TW201446767A - Pyrrolotriazine derivatives as PI3K inhibitors - Google Patents

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 derivative as a phospholipid inositol 3-kinase inhibitor

The present invention relates to a novel pyrrolotriazine derivative; and a process for the preparation thereof, a pharmaceutical composition comprising the same, and its use as a phospholipid inositol 3-kinase (PI3Ks) inhibitor.

When the cells are activated by extracellular stimulation, intracellular signalling cascades involving the regulation of the second messenger are initiated, ultimately producing a response of the cells to the stimulus. Phosphoinositide 3-Kinases (PI3Ks) are one of the enzymes involved in early signal-transmitting events to excessively different types of stimuli. PI3Ks phosphorylate phosphatidylinositol (PtdIns), phospholipid inosine-4-phosphate (PtdIns-4-phosphate, PtdIns4P) and phospholipid inositol-4,5-diphosphate (PtdIns-4, 5-bisphosphate, PtdIns (4,5) P2) The 3 hydroxyl group of the inositol ring. 3- phosphatidyl inositol-derived mediator resulting correctly positioned, and through a specific binding sequence of a lipid, e.g. pleckstrin homology (PH) domain (pleckstrin homology (PH) domain) ( where汉斯布鲁克B, 2010, Nature Review Molecular Cell Biology 5: 11381-6 (Vanhaesebroeck B, 2010, Nat Rev Mol Cell Biol 5: 11381-6)) , and subsequent activation of some downstream effector proteins that bind to lipids.

The PI3K family is divided into 3 different categories (PI3K Class I, II and III). It depends on the preferences of the matrix and the characteristics of the structure.

The best feature is the class I of PI3K and the preferred matrix PtdIns(4,5)P2. It engulfs four different isoforms, which are IA classes (p110a, p110b, p110d), which are initially further subdivided into p85-types that bind to the regulatory subunit, and are p101 and Class IB (p110g) regulated by p87 subunits. In view of the general expression of isoforms of p110a (PI3Ka or PI3Kα) and p110b (PI3Kb or PI3Kβ), p110g (PI3Kg or PI3Kγ) and especially p110d (PI3Kd or PI3Kδ) have more restricted expression patterns and appear to play in white blood cells. An important role (Zucker K, Trend Biochemistry 34: 115-127, 2009 (Kok K, Trends Biochem Science 34: 115-127, 2009)) .

Both PI3Kd and PI3Kg are involved in the activation of immune cells by a large variety of different stimuli. Pharmacological inhibition or genetic defects have been shown to inhibit T cell proliferation in active p110d, as well as cytokine production corresponding to different stimuli such as anti-CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okenhan K, Science 2002; Garzon F 2009; Sud DR, Blood 2010; Hermann SEM, Blood June 3, 2010; William O, Chemistry and Biology 17 , 2010) (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 also Concanavalin A, which inhibits antigen-associated tissues retained in the body, and anti-CD3, which induces cytokine production (Vader DR, Blood 2010; Jiaming SJ, Clinical Investigation, 2008). Furthermore, B cell function is extremely dependent on the PI3Kd activity of the function exhibited by the inhibition of B cell proliferation, and the release of cytokines in vitro corresponds to anti-IgM (Pi Lanxi A, Blood 107, 2006 (Bilancio A) , Blood 107, 2006)), toll like receptor agonists such as LPS and oligodeoxygenation Nucleotide (oligodeoxynucleotides) (Dil N, Molecular Immunology 46, 2009 (Dil N, Mol Immunol 46, 2009)) or impaired ability to stimulate antigen-specific T cells (Al-Evan M) , Journal of Immunology 2007 (Al-Alwan M, JI 2007)) in the absence of functional p110d or drug inhibitors. In vivo, PI3Kg-deficient mice show partially suppressed antibody production based on immunity (Galson F 2009; Sud DR, Blood 2010; Durand CA, Journal of Immunology 2009 (Garcon F, 2009; Durand CA, JI 2009)). Further studies indicate that PI3Kd plays an important role in inhibiting T cell apoptosis and TH17 differentiation (Hellok-Jacob S, 2010, (Haylock-Jacobs S, J. Autoimmun 2010)).

In addition, the degranulation of mast cells in the cells of small mice is sharply reduced, using deactivated PI3Kd or a drug inhibitor by PI3Kd (Ali K, Nature 431: 1007-1011, 2004; Ali K, Journal of Immunology 180 :2538-2544, 2008 (Ali K, Nature 431: 1007-1011, 2004; Ali K, Journal of Immunology 180: 2538-2544, 2008), and activation of basophil via FcE receptor It is inhibited by a drug inhibitor of PI3Kd (Lanuti BJ, Blood October 2010 (Lannutti BJ, Blood Oct. 2010)).

In terms of neutrophil function, in an under-agarose migration assay, PI3Kd inhibition inhibits mouse neutropenia by inhibiting cell polarization and directional movement. Migration of leukocytes to fMLP (Sato C, J. Immunol. 170, 2003 (Sadhu C, JI 170, 2003)), whereas PI3Kd deficiency in mice or inhibitors of neutrophil therapy in vitro to LTB4 chemotaxis The microscopic (25%) reduction is observed in the body, and the accumulation of LPS in the lung is reduced by more than 80% in vivo, which means that in the endothelial cells that mediate the migration of PMN to the endothelial cells, PI3Kd is Important role (Puri KD, Blood 103, 2004 (Puri KD, Blood 103, 2004)). In addition, in the mouse body Intratumoral necrosis factor (TNF) induces neutrophil infiltration into air pockets and elastase release is partially inhibited by PI3Kd selective inhibitors (Satu C, Biochemistry and Biophysics Research Communications 308, 2003 ( Sadhu C, Biochem Biophys Res Comm 308, 2003)). Furthermore, TNF is mediated by human neutrophils to cause oxidative bursts depending on the activity of PI3Kd (Condliffe AM, Blood 106, 2005 (Condliffe AM, Blood 106, 2005)).

Contrary to the leading role of PI3Kd in lymphocyte activation, PI3Kg appears to primarily affect the chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, J. Immunol. 180, 2008; Thomas MS, White Blood Biology Journal 84, 2008; Jiaming SJ, Journal of Clinical Research 2008; Matthew T, Immunology 126, 2008 (Martin AL, JI 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008)), and also affects innate immune cells induced by G-protein coupled receptors (GPCRs) mediated by stimulation such as fMLP, IL-8 or C5a. Degranulation and Oxidation Burst (Kang Lifu AM, Blood 106, 2005; 宥HK, Journal of Immunology 167, 2001; Pinho V, Journal of Immunology 179, 2007 (Condliffe AM, Blood 106, 2005; Yum HK, JI 167, 2001; Pinho V, JI 179, 2007)).

The results of the above studies indicate that selective PI3Kd or dual PI3Kd/PI3Kg drug inhibition is a promising method for the treatment of various diseases, such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD)). , cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory response or autoimmune Mediates disease (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease) Disease), ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, spontaneous thrombocytopenia (spontaneous platelet deficiency) Idiopathic thromocytopenic purpura), Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis , angiodmatitis, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, including but not limited to Blistering diseases, scleroderma, dermatomyositis, etc. of bullous pemphigoid, cardiovascular disease; viral infection; metabolic/endocrine dysfunction; neurological disorders And pain (such as rheumatoid arthritis or osteoarthritis, low back pain, one Inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or pain associated with central pain, and bone marrow and organ transplant Rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas, and solid tumors (solid tumors) (such as pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, liver cancer ( Hepatocellular cancer), lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, non-small cells Non-small cell lung cancer and small-cell lung cancer, melanoma Noma), neuroendocrine cancers, Central nervious system cancers, brain tumors, bone cancer, soft tissue sarcoma, chronic lymphocytic leukemia, B-cell acute lymphocytic leukemia (B-cell acute lymphoblastic leukemia), T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute bone marrow Acute myeloid leukaemia, cutaneous T cell lymphoma, including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or light Premalignant and malignant skin conditions of actinic keratosis (AK).

There is a lot of experimental evidence to support this view. In a model of allergic lung inflammation in rodents, genetic or pharmacological inactivation of PI3Kd or dual PI3Kd/g inhibition reduces cell influx, mucus production, cytokine production, and airway hyperreactivity (N. Xu et al. 2007, European Journal of Immunology 37: 416; Lin et al. 2006, American Society for Experimental Biology J20: 455 & Lin KS et al., 2006, Journal of Allergy and Clinical Immunology 118: 403; Dows J, Journal of Pharmacology and Experimental Therapy 2009; 328: 758; Pa SJ, European Journal of Respiratory Diseases 2010 (Nashed et al. 2007, Eur J Immunol 37: 416; Lee et al. 2006, FASEB J 20: 455 & Lee KS et al .2006, J Allergy Clin Immunol 118: 403; Doukas J, JPET 2009; 328: 758; Par SJ, ERJ 2010)). In addition, LPS that induces lung neutrophil infiltration is limited by PI3Kd inhibition (Puri KD, Blood 2004; 103: 3448), whereas the inflammatory response corresponding to LPS or exposure to tobacco smoke is by a double PI3Kd/g Inhibition by inhibitors (Dowes J, Journal of Pharmacology and Experimental Therapy 2009; 328: 758 (Doukas J, JPET 2009; 328: 758)). In addition, PI3Kd appears to be involved in a reduction in corticosteroid treatment responsiveness associated with oxidative stress and chronic obstructive pulmonary disease (COPD). The concept is based on the findings that tobacco smoke-induced inflammation maintains a response to budesonide treatment in view of the resistance of wild-type or PI3Kg-deficient mice to corticosteroid treatment (Mavik JA, Respiratory and Journal of Intensive Care 179: 542-548, 2009 (Marwick JA, JRCCM 179: 542-548, 2009)). Similar results were obtained from PI3Kd selective inhibitors (To Y, American Journal of Respiratory and Critical Care Medicine 182:897-904, 2010 (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, American Journal of Respiratory and Critical Care Medicine 2010 (To Y, AJRCCM 2010)). In patients with chronic obstructive pulmonary disease (COPD), pulmonary macrophages show enhanced PI3Kd expression and phosphorylation of downstream protein kinase B (Akt), as well as selective inhibition of non-selective PI3K or PI3Kd Role, which repairs the inhibitory effects of dexamethasone in peripheral blood mononuclear cells (PBMC) in patients with chronic obstructive pulmonary disease (COPD) (To Y, American Journal of Respiratory and Critical Care Medicine 182 : 897-904, 2010; Mavik JA, Journal of Allergy and Clinical Immunology 125: 1146-53, 2010 (To Y, AJRCCM 182: 897-904, 2010; Marwick JA, JACI 125: 1146-53, 2010)).

In addition, PI3Kd inhibition is effective in the pattern of contact allergic reactions (Sudd DR, Blood January 2010 (Soond DR, Blood Jan 2010)). In the experimental autoimmune encephalomyelitis model, PI3Kd deficiency or pharmacological inhibition of PI3Kd attenuates T cell activation and function, and reduces the number of T cells in the central nervous system (CNS), suggesting multiple occurrences Therapeutic benefits of PI3Kd inhibitors in sclerosis and other Th17-mediated autoimmune diseases (Hellok-Jacob S, 2010: Haylock-Jacobs S, J. Autoimmun 2010). Consistent with this, genetic defects or pharmacological inhibition of PI3Kd attenuate mouse patterns. Joint damage in inflammatory arthritis (RedisTM, European Journal of Immunology 38, 2008 (RandisTM, Eur J Immunol 38, 2008)).

With regard to metabolic diseases, excessive expression of PI3Kd appears to contribute to excessive vasoconstriction, whereas PI3Kd inhibition normalizes vasoconstriction in a mouse model of type 1 diabetes, suggesting that blockade of PI3Kd has vascular function in treating diabetic patients Therapeutic potential of disorders (Pinio JF, British Journal of Pharmacology 161, 2010 (Pinho JF, Br. J. Pharmacol 161, 2010)).

There is also a large body of experimental evidence supporting that genetic or pharmacological inactivation of PI3Kd or dual PI3Kd/g dual inhibition is effective in the treatment of cancer, including but not limited to leukemias, such as chronic lymphocytic leukemia (chronic) Lymphocytic leukemia), B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymph B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases. In this aspect, the selective PI3Kd inhibitor CAL-101 shows the anti-proliferative properties of different tumor cells in vitro and the efficacy in patients with abnormal PI3Kd activity regulation (such as chronic lymphocytic leukemia) (Herman SE, Blood 116: 2078-88, 2010; Lanuti BJ, Blood October 2010 (Hermann SE, Blood 116: 2078-88, 2010; Lannutti BJ, Blood Oct. 2010)).

Targeting PI3K pathway or regulation of PI3 kinase, particularly PI3Kd or PI3Kd/g, is expected to be therapeutically applicable to the treatment or prevention of symptoms including: respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD)) , cystic fibrosis, idiopathic pulmonary fibrosis Fibrosis), sarcotic disease, allergic rhinitis, inflammatory response or autoimmune-mediated disease (rheumatoid arthritis, multiple sclerosis) Multiple sclerosis), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myasthenia 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, scleroder Ma), dermatomyositis, blistering diseases including, but not limited to, bullous pemphigoid, cardiovascular disease; viral infection; metabolic/endocrine dysfunction; neurological disorders And pain (such as rheumatoid arthritis or osteoarthritis, low back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) (central pain), and 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, liver Hepatocellular cancer, lung cancer Cancer), ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, non-small cell lung cancer, and small cell lung cancer -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, including but not Limited to basal cell carcinoma (BCC) premalignant and malignant skin conditions, scales Cell carcinoma (squamous cell carcinoma (SCC)), or actinic keratosis (actinic keratosis (AK)).

Given that many of the symptoms are expected to benefit from treatments involving modulation of the PI3K pathway or regulation of PI3 kinase, it is immediately apparent that the novel compounds that modulate the PI3K pathway and the use of such compounds provide substantial therapeutic benefit for a wide variety of patients.

Provided herein are novel pyrrolotriazine derivatives useful for treating a target PI3K pathway or inhibiting the symptoms of PI3 kinase that are therapeutically useful.

The compounds described in the present invention are potent PI3K inhibitors, particularly PI3Kd or dual PK3Kd/g inhibitors. This property makes it suitable for the treatment or prevention of pathological symptoms or diseases, Such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), Allergic disease (allergic rhinitis), inflammatory response or autoimmune mediated disease (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis) (amyotrophic lateral sclerosis), Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis (acute) Disseminated encephalomyelitis), idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis (psoriasis), acne dermatitis (acrodermatitis), cutaneous vasculitis (angiodermat (itis), atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, scleroderma, cutaneous blood vessels Cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullous pemphigoid, and epidermis Blistering diseases of epidermolysis bullosa, cardiovascular disease; viral infection; metabolic/endocrine dysfunction; neurological disorders and pain (such as rheumatoid arthritis or osteoarthritis) Osteoarthritis), low back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or pain associated with central pain, and rejection of bone marrow and organ transplants ( Bone marrow and organ transplant rejection); myelo-dysplastic syndrome; myeloproliferative Disease (myeloproliferative Disorders (eg, polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphoma (lymphomas) and solid tumors (such as pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney 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 lymphoid white 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, including but not limited to basal cell carcinoma (BCC), scale Premalignant and malignant skin conditions of squamous cell carcinoma (SCC) or actinic keratosis (AK).

The compounds described in the present invention are particularly useful for treating or preventing pathological conditions or diseases, such as neoplastic diseases (e.g., leukemia, lymphomas, and solid tumors); transplant rejection; bone marrow transplantation Applications (eg, graft-versus-host disease); autoimmune diseases (eg rheumatoid arthritis) (rheumatoid arthritis), multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus ( Systemic lupus erythematosis), autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis Dermatomyositis), and blistering diseases including, but not limited to, pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa; respiratory tract inflammation Diseases (eg, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis); skin inflammatory disease (eg atopic dermatitis, contact dermatitis (contact dermati) (tis), eczema or psoriasis; premalignant and malignant skin conditions (eg basal cell carcinoma (BCC), squamous cell carcinoma, squamous cell carcinoma, SCC)) or actinic keratosis (AK); neurological disorders and pain (such as rheumatoid arthritis or osteoarthritis, low back pain, general inflammatory pain, inflamed nerves) Inflammatory neuropathic pain, trigeminal neuralgia, or pain associated with central pain.

The compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases selected from the group consisting of leukemia, lymphomas and solid tumors, rheumatoid arthritis. , multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis Colitis), systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus Lupus erythematosus, dermatomyositis, blister disease including but not limited to pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa ( Blistering diseases), asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis (allergic rhinitis), atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous Cell carcinoma) and actinic keratosis.

Certain pyrrolotriazine derivatives have been found to be novel and potent PI3K inhibitors and are therefore useful in the treatment or prevention of such diseases.

The invention accordingly relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a nitrogen-oxide, or an isotopically-labeled derivative:

Wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -( CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-(CH ₂ ) _0-3 -yl, -O- (CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 -N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group, a-(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R a chain group in the group ^c or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c ; wherein R ^a and R ^b each independently represent hydrogen An atomic, linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) group; and wherein (*) represents a linkage a point to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and at least one selected from the group consisting of a monocyclic or bicyclic 5- to 7-membered heterocyclic group of a hetero atom of oxygen, sulfur or nitrogen; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from halogen Atom, hydroxyl, cyano, -NH ₂ group, - Substituted by one or more substituents of a CHF ₂ group, a -CF ₃ group or a linear or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or a -CR ₆ group; R ₁ represents a straight or branched chain C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ hydroxyalkyl, -(CH ₂ ) _0-3 N(R ^d )R ^e group, linear or branched C ₁ - a C ₆ haloalkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, a heteroaryl group of 5 to 14 members, containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, Or a monocyclic or bicyclic 5- to 14-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein R ^d and R ^e each independently represent a hydrogen atom or a linear or branched C ₁ - a C ₄ alkyl group; and wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a straight chain or a branched chain C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _1-3 CN , -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) ), -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ Base, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 CN group, -C(O)-O-( Linear or branched C ₁ -C ₄ alkyl), -C(O)-OH, -C(O), -C(O)-(CH ₂ ) _0-3 - (linear or Branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -( Phenyl) group, -C(O)-(CH ₂ ) _0-3 - (monocyclic or bicyclic 5- to 9-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _0-3 - (5 to 7 membered heteroaryl) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O)-(CH _{2 ) 0-3} -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _{0 -3} -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (5 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen) To a 7-membered heteroaryl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (a single atom comprising at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen Heterocyclic or bicyclic 5- to 9-membered heterocyclyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ -, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _{1- 6} -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 a (heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur and nitrogen Monocyclic or bicyclic 5- to 7-membered heterocyclyl), -(CH ₂ ) _0-3 -(phenyl) or -(CH ₂ ) _0-3 -O-(CH ₂ ) _{0- 3} - (phenyl) group with one or more substituents; wherein each phenyl, heteroaryl and heterocyclyl group is unsubstituted lines, or selected from hydroxy, linear or branched C _{a 1-} C ₄ alkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, a -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 -(straight Chain or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group , -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or Substituting one or more substituents of -(CH ₂ ) _0-3 - (a heteroaryl group of at least one selected from the group consisting of a hetero atom of oxygen, sulfur and nitrogen); wherein the heteroaryl group Substituted as one or more substituents which are unsubstituted or selected from a linear or branched C ₁ -C ₃ alkyl group or a -(CH ₂ ) _0-3 NR ^f R ^g group; ^f and R ^g each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group; and R ₂ and R ₃ each independently represent hydrogen. Atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ group, -N(CH ₃ )H group or -N(CH ₃ ) ₂ group; R ₄ represents a hydrogen atom, a straight chain or a branched chain C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 - (containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen 5 Member to 7 members of heteroaryl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _{0 -3} - (a heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _{0- 3-} (heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group , cyano, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy Substituted by one or more substituents; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ - C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _{1 -3} -O- (straight or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -OC(O)- (linear or branched C ₁ -C ₄ alkyl) , -(CH ₂ ) _0-3 -C(O)O-(linear or branched C ₁ -C ₄ alkyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ or a group _{- (CH 2) 0-3 -C (} O) OH group; R ₇ and R ₈ each independently represent a Atom, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl or phenyl a group wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a straight chain or Substituted one or more substituents of a branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₅ represents a chemical formula (II-1), (II-2), (II-3) a group of (II-4), (II-5), (II-6) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0- 3-} NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S(O ) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazinyl) Substituted by one or more substituents; wherein the piperidinyl or piperazinyl group is unsubstituted Substituted or substituted with one or more substituents selected from a linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 NR'R"group; and wherein R' represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or 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 ₁ -C ₄ alkyl group; L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O)-yl, -C(O) a chain group in the -O- group or -(CH ₂ ) _1-4 group.

The invention further provides synthetic methods and intermediates as described herein suitable for use in the preparation of the compounds.

The invention also relates to a compound of the invention for use in the therapeutic use of a human or animal body as described herein.

The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

The invention also relates to a compound of the invention as described herein for use in the treatment of ameliorating pathological symptoms or disorders by inhibiting phosphoinositide 3-kinase (PI3K) The disease, particularly the pathological symptom or disease described therein, is selected from the group consisting of respiratory diseases, allergic diseases, inflammatory or autoimmune-mediated diseases, and functions. Disorders and neurological disorders, cardiovascular diseases, viral infections, metabolism/endocrine function disorders, neurological disorders and pain , bone marrow and organ transplant rejection, myelo-dysplastic syndrome, myeloproliferative disorders (MPDs), cancer and hematologic malignancies (cancer and hematologic malignancies) ), leukemia, lymphomas, and solid tumors; in particular, wherein the pathological symptoms or diseases are selected from leukemia, lymphomas, and solid tumors (solid) Tumors), rheumatoid Arthritis (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, including but not limited to pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa blistering diseases ), asthma (asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis (sarcoidosis) ), atopic dermatitis, allergic rhinitis, contact dermatitis (contac) t dermatitis), eczema (eczema), cattle Psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK).

