-C7 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a linear or branched C^C4 alkyl group, a C C4 haloalkyl group, a linear or branched Ci-C4 hydroxyalkyl group or a C C4 alkoxy group;
R5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
Figure imgf000332_0001
formula (11-1 ) formula (II-5) formula (II-7) wherein:
(*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
Z represents a nitrogen atom or a -CH group;
Rg. Rn, Ri3, Ri4 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C^-C4 alkyl group; R10 and R12 each independently represent a phenyl group, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, or a linear or branched CTC4 hydroxyalkyl group;
L represents a direct bond or a linker selected from -0-(CH2)o-3-, -S- (CH2)o-3-, a -C(0)-NH- group, a -NH-C(O)- group, a -O-C(O)- group, a - C(0)-0- group or a -(CH2) -4 group.
14. A compound according to claim 13, wherein:
W represents a direct bond or a linker selected from a-O-(CH2)0-3- group, a -(CH2)i-4- group, a -(CH2)o-3-NRa-(CH2)o-3- group, a -0-(CH2)2.4-N(*)Ra group, a -(CH2)0-3-N(*)- (CH2) 2.4.N(Ra)R group or a -(CH2)0-3-N(*)-(CH2)o-3-Rc group; wherein Ra and Rb each independently represents hydrogen, a linear or branched C C alkyl group or a -(CH2)0- 3-0-(linear or branched C1-C4 alkyl) group; and wherein (*) represents the point of attachment of the nitrogen atom to R^
R° represents a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
X represents a -CR6 group;
Ri represents a linear or branched C C6 alkyl group, a linear or branched C C6 hydroxyalkyi group, a C3-C7 cycloalkyi group, a phenyl group, a pyridinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group;
wherein the cycloalkyi, phenyl, pyridinyl, piperidinyl, piperazinyl,
tetrahydropyranyl, morpholinyl or pyrrolidinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C C4 alkyl group, a C C4 haloalkyl group, a linear or branched C C4 hydroxyalkyi group, a C3-C4 cycloalkyi group, a - (CH2)o-3-0-(linear or branched d-C4 alkyl) group, a -(CH2)o-3-0-(CH2)2.4-NR7R8 group, a -(CH2)o-3NR7R8 group, a -(CH2)0-3NH-(CH2) 2.4NR7R8 group, a -C(0)-0- (linear or branched C C4 alkyl) group, a -C(O)-(CH2)0.3-NR7R8 group, a -C(O)- (CH2)o-3-NR7-(CH2)2.4-NR7R8 group, a -NR7-S(O)2(CH2)0-3R8 group, a - S(0)2(CH2)o-3R8 group, a -(CH2)0.3-(pyrrolidinyl) group, a -(CH2)0-3-(phenyl) group or a -(CH2)o-3-0-(CH2)o-3-(phenyl) group; wherein said phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a linear or branched CrC4 alkyl group or a -(CH2)0-3-O-(CH2)2-4- NR7R8 group; R2 represents a hydrogen atom;
R3 represents a hydrogen atom; R4 represents a hydrogen atom, a linear or branched C C4 alkyl group, or a -(CH2)o-3- (phenyl group); wherein the phenyl group is unsubstituted or substituted by one or more a hydroxyl groups;
R6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a linear or branched C†-C3 alkyl group;
R7 and R8 each independently represent a hydrogen atom, a linear or branched C C3 alkyl group, a C3-C4 cycloalkyl group, or a phenyl group, which phenyl group is unsubstituted or substituted by one or more C C4 alkoxy groups;
R5 represents a moiety of formula (11-1 ), (II-5) or (II-7)
Figure imgf000334_0001
formula (11-1 ) formula (II-5) formula (II-7) wherein:
• (*) represents the point of attachment of R5 to the carbon atom bonded to R4 and to the pyrrolotriazine group;
• Z represents a nitrogen atom;
· 9, Rii, Ri3. i4 and R15 each independently represent a hydrogen atom, a cyano group, a -NH2 group, or a linear or branched C1-C3 alkyl group;
• R10 and R12 each independently represent a phenyl group; wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C C3 alkyl group;
• L represents a direct bond.
15. A compound according to claim 1 , which is one of:
1. (S)-Tert-butyl 4-(((2-(1-((6-amino-5-cyanopyrimidin-4- yl)amino)ethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)methyl)piperidine-1-carboxylate;
2. (S)-4-Amino-6-((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrinriidine-5-carbonitrile;
3. (S)-4-Amino-6-((1-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
4. (S)-4-Amino-6-((1 -(4-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
5. (S)-4-Amino-6-((1-(4-((1-isopropylpiperidin-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
6. (S)-4-Amino-6-((1 -(4-isopropoxypyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
7. (S)-4-Amino-6-((1 -(5-bromo-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
8. (S)-2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-((tetrahydro-2H-pyran- 4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazine-5-carbonitrile;
9. (S)-4-Amino-6-((1-(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
10. (S)-4-Amino-6-((1 -(5-bromo-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
11. (S)-Tert-butyl 4-((2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- bromopyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)piperidine-1-carboxylate;
12. (S)-4-Amino-6-((1 -(5-bromo-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrrolo[2 -f][1 ,2,4]triazin-2^
13. (S)-4-Amino-6-((1 -(5-methyl-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
14. (S)-4-Amino-6-((1 -(4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
15. (S)-Tert-butyl 4-((2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)piperidine-1 -carboxylate;
16. (S)-4-Amino-6-((1 -(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
17. (S)-4-Amino-6-((1 -(4-((1 -isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
18. (S)-3-(4-Amino-6-((1 -(5-methyl-4-(4-methylpiperazin-1 -yl)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol;
19. (S)-3-(4-Amino-6-((1-(5-methyl-4-((tetrahydro-2H-pyran-4- yl)methoxy)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol;
20. (S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
21. (S)-4-Amino-6-((1-(4-((3-hydroxybenzyl)oxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
22. (S)-4-Amino-6-((1-(4-(3-(hydroxymethyl)phenoxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrirnidine-5-carbonitrile;
23. (S)-4-Amino-6-((1-(4-(3-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
24. (S)-4-Amino-6-((1-(4-(4-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
25. 3-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
26. (S)-4-Amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
27. 3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
28. 4-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol;
29. (S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-2-hydroxybenzamide;
30. (S)-4-Amino-6-((1 -(4-(2-hydroxyphenyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
31. (S)-4-Amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
32. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
33. (S)-4-Amino-6-((1 -(4-(3,5-dihydroxyphenoxy)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
34. (S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide;
35. (S)-4-Amino-6-((1-(4-(5-amino-6-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
36. (S)-4-Amino-6-((1-(4-(5-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
37. (S)-4-Amino-6-((1-(4-(3-hydroxy-5-(hydroxymethyl)phenoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
38. (S)-4-Amino-6-((1-(4-(3-((2-(dimethylamino)ethyl)amino)phenoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboniirile;
39. (S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
40. (S)-4-Amino-6-((1-(4-(4-(3-hydroxybenzyl)piperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
41. (S)-4-Amino-6-((1 -(4-(3,5-difluoro-4-hydroxyphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrirnidine-5-carbonitrile;
42. 3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
43. (S)-4-Amino-6-((1 -(4-((3-hydroxyphenyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
44. (S)-4-Amino-6-((1 -(4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
45. 3-(4-Amino-1-((5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
46. 3-(4-Amino-1 -((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
47. (S)-4-Amino-6-((1-(4-(4-methoxy-3,5-dirnethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
48. 3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylrriorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
49. (S)-4-Amino-6-((1-(4-(4-hydroxy-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
50. (S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-cyclopropyl-5-hydroxybenzamide;
51. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- methoxyphenyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidin 5-carbonitrile;
52. (S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)(2-morpholinoethyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
53. (S)-N-(3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-hydroxyphenyl)methanesulfonamide;
54. 3-(4-Amino-1-((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
55. 3-(4-Amino-1-((4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrro!o[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
56. (S)-4-Amino-6-((1 -(4-((2-(dimethylamino)ethyl)(3-fluoro-5- hydroxyphenyl)amino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidi^ carbonitrile;
57. (S)-4-Amino-6-((1-(4-(4-hydroxy-3-(2-hydroxypropan-2-yl)phenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
58. (S)-N-(5-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-2-methoxypyridin-3-yl)-4- methoxybenzenesulfonamide;
59. (S)-N-(5-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-2-hydroxypyridin-3-yl)-4- methoxybenzenesulfonamide;
60. 3-(4-amino-1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5-fluorophenol;
61. (S)-4-amino-6-((1-(4-((3-methoxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrimidine-5-carbonitrile;
62. 3-(4-amino-1-((5-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
63. (S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
64. 3-(4-amino-1 -((4-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
65. (S)-4-amino-6-((2-(3-hydroxyphenyl)-1 -(4-(4-isopropylpiperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
66. 4-amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
67. (S)-4-amino-6-((1 -(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
68. (S)-4-amino-6-((1 -(5-methyl-4-(4-(pyrrolidin-1 -ylmethyl)piperidin-1 -yl)pyrrolo[2, 1 f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
69. (S)-4-((1-(4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrinriidine-5- carbonitrile;
70. (S)-4-amino-6-((1 -(5-methyl-4-(2-morpholinoethyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
71. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazin-1- yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitril^
72. 3-(4-amino-1 -((4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
73. (S)-4-amino-6-((1-(4-((2-hydroxyethyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
74. (S)-4-amino-6-((1-(4-((3-hydroxyphenyl)(2-methoxyethyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
75. (S)-4-amino-6-((1-(5-methyl-4-(methyl(1-methylpiperidin-4-yl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
76. 4-amino-6-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)-2-(3-hydroxyphenyl)ethyl)amino)pyrimidine-5-carbonitrile;
77. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-hydroxybenzamide;
78. 4-amino-6-(((S)-1 -(5-methyl-4-(methyl((1 S,2S)-2-