The invention also relates to the use of a compound of the invention as described herein for the manufacture of a medicament for the treatment of amelioration of pathological symptoms or diseases by inhibition of phosphoinositide 3-kinase (PI3K), in particular wherein said pathology Symptoms or diseases are as defined above.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibiting phosphoinositide 3-kinase (PI3Ks), particularly wherein the pathological condition or disease is as defined above.

The invention also provides a combination product comprising (i) a compound of the invention as described herein; and (ii) one or more additional active substances known to be useful in the treatment of respiratory diseases (respiratory) Diseases, allergic diseases, inflammatory or autoimmune-mediated diseases, dysfunctional and functional disorders and neurological disorders, cardiovascular diseases, Viral infection, metabolism/endocrine function disorders, neurological disorders and pain, bone marrow and organ transplant rejection, myelodysplastic syndrome (myelo-dysplastic syndrome), myeloproliferative disorders (MPDs), cancer and hematologic malignancies, leukemia, lymphomas, and solid tumors; Especially the one The pathological symptoms or diseases described are selected from the group consisting of leukemia, lymphomas and solid tumors, rheumatoid arthritis (RA), multiple sclerosis (MS). Amyotrophic lateral amyotrophic lateral Sclerosis), Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes Diabetes), cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullous pemphigoid Bullous pemphigoid) and epidermolysis bullosa blistering diseases, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), primary Idiopathic pulmonary fibrosis, sarcoidosis, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema , psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) Actinic keratosis (actinic keratosis, AK).

As used herein, the term C ₁ -C ₆ alkyl includes a straight or branched chain group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, iso-amyl Base, 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-methyl Pentyl, 3-methylpentyl and isohexyl.

When it is mentioned that an alkyl group may be optionally substituted, it is meant to include a straight or branched alkyl group as defined above, which may be unsubstituted or substituted by one or more at any position. Substituents are substituted, for example by 1, 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different.

The term C ₁ -C ₄ haloalkyl, as used herein, is alkyl, for example C ₁ -C ₄ or C ₁ -C ₂ alkyl, bonded to one or more, preferably 1 or 2 Or 3 halogen atoms. Preferably, the haloalkyl group is selected from the group consisting of -CCl ₃ , -CHF ₂ and -CF ₃ .

The term C ₁ -C ₄ hydroxyalkyl, as used herein, includes a straight or branched alkyl group having from 1 to 4 carbon atoms, any of which may be one or more, preferably one or Two, more preferably one, hydroxyl group is substituted. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.

As used herein, the term C ₁ -C ₄ alkoxy (or alkyloxy) embraces a straight or branched oxygen-containing group, each having an alkyl moiety of from 1 to 4 carbon atoms.

The term C ₃ -C ₁₀ cycloalkyl, as used herein, includes a saturated monocyclic or polycyclic carbocyclic group having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. An optionally substituted C ₃ -C ₁₀ cycloalkyl group is generally unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. When the C ₃ -C ₁₀ cycloalkyl group has 2 or more substituents, the substituents may be the same or different. Substituents which are usually on the C ₃ -C ₁₀ cycloalkyl group are themselves unsubstituted. Polycyclic cycloalkyl groups contain two or more fused cycloalkyl groups, preferably two cycloalkyl groups. Typically polycyclic cycloalkyl is selected from the group consisting of decahydronaphthyl (decalyl), bicyclo [2.2.2] octyl, adamantly, camphyl or borneol. (bornyl).

Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Base, cycloheptyl, cyclooctyl, cyclodecyl and cyclodecyl.

The term C ₃ -C ₁₀ cycloalkenyl, as used herein, includes a partially unsaturated carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. The C ₃ -C ₁₀ cycloalkenyl group is usually unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When the C ₃ -C ₁₀ cycloalkenyl group has 2 or more substituents, the substituents may be the same or different. Substituents typically on a cycloalkyl group are themselves unsubstituted.

Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl and cyclodecenyl.

As used herein, the term 5- to 14-membered heteroaryl typically includes a ring system of 5 to 14 members, preferably a ring system of 5 to 10 members, more preferably a ring system of 5 to 9 members. It comprises at least one heteroaromatic ring and contains at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen. A 5- to 14-membered heteroaryl group can be a single ring or two fusion rings in which at least one ring contains a hetero atom.

One such optionally substituted 5 to 14 membered heteroaryl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. When the 5- to 14-membered heteroaryl has 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents typically on the 5 to 14 membered heteroaryl are themselves unsubstituted.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, Oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiazide Thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolinyl (quinolyl), isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, anthraquinone Cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl Imidazolidinyl), pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl (2H-pyrazolo[3,4-d]pyrimidinyl , 1H-pyrazolo[3,4-d]pyrimidinyl (1H-pyrazolo[3,4-d]pyrimidinyl), thieno[2,3-d]pyrimidinyl (thieno[2,3-d] Pyrimidinyl) and various free radicals of pyrrolopyridyl.

As used herein, the term 5-member to 14-membered heterocyclic group generally includes a non-aromatic saturated or unsaturated C ₅ -C ₁₄ carbon ring system, preferably a C ₅ -C ₁₀ carbon ring system, more preferably C. _{a 5-} C ₉ carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, are replaced by a hetero atom selected from nitrogen, oxygen and sulfur . The heterocyclic group may be a single ring or two fusion rings, at least one of which contains a hetero atom. When the heterocyclic group of 5 to 14 members has 2 or more substituents, the substituents may be the same or different.

One of the optionally substituted 5 to 14 membered heterocyclic groups is generally unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. Generally, the substituent on the 5-member to 14-membered heterocyclic group is itself unsubstituted.

Examples of monocyclic or bicyclic 5- to 14-membered heterocyclic groups include piperidyl, pyrrolidyl, pyrrololinyl, piperazinyl. (piperazinyl), morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl , triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, cyclothioethane (thiaranyl), aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxa 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one, 1,3-dioxol-2- Ketone (1,3-dioxol-2-one), tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl , tetrahydrothiopyranyl, 1,4-azathianyl, oxepanyl, thiephanyl , azepanyl, 1,4-dioxane Heterocyclic heptyl (1,4-dioxepnayl), 1,4-oxathiepanyl, 1,4-oxaazepanyl , 1,4-dithiepanyl, 1,4-thirzepanyl, 1,4-diazepanyl (1,4-diazepanyl), tropanyl, (1S,5R)-3-aza-bicyclo[3.1.0]hexyl ((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-tetrahydropyridyl (1,2,3,4- Tetrahydropyridinyl), 1,2,5,6-tetrahydropyridinyl, isoindolinyl, and indolinyl.

When the 5- to 14-membered heterocyclic group of the monocyclic or bicyclic ring has 2 or more substituents, the substituents may be the same or different.

As used herein, some of the atoms, groups, moieties, chains, and ring systems that are present in the general structure of the invention are "optionally substituted." This means that the atom, group, moiety, chain and ring may be unsubstituted or substituted at one position by one or more, for example 1, 2, 3 or 4 substituents, whereby Hydrogen atoms bonded to unsubstituted atoms, groups, moieties, chains and rings are replaced by chemically acceptable atoms, groups, moieties, chains and rings. When two or more substituents are present, each substituent may be the same or different. Substituents are usually unsubstituted by themselves.

As used herein, the term halogen atom contains chlorine, fluorine, bromine and iodine atoms. The halogen atom is usually a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine. When the term halo is used as the prefix, it has the same meaning.

Also included within the scope of the invention are isomers, polymorphs, pharmaceutically acceptable salts, nitrogen-oxides, isotopes, of the compounds of formula (I), Solvents and precursors. Any reference to a compound of formula (I) in the specification, including any isomer, allotrope, pharmaceutically acceptable salt, nitrogen-oxide, of the compound of formula (I) mentioned, Isotope, solvent compound or precursor drug.

Isomers

Compounds containing one or more palm-centered compounds can be used in the form of enantiomerically or diastereoisomerically pure, in the form of racemic mixtures and in one or more stereo Form of a mixture of stereoisomers. The chemical formula (I) as described and claimed The complex comprises not only individual palmo isomers, non-palphaliomers and stereoisomer-rich mixtures, but also racemic forms of the compounds.

Conventional techniques for the preparation/isolation of individual palmomerisomers involve the synthesis of palms from a suitable optically pure precursor, or the use of, for example, chiral high pressure liquid chromatography (HPLC). ) Isolate the racemate. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound such as an alcohol, or in the case where the compound contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethyl Amine reaction. The resulting non-p-isomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both of the non-p-isomers can be obtained in a manner well known to those of ordinary skill in the art. The person is transformed into the corresponding pure palmar isomer. The palm compound of the present invention (and its palm precursor) can be obtained by chromatography in a form of abundance of the palm, and the chromatography is usually carried out on an asymmetric resin using a mobile phase consisting of a mobile phase. And the hydrocarbon is usually 0 to 50%, usually 2 to 20%, of isopropanol and 0 to 5% of an alkylamine, usually 0.1% of diethylamine in heptane or hexane. Concentration of the precipitate provides a rich mixture. Agglomerates of stereoisomers can be separated by conventional techniques known to those of ordinary skill in the art. See, for example, "Stereochemistry of Organic Compounds" by Ernest L. Elie I (Wiley, New York, 1994).

Atropisomers are stereoisomers resulting from hindered rotation of a single bond, wherein the steric strain barrier of rotation is sufficiently high to allow separation of conformers. Oki (Oki), M; the essence of stereochemistry, January 1983 (Oki, M; Topics in Stereochemistry 1983, 1)) defines the retardation isomers to change at half a lifetime with a half-life of more than 1000 seconds at a given temperature. Configuration. The scope of the invention as set forth and claimed includes not only individual stagnation isomers (a a mixture of "substantially free" of its corresponding atropisomers and a mixture of stereoisomers, ie a mixture of stagnation isomers, and also compounds The form of racemic.

Separation of the stagnation isomers is possible by a palmarization method such as selective crystallization. In a stagnation-to-palm selective or stagnation selective synthesis, one stagnation isomerized system is formed by the consumption of another stagnation isomer. The stagnation selective synthesis can be carried out by using a reagent such as a Corey-Bakshi-Shibata (CBS) catalyst in the total synthesis of knipholone (produced by lysine) The asymmetric catalyst is carried out, or when the isomerization reaction is advantageous for one of the atropisomers than for the other atropisomer, by a method based on thermodynamic equilibrium.

The compound of the formula (I) can exhibit the phenomenon of tautomerism and structural isomerism. The tautomer is present as a mixture of tautomeric groups in solution. In solid form, usually a tautomer dominates. Even though one tautomer can be described, the present invention encompasses all tautomers of the compound of formula (I).

Allomorphs (polymorphs)

The compounds of formula (I) may exist in different physical forms, i.e., in amorphous form and in crystalline form.

Furthermore, the compounds of the invention may have the ability to crystallize in more than one form known as polymorphism. Allotropes can be distinguished by various physical properties 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 (homomorphs) or amorphous forms thereof, are within the scope of the invention.

Pharmaceutically acceptable salt

As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from an acceptable base or acid to a patient, such as a mammal. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases, as well as from pharmaceutically acceptable inorganic or organic acids.

The term pharmaceutically acceptable salt, as used herein, includes a salt containing a pharmaceutically acceptable acid or base. The pharmaceutically acceptable acid also contains a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid; and an organic acid such as citric or fumaric. , gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic , oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulphonic, ethanesulphonic, benzene Sulfonic acid (benzenesulphonic), p-toluenesulphonic acid, xinafoic (1-hydroxy-2-naphthoic acid), naphthalisilic acid (napadisilic) (1,5-naphthalenedisulfonic acid) and the like. Particularly preferred are salts derived from fumaric acid, hydrobromic acid, hydrochloric acid, acetic acid, sulfuric acid, methanesulfonic acid, cinnamic acid and tartaric acid.

Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, Zinc salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts.

Salts derived from pharmaceutically acceptable organic bases include salts of the following: primary amines, secondary amines, and tertiary amines, including alkylamines, aralkylamines, heterocyclic amines, Cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine (N,N' -dibenzylethylenediamine), diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine ), isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperididine, polyamine resins, Procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

Other preferred salts according to the invention are quaternary ammonium compounds in which an equivalent amount of anion (X-) is associated with a positive charge of the N atom. X- may be an anion of various inorganic acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate; or an anion of an organic acid, such as acetate, maleate , fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetic acid Trifluoroacetate, methanesulphonate, and p-toluenesulphonate. X- is preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. X- is more preferably chloride, bromide, trifluoroacetate or methanesulfonate.

Nitrogen oxides

As used herein, a nitrogen-oxide is formed from a tertiary amine or imine present in a molecule using a suitable oxidizing agent.

Isotope

The invention also encompasses isotopically-labeled derivatives of the compounds of the invention wherein one or more atoms are replaced by an atom having the same number of atoms but having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes such as 2H and 3H; carbon isotopes such as 11C, 13C and 14C; chlorine isotopes such as 36Cl; fluorine isotopes such as 18F; iodine isotopes such as 123I and 125I Nitrogen isotope such as 13N and 15N; oxygen isotope such as 15O, 17O and 18O; phosphorus isotope such as 32P; and sulfur isotope such as 35S. Specific isotope-labeled compounds of the invention, such as those incorporating radioisotopes, are useful in the study of drug and/or mineral tissue distribution. The radioisotope 氚3H and carbon 14,14C are particularly suitable for this purpose in view of their ease of incorporation and ready detection. Substitution with heavier isotopes such as guanidine, 2H may provide specific therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, or reduced dosage requirements, and thus may be preferred in some circumstances. Substitution with positron emitting isotopes such as 11C, 18F, 150 and 13N is applicable to Positron Emission Topography (PET) studies for examining the receptor occupancy.

Isotopically labeled derivatives of the compounds of the invention may generally be substituted with isotopically labeled reagents in place of non-labeled reagents employed elsewhere, by known techniques known to those of ordinary skill in the art. Or prepared by a process similar to that described herein.

Preferred isotopically-labeled derivatives comprise deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative comprises a compound of the invention which is substituted with at least one hydrogen atom in one particular position. Rhodium (D or 2H) is a stable isotope of hydrogen with a natural rich content of 0.015 mol%.

Solvent compound

The compounds of the invention may exist in both unfused and fused forms. The term solvate is used herein to describe a molecule of a complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the term hydrate is employed. Examples of solvate compound forms include, but are not limited to, water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine or Its mixture. It is expressly contemplated that a solvent molecule of the present invention can bind to a molecule of the compound of the present invention, such as a hydrate.

Furthermore, it is expressly contemplated that in the present invention, more than one solvent molecule can be combined with a molecule of the compound of the present invention, such as a dihydrate. Additionally, it is expressly contemplated that less than one solvent molecule in the present invention can bind to a molecule of the compound of the invention, such as a hemihydrate. Further, the solvent compound of the present invention is a solvent compound which is expected to be a bioavailable form of a non-solvent compound of the compound of the present invention.

Prodrugs

Prodrugs of the compounds described herein are also within the scope of the invention. Thus, a particular derivative of a compound of the invention, the derivative itself may have a small amount or a few It has no pharmacological activity and can be converted into a compound of the invention having the desired activity, for example, by hydrolytic decomposition when it is introduced into the body or on the body. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, a new drug delivery system, Volume 14, The American Chemical Society Seminar Series (T. Henry's and W. Stella). Vol.14, ACS Symposium Series (T. Higuchi and W. Stella) and bioreversible vectors in drug design, Pergamon Press, 1987 (Aide E. B. Roche, American Medical Association) Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association)).

The prodrugs according to the present invention may, for example, be substituted by the appropriate functional groups of the compounds of the invention which are present in a particular part of the art known as "pro-moieties" by those of ordinary skill in the art. This is produced, for example, in the Design of Prodrugs by H. Bundgaard (Elsevier, 1985 (Elsevier, 1985)).

As used herein, the term PI3Kd inhibitor generally refers to a compound that inhibits the activity of PI3Kd isoforms more efficiently than other isoforms that inhibit the PI3K family.

As used herein, the term PI3Kd/g inhibitor generally refers to a compound that inhibits both PI3Kd isoforms and PI3Kg isoforms from being more potent than other isoforms of the PI3K family.

The relative efficacy of a compound that is an inhibitor of enzymatic activity (or other biological activity) can be determined by determining the inhibitory activity of each compound to a predetermined level, and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity of biochemical analysis, i.e., 50% inhibitory concentration or "IC _50." The determination of IC ₅₀ can be accomplished using conventional techniques known in the art. In general, IC ₅₀ can be measured by a predetermined amount to determine the enzyme activity in the presence of a range of concentrations of the inhibitor studies. The experimentally obtained enzyme activity values are then plotted against the inhibitor concentration used. Shows the concentration of inhibitor activity (as compared to the activity in the absence of any inhibitor) ₅₀ 50% deemed value IC.

Accordingly, a PI3Kd inhibitor may alternatively be understood to mean a homogeneous time-resolved fluorescence assay (HTRF assay) of PI3K (eg, Gray et al., Analytical Biochemistry, 2003; 313: 234-45 (Gray et al) .Anal Biochem, 2003; 313: 234-45 ) in the), and 50% PI3Kd exhibit inhibitory concentration (the IC ₅₀₎ with respect to at least less than micromolar to about 100 (μM), preferably less than about 50 A compound having a micromolar concentration (μM), more preferably less than about 20 micromolar (μM), even more preferably less than about 10 micromolar (μM).

In general, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-(CH _{2 0-3} -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 -N( R ^a ) R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group , a-(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(*) -(CH ₂ ) _0-3 -R ^c group or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c group; R ^a and R ^b each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (a straight or branched C ₁ -C ₄ alkane) And wherein (*) represents a point attached to R ₁ ; and wherein R ^c represents a phenyl group or a heterocyclic group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen.

In general, in the compound of the formula (I), X represents a nitrogen atom or a -CR ₆ group. Preferably X represents -CR ₆ .

In general, in the compound of the formula (I), R _a and R _b each independently represent a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group. Preferably, R _a and R _b each independently represent a hydrogen atom, a methyl group or an ethyl group.

In general, in the compound of the formula (I), R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _{0 a -3} N(R ^d )R ^e group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or at least a monocyclic or bicyclic 5- to 9-membered heterocyclic group of a hetero atom selected from oxygen, sulfur and nitrogen; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ -C ₄ alkane a cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic group which is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C _4- alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _1-3 CN, -( CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, - (CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 CN group, -C(O)-O- (linear or branched C ₁ -C ₄ alkyl group) Base, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -(phenyl) group , -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur and nitrogen a monocyclic or bicyclic 5- to 9-membered heterocyclic group of the atom, -C(O)-(CH ₂ ) _0-3 - (containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen) 7-membered heteroaryl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C( O)-(CH ₂ ) _0-3 -NR7(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (5 to 7 membered heteroaryl) group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - a monocyclic or bicyclic 5- to 9-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ , -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ - (CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _{0- 3-} (phenyl)yl, -(CH ₂ ) _0-3 - (heteroaryl group of 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _{0 -3} - (monocyclic or bicyclic 5 to 7 membered heterocyclic) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -(phenyl) group or - Substituted by one or more substituents of (CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group; wherein each phenyl, heteroaryl and heterocyclic group is unsubstituted Substituted, or selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, -(CH ₂ ) _0-3 -O- ( a linear or branched C ₁ -C ₄ alkyl) group, a -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, a -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group, -S( O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH _{2 0-3} R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ ) _0-3 - (including at least one selected from oxygen, Sulfur and nitrogen A child of 5 to 7-membered hetero aryl group) group substituted with one or more substituents; wherein the heteroaryl system is unsubstituted, or is selected from linear or branched C ₁ -C ₃ alkoxy Substituting one or more substituents of a -(CH ₂ ) _0-3 NR ^f R ^g group; wherein R ^f and R ^g each independently represent a hydrogen atom, a straight or branched C ₁ -C ₄ An alkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group.