(methylamino)cyclohexyl)amino)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile;
79. (S)-4-amino-6-((1 -(4-(dimethylamino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
80. (S)-4-amino-6-((1-(4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
81. 3-(4-amino-1-((4-((3S,5R)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5- methylpyrrolo[2 ,1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
82. (S)-4-amino-6-((1-(4-((2-aminoethyl)(methyl)amino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
83. (S)-4-amino-6-((1 -(5-methyl-4-((2-(methylamino)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
84. (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)(rriethyl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
85. N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- ^[1 ,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
86. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimi 5-carbonitrile;
87. N-(3-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
88. N-(3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide;
89. 4-amino-6-(((S)-1 -(4-((3R,5S)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
90. 5-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol ;
91. 4-(((S)-1-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-6-arninopyrimidine-5-carbonitrile;
92. (S)-4-amino-6-((1 -(4-((3-aminopropyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)arriino)pyrimidine-5-carbonitrile;
93. (S)-4-amino-6-((1 -(5-methyl-4-((3-(methylamino)propyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
94. 4-amino-6-(((S)-1-(4-((2S,6R)-2,6-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
95. 3-(4-amino-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)- 1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
96. 3-(4-amino-1-((5-methyl-4-thiomorpholinopyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)- 1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
97. 3-(4-amino-1-((5-methyl-4-((2-(pyrrolidin-1-yl)ethyl)amino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
98. (S)-4-amino-6-((1-(4-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)annino)pyrimidine-5-carbonitrile;
99. (S)-methyl 4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-2,6-dimethylbenzoate;
100. 3-(1 -((4-((1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
101. 3-(4-amino-1 -((4-((3-hydroxypropyl)(methyl)amino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
102. 3-(4-amino-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholino)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirnidin-3-yl)-5-fluorophenol;
103. (S)-methyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
104. (S)-4-amino-6-((1 -(4-(3-cyano-5-hydroxyphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
105. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid;
106. 1 -(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)piperidin-4-ol;
107. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-rnethylbenzanriide;
108. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide;
109. 4-amino-6-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)arnino)pyrirnidine-5-carbonitrile;
110. N-(3-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidiri-5-yl)-5- hydroxyphenyl)methanesulfonannide
1 11. 4-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)piperazin-2-one;
112. 1 -(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)piperidine-4-carboxamide ;
113. 3-(4-amino-1 -((5-methyl-4-(2-(pyrrolidin-1 -yl)ethoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
114. 4-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)thiomorpholine 1 , 1 -dioxide;
115. 3-(1 -((4-(1 ,4-diazepan-1 -yl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-4- amino-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
116. (S)-4-amino-6-((1 -(4-(3-hydroxy-5-methylphenyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
117. 3-(1-((4-((1 R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)methyl)-4-amino-1 H-pyrazolo[3^-d]pyrimidin-3-yl)-5-fluorophenol;
118. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5-methylbenzamide;
119. (S)-4-amino-6-((1-(5-methyl-4-(2-(4-methylpiperazin-1-yl)pyridin-4- yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
120. (S)-4-amino-6-((1 -(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
121. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arnino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide;
122. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-y!)-N-(3-hydroxybenzyl)-5-methylbenzamide
123. 3-(4-amino-1-((5-methyl-4-((1 S,4S)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.2]octan-2-yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-fluorophenol;
124 N-((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)-5-(1 -methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine;
125. 3-(4-amino-1 -((4-((2-(dimethylamino)ethyl)(tetrahydro-2H-pyran-4-yl)amino)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
126. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methyl-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzamide;
127. 3-(4-amino-1-((5-methyl-4-((1 R,4R)-5-(methylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-fluorophenol;
128. (S)-2-((2-((S)-1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)amino)-3-(4-hydroxyphenyl)propanannide;
129. N-(3-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)methanesulfonamide;
130. (S)-4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide;
131. N-(5-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxypyridin- yl)methanesulfonamide;