Preferably, in the compound of formula (I), R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _{0 -3} N(R ^d )R ^e group, C ₃ -C ₇ cycloalkyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazolyl group, piperidinyl group, piperazinyl group, four Tetrahydropyranyl group, morpholinyl group, 1,4-azathianyl group, thiomorpholinyl 1,1-dioxide group Thiomorpholinyl 1,1-dioxide group), 2,5-diazabicyclo[2.2.1]heptan-2-yl (2,5-diazabicyclo[2.2.1]heptan-2-yl group), 2,5 -2,5-diazabicyclo[2.2.1]octan-2-yl group, pyrrolidin-2-one group Or a pyrrolidinyl group; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ -C ₄ alkyl group; wherein cycloalkyl, phenyl, pyridyl, pyrimidinyl, Pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,4-azathianyl, thiomorpholinyl 1,1- Dioxide Rpholinyl 1,1-dioxide), 2,5-diazabicyclo[2.2.1]heptan-2-yl (2,5-diazabicyclo[2.2.1]heptan-2-yl), 2,5-di Azabicyclo[2.2.1]oct-2-yl (2,5-diazabicyclo[2.2.1]octan-2-yl), pyrrolidinyl-2-one or pyrrolidinyl Is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O- (linear or branched C ₁ -C ₄ alkane) Base, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group , -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-( CH ₂ ) _0-3 -(piperazinyl)yl, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) , -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(piperidinyl)yl, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(pyridyl)yl, -C(O)-(CH _{2 0-3} -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _{0 -3} -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 -(pyrrolidinyl) group, -(CH ₂ ) _0-3 -(piperazinyl) group , -(CH ₂ ) _0-3 -(piperidinyl)yl, -(CH ₂ ) _0-3 -(phenyl)yl or -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 Substituting one or more substituents of a -(phenyl) group; wherein each phenyl, pyridyl, pyrrolidinyl, piperazinyl or piperidinyl group is unsubstituted or is selected from hydroxy, straight Chain or branched C ₁ -C ₄ alkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O- (straight or branched C ₁ -C _4- alkyl) group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N ( R ^f R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ a substitution of one or more substituents of _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g or -(CH ₂ ) _0-3 -(pyridyl) group; wherein the pyridyl group is Substituted or substituted with one or more substituents selected from a linear or branched C ₁ -C ₃ alkyl group or a -(CH ₂ ) _0-3 NR ^f R ^g group; and wherein R ^f And R ^g each independently represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group.

In one embodiment, in the compound of formula (I), R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, C ₃ -C ₇ A cycloalkyl, phenyl, 5- to 10-membered heteroaryl group containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridyl A cyclyl, morpholinyl or pyrrolidinyl group; wherein a cycloalkyl group, a phenyl group, a heteroaryl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group or a pyrrolidinyl group is Unsubstituted, or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ -hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _1-3 CN, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) ), -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-O- (straight or branched C ₁ - C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _{2- 4-} NR ₇ R ₈ base, -NR ₇ -S(O) ₂ (CH _{2 0-3} R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _{0 -3} - (a 5- to 7-membered heteroaryl group containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen), -(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur, and nitrogen a heterocyclic group of 5 to 7 members of a hetero atom, -(CH ₂ ) _0-3 -(phenyl) group or -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 - Substituted by one or more substituents of a (phenyl) group; wherein the phenyl group is unsubstituted or is selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group Or one or more substituents of the -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group; and wherein R ₇ and R ₈ each independently represent a hydrogen atom, straight A chain or branched C ₁ -C ₄ alkyl group or a C ₃ -C ₇ cycloalkyl group.

In one embodiment, in the compound of formula (I), R ₁ preferably represents a straight or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl; wherein cycloalkyl, phenyl, pyridyl, piperidinyl, The piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl group is unsubstituted or is selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ - C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O- (straight or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O) -(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ - S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -(CH ₂ ) _0-3 -(pyrrolidinyl) group, - (CH ₂ ) _0-3 -(phenyl) group or one of -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group Substituted by a plurality of substituents; wherein the phenyl group is unsubstituted or selected from a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 - One or more substituents of the O-(CH ₂ ) _2-4 -NR ₇ R ₈ group are substituted.

In general, in the compound of the formula (I), R ₂ represents a hydrogen atom, a halogen atom or a linear or branched C ₁ -C ₄ alkyl group.

Preferably, R ₂ represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. More preferably, R ₂ represents a hydrogen atom.

In general, in the compound of the formula (I), R ₃ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear chain. Or a branched C ₁ -C ₄ hydroxyalkyl group.

Preferably, R ₃ represents a hydrogen atom, a halogen atom, or a linear or branched C ₁ -C ₄ alkyl group. More preferably, R ₃ represents a hydrogen atom, a halogen atom, a methyl group or an ethyl group. Even more preferably R ₃ represents a hydrogen atom.

In general, in the compound of the formula (I), R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group, or -(CH ₂ ) _0-3 -(phenyl) group; wherein benzene The base is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C Substituted by one or more substituents of _1- C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy.

Preferably, R ₄ represents a hydrogen atom, a branched C ₁ -C ₄ alkyl group, or a -(CH ₂ ) _0-3 -(phenyl) group; wherein the phenyl group is unsubstituted or selected Substituted by one or more substituents of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group. More preferably, R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or a -(CH ₂ ) _0-3 -(phenyl) group; wherein the phenyl group is unsubstituted, Or replaced by one or more hydroxyl groups. Even preferably, R ₄ represents a hydrogen atom, or a linear or branched C ₁ -C ₄ alkyl group. Most preferably, R ₄ represents a hydrogen atom, a methyl group or an ethyl group.

In general, in the compound of the formula (I), R ₆ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear chain. Or a branched C ₁ -C ₄ hydroxyalkyl group.

Preferably, R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group. More preferably, R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or a methyl group.

In general, in the compound of the formula (I), R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a straight chain or a branched C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, or a phenyl group, wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear chain or One or more substituents of a branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group Replaced.

Preferably, R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a linear or branched C ₁ -C ₃ hydroxyalkyl group, C ₃ -C ₄ A cycloalkyl group, or a phenyl group, wherein the phenyl group is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups. More preferably, R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a linear or branched C ₁ -C ₃ hydroxyalkyl group, or a C ₃ -C ₇ cycloalkyl.

In one embodiment, in the compound of formula (I), R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, or a benzene group. a group wherein the phenyl group is unsubstituted or selected from a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ Substituted by one or more substituents of a hydroxyalkyl group or a C ₁ -C ₄ alkoxy group.

In one embodiment, R ₇ and R ₈ each independently preferably represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₃ -C ₄ cycloalkyl group, or a phenyl group, wherein phenyl It is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups. More preferably, R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or a C ₃ -C ₇ cycloalkyl group.

In general, in the compound of the formula (I), R ₅ represents the formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6) Or the group of (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14, The R ₁₅ , Z and L systems are as defined above.

Preferably, in the compound of the formula (I), R ₅ represents the formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6) Or the group of (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur and nitrogen, wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0- 3-} NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S(O ) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazinyl) Substituted by one or more substituents; wherein the piperidinyl or piperazinyl group is Substituted, or selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R 'represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or 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 ₁ -C ₄ alkyl group; L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O)-yl, -C(O) a chain group in the -O- group or -(CH ₂ ) _1-4 group.

In a preferred embodiment, in the compound of formula (I), R ₅ represents a formula (II-1), (II-2), (II-5), (II-6) or (II-7) Group:

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, a -NH ₂ group, or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group, a pyridyl group, a pyrazolyl group, Or a fluorenyl group; wherein the phenyl, pyridyl, pyrazolyl, or anthracenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, —O—(linear or branched C ₁ -C ₃ alkyl) group, —(CH ₂ ) _{0 -3} -C(O)-(CH ₂ ) _0-3 -NR,R" group, -(CH ₂ ) _0-3 NR,R" group, -(CH ₂ ) _0-3 -NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _{0- 3} R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)( One or more substituents of CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) group or -(CH ₂ ) _0-3 -(piperazinyl) group Substituted; wherein the piperidinyl or piperazinyl group is not Substituted or selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R 'represents hydrogen An atomic or linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or a phenyl group, wherein the phenyl group is unsubstituted Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl group; L represents a direct bond.

In a preferred embodiment, in the compound of formula (I), R ₅ represents a formula (II-1), (II-2), (II-5), (II-6) or (II-7) Group:

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, an -NH ₂ group or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group, a pyridyl group, a pyrazolyl group, or a fluorenyl group; wherein the phenyl, pyridyl, pyrazolyl, or anthracenyl group is unsubstituted, or is selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, Chain or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group, -(CH ₂ ) _0-3 NR'R" group, -( CH ₂ ) _0-3 -NR'-(CH ₂ ) _1-6 -NR'R" group, -NR'-S(O) ₂ (CH ₂ ) _0-3 R" group, -NR'-S ( O) ₂ (CH ₂ ) _0-3 NR'R" group, -NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) Substituting one or more substituents of a -(CH ₂ ) _0-3 -(piperazinyl) group; wherein the piperidinyl or piperazinyl group is unsubstituted or is selected from a straight-chain or branched C ₁ -C ₄ alkyl or - one or more (CH _{2) 0-3} NR'R "group substituents; and wherein R 'represents Atom or a linear or branched C ₁ -C ₃ alkyl and wherein R "represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl or phenyl, wherein phenyl is unsubstituted based Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl group; L represents a direct bond.

In a particularly preferred embodiment, in the compound of formula (I), R ₅ represents a portion of formula (II-5), (II-6) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0- 3-} NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S(O ) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazinyl) Substituted by one or more substituents; wherein the piperidinyl or piperazinyl group is Substituted, or selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R 'represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or a phenyl group, wherein the phenyl group is unsubstituted Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl group.

In one embodiment, in the compound of formula (I), R ₅ preferably represents a group of formula (II-1), (II-5) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14, R ₁₅ and Z are as defined above.

In one embodiment, R ₅ preferably represents a group of formula (II-1), (II-5) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C Substituted by one or more substituents of ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, or a linear or branched C ₁ -C ₄ hydroxyalkyl group.

In general, in the compound of formula (I), L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O) -NH- group, -NH-C(O)- group, -OC(O)- group, -C(O)-O- group or -(CH ₂ ) _1-4 group.

Preferably, L represents a direct bond or a chain selected from the group consisting of -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, or -(CH ₂ ) _1-4 Base.

Preferably, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-(CH _{2 0-3} -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 -N( R ^a ) R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group , -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(*)- (CH ₂ ) _0-3 -R ^c group or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c group; ^a and R ^b each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) And wherein (*) represents a point attached to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a member of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen a heteroaryl group, a monocyclic or bicyclic 5- to 7-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein the cycloalkyl group, the phenyl group, the heteroaryl group and the heterocyclic group are Substituted, or selected from a halogen atom Hydroxyl, cyano, -NH ₂ group, -CHF ₂ group, -CF ₃ group or a straight-chain or a branched C ₁ -C ₄ alkyl group substituted with one or more substituents; X-represents a nitrogen atom or -CR ₆ base; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _0-3 N(R ^d )R ^e a C ₁ -C ₆ haloalkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, or at least one selected from the group consisting of oxygen, sulfur, and nitrogen a heteroaryl group of 5 to 7 members of the atom, or a monocyclic or bicyclic 5 to 9 membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein R ^d and R ^e are independently a C ₁ -C ₄ alkyl group representing a hydrogen atom or a straight or branched chain; and wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from halogen Atom, hydroxy, cyano, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ Cycloalkyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O-( Linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 - NR ₇ R _{8 group, - (CH 2) 0-3 NR} 7 R 8 _{group, - (CH 2) 0-3 NH-} (CH 2) 2-4 NR 7 R 8 group, -C (O) - ( CH ₂ ) _1-3 CN group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -(phenyl) group , -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur and nitrogen a monocyclic or bicyclic 5- to 9-membered heterocyclic group of the atom, -C(O)-(CH ₂ ) _0-3 - (containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen) 7-membered heteroaryl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C( O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (5 to 7 membered heteroaryl) containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _{0- 3-} (monocyclic or bicyclic 5- to 9-membered heterocyclic) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ -yl, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR _{7 - (CH 2) 1-6 -NR} 7 - (CH 2) 1-6 -NR 7 R 8 _{group, -NR 7 -S (O) 2} (CH 2) 0-3 R 8 groups, -S ( O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 - (having at least one heteroaryl group of 5 to 7 members selected from oxygen, sulfur and nitrogen), -( CH ₂ ) _0-3 - (monocyclic or bicyclic 5- to 7-membered heterocyclic) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -(phenyl Substituted with one or more substituents of -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group; wherein each phenyl, heteroaryl and heterocyclic group Is unsubstituted or selected from a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O) -OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group , -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^{g _{Group, -NR f -S (O) 2}} (CH 2) 0-3 NR f R g _{^{group, -NR f -S (O) 2}} (CH 2) 0-3 R g group, - (CH _{2) 0 -3} -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ ) _0-3 - (mixed with 5 to 7 members of at least one hetero atom selected from oxygen, sulfur and nitrogen) Substituted by one or more substituents of the aryl) group; wherein the heteroaryl group is unsubstituted or is selected from a linear or branched C ₁ -C ₃ alkyl group or -(CH ₂ ) _{0- 3} or more of a group NR ^f R ^g substituents; and wherein R ^f and R ^g each independently represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or a linear or branched, C ₁ -C ₄ hydroxyalkyl; 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 ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group; Base, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ group, -N(CH ₃ )H group or - N(CH ₃ ) ₂ group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkane , C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 - (including at least one selection From 5 to 7 heteroaryls of heteroatoms of oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 - (having at least one heteroaryl group of 5 to 7 members selected from hetero atoms of oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 - ( _{phenyl), - (CH 2) 0-3} - ( 5 comprising at least one hetero atoms selected from oxygen, sulfur and nitrogen to 7-membered heteroaryl), wherein the phenyl and heteroaryl is not based Substituted, or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxy group Substituted by one or more substituents of an alkyl group or a C ₁ -C ₄ alkoxy group; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, C _1- C ₄ alkoxy, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _1-3 -O- (straight or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -OC(O)- (straight chain or Branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -C(O)O- (straight or branched C ₁ -C ₄ alkyl), -C(O)-( CH _{2) 0-3} -NR ₇ R ₈ group, or _{- (CH 2) 0-3 -C (} O) OH group R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, a C ₃ -C ₇ cycloalkyl group or a phenyl group, wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ Substituted with one or more substituents of a C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₅ represents a chemical formula (II-1), Groups of (II-2), (II-5), (II-6) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14, The R ₁₅ , Z and L systems are as defined above.

In a particularly preferred embodiment, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl , -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O) -(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _{2- 4-} N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a R ^b group, -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N (*)-(CH ₂ ) _0-3 -R ^c group or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c group And wherein R ^a and R ^b each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (straight or branched C ₁ - a C ₄ alkyl group; and wherein (*) represents a point of attachment to R ₁ ; R ^c represents a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, including a monocyclic or bicyclic 5- to 7-membered heterocyclic group of a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein the phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from halogen Atom, hydroxyl, cyanide , -NH ₂ group, a ₁ -C ₄ alkyl group -CHF _2, -CF ₃ group or a linear or branched C or more substituents; X-represents a nitrogen atom or a -CR ₆ group; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, a -(CH ₂ ) _0-3 N(R ^d )R ^e group, C ₃ a C ₇ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or a single atom comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen a heterocyclic group of 5 or 9 members; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ -C ₄ alkyl group; wherein cycloalkyl, phenyl, heteroaryl And the heterocyclic group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a straight chain or Branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _{0 -3} -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O- (straight or branched C ₁ -C ₄ Alkyl) group, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) , -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)- (CH ₂ ) _0-3 - (monocyclic or bicyclic 5- to 9-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _{0 -3} - (heteroaryl group of 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C _1- C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C (O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (a heteroaryl group of 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen), - C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (monocyclic or bicyclic 5-member to 9-membered heterocyclic ring containing at least one hetero atom selected from oxygen, sulfur and nitrogen Base, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R _{8 , -S (O) 2 CH 2} ) 0-3 -NR 7 (CH 2) 0-3 - ( phenyl) _{group, - (CH 2) 0-3 -} ( comprising at least one selected from oxygen, nitrogen and sulfur, 5 to 7 heteroaryl groups of the hetero atom, -(CH ₂ ) _0-3 - (monocyclic or bicyclic 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen) One or more of a heterocyclyl) group, a -(CH ₂ ) _0-3 -(phenyl) group, or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group Substituted by a substituent; wherein each phenyl, heteroaryl, and heterocyclic group is unsubstituted or selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group, a straight chain or Branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O- (straight Chain or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ Alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH _{2 0-3} (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ ( CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ ) _0-3 Substituting one or more substituents of a 5- to 7-membered heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen; wherein the heteroaryl group is unsubstituted or Substituting one or more substituents selected from a linear or branched C ₁ -C ₃ alkyl group or a -(CH ₂ ) _0-3 NR ^f R ^g group; and wherein R ^f and R ^g are each independently represented Hydrogen, linear or branched C ₁ -C ₄ alkyl or straight or branched C ₁ -C ₄ hydroxyalkyl; R ₂ represents a hydrogen atom, or a linear or branched C ₁ -C ₄ alkane R ₃ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _{0- 3-} (phenyl); wherein the phenyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₄ alkyl group; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxy group. alkyl group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl, linear or branched C ₁ -C ₃ hydroxyalkyl, C ₃ -C ₇ Alkyl, or phenyl; wherein the phenyl is unsubstituted lines, or selected from linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched, Substituted by one or more substituents of a C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₅ represents a chemical formula (II-1), (II-2), (II-5), Groups of II-6) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; Z represents a nitrogen atom or a -CH _{group; R 9, R 11, 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 ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group, or at least a heteroaryl group of 5 to 9 members of a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a straight chain or a branched chain C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O- (straight or branched C ₁ -C ₃ alkyl) ), -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S (O) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0 -3} NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazine) Substituted by one or more substituents of the group; wherein the piperidinyl or piperazinyl group It is unsubstituted, or is selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R ' represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or a phenyl group, wherein the phenyl group is not Substituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl group; L represents a direct bond or is selected from -O-(CH) ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O)-yl, -C( A chain group in the O)-O- group or the -(CH ₂ ) _1-4 group.

In a particularly preferred embodiment, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 - N(*)-(CH ₂ ) _2-4- N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _{0- 3-} C(O)-N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group , -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _{0-3 -} ^a linking group in the R ^c group; wherein R ^a and R ^b each independently represent hydrogen, a straight or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) group; and wherein (*) represents a point attached to R ₁ ; R ^c represents a 5 to 7 ring comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen a heterocyclic group; X represents a -CR ₆ group; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _0-3 N(R ^d )R ^e group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholine Base, 1,4-nitrothiamethane 1,4-azathianyl group, thiomorpholinyl 1,1-dioxide group, 2,5-diazabicyclo[2.2.1]heptane-2- (2,5-diazabicyclo[2.2.1]heptan-2-yl group), 2,5-diazabicyclo[2.2.1]oct-2-yl (2,5-diazabicyclo[2.2.1]octan -2-yl group), pyrrolidin-2-one group, or pyrrolidinyl; wherein R ^d and R ^e each independently represent hydrogen or a straight or branched C ₁ - C ₄ alkyl; wherein cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,4-azetidine Alkyl (1,4-azathianyl), thiomorpholinyl 1,1-dioxide, 2,5-diazabicyclo[2.2.1]heptan-2-yl (2,5-diazabicyclo[2.2.1]heptan-2-yl), 2,5-diazabicyclo[2.2.1]oct-2-yl (2,5-diazabicyclo[2.2.1]octan-2 -yl), pyrrolidin-2-one or pyrrolidinyl is unsubstituted or is selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ - C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (straight or branched C ₁ - C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH _{2 0-3} NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)- OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -(piperazine) Base, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(piperidinyl ), -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(pyridyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ -yl, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 -(pyrrolidinyl)yl, -(CH ₂ ) _0-3 -(piperazinyl), -(CH ₂ ) _0-3 -(piperidinyl)yl, -(CH ₂ ) _0-3 - ( Substituted by one or more substituents of a phenyl) group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group; wherein each phenyl, pyridyl, pyrrolidine The phenyl, piperazinyl or piperidinyl group is unsubstituted or is selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group. , -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O- (linear or branched C ₁ -C ₄ alkane) Base, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)- (CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (straight or branched) C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group , -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ Substituted by one or more substituents of _0-3 -(pyridyl) group; wherein the pyridyl group is unsubstituted or is selected from a linear or branched C ₁ -C ₃ alkyl group or -( CH ₂ ) _0-3 NR ^f R Substituted by one or more substituents of the ^g group; and wherein R ^f and R ^g each independently represent hydrogen, straight or branched C ₁ -C ₄ alkyl or straight or branched C ₁ -C ₄ Hydroxyalkyl; R ₂ represents a hydrogen atom; R ₃ represents a hydrogen atom; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 -(phenyl) Wherein the phenyl group is unsubstituted or substituted by one or more hydroxyl groups; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a linear or branched C ₁ -C ₃ alkyl group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a linear or branched C ₁ -C ₃ hydroxyalkyl group, a C ₃ -C ₄ cycloalkyl group, Or a phenyl group, wherein the phenyl group is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups; and R ₅ represents a chemical formula (II-1), (II-2), (II- 5), (II-6) or (II-7) groups:

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, a -NH ₂ group, or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group, a pyridyl group, a pyrazolyl group, Or a fluorenyl group; wherein the phenyl, pyridyl, pyrazolyl, or anthracenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, —O—(linear or branched C ₁ -C ₃ alkyl) group, —(CH ₂ ) _{0 -3} -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _{0- 3} R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)( CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) group or one or more substituents of -(CH ₂ ) _0-3 -(piperazinyl) group Substituted; wherein the piperidinyl or piperazinyl group is unsubstituted Or selected from linear or branched C ₁ -C ₄ alkyl or - one or more (CH _{2) 0-3} NR'R "group substituents; and wherein R 'represents a hydrogen atom or a straight a chain or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or 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 ₁ -C ₄ alkyl group; L represents a direct bond.

In a particularly preferred embodiment, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 - , -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O )-(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _{2 a -4} -N(R ^a )R ^b group or a -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; wherein R ^a and R ^b are respectively Independently representing a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) group; and wherein *) represents a point attached to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, including a heterocyclic group of at least one member selected from the group consisting of oxygen, sulfur and nitrogen heteroatoms; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from halogen Substituted by one or more substituents of an 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 ₁ -C ₄ alkyl group; X represents a nitrogen atom or -CR ₆ base; R ₁ represents Linear or branched C ₁ -C ₆ alkyl; linear or branched C ₁ -C ₆ hydroxyalkyl, straight or branched C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ ring An alkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or comprising at least one selected from the group consisting of oxygen, sulfur and nitrogen a heterocyclic group of 5 to 7 members of a hetero atom, wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, and a cyanogen group. Base, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, - (CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-( CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O _{) 2 (CH 2) 0-3 R} 8 _{groups, -S (O) 2 (CH} 2) 0-3 R 8 _{groups, -S (O) 2 (CH} 2) 0-3 NR 7 R 8 _{, - (CH 2) 0-3 -} ( 5 comprising at least one hetero atoms selected from oxygen, sulfur and nitrogen to 7-membered heteroaryl) _{group, - (CH 2) 0-3 -} ( comprising at least one a heterocyclic group of 5 to 7 members of a hetero atom selected from oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -(phenyl) group or -(CH ₂ ) _0-3 -O- ( CH ₂ ) _0-3 - substituted by one or more substituents of a (phenyl) group; wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a straight chain or a branched chain Substituting one or more substituents of a C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group; R ₂ and R ₃ are independently Representing a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxyalkyl group ; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ Cycloalkyl, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl , or -(CH ₂ ) _0-3 -(phenyl); wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a straight chain or a branched chain Substituted by one or more substituents of a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group ; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C _{4 group;} Hydroxyalkyl; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ a hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, or a phenyl group, wherein the phenyl group is unsubstituted or is selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ Substituted by one or more substituents of an alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₅ represents a chemical formula ( Groups of II-1), (II-5) or (II-7):

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14, The R ₁₅ , Z and L systems are as defined above.

In another particularly preferred embodiment, in the compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 - , -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O )-(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _{2 a -4} -N(R ^a )R ^b group or a -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; wherein R ^a and R ^b are respectively Independently representing a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) group; and wherein *) represents a point at which a nitrogen atom is bonded to R ₁ ; R ^c represents a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and at least one selected from the group consisting of oxygen and sulfur And a heterocyclic group of 5 to 7 members of a nitrogen hetero atom; wherein the phenyl group, the heteroaryl group and the heterocyclic group are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, or a -NH ₂ group Substituted by one or more substituents of a -CHF ₂ group, a -CF ₃ group or a linear or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or a -CR ₆ group; R ₁ represents a straight chain or Branched C ₁ a C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a member comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen to a heteroaryl group of 7 members, or a heterocyclic group of 5 to 7 members containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein the cycloalkyl group, the phenyl group, the heteroaryl group, and the heterocyclic group are Unsubstituted, or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkane , C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O- (CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group , -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O )-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S( O) ₂ (CH ₂ ) _0-3 R ₈ group, -(CH ₂ ) _0-3 - (heterocyclic group of 5 to 7 members including at least one hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 -(phenyl) group or one of -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group or Substituted by a plurality of substituents; wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0- Substituting one or more substituents of a ₃ -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group; R ₂ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₃ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or a -(CH ₂ ) _0-3 -(phenyl group) a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₄ alkyl group; R ₆ represents hydrogen Atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxyalkyl group; ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, or a phenyl group, wherein the phenyl group is unsubstituted or One selected from a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group Or multiple substitutions Substituted; R ₅ representatives of formula (II-1), (II -5) or (II-7) a group:

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ and R ₅ is the point of attachment to the pyrrole and triazinyl point of attachment; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or comprise at least one a 5- to 9-membered heteroaryl group selected from the group consisting of oxygen, sulfur, and nitrogen heteroatoms; wherein the phenyl and heteroaryl groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a straight chain or a branched chain. Substituted by one or more substituents of C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, or linear or branched C ₁ -C ₄ hydroxyalkyl; L represents direct bonding or selection From -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O) - a chain group in the -C(O)-O- group or -(CH ₂ ) _1-4 group.

In a further embodiment, preferably a compound of formula (I), W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl , -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4- N(R ^a )R ^b group or -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group a linking group; wherein R ^a and R ^b each independently represent hydrogen, a straight or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (straight or branched C ₁ a -C ₄ alkyl group; and wherein (*) represents a point at which a nitrogen atom is bonded to R ₁ ; R ^c represents a heterocyclic group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; Represents a -CR ₆ group; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, Pyridyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl; wherein cycloalkyl, phenyl, pyridyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl system is unsubstituted, or is selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl A straight-chain or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C _{4 cycloalkyl, - (CH 2) 0-3 -O-} ( linear or branched C ₁ -C ₄ alkyl) , -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH -(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _{0 -3} -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ ( CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -(CH ₂ ) _0-3 -(pyrrolidinyl) group, -(CH ₂ ) _{0- 3} - (phenyl) group, or _{- (CH 2) 0-3 -O- (} CH 2) 0-3 - a (phenyl) group substituted with one or more substituents; wherein said phenyl is based Unsubstituted, or selected from a hydroxy, linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group Substituted by one or more substituents; R ₂ represents a hydrogen atom; R ₃ represents a hydrogen atom; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 - (phenyl); wherein the phenyl is unsubstituted based, substituted by one or more hydroxyl groups; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, A straight-chain or branched C ₁ -C ₃ alkyl; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl group, or a phenyl group in which the phenyl group is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups; and R ₅ represents a chemical formula (II-1), (II-5) or (II-7) ) group:

Wherein: (*) represent R ₅ to be bound to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, an -NH ₂ group or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group; wherein the phenyl group is unsubstituted Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₃ alkyl group; L represents a direct bond.

Specific individual compounds of the invention comprise: 1. 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-carboxylic acid (S)-t-butyl ester; 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 ;(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-(methyl)) Mercapto)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; 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-((four Hydrogen-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazin-5-carbonitrile; 9. (S)-4-amino-6 -((1-(5-methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazine- 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. 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-carboxylic acid (S)-t-butyl ester; 12. (S)-4-amino-6-((1-(5-bromo-4-((tetrahydro-2H-pyran-4-) 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. 4-((2-(1-(6-amino-5-cyano)) Pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)piperidine-1-carboxylic acid ( S)-t-butyl ester; 16 (S)-4-Amino-6-((1-(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1-f][1,2,4]3 Pyridin-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]3 (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)pyrimidine-5- (5)-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]triazine- 2-(yl)ethyl)amino)pyrimidine-5-carbonitrile; 23. (S)-4-amino-6-((1-(4-(3-hydroxyphenyl)-5-methylpyrrolo[ 2,1-f][1,2,4]triazine -2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 24. (S)-4-amino-6-((1-(4-(4-hydroxyphenyl)-5-methylpyrrole) [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)-1H-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)-1H-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)-1H-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]triazine-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-methylpyridyl [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-yl Oxypyridin-3-yl)methanesulfonamide; 35. (S)-4-amino-6-((1-(4-(5-amino-6-hydroxypyridin-3-yl)-5-) (pyrido[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) (amino)pyrimidine-5-carbonitrile; 39. (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)))) 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]3 (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) -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 43. (S)-4-amino-6-((1-(4-((3-hydroxybenzene)) (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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile; 45. 3-(4-Amino-1-((tetrahydro-2H-pyran-4-yl)methoxy) Pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- Fluorophenol; 4 6. 3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)methyl)-1H-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-dimethylmorpholinyl)-5-methylpyrrolo[2, 1-f][1,2,4]triazin-2-yl)methyl)-1H-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-methylpyrrole And [2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 52. (S)-4-amino-6-((1- (4-((3-Hydroxyphenyl)(2-morpholinylethyl)amino)-5-methylpyrrolo[2,1-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-methylpyrrole [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)-1H-pyridyl Zizo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 55. 3-(4-Amino-1-((4-((2-(dimethylamino)ethyl))) 3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-fluorophenol; 56. (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)))) -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[2,1- 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-methoxy Pyridin-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-methoxybenzenesulfonate Indoleamine; 60. 3-(4-Amino-1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 61. (S)-4-amino -6-((1-(4-(3-methoxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 62. 3-(4-Amino-1-((5-methyl-4-(4-(methylsulfonyl))piperazine-1 -yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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-(dimethyl))) Amino)ethyl)(methyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3 , 4-d]pyrimidin-3-yl)-5-fluorophenol; 65. (S)-4-amino-6-((2-(3-hydroxyphenyl)-1-(4-(4-) Propyl piperazin-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; 67. (S)-4-amino-6-((1-(4-(2,6-dimethyl) Pyridin-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[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrole [2,3-d]pyrimidine-5-carbonitrile; 70. (S)-4-Amino-6-((1-(5-methyl-4-(2-morpholinylethyl)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)-1H-pyrazolo[ 3,4-d]pyrimidin-3-yl)-5-fluorophenol;7 3. (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- (hydroxy)phenyl)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-hydroxybenzoate醯amine; 78. 4-Amino-6-(((S)-1-(5-methyl-4-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)pyrrole And [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))))))) [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) -1H-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-1H-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-Dimethylpiperazine-1- -5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-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)-1H-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) -1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol; 91. 4-(((S)-1-(4-((3R,5S)-4-B) Mercapto-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-methylpyrrole And [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]triazine-2 -ethyl)amino)pyrimidine-5-carbonitrile; 95. 3-(4-Amino-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 96. 3-(4 -amino-1-((5-methyl-4-thiomorpholinylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazole And [3,4-d]pyrimidin-3-yl)-5-fluorophenol; 97. 3-(4-amino-1-((5-methyl-4-((2-(pyrrolidin-1-) Ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl -5-fluorophenol; 98. (S)-4-amino-6-((1-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylpyrrole) And [2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 99. 4-(2-(1-((6-amino-)- 5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,6-dimethyl (S)-methyl ester of benzoic acid; 00. 3-(1-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-methylpyrrolo[2,1-f ][1,2,4]triazin-2-yl)methyl)-4-amino-1H-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]triazine- 2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 102. 3-(4-Amino-1-((5-methyl-) 4-(2,2,6,6-tetramethylmorpholinyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazole [3,4-d]pyrimidin-3-yl)-5-fluorophenol; 103. 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 (S)-methyl ester; 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)-1H-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-methylbenzamide; 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) - dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 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)methanesulfonate Indoleamine; 111. 4-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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)-1H-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-) Ethyloxy)pyrrole And [2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 114. 4-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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 -1H-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-R(4R)-2,5-diazabicyclo[2.2.2]oct-2-yl)-5-methylpyrrolo[2,1-f][1, 2,4]triazin-2-yl)methyl)-4-amino-1H-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] (Z)-4-yl)-N-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5-methylbenzimidamide; 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- Nitrile; 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-Aminosulfonylbenzyl)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-((5S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2] octyl -2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) -5-fluorophenol; 124. N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine 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)-1H-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]triazine-4- 5-)-methyl-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzamide; 127. 3-(4-amino-1-((5) -Methyl-4-((1R,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)methyl)-1H-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)propanamine; 129. N-(3-(4-((()))) (2S,6R)-2,6-dimethylmorpholinyl)-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-hydroxyl Ethyl)-2,6-dimethylbenzamide;131. N-(5-(4-(((S))))) 5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d] Pyrimidin-5-yl)-2-methoxy 3-(4-amino-1-((5-methyl-4-(2-morpholinylethoxy)pyrrolo[2,1-f]) [1,2,4] Triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 133. 1-(2-( (2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrole And [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-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrole [2,3-d]pyrimidin-4-amine; 136. N-(3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylmorpholinyl)-) 5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 5-hydroxyphenyl)methanesulfonamide; 137. (S)-4-amino-6-((1-(4-(3-cyano)-5-((4-(methylsulfonyl))benzyl) Ethyl)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]triazine 4-yl)-5-methyl-N-(4-(methylsulfonylamino)benzyl)benzamide; 139. 4-((3-(2-(1-((6-) Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methyl (S)-methyl benzylamino)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-methylbenzimidamide; 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-methylbenzene Methionine; 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-methylbenzimidino)methyl)benzoic acid; 143. 1-(2-((2-) (4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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 ethyl ester; 144. N-(4-(4-( ((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4] (azine)-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. 3-(2-(1-((6-amino)) -5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzene (S)-3-aminophenyl formate; 147. (S)-3-(2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7H-pyrrole) [2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-( 2-hydroxyethyl)-5-methylbenzimidamide; 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-dimethylbenzhydrazide Amine; 149. 3-(4-Amino-1-((R)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrole And [2,1-f][1,2,4]triazin-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 150. 3-(4-Ammonia 1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 151. 1-(2-((2) -((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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)amine)methyl)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-(Aminosulfonylamino)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-(methylsulfonylamino) Benzyl)-5-methylbenzamide; 155. 3-(2-(1-(6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methyl Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-cyanobenzoic acid (S)-methyl ester; 156. (S)-3-(2-(1) -((6-amino-5-cyanide Pyrimidin-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-(methylsulfonylamino)benzyl)-5-methylbenzamide; 158. (S)-3 -(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] (S)-3-(2-(1-((6-amino-5)-5) -Cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-hydroxy- 5-(methylsulfonylamino)benzyl)-5-methylbenzimidamide; 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)amino)ethyl)-5-methylpyrrole [2,1-f][1,2,4]triazin-4-yl)-6-methyl-N-(4-aminesulfonylbenzyl)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-methylbenzimidamide; 165. 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 (S)-4-amine sulfonylbenzyl Ester; 166. (S)-4-Amino-6-((1-(4-(2-(4-(dimethylamino))piperidin-1-yl)pyridin-4-yl)-5-A (pyrido[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-methylpyrrole And [2,1-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[2,1-f][1,2,4] Triazine-2- 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-dimethyl Piperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine; 171. 3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Ethyl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzoic acid ethyl ester; 172. 3-(2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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)ethane Sulfonamide; 174. (S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)) 4-(4-(dimethylamino))piperidine -1-yl)benzyl)ammonia 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]triazine -2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 176. 3-(4-amino-1-((4-(2-(4-)) -amino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazole And [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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile; 178. (S)-4-Amino-6-((1-(4-(2-(4-(dimethylamino))piperidin-1-) -6-methylpyridin-4-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Nitrile; 179. 5-(2-Aminopyridin-4-yl)-N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)pyrrolo [2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 180. (1-(2- ((2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl Pyrrolo[2,1-f][1,2,4]triazine- 4-yl)oxy)ethyl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone; 181. 5-(2-(4-(dimethylamino))piperidine -1-yl)pyridin-4-yl)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[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-amine; 183. 3- (2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrole And [2,1-f][1,2,4]triazin-4-yl)-N-(3-(4-(dimethylamino)piperidin-1-yl)propyl)-5- Methyl benzamide; 184. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- Methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-((3-(dimethylamino))propyl (M)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-cyanopyrimidine) 4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzoate Indoleamine; 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-aminesulfonylbenzyl)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-A Nitrile; 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-cyanopyrimidine)) 4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethyl Benzobenzamide; 191. N-(3-(4-((S))-(4-((2S,6R)-2,6-dimethylmorpholinyl)pyrrolo[2, 1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide; 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)-1H-indole-6- Methanesulfonamide 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[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl)methanesulfonamide ; 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)-1H-indol-6-yl)methanesulfonate Guanamine; 195. (S)-5-(2-Aminopyridin-4-yl)-N-(1-(4-(2-(4-(dimethylamino)piperidin-1-yl)) Oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Amine; 196. (S)-3-(4-(4-((1-(4-(2-(4-(dimethylamino))piperidin-1-yl)ethoxy)-5-) Pyryrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H- Pyrazol-1-yl)propan-1-ol; 197. (S)-1-(5-(4-((1-(4-(4-(4-(4-(methylamino))piperidine-1 -yl)ethoxy)-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) Urea; 198. N1-(4-(4-((S))-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrole And [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-N2,N2-di Methyl ethane-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)pyridine-4- -7H-pyrrolo[2,3-d]pyrimidin-4-amine; 200. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyridyl) Zoxao[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-methylbenzimidamide; 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)-1H-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 -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 203. 3-(4-amino-1-((4-(3-(4-)) -amino)piperidin-1-yl)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazole And [3,4-d]pyrimidine-3- -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)-1H-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)-1H-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)-1H-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)-1H-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] Benz-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 209. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-hydroxyl) Benzyl)-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-(dimethylamino)ethoxy)benzyl)-3,5-dimethylperidyl) Pyrazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; or pharmaceutically thereof Acceptable salts, or nitrogen-oxides, or isotopically-labeled derivatives.

An example of a preferred compound is: 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) (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; (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]triazine -2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 32. (S)-4-amino-6-((1-(4-(3-hydroxy-5-(trifluoromethyl))benzene (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; 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-isopropyl) Piperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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)-1H-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)-1H-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) -Dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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))) Fluoro-5-methoxyphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Nitrile; 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-)) Propylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[ 3,4-d]pyrimidine 3-yl)-5-fluorophenol; 55. 3-(4-Amino-1-((4-((2-(dimethylamino)ethyl))(3-hydroxyphenyl)amino)-5) -Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5 -fluorophenol; 56. (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)))) 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-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)-1H-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 -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 63. (S)-4-amino-6-((1-(4-((3-hydroxy))) Phenyl)(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)-1H-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-dimethylpyridine-4-) -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[2,1-f][1,2,4] Pyrazin-2-yl)ethyl)amino)-7H- [2,3-d]pyrimidine-5-carbonitrile; 72. 3-(4-amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-) 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3- 5-)-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-1H-pyrazol-4-yl)-7H-pyrrole And [2,3-d]pyrimidine-4-amine; 87. N-(3-(4-((S))-(4-((3S,5R)-3,5-dimethylper Pyrazin-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-dimethylpiperazine)- 1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 3-yl)-5-hydroxyphenyl)methanesulfonamide; 90. 5-(4-Amino-1-((4-((3S,5R)-3,5-dimethylpiperazin-1-) 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3- 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 99. 4-( 2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- (4-)-(2)-dimethyl benzoic acid (S)-methyl ester; 100. 3-(1-((4-((1S,4S)-2,5-diazabicyclo[2.2. 1]hept-2-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-4-amino-1H-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]triazine-2 -yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 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; 110. N-(3-(4-((S))-(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-methylpyrrole [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- -N-(4-Aminesulfonylbenzyl)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-methylbenzimidazole Amine; 131. N-(5-(4-((S))-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2 ,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxypyridine- 3-yl) methanesulfonamide; 144. N-(4-(4-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5) -Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene Methanesulfonamide; 1 45. (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 Indoleamine; 150. 3-(4-Amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-1H-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-(methylsulfonylamino)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-methylbenzimidamide; 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] 5-(2-aminopyridin-3-yl)-N-((S)-1 -(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-2 -yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 172. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)) -1H-pyrazolo[3,4-d]pyrimidin-1- Methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzoate Guanidine; 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 179. 5-(2-Aminopyridin-4-yl)-N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)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- -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-dimethylpiperazine- 1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-4 An amine; or a pharmaceutically acceptable salt thereof, or a nitrogen-oxide, or an isotope-labeled derivative.

In one embodiment, a particular individual compound of the invention comprises: 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-carboxylic acid (S)-t-butyl ester; (S)-4-amino-6- ((1-(4-(piperidin-4-ylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- (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]triazine- 2-(yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(4-isopropoxypyrrolo[2,1-f][1,2 , 4] triazin-2-yl)ethyl)amino)pyrimidine-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]triazin-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-methyl) Piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 4-((2-(1) -((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy (S)-T-butyl ester; (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) 4-pyrimidine-5-carbonitrile; 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-carboxylic acid (S)-t-butyl ester; (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- (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; (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; (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)pyrimidine- 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)-1H- Pyrazolo[3,4-d]pyrimidin-3-yl -5-fluorophenol; (S)-4-amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1-f][1,2,4]triazine 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)-1H-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)-1H-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]triazine-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)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6 -((1-(4-(5- Pyridin-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- Nitrile; (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; (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-) 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3- ())-5-fluorophenol; (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; (S)-4-amino-6-((1-(4-(3-fluoro-5-hydroxyl) Phenyl)-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]triazine-2- Methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 3-(4-amino-1-((4-(3-fluoro-5-) Hydroxyphenyl)-5-methylpyridyl And [2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2, 4] triazin-2-yl)methyl)-1H-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[2,1-f][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(4-((3-hydroxyphenyl)) 2-morpholinyl) Ethyl)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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl )-5-fluorophenol 3-(4-Amino-1-((4-(2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-2-yl)methyl)-1H-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-methoxybenzenesulfonamide; (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-methoxy Benzenesulfonamide; 3-(4-amino-1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; (S)-4-amino-6 -((1-(4-(3-methoxyphenyl)(methyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile; 3-(4-amino-1-((5-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pyrrole) And [2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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)-1H-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-morpholinylethyl)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)pyrimidine-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)-1H -pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; (S)-4-amino-6-((1-(4-((2-hydroxyethyl))) (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)) Ammonia (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]triazine- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 4-amino-6-(((S)-1-(4-((3S,5R)-3,5-dimethylpiperazine-) 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-methylpyrrolo[2,1-f ][1,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-hydroxybenzamide; 4-amino-6-(((() 1-(5-methyl-4-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)pyrrolo[2,1-f][1,2,4] (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)amino)pyrimidine-5-carbonitrile 3-(4-Amino-1-((4-((3S,5R)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-A Pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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)-1H-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)-1H-pyrazolo[3,4-d]pyrimidin-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)-1H- 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5 -fluorophenol; 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-hydroxybenzyl)-3,5-dimethylpiperazin-1- 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-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5-dimethylpiperazin-1- 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-carbonitrile; 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 5-5-carbonitrile; or a pharmaceutically acceptable salt thereof, or a nitrogen-oxide, or an isotope-labeled derivative.