132. 3-(4-amino-1 -((5-methyl-4-(2-morpholinoethoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin-2- yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
133. 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
134. (S)-4-amino-6-((1-(4-(3-cyano-5-(3-hydroxypropoxy)phenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
135. 5-(5-amino-6-methoxypyridin-3-yl)-N-((S)-1 -(4-((2S,6R)-2,6- dimethylmorpholino)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
136. N-(3-(4-amino-1 -((4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- hydroxyphenyl)methanesulfonamide;
137. (S)-4-amino-6-((1 -(4-(3-cyano-5-((4-(methylsulfonyl)benzyl)oxy)phenyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
138. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-(methylsulfonarriido)benzyl)benzamide;
139. (S)-methyl 4-((3-(2-(1-((6-amino-5-cyanopyrinnidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-methylbenzamido)methyl)benzoate;
140. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arriino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-5- methylbenzamide;
141. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxyphenyl)-5-methylbenzamide;
142. (S)-4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-4-yl)-5-methylbenzarriido)methyl)benzoic acid;
143. ethyl 1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4- carboxylate;
1 . N-(4-(4-(((S)-1 -(4-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)methanesulfonamide;
145. (S)-N-(3-(4-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2 yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide;
146. (S)-3-aminophenyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
147. (S)-3-(2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
148. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-N,5-dimethylbenzamide;
149. 3-(4-amino-1-((R)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 f][1 ,2,4]triazin-2-yl)ethyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
150. 3-(4-amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 f][1 ,2,4]triazin-2-yl)ethyl)-1 l-l-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
151. 1-(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylic acid
152. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]tria2in-4-yl)-N-(4-((2-hydroxyethyl)carbamoyl)benzyl)-5-methylbenzamide;
153. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-(sulfamoylamino)benzyl)benzamide;
154. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-(3-methoxy-5-(methylsulfonamido)benzyl)-5-methylbenzarnide;
155. (S)-methyl 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-5-cyanobenzoate;
156. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-rnethylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-cyanobenzoic acid;
157. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-methoxy-4-(methylsulfonamido)benzyl)-5-methylbenzamide;
158. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-cyano-N-(4-sulfamoylbenzyl)benzamide;
159. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxy-5-(methylsulfonamido)benzyl)-5-methylbenzamide;
160. (S)-4-amino-6-((1 -(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1 -yl)pyrimidin-4- yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
161. (S)-2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arnino)ethyl)-5-methylpyrrolo[2,1- H[1 ,2,4]triazin-4-yl)-6-methyl-N-(4-sulfamoylbenzyl)pyrimidine-4-carboxamide;
162. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5-methylbenzenesulfonamide;
163. (S)-4-amino-6-((1 -(4-((2-(dimethylamino)ethyl)(4-(4-methylpiperazin-1 - yl)benzyl)amino)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
164. 3-(2-((S)-1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-N-((S)-1-(3-hydroxyphenyl)ethyl)-5-methylbenzamide;
165. (S)-4-sulfamoylbenzyl 3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
166. (S)-4-amino-6-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)pyridin-4-yl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
167. (S)-4-amino-6-((1-(4-(2-(4-(4-(dimethylamino)-6-methylpyridin-2-yl)piperidin-1- yl)pyridin-4-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
168. (S)-4-amino-6-((1 -(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1 -yl)pyridin-4- yl)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
169. 5-(2-aminopyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
170. 5-(6-aminopyridin-3-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
171. ethyl 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin- 1-yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-5-methylbenzoate;
172. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5- methylbenzamide;
173. 2-(dimethylamino)-N-(3-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5- hydroxyphenyl)ethanesulfonamide;
174. (S)-4-amino-6-((1 -(4-((2-(dimethylamino)ethyl)(4-(4-(dimethylamino)piperidin-1 - yl)benzyl)amino)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- carbonitrile;
175. N-((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
176. 3-(4-amino-1-((4-(2-(4-(dimethylamino)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
177. (S)-4-amino-6-((1 -(5-methyl-4-((4-(4-methylpiperazin-1 -yl)benzyl)(2-(pyrrolidin- 1 -yl)ethyl)amino)pyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
178. (S)-4-amino-6-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)-6-methylpyridin-4-yl)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
179. 5-(2-aminopyridin-4-yl)-N-((S)-1 -(4-((2S,6R)-2,6- dimethylmorpholino)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin amine;
180. (1 -(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)oxy)ethyl)piperidin-4-yl)(4- methylpiperazin-1 -yl)methanone;