An example of a preferred compound in this example is: (S)-4-amino-6-((1-(5-methyl-4-((tetrahydro-2H-pyran-4-yl))) Oxy)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[2,1-f][1,2,4]triazin-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] (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- (S)-N-(5-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-) (pyrido[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]triazine-2- (ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl)))) Amino)-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) A -1H-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)-1H-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)-1H-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]3 3-(4-amino-1-((4-((2S,6R)-2,6-dimethylmorpholinyl)-5 -Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5 -fluorophenol; (S)-4-amino-6-((1-(4-(4-hydroxy-3,5-) Methylphenyl)-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]triazine 4-yl)-N-cyclopropyl-5-hydroxybenzamide; (S)-4-amino-6-((1-(4-((2-(dimethylamino)ethyl))) (3-fluoro-5-methoxy Phenyl)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)-1H-pyrazolo[3,4-d]pyrimidine-3- 5-)-5-fluorophenol; 3-(4-amino-1-((4-(2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5-methylpyrrole [2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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; 3-(4-amino-1-((4-(4-(2) -hydroxyethyl)piperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[ 3,4-d]pyrimidin-3-yl)-5-fluorophenol; 3-(4-amino-1-((5-methyl-4-(4-(methylsulfonyl))piperazine-1 -yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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))) Amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3- 5-)-fluorophenol; or a pharmaceutically acceptable salt thereof, or a nitrogen-oxide, or an isotope-labeled derivative.

The invention also relates to a compound of the invention as described herein for use in the treatment of amelioration of pathological symptoms or diseases, in particular pathological symptoms or diseases thereof, by inhibition of phospholipid inositol 3-kinase (PI3K) Selected from respiratory diseases, allergic diseases, inflammatory or autoimmune-mediated diseases, function disorders, and neurological disorders. Pain, cardiovascular diseases, viral infection, metabolism/endocrine function disorders, bone marrow and organ transplant rejection, myelodysplastic syndrome ( Myelo-dysplastic syndrome), myeloproliferative disorders (MPDs), cancer and hematologic malignancies, leukemia, lymphomas, and solid tumors; Particularly, wherein the pathological symptom or disease is selected from Leukemia, lymphomas and solid tumors, rheumatoid arthritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type 1 diabetes (type I diabetes), cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullous type Bullous (pemphigoid) and epidermal loose vesicular disease (epidermolysis bullosa) blistering diseases, asthma (asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), primary pulmonary fibrosis (idiopathic) Pulmonary fibrosis), sarcotic disease, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema, psoriasis, Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK).

The invention also relates to the use of a compound of the invention as described herein for the manufacture of pathological conditions or diseases which are susceptible to treatment by inhibition of phosphosinoinositide 3-Kinases (PI3Ks). The drug, particularly the pathological condition or disease system therein, is as defined above.

The present invention also provides a method for treating pathological symptoms or diseases which are easily ameliorated by inhibiting phosphosinoinositide 3-Kinases (PI3Ks), particularly wherein the pathological symptoms or diseases are as defined above. The method comprises administering to the 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, comprising: (a) preventing the occurrence of a disease or medical condition, ie, a preventive treatment of the patient; (b) To improve the disease or medical condition, that is, to cause the disease or medical symptoms in the patient to subside; (c) to suppress the disease or medical symptoms, that is, to slow down the disease or medical symptoms in the patient's body. Development; or (d) alleviating the symptoms of a 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 understood that the general or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given; unless otherwise stated, otherwise other process conditions Can also be used. The optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by routine knowledge of those skilled in the art by routine optimization procedures.

Moreover, as will be apparent to those of ordinary skill in the art, conventional protecting groups may be necessary to prevent certain functional groups from being undesirably reacted. The selection of protecting groups for a particular functional group and conditions suitable for the addition of protecting groups and removal of protecting groups are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in TW Green and GM Uz, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999 (TWGreene and GMWuts, 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 the amine nitrogen. Representative amine protecting groups include, but are not limited to, formyl; acyl groups, such as alkanoyl groups, such as acetoxy (acetyl); alkoxycarbonyl (alkoxycarbonyl) Groups), such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl ( 9-fluorenylmethoxycarbonyl, Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr) and 1,1- 1,1-di-(4'-methoxyphenyl)methyl); silyl groups, such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldimethylsilyl (TBS).

The term hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl groups, such as Ethylmethyl group; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (9-fluorenylmethyl) , Fm) and diphenylmethyl (benzhydryl (DPM)); silyl groups, such as trimethylsilyl (TMS) and tributyl dimethyl Tert-butyldimethylsilyl (TBS) and the like.

The compound of the formula (I) can be produced from the compound of the formula (IV) by the synthetic route shown in Scheme 1. Thus, a compound of formula (IV) can be converted in a compound of formula (III) by a compound of formula (IV) with a suitable reagent such as phosphorus oxychloride or phosphorus pentachloride or chlorination. Thionyl chloride or a mixture thereof is treated at a temperature ranging from room temperature to reflux with or without the presence of a suitable solvent such as dichloromethane.

In the specific case of the compound of formula (I) wherein W represents a direct bond, the compound of formula (III) may be in the presence of a suitable catalyst, such as a palladium (0) catalyst in standard Suzuki coupling conditions, and corresponding Treatment with boric acid or borate esters is widely described in the literature. Alternatively, it can be prepared by reacting a compound of formula (III) in the presence of a suitable catalyst, such as a palladium (0) catalyst, under standard Stillling coupling conditions, with the corresponding organotin derivative. .

In the specific case of the compound of formula (I), wherein W represents a group selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -NR ^a -(CH ₂ ) _{0 -3} -, -O-(CH ₂ ) _0-3 -N(*)R ^a , -N(*)-(CH ₂ ) _0-3 -N(R ^a )R ^b and -N(*)- (CH ₂ ) _{0-3 -} Link group in R ^c , the compound of formula (III) can be treated with the corresponding R ₁ -WH group in a suitable base such as potassium carbonate, diisopropylethylamine or hydrogenation the presence of sodium, in a suitable solvent such as tert-butanol, N, N - dimethyl 2carboxamide (N, N -dimethylformamide), THF (tetrahydrofuran), or acetone, at a temperature ranging from room temperature to 160 ℃ With or without microwave irradiation.

In one embodiment of the present invention, the compound of the formula (IV) can be obtained from a compound of the formula (V) wherein the Z ₁ group is a -NH ₂ group by the chemical formula (II-1) as shown in Scheme 2. The compounds of (II-2), (II-3), (II-4), (II-5) and (II-6) are treated in a suitable base such as sodium carbonate or diisopropylethylamine. in the presence, in a suitable solvent such as tert-butanol, N, N - dimethyl 2carboxamide (N, N -dimethylformamide) or tetrahydrofuran (tetrahydrofuran) at a temperature ranging from room temperature to 160 ℃, use or No microwave irradiation is used, and with or without the use of a suitable catalyst such as cesium fluoride.

In another embodiment of the invention, a compound of general formula (IV) can be prepared from a compound of formula (V) wherein the group Z ₁ represents a halogen atom such as chlorine, bromine and iodine, or another suitable leaving group such as methane a methanesulfonate or a trifluoromethanesulfonate or other group such as a hydroxyl group, which can be by a standard method described in the literature, such as a Mitsunobu reaction, etc., by the chemical formula (V) The compound and the compound of the formula (II-7) are treated under the same conditions as above to be converted into a suitable leaving group.

When Z ₁ is a halogen atom such as chlorine, it can be converted to another more active halogen atom such as iodine by treating the compound with a chlorine atom and sodium iodide in acetone at room temperature to reflux temperature. .

Compounds of formula (II) can be prepared commercially or by synthetic methods well described in the literature.

Alternatively, a compound of formula (IV) can be obtained by a two-step synthesis as shown in Scheme 3, by formulating a compound of formula (V) with formulas (VII-1), (VII-2) and (VII- The compound of 3) is treated with a suitable base such as potassium carbonate or diisopropylethylamine in a suitable solvent such as tert -butanol, N , N -dimethyl In N , N- dimethylformamide or tetrahydrofuran, at temperatures ranging from room temperature to 160 ° C, with or without microwave irradiation, and with or without cesium fluoride.

In a particular case of a compound of general formula (IV) wherein R ₅ represents a group of formula (II-1), (II-2) or (II-4), wherein L represents a direct bond or —(CH ₂ ) _1-4 group, the compound of formula (IV) from the formula (VI-1), (VI -2) and (VI-3) a compound in which Z ₃ represents a halogen atom, by the presence of a suitable catalyst, For example, a palladium (0) catalyst is prepared by reacting with a corresponding boric acid or boric acid ester under standard Suzuki coupling conditions.

In a specific case of a compound of general formula (IV), wherein R ₅ represents a group of formula (II-1), (II-2) or (II-4), wherein L represents a group selected from -O-(CH ₂ ) a chain group of _0-3 - or -S-(CH ₂ ) _0-3 -, which can be catalyzed by a compound of formula (VI-1), (VI-2), (VI-3) by using copper or palladium The coupling method or other methods well known to those of ordinary skill in the art are obtained by reacting with the corresponding thiol or alcohol of the formula HL-R ₁₀ or HL-R ₁₂ .

Boric acid or borate esters, mercaptans and alcohols can be commercially available or prepared by standard methods and can be used in protected form to prevent undesired reactions of certain functional groups. In these cases, these protecting groups can be removed using standard methods at the most appropriate step of the synthesis. Numerous protecting groups, as well as their introduction and removal, are described in TW Green and GM Uz, Protecting Groups in Organic Synthesis, 3rd Edition, Wilhelm, New York, 1999 (TWGreene and GMWuts, Protecting Groups in Organic Synthesis , Third Edition, Wiley, New York, 1999) and references cited therein.

In a particular case of a compound of general formula (IV), R ₅ represents a group of formula (II-1), (II-2) or (II-4), wherein L represents a -C(O)-NH- group or -C(O)-O- group; the compound of formula (IV) can be prepared from compounds of formula (VI-1), (VI-2), (VI-3), and Z ₃ represents a carboxylic acid, which is prepared by The corresponding guanamine or ester is treated with a carboxylic acid and an activator by methods and conditions well described in the literature, for example using T ₃ P ^® , EDC or HATU as an activator in a solvent, such as dimethyl carboxy hydrazine. A dimethylformamide, tetrahydrofuran, ethyl acetate or dichloromethane is present at a temperature ranging from room temperature to 80 °C.

A compound of general formula (V) can be prepared from a compound of formula (IX) as shown in Scheme 4, wherein Z ₂ represents a -NH ₂ group or a protected amino group such as -NHBz(OMe) or -NHBz(OME) ₂ Or -O-alkyl.

The compound of formula (IX) can be treated by treating the compound of formula (IX) with the appropriate acid chlorides of formula (X) in a solvent such as acetic acid, toluene, xylene, dioxane or dichloromethane. , in the temperature range from room temperature to 50 ° C, Conversion in the guanamine of formula (VIII) in the presence or absence of a suitable base such as triethylamine or pyridine.

Alternatively, the compound of formula (IX) can be converted in the guanamine of formula (VIII) by treatment of a carboxylic acid of formula (XI) in the presence of an activator, the activator being by methods and conditions well described in the literature. For example, using T3P ^® , EDC or HATU as an activator in a solvent such as dimethylformamide, tetrahydrofuran or dichloromethane or a mixture of these solvents, the temperature range is from room temperature to 80 ° C.

a compound of formula (VIII) wherein Z ₂ is a -NH ₂ group or a protected amino group such as -NHBz (OMe) or -NHBz(OMe) ₂ group, which can be treated by treatment with acetic acid at a temperature ranging from room temperature to 150 ° C. Alternatively, it can be converted in the compound of formula (V) by treatment with pyridinium p-toluenesulfonate in a suitable solvent such as toluene or xylene at a temperature ranging from room temperature to 150 °C.

Deprotection of the benzyl group can be carried out by standard methods well described in the literature, such as palladium-catalyzed hydrogenolysis, or by acid-promoted debenzylation synthesis of trifluoroacetic acid, or by other convenient synthetic procedures. .

A compound of formula (VIII), Z ₂ is -O-alkyl, which can be converted in a compound of formula (V) by treatment of a compound of formula (VIII) with a complex wherein the complex is from triphenyl Phosphine and bromine in a solvent such as dichloromethane, in the presence of a base such as triethylamine, the temperature is treated from room temperature to reflux, and then concentrated ammonium hydroxide or ammonia solution in an organic solvent such as methanol or dioxane in the temperature range The result of subsequent treatment at room temperature to 150 °C.

A compound of the general formula (IX) can be obtained from a compound of the formula (XII) as shown in Scheme 5. Thus, the chemical compounds of general formula (XII) may be described in the literature wherein one of the amine reagent (aminating reagents), such as O - (mesitylene sulfonic acyl) hydroxylamine (O - (mesitylenesulfonyl) hydroxylamine) , O - ( on - acyl-nitrobenzoyl) - hydroxylamine (O - (p -nitrobenzoyl) -hydroxylamine ), O - ( diphenyl - phosphino) - hydroxylamine (O - (diphenyl-phosphinyl) -hydroxylamine), O - (2,4-dinitrophenyl) - hydroxylamine (O - (2,4-dinitrophenyl) -hydroxylamine), hydroxylamine - O - sulfonic acid (hydroxylamine- O -sulfonic acid), using a suitable base such as Triethylamine, potassium carbonate, sodium hydride or butyl lithium in a suitable solvent such as N , N' -dimethylcarboxime ( N , N ' -dimethylformamide), tetrahydrofuran, 1,4-dioxane, at a temperature ranging from -78 to 100 ° C, the nitrogen atom at position 1 is aminated. Alternatively, the amination reaction may use an aqueous solution of ammonia, sodium hydroxide, ammonium chloride, and sodium hypochlorite, and a suitable organic solvent such as a dialkyl ether, and a phase transfer catalyst such as Aliquat 336 ^{® may be added} at a temperature ranging from 0 ° C to room temperature. Warm, in a two-phase system.

Compounds of general formula (II) may be commercially available or may be prepared by known synthetic routes which are described elsewhere in the literature and which will be apparent to those skilled in the art.

In the particular case of the compound of formula (I), X represents CR ₆ wherein R ₆ is C ₃ -C ₇ cycloalkyl, or a linear or branched C ₁ -C ₄ alkyl group, and the compound of formula (1b) Prepared from the compound of formula (1c) as shown in Scheme 6 by coupling with the corresponding boronic acid or organotin compound in Suzuki or Stirling, in a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) Or in the presence of palladium acetate, with or without a suitable base such as potassium carbonate or cesium carbonate, and in a suitable solvent such as toluene or dioxane or N,N -dimethylcarboxamide, at temperatures ranging from 60 ° C to 150 ° C.

In a specific case, X represents CR ₆ wherein R ₆ is trifluoromethyl, and the bromine atom in the compound of formula (1c) can be first converted to an iodine atom by using sodium iodide in a catalyst such as copper iodide (I). and the chelating amine such as trans-1,2-bis (methylamino) cyclohexane in the presence of (trans -1,2-bis (methylamino) cyclohexane) in a suitable solvent such as 1,4-dioxane The temperature is in the range of 60 ° C to reflux for treatment. Next, the iodine intermediate is treated with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate or any other trifluoromethylating agent using a suitable catalyst such as copper (I) iodide. Or no chelating agent such as hexamethylphosphoramide and in a suitable solvent such as N,N' -dimethylcarboxamide to give the desired compound.

In certain instances, wherein R ₆ is a cyano group, the bromine atom in the compound of formula (Ic) can be first converted to iodine in the manner previously described, or directly treated with zinc dicyanate (zinc dicyanate) in a palladium catalyst such as In the presence of tetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as N,N' -dimethylcarboxamide, at a temperature ranging from 60 ° C to 150 ° C, or by using copper cyanide A solvent such as pyridine is used at a temperature ranging from 60 ° C to 150 ° C.

Example

General rule

The synthesis of the compounds of the present invention and the intermediates used herein is given by the following Examples 1 to 210 (including Preparation Examples (Preparations 1 to 146)), in order to provide those having ordinary knowledge in the art. The invention is to be considered in all respects as illustrative and not restrictive

Reagents, starting materials and solvents are commercially available from commercial suppliers and used as received. Concentration or evaporation refers to evaporation under vacuum using a Büchi rotary evaporator.

If necessary, the reaction product was purified by flash chromatography on silica gel (40-63 μm) with the indicated solvent system. Purification by reverse phase chromatography was performed in a Biotage SP1 ^® automated purification system equipped with a C ₁₈ column and used in 40 column volumes with a gradient of water-acetonitrile/methanol (1:1) from 0% To 100% acetonitrile/methanol (1:1) (both phases contain 0.1% v/v ammonium formate). The appropriate fractionation is collected and the solvent is evaporated under reduced pressure and/or freeze-dried.

Preparative high performance liquid chromatography-mass spectrometry (HPLC-MS) is performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, and a 2996 PDA detection. The instrument, the 515 pump as a make-up pump, and the ZQ4000 mass spectrometer detector, or the Agilent 1200 Series coupled to an Agilent 6120 mass spectrometer detector. Both systems were equipped with a symmetrical C ₁₈ (XBridge Prep C ₁₈ ) (19 x 100 mm, 5 μm) column for the preparation of a C ₁₈ (Symmetry Prep C ₁₈ ) (19 x 300 mm, 7 μm) column or X bridge. 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 gradient is specified in each particular case. The flow rate was 20 mL/min.

Purity and mass spectrometry were performed on a Waters 2795 system coupled to a 2996 diode array detector and to a Waters ZQ mass spectrometer detector, or a Waters Acquity coupled to an SQD mass spectrometer detector. UPLC system to carry out. The injection volume was 5 μl on HPLC and 0.5 μl on UPLC. The chromatogram was performed at 210 nM or 254 nM. The mass spectrum of the chromatogram is obtained using positive and negative electrospray ionization. The mobile phases were 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 used A gradient of 0 to 95% B. Column: High Performance Liquid Chromatography (HPLC): Waters Symmetry (2.1x50mm, 3.5m); Ultra High Performance Liquid Chromatography (UPLC): ACQUITY UPLC BEH C-18 (2.1x50mm, 1.7m).

^{The 1} H NMR spectrum was recorded in a Varian Gemini-2000 spectrometer with a ¹ H spectral operating frequency of 300 megahertz (MHz) or at a ¹ H spectral operating frequency of 400 MHz (MHz). In Varian Mercury plus. The sample is dissolved in the designated deuterated solvent. Tetramethyl decane was used as a reference.

abbreviation:

DMSO Dimethylsulfoxide

CDCl ₃ Deuterated chloroform

CD ₃ OD Deuterated methanol

NMR nuclear magnetic resonance (Nuclear magnetic resonance)

s Single peak (Singlet)

d double peak (Doublet)

Dd Double Doublet (Doublet of doublets)

Td triplet doublets

Br broad peak (Broad)

q Quadruple (Quartet)

t Triplet (Triplet)

m multiple peaks (Multiplet)

LRMS low resolution mass spectrometry

h hours (hours)

Min minutes (minutes)

DMF N, N - dimethyl 2carboxamide (N, N -Dimethylformamide)

DCM Dichloromethane, methylene chloride

AcOEt ethyl acetate (Ethyl acetate)

DMSO Dimethylsufoxide

DMTBE dimethyl- tert -butyl ether (Dimethyl- tert- buthylether)

Et ₂ O Diethylether

EtOH Ethanol

EDC. Chloride HCl 3 - ((ethanimidoyl) iminomethyl) - N, N - dimethyl-1-aminium (3 - ((ethylimino) methyleneamino ) - N, N -dimethylpropan-1-aminiumchloride)

THF tetrahydrofuran

DIEA Diisopropylethylamine

HOBt 1-Hydroxybenzotriazole hydrate

MeOH methanol (methanol)

iPrOH isopropanol (propan-2-ol, 2-propanol)

DPPONH ₂ (aminooxy)diphenylphosphine oxide

PPTS p-toluenesulphonate (Pyridinium p- toluenesulphonate)

PPh ₃ Triphenylphosphine

Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphane)palladium(0)(Tetrakis(triphenylphosphane)palladium(0))

PdCl ₂ dppf. DCM [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride with a complex of dichloromethane (1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium( II), complex with dichloromethane)

Dppf 1,1'-bis(diphenylphosphino)ferrocene

Celite ^® diatomaceous earth

T3P ^® 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide (2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide)

HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2-(1H-7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphate)

Preparation 1

(S) -2-(1-Aminoethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S )-2-(1-Aminoethyl )pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

a) (1-((2-Aminomethyl)-1 H -pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamic acid (S) -T-butyl ester (( S )- Tert- 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-((t-butoxycarbonyl)amino)propionic acid (( S )-2-(( tert- butoxycarbonyl)amino) Propanoic acid) (available from Aldrich ^® , catalog number 15380) was dissolved in 50 ml of a 1:1 mixture of DCM and DMF. 4.0 ml (22.9 mmol) of DIEA was added, and the resulting solution was stirred at room temperature for 1 hour. Then was added 2.55g (20.4 mmol) of 1-amino -1 H - pyrrole-2carboxamide ^{1 (1-amino-1 H} -pyrrole-2-carboxamide 1), and the reaction mixture was stirred for 3 hours. The solvent was then removed in vacuo. The aqueous solution was extracted with dichloromethane, washed with water and brine, dried over magnesium sulfate. This crude product was purified by flash chromatography (EtOAc:EtOAc) Total yield: 95%.

LRMS(m/z): 297(M+1) ⁺

b) (1-(4-Sideoxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - Third butyl ester (( S )- Tert- butyl(1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

2.65 g (8.94 mmol) of (1-((2-aminocarbamimidino-1 H -pyrrol-1-yl)amino)-1-yloxypropan-2-yl)carbamic acid (S) - third butyl ester ((S) - tert -butyl ( 1 - ((2-carbamoyl-1 H -pyrrol-1-yl) amino) -1-oxopropan-2-yl) carbamate) and 2.25g (8.95mmol) of PPTS It was suspended in 105 ml of 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 ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. 320 mg (yield 8%) of the title compound were obtained.

LRMS(m/z): 279(M+1) ⁺

c) (S) -2-(1-Aminoethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S )-2-(1) -Aminoethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

786 mg (2.82 mmol) of (1-(4-o-oxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - tert- butyl ester (( S )- Tert- butyl(1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl Carbatum) was dissolved in 30 ml of a 4 M hydrochloric acid solution in dioxane. The solution was stirred at room temperature overnight and the volatiles were removed in vacuo. 606 mg (yield 100%) of the title compound as a white solid.

LRMS(m/z): 179(M+1) ⁺

Preparation 2

(S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Formonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile )

a) (S) -4-Amino-6-((1-(4-trioxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazine-2-) Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2, 4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

606 mg (2.82 mmol) of (S) -2-(1-aminoethyl)pyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (( S )- 2-(1-Aminoethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) (hydrogen chloride) and 480 mg (3.11 mmol) of 4-amino-6-chloro pyrimidine-5-carbonitrile ^{2 (4-amino-6-} chloropyrimidine-5-carbonitrile 2) was suspended in 50ml of tert-butoxide. 2.46 ml (11.75 mmol) of DIEA was added, and the resulting suspension was stirred at 120 ° C overnight in a closed vessel. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 297(M+1) ⁺

b) (S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5 -carbonitrile)

600 mg (2.03 mmol) of (S) -4-amino-6-((1-(4-trioxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]3 Pyrazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) was stirred at 10 ml of phosphorus oxychloride at reflux temperature for 2 hours. The volatiles were then removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with EtOAc EtOAc EtOAc EtOAc.

LRMS(m/z): 315(M+1) ⁺

Preparation 3

1-amino-3-bromo -1 H - pyrrole-2-carboxylate (Methyl 1-amino-3- bromo-1 H -pyrrole-2-carboxylate)

a) 3- bromo -1 H - pyrrole-2-carboxylate (Methyl 3-bromo-1 H -pyrrole-2-carboxylate)

29.5 g (85.6 mmol) of 3-bromo-1-(phenylsulfonyl)-1 H -pyrrole-2-carboxylic acid methyl ester ³ (methyl 3-bromo-1-(phenylsulfonyl)-1 H- pyrrole- 2-carboxylate ³ ) was dissolved in 560 ml of methanol and cooled in an ice bath under a nitrogen atmosphere. 6.79 g (123 mmol) of sodium methoxide was 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. The combined organic extracts were washed with water and brine, dried over magnesium sulfate. The residue was dissolved in a mixture of 140 ml of methanol and 140 ml of concentrated aqueous ammonia, and stirred at room temperature for 1 hour. It was then 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 EtOAc EtOAc.

LRMS(m/z): 204,206(M+1) ⁺

b) 1- amino-3-bromo -1 H - pyrrole-2-carboxylate (Methyl 1-amino-3- bromo-1 H -pyrrole-2-carboxylate)

2.43 g (60.7 mmol) of sodium hydride (60% dispersion in mineral oil) was suspended in 225 ml of anhydrous DMF and cooled in an ice bath. 7.50g in 75ml of DMF (36.8mmol) 3- bromo -1 H - pyrrole-2-carboxylate (Methyl 3-bromo-1 H -pyrrole-2-carboxylate) was then added dropwise under nitrogen atmosphere After the addition, the mixture was stirred at 0 ° C for 30 minutes. It was then diluted with 115 ml of DMF and 13.7 g (58.8 mmol) of DPPOONH _{2 was} added to the two fractions. The resulting mixture was stirred at room temperature for 3 hours and then poured into 500 ml of a 10% aqueous sodium thiosulfate solution. The product was extracted with EtOAc (EtOAc)EtOAc. Yield: 59%.

LRMS(m/z): 219,221(M+1) ⁺

Preparation 4

(S) -2-(1-Aminoethyl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S )-2- (1-Aminoethyl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

a) 3- bromo-1- (2 - ((tertiary-butoxycarbonyl) amino) propylamino) -1 H - pyrrole-2-carboxylic acid (S) - ester ((S) -Methyl 3-bromo- 1-(2-(( tert- butoxycarbonyl)amino)propanamido)-1 H -pyrrole-2-carboxylate)

The crude product obtained in Preparation 3b (18.38 mmol) was dissolved in 40 ml of ethyl acetate. 3.50 g (18.5 mmol) of (S)-2-(( tert- butoxycarbonyl)amino)propanoic acid (( S )-2-(( tert- butoxycarbonyl)amino)propanoic acid) (purchased from Aldrich ^® , Cat. No. 15380), and the resulting mixture was cooled in an ice bath under argon. Then 10.6 ml (60.9 mmol) of DIEA was added and after 15 minutes, 15.3 ml (25.7 mmol) of T3P ^® (50% solution in ethyl acetate) was added dropwise. The mixture was stirred at 0 ° C for 20 minutes and then at room temperature for 1 hour. For the separation of the product, the solution was washed with water and brine. The crude product was purified by flash chromatography (EtOAc:EtOAc:

LRMS(m/z): 390,392 (M+1) ⁺

b) (1-(5-Bromo-4-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - tert- butyl ester (( S )- Tert- butyl(1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2 -yl)ethyl)carbamate)

1.0 g (2.56 mmol) of 3-bromo-1-(2-((t-butoxycarbonyl)amino)propylamino)-1 H -pyrrole-2-carboxylic acid (S) -methyl ester (( S ) -Methyl3-bromo-1-(2-(( tert- butoxycarbonyl)amino)propanamido)-1 H- pyrrole-2-carboxylate) was stirred overnight in a sealed tube of 7M ammonia in methanol at 85 °C. The volatiles were removed in vacuo to give crystals crystals crystals crystals

LRMS(m/z): 357,359 (M+1) ⁺

c) (S) -2-(1-Aminoethyl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S )- 2-(1-Aminoethyl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

360 mg (1.01 mmol) of (1-(5-bromo-4-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl) Carbamate (S) -tert-butyl ester (( S )- Tert- butyl(1-(5-bromo-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4 ]triazin-2-yl)ethyl)carbamate) was stirred overnight at room temperature in a solution of 4M hydrochloric acid in dioxane. The volatiles were removed under vacuum, the residue was dissolved in water and the solution was basified with saturated aqueous sodium carbonate. The product was extracted with dichloromethane and the aqueous layer was saturated with sodium chloride and extracted again. The combined organic solution was dried with MgSO4, filtered andEtOAc

LRMS(m/z): 257,259 (M+1) ⁺

Preparation 5

(S) -4-Amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino) Pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl )amino)pyrimidine-5-carbonitrile)

a) (S) -4-amino-6-((1-(5-bromo-4-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]3 Pyrazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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- f ][1,2,4]triazin-4( 3H )-one (( S )-2-(1-Aminoethyl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) and 710 mg (4.59 mmol) of 4-amino 4-amino-6-chloropyrimidine-5-carbonitrile was suspended in 50 ml of third butanol. 2.90 ml (16.65 mmol) of DIEA was added and the resulting suspension was stirred at 120 ° C overnight in a closed vessel. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc:EtOAc

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 (( 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-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2 ,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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) was stirred at 15 ml of phosphorus oxychloride at reflux temperature for 3 hours. The volatiles were then removed in vacuo 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 an aqueous potassium carbonate solution and stirred at room temperature for 4 hours. The product was then extracted with EtOAc (EtOAc)EtOAc.

LRMS(m/z): 393,395 (M+1) ⁺

Preparation 6

(S) -2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S )-2 -(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

a1) 1- amino-3-methyl -1 H - pyrrole-2-carboxylate (Ethyl 1-amino-3- methyl-1 H -pyrrole-2-carboxylate)

3.39 g (84.7 mmol) of sodium hydride (60% dispersion in mineral oil) was suspended in 550 ml of anhydrous DMF and cooled in an ice bath. 10.0 g (65.3 mmol) of ethyl 3-methyl-1 H- pyrrole-2-carboxylate (purchased from Ace) in 200 ml of DMF under nitrogen atmosphere Astatech ^® , Cat. No. 59362) was solutiond for 30 minutes and mechanically stirred at 0 ° C for 30 minutes. Then, 24.36 g (104 mmol) of DPPOONH _{2 was} added to 5 portions. The resulting mixture was stirred at room temperature for 4 hours and then poured into 500 ml of a 10% aqueous sodium thiosulfate solution. The product was extracted with EtOAc (EtOAc)EtOAc. Yield: 72%.

LRMS(m/z): 169(M+1) ⁺

B1) 1-(2-((Tertidinoxycarbonyl)amino)propylamino)-3-methyl-1 H -pyrrole-2-carboxylic acid (S) -ethyl ester ((S)-Ethyl 1- (2-((tert-butoxycarbonyl)amino)propanamido)-3-methyl-1 H -pyrrole-2-carboxylate)

12.66g (66.9mmol) of (S) -2 - ((tertiary-butoxycarbonyl) amino) propanoic acid ((S) -2 - (( tert -butoxycarbonyl) amino) propanoic acid) ( available from Aldrich ^®, directory No. 15380) and 25.44h (66.9 mmol) of HATU were dissolved in 40 ml of DMF and 40 ml of DCM mixture. The solution was cooled in an ice bath, 11.65 ml (66.9 mmol) of DIEA was added, and the mixture was stirred at room temperature for 1 hour. Was then added 10.23g (46.8mmol) of 1-amino-3-methyl -1 H - pyrrole-2-carboxylate (Ethyl 1-amino-3- methyl-1 H -pyrrole-2-carboxylate) ( on The crude product obtained in one step was obtained (yield: 66%), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

LRMS(m/z): 340(M+1) ⁺

C1) (1-(5-Methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino Formic acid (S) -T-butyl ester (( S )-Tert-butyl(1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin- 2-yl)ethyl)carbamate)

24.8 g (94.5 mmol) of PPH _{3 was} dissolved in 200 ml of dichloromethane and cooled in an ice bath. Then 4.84 ml (94.5 mmol) of bromine was added, and the resulting solution was stirred at room temperature for 30 minutes. Then, 33 ml (238 mmol) of triethylamine and 16.07 g (38.4 mmol) of 1-(2-((t-butoxycarbonyl)amino)propylamino)-3-methyl-1 were added to 100 ml of dichloromethane. H -pyrrole-2-carboxylic acid (S) -ethyl ester (( S )-Ethyl 1-(2-((tert-butoxycarbonyl)amino)propanamido)-3-methyl-1 H- pyrrole-2-carboxylate)( The crude product obtained in the previous step was 81% pure). The resulting solution was stirred at room temperature for 2 hours and the volatiles were removed under reduced pressure. The residue was suspended in 250 ml of a concentrated aqueous ammonia solution, and the resulting suspension was stirred at 100 ° C overnight in a closed vessel. Once the mixture reached room temperature, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate. 40.51 g of (1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl Carboxylic acid (S) -tert-butyl ester (( S )- Tert- butyl(1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)carbamate) and triphenylphosphine oxide were used in the next step without further purification.

LRMS(m/z): 293(M+1) ⁺

D1) (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S ) -2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

The crude product obtained in the previous step, 40.51 g, was stirred in 300 ml of a 4M hydrochloric acid solution of dioxanol for 1 hour. The volatiles were then removed under reduced pressure and the residue was partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The aqueous layer was washed twice with ethyl acetate and basified to pH = 8-9 with concentrated aqueous sodium hydroxide. The product was extracted with EtOAc (3 mL). 5.68 g of a brown solid were obtained without triphenylphosphine residue. Yield: 47% (in two steps).

LRMS(m/z): 193(M+1) ⁺

a2) 1- amino-3-methyl -1 H - pyrrole-2-carboxylate (Methyl 1-amino-3- methyl-1 H -pyrrole-2-carboxylate)

3.74 g (93.5 mmol) of sodium hydride (60% dispersion in mineral oil) was suspended in 550 ml of anhydrous DMF and cooled in an ice bath. 10.0 g (65.3 mmol) of 3-methyl-1 H -pyrrole-2-carboxylic acid methyl ester (purchased from Otava Chemicals ^® , catalog number 1056278) in 200 ml of DMF was added under nitrogen atmosphere for 30 minutes. The mixture was mechanically stirred at 0 ° C for 30 minutes. Then 26.8 g (115 mmol) of DPPOONH _{2 was} added to 5 fractions. The resulting mixture was stirred at room temperature for 5 hours and then poured into 500 ml of a 10% aqueous sodium thiosulfate solution. The product was extracted with diethyl ether. EtOAc (EtOAc)EtOAc. This crude product was dissolved in diethyl ether and the product was extracted twice with 2M aqueous hydrochloric acid. The aqueous solution was then neutralized with a 2M sodium hydroxide solution and the product was again extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate 5.90 g (yield 53%) of the title product as a white solid was isolated.

LRMS(m/z): 155(M+1) ⁺

b2) 1- (2 - ((tert-butoxy carbonyl) amino) propylamino) -3-methyl -1 H - pyrrole-2-carboxylic acid (S) - ester ((S) -Methyl 1- (2-((tert-butoxycarbonyl)amino)propanamido)-3-methyl-1 H -pyrrole-2-carboxylate)

The title compound was obtained according to the experimental procedure of Preparation 6b1 from 2.5 g (16.41 mmol) of methyl 1-amino-3-methyl-1 H -pyrrole-2-carboxylate (Methyl 1-amino-3-methyl-) Prepared by 1 H -pyrrole-2-carboxylate). The crude product was purified by flash chromatography eluting elut elut elut elut elut

LRMS(m/z): 326(M+1) ⁺

C2) (1-(5-Methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino Formic acid (S) - tert- butyl ester (( S )- Tert- butyl(1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin- 2-yl)ethyl)carbamate)

The title compound was obtained according to the procedure of the procedure of Preparation 6c1 from 914 mg (2.81 mmol) of 1-(2-((t-butoxycarbonyl)amino)propylamino)-3-methyl-1 H -pyrrole-2 - carboxylic acid (S) -methyl ester (( S )-Methyl 1-(2-((tert-butoxycarbonyl)amino)propanamido)-3-methyl-1 H- pyrrole-2-carboxylate). The crude product was purified by flash chromatography eluting elut elut elut elut

LRMS(m/z): 293(M+1) ⁺

D2) (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (( S ) -2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

The title compound was obtained according to the experimental procedure described in Preparation 6d1 from (1-(5-methyl-4-oxooxy-3,4-dihydropyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)carbamic acid (S) -t-butyl ester (( S )- Tert- butyl(1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- Prepared by f ][1,2,4]triazin-2-yl)ethyl)carbamate). 196 mg (yield 79%) of title product as a white solid.

LRMS(m/z): 193(M+1) ⁺

Preparation 7

(S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino Pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Ethyl)amino)pyrimidine-5-carbonitrile)

a) (S) -4-amino-6-((1-(5-methyl-4-oxooxy-3,4-dihydropyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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- f ][1,2,4]triazin-4( 3H )-one (( S )-2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) and 770 mg (4.98 mmol) of 4-amino pyrimidine-5-carbonitrile ^{6-chloro-2 (4-amino-6-} chloropyrimidine-5-carbonitrile 2) was suspended in 30ml of tert-butoxide. 2.37 ml (13.6 mmol) of DIEA was added, and the resulting suspension was stirred at 120 ° C overnight in a closed vessel. 770 mg excess of 4-amino-6-chloropyrimidine-5-carbonitrile and 2.37 ml of DIPEA were added and the reaction was stirred at 120 °C for 24 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 876 mg (yield: 62%)

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 (( 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-oxooxy-3,4-dihydropyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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) is suspended in 15 ml of phosphorus oxychloride and stirred at reflux temperature 1 hour. The volatiles were removed under reduced pressure and the residue was suspended in saturated sodium hydrogen carbonate. The pH was adjusted to 7 with a saturated potassium carbonate solution, and the suspension was stirred vigorously for 4 hours. The product was extracted twice with EtOAc (EtOAc)EtOAc.

LRMS(m/z): 329(M+1) ⁺

Preparation 8

6-Chloro-5-iodopyrimidin-4-amine (6-Chloro-5-iodopyrimidin-4-amine)

To a solution of 3.03 g (23.4 mmol) of 6-chloropyrimidin-4-amine (purchased from Aldrich ^® , catalog number 735272) in 60 ml of DMF was added dropwise 2.34 ml (46.7 mmol) of chlorine in 40 ml of DMF. The iodine solution was turned into and the mixture was stirred at 45 ° C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM and sat. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography (0% to 20% EtOAc) elute

LRMS(m/z): 256(M+1) ⁺

Preparation 9

(S) - N ⁴ -(1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5-iodopyrimidine -4,6-diamine (( S ) -N ⁴ -(1-(4-Chloro-5-methylpyrrolo[2,1- f ][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- f ][1,2, 4] Triazine-4( 3H )-one (( S )-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

280 mg (1.46 mmol) of (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (( S )-2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one) (Preparation 6), 744 mg (2.91 mmol) 6-chloro-5-iodopyrimidine-4-amine, 422 mg (2.91 mmol) of cesium fluoride and 1.27 ml (7.29 mmol) of DIEA were suspended in 8 ml of tert-butanol in a sealed container at 140 ° C Heat for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc:

LRMS(m/z): 412(M+1) ⁺

b) (S) - N ⁴ -(1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5- Iodopyrimidine-4,6-diamine (( S ) -N ⁴ -(1-(4-Chloro-5-methylpyrrolo[2,1- f ][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- f ][ 1,2,4]triazin-4( 3H )-one (( S )-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2 , 1- f ][1,2,4]triazin-4(3 H )-one) was 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 purified mjjjjjjjjj The product was then extracted twice with dichloromethane, and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc EtOAc EtOAc:

LRMS(m/z): 430(M+1) ⁺

Preparation 10

(S) -5-iodo- N ⁴ -(1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)pyrimidine-4,6-diamine (( S )-5-Iodo- N ⁴ -(1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo [2,1- f ][1,2,4]triaz in-2-yl)ethyl)pyrimidine-4,6-diamine)

54 mg (0.13 mmol) of (S) -N ⁴ -(1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl -5-Iodopyrimidine-4,6-diamine (( S ) -N ⁴ -(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2- Yl)ethyl)-5-iodopyrimidine-4,6-diamine) and 70 μl (0.63 mmol) of 1-methylpiperazine were dissolved in 3 ml of THF and stirred under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with EtOAcq.

LRMS(m/z): 494(M+1) ⁺

Preparation 11

(S) -5-iodo- N ⁴ -(1-(5-methyl-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ] [1,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine (( S )-5-Iodo- N ⁴ -(1-(5-methyl-4-((tetrahydro) -2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine)

The 112mg (0.96mmol) of (tetrahydro -2 H - pyran-4-yl) methanol ((tetrahydro-2 H -pyran- 4-yl) methanol) (. Available from Maybridge int ^®, Cat. No. CC29909DA) was added A suspension of 19 mg (0.48 mmol) of sodium hydride (60% dispersion in mineral oil) in 2 ml of dry THF was stirred for 30 min under nitrogen atmosphere. This solution was then poured into 188 mg (0.44 mmol) of (S) -N ⁴ -(1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2 in 3 ml of THF. ,4]triazin-2-yl)ethyl)-5-iodopyrimidine-4,6-diamine (( S ) -N ⁴ -(1-(4-Chloro-5-methylpyrrolo[2,1- f In a solution of [1,2,4]triazin-2-yl)ethyl)-5-iodopyrimidine-4,6-diamine), the resulting mixture was stirred at room temperature for 2 hours. The product was isolated, EtOAc (EtOAc m. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 135 mg (yield: 61%) of white title product.

LRMS(m/z): 510(M+1) ⁺

Preparation 12

2-(Chloromethyl)pyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2-(Chloromethyl)pyrrolo[2,1- f ][1, 2,4]triazin-4(3 H )-one)

a) 1-(2-Chloroacetamido-1 H -pyrrole-2-carboxamide) 1-(2-Chloroacetamido-1 H- pyrrole-2-carboxamide)

3.00g (24.0mmol) of 1-amino -1 H - pyrrole-2carboxamide ^{1 (1-amino-1 H} -pyrrole-2-carboxamide 1) was dissolved in 45ml of glacial acetic acid in an ice bath and cool down. 2.80 ml (35.1 mmol) of 2-chloroacetamidine chloride was added dropwise, and the reaction mixture was stirred at room temperature for 90 minutes. The formed precipitate was collected by filtration, washed with cyclohexane and dried in a stream of air. 4.43 g (yield 92%) of title compound as a white solid.