181. 5-(2-(4-(dimethylamino)piperidin-1 -yl)pyridin-4-yl)-N-((S)-1 -(4-((3S,5R)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
182. 5-(2-(dimethylamino)pyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1- yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
183. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - y!)methyl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-4-yl)-N-(3-(4-(dimethylamino)piperidi yl)propyl)-5-methylbenzamide;
184. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)-N-(3-((3- (dimethylamino)propyl)(rnethyl)amino)propyl)-5-methylbenzamide;
185. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)arriino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-5-methylbenzoic acid;
186. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide;
187. (S)-3-(2-(1 -((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2, 1 - f][1 ,2,4]triazin-4-yl)-5-methyl-N-(4-sulfamoylbenzyl)benzamide;
188. (S)-4-amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile;
189. (S)-4-amino-6-((1-(4-(4-(hydroxymethyl)-3,5-dimethylphenyl)pyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
190. (S)-4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide;
191. N-(3-(4-(((S)-1-(4-((2S,6R)-2,6-dimethylmorpholm^^
yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonarnide;
192. N-(4-(4-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6- yl)methanesulfamide;
193. (S)-N-(4-(4-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2- yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl)methanesulfamide;
194. (S)-N-(4-(4-((1 -(5-methyl-4-(2-(pyrrolidin-1 -yl)ethoxy)pyrrolo[2, 1 -f][1 ,2,4]triazin- 2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl)methanesulfamide;
195. (S)-5-(2-aminopyridin-4-yl)-N-(1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)- 5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
196. (S)-3-(4-(4-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- pyrazol-1 -yl)propan-1 -ol;
197. (S)-1 -(5-(4-((1 -(4-(2-(4-(dimethylamino)piperidin-1 -yl)ethoxy)-5- methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxypyridin-3-yl)urea;
198. N1 -(4-(4-(((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-N2,N2- dimethylethane-1 ,2-diamine;
199. N-((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-5-methylpyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)ethyl)-5-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine;
200. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)methyl)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-N-(1-(3- (dimethylamino)propyl)piperidin-4-yl)-5-methylbenzamide;
201. 3-(4-amino-1-((4-(2-((3-(dimethylamino)propyl)(methyl)amino)ethoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
202. 3-(4-amino-1-((4-(2-(4-((dimethylamino)methyl)piperidin-1-yl)ethoxy)-5- methylpyrrolo[2,1-f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
203 3-(4-amino-1 -((4-(3-(4-(dimethylamino)piperidin-1 -yl)propoxy)-5- methylpyrrolo[2 ,1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
204. 3-(4-amino-1 -((4-(2-(3-((dimethylamino)methyl)pyrrolidin-1 -yl)ethoxy)-5- methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- fluorophenol;
205. 3-(4-amino-1 -((5-methyl-4-((1 -(3-(piperidin-1 -yl)propyl)piperidin-4- yl)oxy)pyrrolo[2 -f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrirriidin-3-yl)-5- fluorop enol;
206. 3-(4-amino-1 -((5-methyl-4-(methyl(2-(pyrrolidin-1 -yl)ethyl)amino)pyrrolo[2, 1 - f][1 ,2,4]triazin-2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
207. 3-(4-amino-1-((4-(2-(dimethylamino)ethoxy)-5-methylpyrrolo[2 -f][1 ,2,4]triazin- 2-yl)methyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol;
208. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
209. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-hydroxybenzyl)-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
210. 4-amino-6-(((S)-1 -(4-((3S,5R)-4-(3-(2-(dimethylannino)ethoxy)benzyl)-3,5- dimethylpiperazin-1-yl)-5-methylpyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimi 5-carbonitrile; or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivate thereof.
16. A compound according to any one of claims 1 to 15, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of
Phosphoinositide 3-Kinase (PI3K).
17. A compound according to claim 16, wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated diseases; function disorders and neurological disorders and pain;
cardiovascular diseases; viral infection; 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.
18. A compound according to claims 16 or 17, 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.
19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15 in association with a pharmaceutically acceptable diluent or carrier. 20. Use of a compound as defined in any one of claims 1 to 15, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in any one of claims 6 to 18.
21. A method for treating a subject afflicted with a pathological condition or disease as defined in any one of claims 16 to 18 which comprises administering to said subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 15, or a pharmaceutical composition as defined in claim 19.
22. A combination product comprising (i) a compound as defined in any one of claims 1 to 15; 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 2-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.
PCT/EP2014/000432 2013-02-15 2014-02-17 Pyrrolotriazine derivatives as pi3k inhibitors WO2014124757A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP13382046.4 2013-02-15
EP13382046 2013-02-15
US201361775966P 2013-03-11 2013-03-11
US61/775,966 2013-03-11