LRMS(m/z): 202(M+1) ⁺

b) 2-(Chloromethyl)pyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2-(Chloromethyl)pyrrolo[2,1- f ][ 1,2,4]triazin-4(3 H )-one)

4.43 g (22.0 mmol) of 1-(2-chloroethylamino)-1 H -pyrrole-2-carboxamide (1-(2-Chloroacetamido)-1 H- pyrrole-2-carboxamide) suspended in 160 ml In xylene, 5.50 g (22.0 mmol) of PPTS was added. The mixture was stirred at 140 ° C for 1 hour and then the solvent was removed. The residue was partitioned between EtOAc EtOAc m.

LRMS(m/z): 184(M+1) ⁺

Preparation 13

1-((4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4-d Pyrimidine-4-amine (1-((4-Chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4- d]pyrimidin-4-amine)

a) 2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)pyrrolo[2,1- f ][1,2, 4] Triazine-4( 3H )-one (2-((4-Amino-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

3.80 g (14.6 mmol) of 3-iodo-1 H -pyrazolo[3,4-d]pyrimidin-4-amine (3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine (purchased from Ark Pharm ^® , catalog number AK-32203) dissolved in 45 ml of DMF and cooled in an ice bath. To this solution was added 2.0 g (14.6 mmol) of potassium carbonate, followed by dropwise addition of 2.90 g (14.6 mmol) of 2-(chloromethyl)pyrrolo[2,1- f ][1,2,4] oxazin -4 (3 H) - one (2- (Chloromethyl) pyrrolo [2,1- f] [1,2,4] triazin-4 (3 H) -one). The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was adjusted to pH = 7 and extracted with ethyl acetate. The combined organics were washed with EtOAc EtOAc m. Total yield: 19%.

LRMS(m/z): 409(M+1) ⁺

b) 1-((4-Chloropyrrol[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4 -d]pyrimidine-4-amine (1-((4-Chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3, 4-d]pyrimidin-4-amine)

490 mg (1.04 mmol) of 2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)pyrrolo[2,1- f ][ 1,2,4]triazin-4( 3H )-one (2-((4-Amino-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)pyrrolo[ 2,1- f ][1,2,4]triazin-4(3 H )-one) was 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 dichloromethane and water. Solid sodium bicarbonate was added until a neutral pH was obtained, and the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated. 477 mg (yield 88%) of title product as a pale yellow solid.

LRMS(m/z): 427(M+1) ⁺

Preparation 14

3-iodo-1-((4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazine-2- Methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((4-((tetrahydro-2 H- pyran-4-yl)methoxy))) Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

The title compound was subjected to the experimental procedure described in Preparation 11 from 238 mg (0.56 mmol) of 1-((4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl) 3-iodo-1 H -pyrazolo[3,4-d]pyrimidin-4-amine (1-((4-Chloropyrrolo[2,1- f ][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-2 H -pyran-4-yl)methanol ( Prepared by tetrahydro-2 H- pyran-4-yl)methanol). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 89 mg (yield: 32%) of white title product.

LRMS(m/z): 283(M+1) ⁺

Preparation 15

Amino - N - (2,4- dimethoxybenzyl) -3-methyl -1 H - pyrrole-2carboxamide (Amino- N - (2,4-dimethoxybenzyl ) -3-methyl-1 H -pyrrole-2-carboxamide)

a) 3- methyl -1 H - pyrrole-2-carboxylic acid (3-Methyl-1 H -pyrrole -2-carboxylic acid)

10.0g (65.3mmol) of 3-methyl -1 H - pyrrole-2-carboxylic acid ethyl ester (ethyl 3-methyl-1 H -pyrrole-2-carboxylate) ( available from Love Lancaster Astatech ^®, Cat. No. 59362) Dissolved in 200 ml of ethanol. 150 ml of a 2M sodium hydroxide solution was added, and the resulting solution was stirred at room temperature overnight. The organic matter was removed under reduced pressure, and the obtained aqueous solution was neutralized with a 5M hydrochloric acid solution. A white solid precipitated which was filtered, washed with water and dried in an oven. 6.80 g (yield 83%) of the title compound was obtained.

LRMS(m/z): 126(M+1) ⁺

b) N - (2,4- dimethoxybenzyl) -3-methyl -1 H - pyrrole-2carboxamide (N - (2,4-Dimethoxybenzyl) -3-methyl-1 H - Pyrrole-2-carboxamide)

6.13 g (49.4 mmol) of 3-methyl-1 H -pyrrole-2-carboxylic acid (3-Methyl-1 H- pyrrole-2-carboxylic acid) was dissolved in 150 ml of DCM and 1 ml of DMF was added. To this solution was added 4.72 ml (54.3 mmol) of an oxalyl chloride solution in 50 ml of DCM over 1 hour. The solution was stirred for 2 hours and then the volatiles were removed under reduced pressure. The residue was taken up in 135 mL of DCM and cooled in ice. To this solution, 9.5 ml (54.5 mmol) of DIEA and 8.50 ml (56.6 mmol) of (2,4-dimethoxyphenyl)methylamine (2,4-dimethoxyphenyl) dissolved in 40 ml of DCM were added dropwise. Methamine) and the reaction was stirred at room temperature overnight. The organics were removed in vacuo, EtOAcqqqqqm The crude product was purified by EtOAcqqqqqq

LRMS(m/z): 275(M+1) ⁺

c) 1-Amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-Amino- N- (2,4-dimethoxybenzyl) -3-methyl-1 H -pyrrole-2-carboxamide)

91 ml (0.64 mol) of an 8 M aqueous sodium hydroxide solution and 40 ml (0.32 mol) of concentrated aqueous 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 8.71 g (31.8 mmol) of N- (2,4-dimethoxybenzyl)- A solution of 3-methyl-1 H -pyrrol-2-carboxylamine ( N- (2,4-Dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide) was suspended in a mixture of 240 ml of diethyl ether and added to 120 ml. DMTBE. To this suspension was added dropwise 337 ml (0.45 mol) of a 10% aqueous sodium hypochlorite solution (within 2 hours) with vigorous stirring to maintain the temperature at 0 to 5 °C. Subsequently, the reaction mixture was stirred at room temperature for 1 hour, and then, 100 ml of a sodium hypochlorite solution was additionally added. The reaction was allowed to stand at room temperature overnight. The reaction mixture was then diluted with diethyl ether and two layers were separated. The aqueous layer was extracted with EtOAc (EtOAc) EtOAc. Purification with ethyl acetate) gave 4.5 g (yield: 49%)

LRMS(m/z): 290(M+1) ⁺

Preparation 16

2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-4 (3 H -keto(2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

a) 1- (2- chloro-acetylamino) - N - (2,4- dimethoxybenzyl) -3-methyl -1 H - pyrrole-2carboxamide (1- (2-Chloroacetamido ) - N - (2,4-dimethoxybenzyl ) -3-methyl-1 H -pyrrole-2-carboxamide)

4.51 g (15.6 mmol) of 1-amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-Amino- N- (2) 4-dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide) was dissolved in 70 ml of glacial acetic acid and cooled in an ice bath. 1.36 ml (17.1 mmol) of 2-chloroacetamidine chloride was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. Most of the solvent was removed under reduced pressure and the residue was taken up in hexanes to leave a solid. The product was collected by filtration, washed with cyclohexane and dried in air. 5.24 g (yield 92%) of the title compound as a light brown solid.

LRMS(m/z): 366(M+1) ⁺

b) 2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-4 ( 3 H )-ketone (2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

5.24g (14.3mmol) 1- (2-chloro-acetylamino) - N - (2,4- dimethoxybenzyl) -3-methyl -1 H - pyrrole-2carboxamide (1 - (2-Chloroacetamido) - N - (2,4-dimethoxybenzyl) -3-methyl-1 H -pyrrole-2-carboxamide) was suspended in 500ml of xylene was added 3.65g (14.5mmol) of PPTS. The mixture was stirred at 140 ° C for 2 hours and then the solvent was removed. The residue was partitioned between EtOAc EtOAc m.

LRMS(m/z): 348(M+1) ⁺

Preparation 17

1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[ 3,4- d ]pyrimidine-4-amine (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)

a) 2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-3-(2,4-dimethoxybenzyl) -5-Methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2-((4-Amino-3-iodo-1 H- pyrazolo[ 3,4- d ]pyrimidin-1-yl)methyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )- One)

To 4.98 g (14.32 mmol) of 2-(chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f in DMF (180 mL) ][1,2,4]trizino-4( 3H )-one (2-(Chloromethyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2, 4]triazin-4(3 H )-one) was added 4.12 g (15.8 mmol) of 3-iodo-1 H -pyrazolo[3,4- d ]pyrimidine-4-amine (purchased from the ark medicine) Ark Pharm ^® , catalog number 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 ethyl acetate. The solid formed was filtered, washed with water and dried in oven to give 3.80 g of pale orange solid. The aqueous layer was extracted with ethyl acetate and DCM. The combined organics were washed with EtOAc EtOAc m. The product was purified by flash chromatography (0% to 10%EtOAc) Total yield: 56%.

LRMS(m/z): 573(M+1) ⁺

b) 2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-4( 3H )-one (2-((4-Amino-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)- 5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

3.27 g (5.71 mmol) of 2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-3-(2,4-di Methoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2-((4-amino-3-iodo-) 1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-3-(2,4-dimethoxybenzyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4 (3 H )-one) was dissolved in 50 ml of trifluoroacetic acid. 18 ml (28 mmol) of anisole was 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 hexanes and the mixture was stirred vigorously overnight. The solid which formed was filtered, washed with hexanes and dried in vacuo to afford 2.23 g (yield 97%) of title compound.

LRMS(m/z): 423(M+1) ⁺

c) 1-((4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazole And [3,4- d ]pyrimidine-4-amine (1-((4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3- Iodo-1 H -pyra zolo[3,4- d ]pyrimidin-4-amine)

2.33 g (5.52 mmol) of 2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2 , 1- f ][1,2,4]triazin-4(3 H )-one (2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1- Yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) suspended in 15 ml of phosphorus oxychloride at 80 ° C Stir for 2 hours. The volatiles were removed under reduced pressure and the residue was suspended in a saturated aqueous sodium hydrogen carbonate. After 30 minutes. After stirring, the product was extracted with EtOAc. EtOAc. 1.59 g (yield 66%) of the title product as a light brown solid.

LRMS(m/z): 441(M+1) ⁺

Preparation 18

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 ]pyrimidine-4-amine (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)

100 mg (0.23 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 (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) and 97 mg (0.76 mmol) of 1-isopropylpiperazine are dissolved in 2 ml of acetone and Stir under reflux for 1 hour. The reaction mixture was partitioned between EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

LRMS(m/z): 533(M+1) ⁺

Preparation 19

3-iodo-1-((5-methyl-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-((tetrahydro-2 H) -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

The title compound was obtained according to the procedure of Preparation 11 from 102 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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) and 114 mg (0.98 mmol) of (tetrahydro-2 H - Prepared by (tetrahydro-2 H- pyran-4-yl)methanol. After isolation, 92 mg (yield: 76%) ofyield of the title compound as a pale orange solid.

LRMS(m/z): 521(M+1) ⁺

Preparation 20

1-((4-(( 2S ,6 R )-2,6-dimethylmorpholine)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2 -yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-(( 2S ,6 R )-2,6-Dimethylmorpholino) )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine)

The title compound was obtained according to the procedure from the preparation of 18, from 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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) and 140 μl (1.14 mmol) of cis-2,6- Obtained from cis -2,6-dimethylmorpholine. Obtained 102 mg (yield: 87%) of mp.

LRMS(m/z): 520(M+1) ⁺

Preparation 21

N -cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)benzamide ( N- Cyclopropyl) -3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

a) 3- bromo - N - cyclopropyl-5-hydroxybenzamide Amides (3-Bromo- N -cyclopropyl-5 -hydroxybenzamide)

100 mg (0.46 mmol) of 3-bromo-5-hydroxybenzoic acid (available from Aldrich ^® , catalog number 686417), 58 μl (0.83 mmol) of cyclopropylamine (available from Aldrich ^® , Cat. No. 125504), 263 mg (0.69 mmol) of HATU and 281 μl (1.61 mmol) of DIEA were dissolved in 2 ml of DMF under a nitrogen atmosphere and stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was taken-up from ethyl acetate. The resulting organic solution was washed with EtOAc EtOAc EtOAc.

LRMS(m/z): 257(M+1) ⁺

b) N -cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)benzamide ( N -Cyclopropyl-3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

The crude product of Preparation 21a was dissolved in dioxane (20 ml), and 371 mg (1.46 mmol) of 4,4,4',4',5,5,5',5' was added to the solution. - octamethyl-2,2'-bis(1,3,2-dioxacyclopentane) (4,4,4',4',5,5,5',5'-octamethyl-2, 2'-bi(1,3,2-dioxaborolane)), 30 mg (0.04 mmol) of PdCl ₂ dppf. 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 overnight under a nitrogen atmosphere. An additional 30 mg of palladium catalyst was added and the reaction was allowed to continue for more than 24 hours. After cooling, the reaction mixture was filtered through diatomaceous earth (Celite ^®) bed, and the solid was sufficiently washed with ethyl acetate. The filtered organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated. Isolated without further purification and using 244 mg of a dark oil containing 48% of the title product.

LRMS(m/z): 222(M+1) ⁺

Preparation 22

N- (3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaboro-2-yl)phenyl)methanesulfonamide ( N- ( 3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide)

a) N - (3- hydroxyphenyl) methane sulfonamide Amides (N - (3-Hydroxyphenyl) methanesulfonamide)

500 mg (4.58 mmol) of 3-aminophenol was dissolved in 8 ml of tetrahydrofuran. 747 μl (9.16 mmol) of pyridine and 425 μl (5.49 mmol) of methanesulfonium chloride were added. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. It was then cooled at 0 ° C and 7 ml of 1N hydrochloric acid was added. The mixture was stirred for 5 minutes and poured into water. The product was extracted with ethyl acetate, dried over sodium sulfate and filtered It was concentrated under reduced pressure to give 980 mg (yield:

LRMS(m/z): 188(M+1) ⁺

b) N - (3- bromo-5-hydroxyphenyl) methanesulfonamide Amides (N - (3-Bromo- 5-hydroxyphenyl) methanesulfonamide)

857mg (4.58mmol) of N - (3- hydroxyphenyl) methane sulfonamide Amides (N - (3-Hydroxyphenyl) methanesulfonamide) was suspended in 10ml of acetic acid. The mixture was cooled at 0 ° C, and 281 μl (5.49 mmol) of bromine was added dropwise. The reaction mixture was stirred for 4 hours. Diethyl ether was added and the organics were washed with 4% aqueous sodium bicarbonate, water and brine. The aqueous layer was extracted with EtOAc. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 451 mg (yield: 37%) of title compound.

LRMS(m/z): 267(M+1) ⁺

c) N- (3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl)methanesulfonamide ( N -(3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide)

451mg (1.68mmol) of N - (3- bromo-5-hydroxyphenyl) methanesulfonamide Amides (N - (3-Bromo- 5-hydroxyphenyl) methanesulfonamide) and 430mg (1.69mmol) of 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentane)(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 PdCl ₂ dppf. DCM and 60 mg (0.09 mmol) of dppf were treated according to the procedure described for Preparation 21b. The crude product was purified by EtOAc EtOAc (EtOAc) Purity: 100%.

LRMS(m/z): 314(M+1) ⁺

Preparation 23

3-iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl -1 H -pyrazolo[3,4- d ]pyrimidine-4-amine (3-Iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- f ] [1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

a) 4-((2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2, 1- f ][1,2,4]triazin-4-yl)oxy)piperidine-1-carboxylic acid tert- butyl ester ( Tert- butyl 4-((2-((4-amino-3-iodo) -1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy)piperidine-1- Carboxylate)

The title compound was obtained according to the procedure of Preparation 11 from 200 mg (0.45 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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) and 183 mg (0.91 mmol) of 4-hydroxypiperidine-1 - tert -butyl 4-hydroxypiperidine-1-carboxylate (available from Aldrich ^® , catalog number 495484). The reaction was completed in 16 h and the crude was used in the next step without further purification.

LRMS(m/z): 606(M+1) ⁺

b) 3-iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl) Methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

Preparation of the crude product 4-((2-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole) And [2,1- f ][1,2,4]triazin-4-yl)oxy)piperidine-1-carboxylic acid tert- butyl ester ( Tert- butyl 4-((2-(4-amino) -3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy) Piperidine-1-carboxylate) was treated with 10 ml of 4 M hydrogen chloride solution in dioxane. The reaction mixture was stirred at room temperature overnight, and then evaporated. The residue was partitioned between DCM and diluted aqueous HCl and the layers were separated. The aqueous layer was basified with 2M aqueous sodium hydroxide and the product was extracted twice with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesium sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 39 mg (yield: 17%)

LRMS(m/z): 506(M+1) ⁺

Preparation 24

3-iodo-1-((4-((1-isopropylpiperidin-4-yl)oxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazine 2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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-4-amine)

39 mg (0.08 mmol) of 3-iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-(piperidin-4-yloxy)pyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine) was suspended in 2 ml of acetonitrile. 17 mg (0.11 mmol) of sodium iodide, 27 mg (0.20 mmol) of potassium carbonate and 11 μl (0.12 mmol) of 2-bromopropane were added. The resulting mixture was heated at 140 ° C for 2 hours using microwave irradiation. The reaction mixture was partitioned between aqueous 2M hydrochloric acid and dichloromethane and organic layer was evaporated. The aqueous solution was adjusted to pH = 8 to 9 with 8M sodium hydroxide and the product was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate 27 mg (yield 64%) of the title product as a white solid was isolated.

LRMS(m/z): 548(M+1) ⁺

Preparation 25

3-((2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)(2-(dimethylamino)ethyl)amino)phenol (3-((2-((4-Amino-3-iodo-1 H) -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)(2-(dimethylamino)ethyl)amino Phenol)

96 mg (0.22 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 (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) and 82 mg (0.45 mmol) of 3-((2-(dimethylamino)ethyl)amino)phenol ⁴ ( 3-((2-(dimethylamino)ethyl)amino)phenol ⁴ ) was suspended in 1 ml of acetone and heated at 150 ° C for 20 minutes using microwave irradiation. Ethyl acetate was added to the reaction mixture, and a precipitate formed. The solid was filtered and washed with EtOAc EtOAc (EtOAc)

LRMS(m/z): 585(M+1) ⁺

Preparation 26

2-(2-Hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenol (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 ^® , catalog number 383406) dissolved in 15 ml It was cooled in THF under a nitrogen atmosphere. 4.65 ml (13.9 mmol) of a 3 M methylmagnesium bromide solution in diethyl ether was added dropwise, and the resulting mixture was stirred at 0 ° C for 3 hours. The reaction mixture was poured into a mixture of 15 ml of water and 15 ml of saturated ammonium chloride. The organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated. 1.27 g of a pale pink solid were obtained which contained 71% of crude title product which was used in the next synthetic step without further purification. Yield: 84%.

LRMS(m/z): 231,233 (M+1) ⁺

b) 2-(2-Hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenol (2 -(2-Hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol)

The title compound was prepared according to the experimental procedure for the preparation of 21b from 1.27 g (3.90 mmol). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give a white solid (yield: <RTIgt; Yield: 28%.

LRMS(m/z): 279(M+1) ⁺

Preparation 27

2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridin-3-amine (2-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine)

a) 5-Bromo-2-methoxypyridin-3-amine (5-Bromo-2-methoxypyridin-3-amine)

2.0 g (8.58 mmol) of 5-bromo-2-methoxy-3-nitropyridine (purchased from Combi-blocks ^® , catalog number PY-7161), 2.0 g (35.8 mmol) of iron and 2.0 g (37.4 mmol) of ammonium chloride were stirred at 95 ° C for 15 minutes in 15 ml of a 1:1 water/ethanol mixture. After cooling, the reaction mixture was passed through a layer of diatomaceous earth (Celite ^®) and filtered, 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 sulfate, filtered and evaporated. 1.73 g of a dark oil containing 80% of the title compound.

LRMS(m/z): 204(M+1) ⁺

b) 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl) Pyridin-3-amine (2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine)

The title compound was 1.73 g (6.82 mmol) of crude product 5-bromo-2-methoxypyridin-3-amine (5-Bromo-2-methoxypyridin-) obtained from Preparation 27a. Prepared by 3-amine). The reaction was completed in 2 hours at 80 °C. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 251(M+1) ⁺

Preparation 28

N- (2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-3-yl)methanesulfonate Amine ( N- (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-dioxocyclopentan-2-yl)pyridin-3-amine ( 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine) was dissolved in 20 ml of pyridine and cooled in an ice bath. 600 μl (7.75 mmol) of methanesulfonium chloride was added dropwise, 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 sat. The combined organic layers were washed with EtOAc EtOAc m. The crude product was treated with a mixture of diethyl ether and diisopropyl ether and stirred until solids precipitated. The product was filtered and dried in vacuo to give EtOAc (yield: 58%)

LRMS(m/z): 329(M+1) ⁺

Preparation 29

4-methoxy- N- (2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridine-3 -Methoxy- N- (2-methoxy-5-(4,4,5,5-tetramethyl-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-dioxocyclopentan-2-yl)pyridin-3-amine ( 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine) was 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 ^® , catalog number M10204) dissolved in 5 ml of pyridine was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The combined organic layers were washed with EtOAc EtOAc m. Yield 304 mg (yield 90%) of the title compound.