Publications (1)

Publication Number Publication Date
WO2014124757A1 true WO2014124757A1 (en) 2014-08-21

Family

ID=47739187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/000432 WO2014124757A1 (en) 2013-02-15 2014-02-17 Pyrrolotriazine derivatives as pi3k inhibitors

Country Status (4)

Country Link
AR (1) AR094797A1 (en)
TW (1) TW201446767A (en)
UY (1) UY35332A (en)
WO (1) WO2014124757A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2877472A4 (en) * 2012-07-27 2016-01-06 Hutchison Medipharma Ltd Novel heteroaryl and heterocycle compounds, composition and methods thereof
US9512114B2 (en) 2013-09-22 2016-12-06 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
WO2017004134A1 (en) * 2015-06-29 2017-01-05 Nimbus Iris, Inc. Irak inhibitors and uses thereof
WO2018055040A1 (en) 2016-09-22 2018-03-29 Astrazeneca Ab 5-[2-(pyridin-2-ylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1 h-isoindol-1 -one derivatives and their use as dual inhibitors of phosphatidylinositol 3-kinase delta & gamma
US9944639B2 (en) 2014-07-04 2018-04-17 Lupin Limited Quinolizinone derivatives as PI3K inhibitors
CN110869359A (en) * 2017-07-06 2020-03-06 加拉帕戈斯股份有限公司 Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2041763A (en) 1979-02-05 1980-09-17 Chiesi P An inhalor for pulverulent medicinal substances
EP0069715A1 (en) 1981-07-08 1983-01-12 Aktiebolaget Draco Powder inhalator
EP0166294A2 (en) 1984-06-18 1986-01-02 Miles Inc. Medicament inhalation device
GB2165159A (en) 1984-10-04 1986-04-09 Orion Yhtymae Oy Dosing device
WO1991002558A1 (en) 1989-08-17 1991-03-07 Boehringer Ingelheim Kg Inhalator
EP0424790A2 (en) 1989-10-27 1991-05-02 Miat S.P.A. Multi-dose inhaler for medicaments in powder form
GB2242134A (en) 1990-03-02 1991-09-25 Glaxo Group Ltd Inhalation device
WO1991014468A1 (en) 1990-03-21 1991-10-03 Dmw (Technology) Limited Atomising devices and methods
WO1992000771A1 (en) 1990-07-13 1992-01-23 Innovata Biomed Limited Inhaler
WO1992003175A1 (en) 1990-08-11 1992-03-05 Fisons Plc Inhalation device
WO1992004068A1 (en) 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalator without propeller gas with foreign air stream
WO1992004928A2 (en) 1990-09-26 1992-04-02 Pharbita B.V. Inhaler devices provided with a reservoir for several doses of medium for inhaling, transporting device, whirl chamber
WO1992009322A1 (en) 1990-11-29 1992-06-11 Boehringer Ingelheim Kg Inhalation device
EP0505321A2 (en) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhaler
US5201308A (en) 1990-02-14 1993-04-13 Newhouse Michael T Powder inhaler
DE4239402A1 (en) 1992-11-24 1994-05-26 Bayer Ag Multiple dosage powder inhaler - has acceleration channel and dwell chamber for uniformly high drug dispersion
EP0674533A1 (en) 1992-12-18 1995-10-04 Schering Corporation Inhaler for powdered medications
WO1997000703A1 (en) 1995-06-21 1997-01-09 Asta Medica Aktiengesellschaft Pharmaceutical powder cartridge with integrated metering device and inhaler for powdered medicaments
WO1997012687A1 (en) 1995-10-04 1997-04-10 Boehringer Ingelheim International Gmbh Device of miniaturised construction for producing high pressure in a fluid to be atomised
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2003000325A1 (en) 2001-06-22 2003-01-03 Sofotec Gmbh & Co. Kg Powder formulation disintegrating system and method for dry powder
WO2003097613A1 (en) 2002-05-16 2003-11-27 Almirall Prodesfarma Sa Pyridazin-3(2h)-one derivatives as pde4 inhibitors
WO2004058729A1 (en) 2002-12-26 2004-07-15 Almirall Prodesfarma Sa New pyridazin-3(2h)-one derivatives
WO2005049581A1 (en) 2003-11-10 2005-06-02 Almirall Prodesfarma, S.A. Pyridazin-3 (2h) -one derivatives and their use as pde4 inhibitors
WO2005123693A1 (en) 2004-06-21 2005-12-29 Laboratorios Almirall, S.A. Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors
WO2005123692A1 (en) 2004-06-18 2005-12-29 Laboratorios Almirall, S.A. Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors
WO2006008027A1 (en) 2004-07-16 2006-01-26 Laboratorios Almirall, S.A. Inhaler for the administration of powdered pharmaceuticals, and a powder cartridge system for use with this inhaler
WO2006035061A1 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hcv inhibiting bi-cyclic pyrimidines
WO2006122788A1 (en) 2005-05-20 2006-11-23 Laboratorios Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2007124898A1 (en) 2006-04-27 2007-11-08 Laboratorios, Almirall S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXIETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2008046598A1 (en) 2006-10-20 2008-04-24 Laboratorios Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2008077639A1 (en) 2006-12-22 2008-07-03 Laboratorios Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
WO2008095720A1 (en) 2007-02-09 2008-08-14 Almirall, S.A. Napadisylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one as agonist of the beta 2 adrenergic receptor
WO2009021696A1 (en) 2007-08-10 2009-02-19 Almirall, S.A. Azabiphenylaminobenzoic acid derivatives as dhodh inhibitors
WO2009068177A1 (en) 2007-11-28 2009-06-04 Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1 -HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2009153043A1 (en) 2008-06-20 2009-12-23 Almirall, S.A. Combinations comprising methotrexate and dhodh inhibitors
WO2010069504A1 (en) 2008-12-15 2010-06-24 Almirall, S.A. (3-oxo)pyridin-4-ylurea derivatives as pde4 inhibitors
WO2010072354A1 (en) 2008-12-22 2010-07-01 Almirall, S.A. MESYLATE SALT OF 5-(2-{[6-(2,2-DIFLUORO-2-PHENYLETHOXY)HEXYL]AMINO }-1-HYDROXYETHYL)-8-HYDROXYQUINOLIN-2(1H)-ONE AS AGONIST OF THE β2 ADRENERGIC RECEPTOR
WO2010083975A1 (en) 2009-01-21 2010-07-29 Almirall, S.A. Combinations comprising methotrexate and dhodh inhibitors
WO2010151735A2 (en) 2009-06-25 2010-12-29 Amgen Inc. Heterocyclic compounds and their uses
WO2011058109A1 (en) * 2009-11-12 2011-05-19 Ucb Pharma S.A. Fused bicyclic pyrrole and imidazole derivatives as kinase inhibitors
WO2012064973A2 (en) 2010-11-10 2012-05-18 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2012146666A1 (en) * 2011-04-29 2012-11-01 Almirall, S.A. Pyrrolotriazinone derivatives as pi3k inhibitors

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2041763A (en) 1979-02-05 1980-09-17 Chiesi P An inhalor for pulverulent medicinal substances
EP0069715A1 (en) 1981-07-08 1983-01-12 Aktiebolaget Draco Powder inhalator
EP0166294A2 (en) 1984-06-18 1986-01-02 Miles Inc. Medicament inhalation device
GB2165159A (en) 1984-10-04 1986-04-09 Orion Yhtymae Oy Dosing device
WO1991002558A1 (en) 1989-08-17 1991-03-07 Boehringer Ingelheim Kg Inhalator
EP0424790A2 (en) 1989-10-27 1991-05-02 Miat S.P.A. Multi-dose inhaler for medicaments in powder form
US5201308A (en) 1990-02-14 1993-04-13 Newhouse Michael T Powder inhaler
GB2242134A (en) 1990-03-02 1991-09-25 Glaxo Group Ltd Inhalation device
WO1991014468A1 (en) 1990-03-21 1991-10-03 Dmw (Technology) Limited Atomising devices and methods
WO1992000771A1 (en) 1990-07-13 1992-01-23 Innovata Biomed Limited Inhaler
WO1992003175A1 (en) 1990-08-11 1992-03-05 Fisons Plc Inhalation device
WO1992004068A1 (en) 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalator without propeller gas with foreign air stream
WO1992004928A2 (en) 1990-09-26 1992-04-02 Pharbita B.V. Inhaler devices provided with a reservoir for several doses of medium for inhaling, transporting device, whirl chamber
WO1992009322A1 (en) 1990-11-29 1992-06-11 Boehringer Ingelheim Kg Inhalation device
EP0505321A2 (en) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhaler
DE4239402A1 (en) 1992-11-24 1994-05-26 Bayer Ag Multiple dosage powder inhaler - has acceleration channel and dwell chamber for uniformly high drug dispersion
EP0674533A1 (en) 1992-12-18 1995-10-04 Schering Corporation Inhaler for powdered medications
WO1997000703A1 (en) 1995-06-21 1997-01-09 Asta Medica Aktiengesellschaft Pharmaceutical powder cartridge with integrated metering device and inhaler for powdered medicaments
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO1997012687A1 (en) 1995-10-04 1997-04-10 Boehringer Ingelheim International Gmbh Device of miniaturised construction for producing high pressure in a fluid to be atomised
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
WO2003000325A1 (en) 2001-06-22 2003-01-03 Sofotec Gmbh & Co. Kg Powder formulation disintegrating system and method for dry powder
WO2003097613A1 (en) 2002-05-16 2003-11-27 Almirall Prodesfarma Sa Pyridazin-3(2h)-one derivatives as pde4 inhibitors
WO2004058729A1 (en) 2002-12-26 2004-07-15 Almirall Prodesfarma Sa New pyridazin-3(2h)-one derivatives
WO2005049581A1 (en) 2003-11-10 2005-06-02 Almirall Prodesfarma, S.A. Pyridazin-3 (2h) -one derivatives and their use as pde4 inhibitors
WO2005123692A1 (en) 2004-06-18 2005-12-29 Laboratorios Almirall, S.A. Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors
WO2005123693A1 (en) 2004-06-21 2005-12-29 Laboratorios Almirall, S.A. Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors
WO2006008027A1 (en) 2004-07-16 2006-01-26 Laboratorios Almirall, S.A. Inhaler for the administration of powdered pharmaceuticals, and a powder cartridge system for use with this inhaler
WO2006035061A1 (en) 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hcv inhibiting bi-cyclic pyrimidines
WO2006122788A1 (en) 2005-05-20 2006-11-23 Laboratorios Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2007124898A1 (en) 2006-04-27 2007-11-08 Laboratorios, Almirall S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXIETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2008046598A1 (en) 2006-10-20 2008-04-24 Laboratorios Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1-HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2008077639A1 (en) 2006-12-22 2008-07-03 Laboratorios Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
WO2008095720A1 (en) 2007-02-09 2008-08-14 Almirall, S.A. Napadisylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one as agonist of the beta 2 adrenergic receptor
WO2009021696A1 (en) 2007-08-10 2009-02-19 Almirall, S.A. Azabiphenylaminobenzoic acid derivatives as dhodh inhibitors
WO2009068177A1 (en) 2007-11-28 2009-06-04 Almirall, S.A. DERIVATIVES OF 4-(2-AMINO-1 -HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2009153043A1 (en) 2008-06-20 2009-12-23 Almirall, S.A. Combinations comprising methotrexate and dhodh inhibitors
WO2010069504A1 (en) 2008-12-15 2010-06-24 Almirall, S.A. (3-oxo)pyridin-4-ylurea derivatives as pde4 inhibitors
WO2010072354A1 (en) 2008-12-22 2010-07-01 Almirall, S.A. MESYLATE SALT OF 5-(2-{[6-(2,2-DIFLUORO-2-PHENYLETHOXY)HEXYL]AMINO }-1-HYDROXYETHYL)-8-HYDROXYQUINOLIN-2(1H)-ONE AS AGONIST OF THE β2 ADRENERGIC RECEPTOR
WO2010083975A1 (en) 2009-01-21 2010-07-29 Almirall, S.A. Combinations comprising methotrexate and dhodh inhibitors
WO2010151735A2 (en) 2009-06-25 2010-12-29 Amgen Inc. Heterocyclic compounds and their uses
WO2011058109A1 (en) * 2009-11-12 2011-05-19 Ucb Pharma S.A. Fused bicyclic pyrrole and imidazole derivatives as kinase inhibitors
WO2012064973A2 (en) 2010-11-10 2012-05-18 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2012146666A1 (en) * 2011-04-29 2012-11-01 Almirall, S.A. Pyrrolotriazinone derivatives as pi3k inhibitors

Non-Patent Citations (52)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Remington: The Science and Practice of Pharmacy", 2001, LIPPINCOTT WILLIAMS & WILKINS
AI-ALWAN M, JI, 2007
ALI K, JOURNAL OF IMMUNOLOGY, vol. 180, 2008, pages 2538 - 2544
ALI K, NATURE, vol. 431, 2004, pages 1007 - 1011
BILANCIO A, BLOOD, vol. 107, 2006
CONDLIFFE AM, BLOOD, vol. 106, 2005
DIL N, MOL IMMUNOL, vol. 46, 2009
DOUKAS J, JPET, vol. 328, 2009, pages 758
ERNEST L. ELIEL: "Stereochemistry of Organic Compounds", 1994, WILEY
EUR RESPIR J, vol. 22, no. 45, 2003
GRAY ET AL., ANAL BIOCHEM, vol. 313, 2003, pages 234 - 45
H. BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
H. LIEBERMAN; L. LACHMAN: "Pharmaceutical Dosage Forms:Tablets", vol. 1, 1980, MARCEL DEKKER
HAYLOCK-JACOBS S, J. AUTOIMMUN, 2010
HERMAN SEM, BLOOD, 3 June 2010 (2010-06-03)
HERMANN SE, BLOOD, vol. 116, 2010, pages 2078 - 88
JARMIN SJ, JCI, 2008
JI H, BLOOD, 2007
KOK K, TRENDS BIOCHEM SCIENCE, vol. 34, 2009, pages 115 - 127
LANNUTTI BJ, BLOOD, October 2010 (2010-10-01)
LEE ET AL., FASEB J, vol. 20, 2006, pages 455
LEE KS ET AL., J ALLERGY CLIN IMMUNOL, vol. 118, 2006, pages 403
MARTIN AL, JI, vol. 180, 2008
MARWICK JA, JACI, vol. 125, 2010, pages 1146 - 53
MARWICK JA, JRCCM, vol. 179, 2009, pages 542 - 548
MATTHEW T, IMMUNOLOGY, vol. 126, 2008
MAZARO, G. ET AL., GREEN CHEM., vol. 11, 2009, pages 774 - 776
NASHED, EUR J IMMUNOL, vol. 37, 2007, pages 416
OHTA, T.; FUKUDA, T.; ISHIBASHI, F.; IWAO, M., J. ORG. CHEM., vol. 74, 2009, pages 8143 - 8153
OKI, M, TOPICS IN STEREOCHEMISTRY, 1983, pages 1
OKKENHAUG K, SCIENCE, 2002
PAR SJ, ERJ, 2010
PINHO JF, BR. J. PHARMACOL, vol. 161, 2010
PINHO V, JI, vol. 179, 2007
PURI KD, BLOOD, vol. 1 03, 2004, pages 3448
PURI KD, BLOOD, vol. 103, 2004
RANDIS TM, EUR J IMMUNOL, vol. 38, 2008
SADHU C, BIOCHEM BIOPHYS RES COMM, vol. 308, 2003
SADHU C, JI, vol. 170, 2003
SOOND DR, BLOOD, 2010
SOOND DR, BLOOD, January 2010 (2010-01-01)
T. HIGUCHI; W. STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, ACS SYMPOSIUM SERIES
T. W. GREENE; G. M. WUTS: "Protecting Groups in Organic Synthesis", 1999, WILEY
THOMAS MS, J LEUKOC BIOL, vol. 84, 2008
TO Y, AJRCCM, 2010
TO Y, AJRCCM, vol. 182, 2010, pages 897 - 904
VANHAESEBROECK B, NAT REV MOL CELL BIOL, vol. 5, 2010, pages 11381 - 6
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
WILLIAM O, CHEMISTRY & BIOLOGY, vol. 17, 2010
WU, Y.-C., J. AM. CHEM. SOC., vol. 130, no. 22, 2008, pages 7148 - 7152
YUM HK, JI, vol. 167, 2001

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2877472A4 (en) * 2012-07-27 2016-01-06 Hutchison Medipharma Ltd Novel heteroaryl and heterocycle compounds, composition and methods thereof
US9512114B2 (en) 2013-09-22 2016-12-06 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US9518046B2 (en) 2013-09-22 2016-12-13 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US9657007B2 (en) 2013-09-22 2017-05-23 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US9670194B2 (en) 2013-09-22 2017-06-06 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US9944639B2 (en) 2014-07-04 2018-04-17 Lupin Limited Quinolizinone derivatives as PI3K inhibitors
WO2017004134A1 (en) * 2015-06-29 2017-01-05 Nimbus Iris, Inc. Irak inhibitors and uses thereof
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10961236B2 (en) 2016-09-22 2021-03-30 Astrazeneca Ab (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino) thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one as a phosphatidylinositol 3-kinase inhibitor
WO2018055040A1 (en) 2016-09-22 2018-03-29 Astrazeneca Ab 5-[2-(pyridin-2-ylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1 h-isoindol-1 -one derivatives and their use as dual inhibitors of phosphatidylinositol 3-kinase delta & gamma
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
CN110869359A (en) * 2017-07-06 2020-03-06 加拉帕戈斯股份有限公司 Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis

Also Published As

Publication number Publication date
TW201446767A (en) 2014-12-16
AR094797A1 (en) 2015-08-26
UY35332A (en) 2014-11-28

Similar Documents

Publication Publication Date Title
JP6776399B2 (en) Use of pyrazolopyrimidine derivatives for the treatment of PI3Kδ-related disorders
US9388189B2 (en) Pyrrolotriazinone derivatives as PI3K inhibitors
AU2012247491B2 (en) Pyrrolotriazinone derivatives as PI3k inhibitors
WO2014124757A1 (en) Pyrrolotriazine derivatives as pi3k inhibitors
WO2012146667A1 (en) Imidazopyridine derivatives as pi3k inhibitors
WO2014060431A1 (en) Pyrrolotriazinone derivatives as pi3k inhibitors
WO2015091531A1 (en) Imidazolopyrimidin-2-yl derivatives as jak inhibitors
WO2015091532A1 (en) Pyrrolopyrimidine derivatives as pi3k inhibitors
WO2016202800A1 (en) Pyrrolotriazinone derivatives as pi3k inhibitors
JP7556010B2 (en) Use of pyrazolopyrimidine derivatives for the treatment of pi3k delta-associated disorders - Patents.com
NZ614082B2 (en) Pyrrolotriazinone derivatives as pi3k inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14705047

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14705047

Country of ref document: EP

Kind code of ref document: A1