LRMS(m/z): 421(M+1) ⁺

Preparation 30

2-(4-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2, 1- f ][1,2,4]triazin-4-yl)piperazin-1-yl)ethanol (2-(4-(2-((4-Amino-3-iodo-1 H- pyrazolo[ 3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperazin-1-yl)ethanol)

100 mg (0.23 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 (1-((4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl) )-3-iodo-1 H- pyra zolo[3,4- d ]pyrimidin-4-amine) and 114 mg (0.88 mmol) of 2-(piperazin-1-yl)ethanol (purchased from Aldrich ^® , catalog number H28807) was stirred in 2 ml of acetone at reflux temperature for 90 minutes. The reaction mixture was partitioned between water and ethyl acetate. 90 mg (yield 68%) of title compound as a white solid. Purity: 92%.

LRMS(m/z): 535(M+1) ⁺

Preparation 31

3-iodo-1-((5-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pyrrolo[2,1- f ][1,2,4]triazine -2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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-4-amine)

100 mg (0.23 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 (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) and 123 mg (0.75 mmol) of 1-(methylsulfonyl)piperazine (purchased from ABCR ^® , catalog number AB169005 ) Stir in 2 ml of acetone at reflux temperature for 75 minutes. The reaction mixture was partitioned between water and ethyl acetate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 63 mg (yield: 49%) Purity: 100%.

LRMS(m/z): 569(M+1) ⁺

Preparation 32

N ¹ -(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)- N ¹ , N ² , N ² -trimethylethane-1,2-diamine ( N ¹ -(2-((4-Amino) -3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)- N ¹ , N ² , N ² -trimethylethane-1,2-diamine)

100 mg (0.23 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 (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) and 77 mg (0.75 mmol) of N ¹ , N ¹ , N ² -trimethylethane-1,2-di The amine ( N ¹ , N ¹ , N ² -trimethylethane-1, 2-diamine) was stirred in 2 ml of acetone at reflux temperature for 90 minutes. The reaction mixture was partitioned between water and ethyl acetate. The title compound was obtained in EtOAc (EtOAc) Purity: 86%.

LRMS(m/z): 507(M+1) ⁺

Preparation 33

(S) -3-(3-(Benzyloxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoic acid (( S )-3-(3-(Benzyloxy)phenyl)-2 -(( tert -butoxycarbonyl)amino)propanoic acid)

a) 2-amino-3-(3-hydroxyphenyl)propionic acid ( S )-methylethyl chloride (( S )-Methyl 2-amino-3-(3-hydroxyphenyl)propanoate hydrochloride)

1.08g (6.0mmol) of (S) -2- amino-3- (3-hydroxyphenyl) propanoic acid ((S) -2-amino- 3- (3-hydroxyphenyl) propanoic acid) ( available from Alfa Aesar ^® , catalog number H27224) was suspended in 20 ml of methanol and cooled in an ice bath. Then 872 μl (12 mmol) of thionium chloride was added, and the resulting solution was stirred at room temperature overnight, then at 50 ° C for 4 hours. The volatiles were then removed under reduced pressure to give 1.38 g (yield: 100%)

LRMS(m/z): 196(M+1) ⁺

b) 2- (tert-butoxy-carbonyl) -3- (3-hydroxyphenyl) propionic acid (S) - ester ((S) -Methyl 2- (tert -butoxycarbonylamino) -3- (3- Hydroxyphenyl)propanoate)

1.38g (6.0mmol) of 2-amino-3- (3-hydroxyphenyl) propionic acid (S) - methyl ester hydrogen chloride ((S) -Methyl 2-amino -3- (3-hydroxyphenyl) propanoate hydrochloride) was suspended In 10 ml of THF. 1.66 ml (12 mmol) of triethylamine and 1.30 g (6.0 mmol) of di- tert- butyl dicarbonate were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride. The title compound was obtained in the next step.

LRMS(m/z): 296(M+1) ⁺

c) 3- (3- (benzyloxy) phenyl) -2- (tert-butoxy carbonyl amino) propanoic acid (S) - ester ((S) -Methyl 3- (3- (benzyloxy) phenyl )-2-( tert -butoxycarbonylamino)propanoate)

To 1.76g (5.9mmol) 2- (tert-butoxy-carbonyl) -3- (3-hydroxyphenyl) propionic acid (S) - ester ((S) -Methyl 2- (tert -butoxycarbonylamino) -3-(3-hydroxyphenyl)propanoate) To a solution of 20 ml of acetone was 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 under reflux for 16 hours and then partitioned between ethyl acetate and water. The two layers were separated and the organic solution was washed with water and brine. The crude product was purified by flash chromatography (EtOAc: EtOAc)

LRMS(m/z): 386(M+1) ⁺

d) (S) -3-(3-(Benzyloxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoic acid (( S )-3-(3-(Benzyloxy)phenyl) -2-(( tert -butoxycarbonyl)amino)propanoic acid)

To 1.37g (3.6mmol) of 3- (3- (benzyloxy) phenyl) -2- (tert-butoxy carbonyl amino) propanoic acid (S) - ester ((S) -Methyl 3- ( 3-(benzyloxy)phenyl)-2-( tert- butoxycarbonylamino)propanoate) A solution of 180 mg (4.3 mmol) of lithium hydroxide monohydrate in 20 ml of water was added to a solution of 20 ml of tetrahydrofuran. 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 2N aqueous hydrochloric acid solution were added, and the reaction product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate. The title compound was obtained in EtOAc (m.)

LRMS(m/z): 372(M+1) ⁺

Preparation 34

(S) -2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine -4( 3H )-one (( S )-2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-4(3 H )-one)

a) 1-(3-(3-(Benzyloxy)phenyl)-2-((t-butoxycarbonyl)amino)propylamino)-3-methyl-1 H -pyrrole-2-carboxylic acid (S) - ethyl ester ((S) -Ethyl 1- (3- (3- (benzyloxy) phenyl) -2 - ((tert -butoxycarbonyl) amino) propanamido) -3-methyl-1 H -pyrrole-2- Carboxylate)

1.32 g (3.6 mmol) of (S) -3-(3-(benzyloxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoic acid (( S )-3-(3- (Benzyloxy)phenyl)-2-(( tert- butoxycarbonyl)amino)propanoic acid) and 1.36 g (3.6 mmol) of HATU were dissolved in 10 ml of DMF and 10 ml of DCM mixture. The solution was cooled in an ice bath, 620 μl (3.6 mmol) of DIEA was added, and the mixture was stirred at room temperature for 1 hour. Was added followed by 1.2g (7.2mmol) 1-amino-3-methyl -1 H - pyrrole-2-carboxylate (Ethyl 1-amino-3- methyl-1 H -pyrrole-2-carboxylate), 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 EtOAcq. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 522(M+1) ⁺

b) (2-(3-(Benzyloxy)phenyl)-1-(5-methyl-4-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2 , 4] triazin-2-yl)ethyl)carbamic acid (S) -t-butyl ester (( S )- Tert- 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 PPh _{3 was} dissolved in 20 ml of dichloromethane and cooled in an ice bath. Then 348 μl (6.8 mmol) of bromine was added, and the resulting solution was stirred at room temperature for 30 minutes. Then 2.3 ml (16.4 mmol) of triethylamine and 1.42 g (2.7 mmol) of 1-(3-(3-(benzyloxy)phenyl)-2-((third) in 10 ml of dichloromethane were added. butoxycarbonyl) amino) propyl) -3-methyl -1 H - pyrrole-2-carboxylic acid (S) - ethyl ester ((S) -Ethyl 1- (3- (3- (benzyloxy) phenyl) 2-(( tert- butoxycarbonyl)amino)propanamido)-3-methyl-1 H- pyrrole-2-carboxylate) solution. The resulting solution was stirred at room temperature for 2 hours and the volatiles were removed under reduced pressure. The residue was suspended in diethyl ether and evaporated twice to a solid. The solid was then suspended in 25 ml of concentrated aqueous ammonia solution, and the resulting suspension was stirred at 100 ° C overnight in a closed vessel. Once the mixture reached room temperature, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate. Obtained 3.22 g of (2-(3-(benzyloxy)phenyl)-1-(5-methyl-4-oxooxy-3,4-dihydropyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)carbamic acid (S) -t-butyl ester (( S )- Tert- butyl(2-(3-(benzyloxy)phenyl)-1-(5- Methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate) and triphenylphosphine oxide, which are used without 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- f ][1,2,4] Triazine-4( 3H )-one (( S )-2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- f ][1,2, 4]triazin-4(3 H )-one)

The 3.22 g of the crude product obtained in the previous step was stirred in a solution of 30 ml of 4 M hydrogen chloride in dioxane for 2 hours. The solid formed was filtered and washed with hexane. The title compound (hydrogen chloride) was obtained as a white solid (yield: 39%).

LRMS(m/z): 375(M+1) ⁺

Preparation 35

(S) -4-amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2 ,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-) Chloro-5-methylpyrrolo[2,1- f ][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-dihydropyrrole) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2-(3- (benzyloxy)phenyl)-1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][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- f ][1, 2,4]triazin-4( 3H )-one hydrogen chloride (( S )-2-(1-Amino-2-(3-(benzyloxy)phenyl)ethyl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-4(3 H )-one hydrochloride) and 164 mg (1.1 mmol) of 4-amino-6-chloropyrimidine-5-carbonitrile ² (4-amino-6-chloropyrimidine-5- Carbonitrile ² ) was suspended in 15 ml of third butanol. 0.84 ml (4.8 mmol) of DIEA was added, and the resulting suspension was stirred at 120 ° C for 48 hours in a closed vessel. The solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc):

LRMS(m/z): 493(M+1) ⁺

b) (S) -4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5-methylpyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2-(3-(benzyl)))) 4-chloro-5-methylpyrrolo[2,1- f ][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-yloxy-3,4-) Dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2) -(3-(benzyloxy)phenyl)-1-(5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino) Pyrimidine-5-carbonitrile was 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 sulfate.

LRMS(m/z): 511(M+1) ⁺

Preparation 36

(S) -4-Amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-(4-isopropyl-1-yl)-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2-(3-(( Benzyloxy)phenyl)-1-(4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((2-(3-(benzyloxy)phenyl)) 1-(4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 30 μl (0.21 mmol) of 1- Isopropylpiperazine was 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 &lt The aqueous layer was separated and treated with aqueous 8N sodium hydroxide until basic pH was obtained. The product was then re-extracted with ethyl acetate. EtOAc (EtOAc)EtOAc.

LRMS(m/z): 603(M+1) ⁺

Preparation 37

(2 S ,6 R )-2,6-Dimethylpiperazine ((2 S ,6 R )-2,6-Dimethylpiperazine)

250 mg (1.17 mmol) of 3,5-dimethylpiperazine-1-carboxylic acid (3S,5R)-t-butyl ester (available from AK Scientific ^® 166098) suspended in 5 ml of 4M hydrochloric acid solution in dioxanol in. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 218 mg (yield 100%) of the title compound (dihydrochloride) was obtained without any further purification.

LRMS(m/z): 115(M+1) ⁺

Preparation 38

(S) -4-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (( S )-4-((1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin -2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile)

a) (S) -4 - ( (1- (5- methyl-4-oxo-3,4-dihydro-pyrrolo [2,1- f] [1,2,4] triazin -2 -yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (( S )-4-((1-(5-Methyl-4-oxo-3,4) -dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H- pyrrolo[2,3- d ]pyrimidine-5-carbonitrile)

133 mg (0.69 mmol) of (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (( S )-2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) and 121 mg (0.69 mmol) of 4-chloro -7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (4-chloro-7 H- pyrrolo[2,3- d ]pyrimidine-5-carbonitrile) was suspended in 4 ml of tert-butanol. 290 μl (1.66 mmol) of DIEA was added, and the resulting suspension was stirred at 120 ° C overnight in a closed vessel. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (1% to 10%EtOAc)

LRMS(m/z): 335(M+1) ⁺

b) (S) -4-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)- 7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (( S )-4-((1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4 ]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile)

62 mg (0.17 mmol) of (S) -4-((1-(5-methyl-4-yloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (( S )-4-((1-(5-Methyl-4-oxo) -3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H- pyrrolo[2,3- d ]pyrimidine-5-carbonitrile) in 2ml Phosphorus oxychloride was stirred at 70 ° C for 7.5 hours. The volatiles were then removed in vacuo, the residue was treated with ice-water, and washed with saturated aqueous NaHCO ₃ solution. The aqueous suspension was extracted three times with EtOAc. EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 353(M+1) ⁺

Preparation 39

(S) -4-Amino-6-((1-(5-methyl-4-vinylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl) Amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-methyl-4-vinylpyrrolo[2,1- f ][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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 dissolved in 6 ml under argon In anhydrous tetrahydrofuran. The solution was stirred at room temperature for 5 minutes, and then 320 μl (1.07 mmol) of tributyl(vinyl)stannane was added. The reaction mixture was stirred at reflux temperature for 2 hr and then evaporated and evaporated. The crude product was purified by flash chromatography (1% to EtOAc EtOAc)

LRMS(m/z): 321(M+1) ⁺

Preparation 40

(2 S ,6 R )-1-(2-(Benzyloxy)ethyl)-2,6-dimethylpiperazine ((2 S ,6 R )-1-(2-(Benzyloxy)ethyl) -2,6-dimethylpiperazine)

a) 4- (2- (benzyloxy) ethyl) -3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) - tert-butyl ester ((3 S, 5 R) - Tert- butyl 4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate)

160mg (0.75mmol) of 3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) tert-butyl ester ((3 S, 5 R) - tert -butyl 3,5-dimethylpiperazine-1 -carboxylate) (available from AK Scientific ^® 166098) was dissolved in 2.5 ml of DMF. 142 μl (0.90 mmol) of ((2-bromoethoxy)methyl)benzene ((2-bromoethoxy)methyl)benzene) (Aldrich ^® , reference 47, 481-9) and 114 mg (0.82 mmol) of potassium carbonate were added. 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 sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purification to give 121 mg (yield: 60%, yield: 28%) of the title compound as a colorless oil of ((2-bromoethoxy)methyl)benzene.

LRMS(m/z): 349(M+1) ⁺

b) (2 S ,6 R )-1-(2-(Benzyloxy)ethyl)-2,6-dimethylpiperazine ((2 S ,6 R )-1-(2-(Benzyloxy)) Ethyl)-2,6-dimethylpiperazine)

3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) obtained in the previous step 121mg of impure 4- ((benzyloxy) ethyl 2-) - tert-butyl ester (( 3 S , 5 R )- Tert -butyl 4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate) was suspended in 4 ml of a 4 M hydrochloric acid solution in dioxanol. The mixture was stirred at room temperature overnight, then the volatiles were removed under reduced pressure. The residue was re-dissolved in 20 ml of 2M hydrochloric acid and the aqueous was washed with dichloromethane. Aqueous 23% sodium hydroxide solution was then added until the solution reached an alkaline pH. The product was extracted with EtOAc. EtOAc (EtOAc)EtOAc. 42 mg (yield 81%) of the pure title compound were obtained without any further purification.

LRMS(m/z): 249(M+1) ⁺

Preparation 41

1-((4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) oxy) methyl) -3-iodo -1 H - pyrazolo [3,4- d] pyrimidin-4-amine (1 - ((4 - ( (3 S, 5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3, 4- d ]pyrimidin-4-amine)

100 mg (0.23 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 (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) and 51mg (0.27mmol) of (2 S, 6 R) -2,6- dimethyl-piperazine (dihydrochloride ((2 S , 6 R )-2,6-dimethylpiperazine (dihydrochloride)) was dissolved in 5 ml of acetone and stirred at room temperature overnight. The solvent was removed, the residue was crystalljjjjjjjjjjjjjjjjjj The crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 100: 1:} 8) was purified to yield the title compound as a white solid 79 mg (yield 67%).

LRMS(m/z): 519(M+1) ⁺

Preparation 42

3-((2-Methoxyethyl)amino)phenol (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 was added and the solvent was evaporated under reduced pressure. Then the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / volume of ammonium formate buffered] 0% to Purified to give 770 mg (yield: 50%)

LRMS(m/z): 168(M+1) ⁺

Preparation 43

4-amino-6-(( (S) -2-(3-(benzyloxy)phenyl)-1-(4-(( 3S ,5 R )-3,5-dimethylpiperazine- 1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (4-Amino-6- (( S )-2-(3-(benzyloxy)phenyl)-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to 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 ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6 -((2-(3-(benzyloxy)phenyl)-1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine- Prepared by 5-carbonitrile). The reaction was carried out 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-dioxocyclopentan-2-yl)benzoate (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 (available from Alfa Aesar ^® , catalog number H51724) and 2.2 g (8.7 mmol) of 4,4 ,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentane) (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 PdCl ₂ dppf. DCM and 120 mg (0.22 mmol) of dppf were treated according to the method described in Example 21b. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 783 mg (yield: 65%)

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 (( 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) 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 (S) -methyl ester (( 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-hydroxybenzoate)

350 mg (1.1 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 492 mg (2.1 mmol) of 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 62 mg (0.05 Mold) of Pd(PPh ₃ ) 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 at 90 ° C overnight under an argon atmosphere. The reaction mixture through diatomaceous earth (Celite ^®) was filtered, and diluted with ethyl acetate, the organic solution was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut

LRMS(m/z): 445(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-hydroxybenzoic acid (( 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)

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 evaporated under reduced pressure. The residue was diluted with water and 2N hydrochloric acid was added until a solid precipitated. The product was extracted with EtOAc. EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography eluting elut elut elut elut

LRMS(m/z): 431(M+1) ⁺

Preparation 46

1-((4-((3 S ,5 R )-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-methylpyrrolo[2,1 - f] [1,2,4] triazin-2-yl) methyl) -3-iodo -1 H - pyrazolo [3,4- d] pyrimidin-4-amine (1 - ((4- ((3 S ,5 R )-3,5-Dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

100 mg (0.19 mmol) of 1-((4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)oxy)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-) (3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo [3,4- d ]pyrimidin-4-amine) was dissolved in 2 ml of anhydrous dichloromethane. 55 μl (0.39 mmol) of triethylamine and 18 μl (0.23 mmol) of methanesulfonium chloride were added, and the mixture was stirred at room temperature for 1 hour. The solution was then diluted with dichloromethane and washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc EtOAc EtOAc:

LRMS(m/z): 597(M+1) ⁺

Preparation 47

Chloro-5-iodo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine (4-Chloro-5-iodo -7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine)

344 mg (8.6 mmol) of sodium hydride (60% dispersion in mineral oil) was suspended in 10 ml of dimethylformamide. The mixture was cooled in an ice bath at 0 ° C, and 2.0 g (7.2 mmol) of 4-chloro-5-iodo-7 H -pyrrole [2,3-] in 10 ml of dimethylcarboxamide was added dropwise. d ] A solution of pyrimidine (4-chloro-5-iodo-7 H -pyrrolo[2,3- d ]pyrimidine) (available from Aldrich ^® , catalog number 699497). The resulting mixture was stirred at 0 ° C for 30 minutes, then 1.6 ml (9.0 mmol) of [2-(chloromethoxy)ethyl](trimethyl) in 10 ml of dimethylcarboxamide was added dropwise. A solution of [2-(chloromethoxy)ethyl](trimethyl)silane) (available from Aldrich ^® , Cat. No. 238902) was stirred at room temperature overnight. The mixture was poured into water and a solution of potassium carbonate was added until basic pH was obtained. The organics were dried over sodium sulfate and evaporated. The residue was treated with hexanes and the residual solid was filtered, washed with more hexanes and dried in air. 2.2 g (yield 71%) of title compound as a white solid.

LRMS(m/z): 410(M+1) ⁺

Preparation 48

4-chloro-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ 2,3- d ]pyrimidine (4-Chloro-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2, 3- d ]pyrimidine)

500mg (1.2mmol) of 4-chloro-5-iodo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine (4 -Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidine), 310 mg (1.5 mmol) of 1-methyl-4-(4) ,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)-1 H -pyrazole (1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazole) (available from Aldrich ^® , catalog number 595314), 315 mg (1.5 mmol) of potassium phosphate and 95 mg (0.12 mmol) of PdCl ₂ dppf. The DCM was suspended in a mixture of 16 ml of tetrahydrofuran and 1.6 ml of water. 1.0 ml (7.2 mmol) of triethylamine was added, and the resulting mixture was heated under reflux for 3 hours under nitrogen. 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 sulfate. The crude product was purified by EtOAc EtOAcjjjjjjj

LRMS(m/z): 364(M+1) ⁺

Preparation 49

(S) - N - (1- (4- chloro-5-methyl-pyrrolo [2,1- f] [1,2,4] triazin-2-yl) ethyl) -5- (1- Methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine-4 - amine ((S) - N - ( 1- (4-Chloro-5-methylpyrrolo [2,1- f] [1,2,4] triazin-2-yl) ethyl) -5- (1-methyl- 1 H -pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

a) (S) -5-Methyl-2-(1-((5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl))) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazine- 4( 3H )-one (( S )-5-Methyl-2-(1-((5-(1-methyl-1 H- pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy) )methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

93 mg (0.48 mmol) of (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (( S )-2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one), 190 mg (0.52 mmol) of 4-chloro -5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ] pyrimidine (4-Chloro-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine), 190 mg (1.3 mmol) of cesium fluoride and 450 μl (2.6 mmol) of DIEA were stirred in 5 ml of third 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 sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 520(M+1) ⁺

b) (S) - N -(1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5-( 1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine 4-amine ((S) - N - ( 1- (4-Chloro-5-methylpyrrolo [2,1- f] [1,2,4] triazin-2-yl) ethyl) -5- (1- Methyl-1 H- pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

53 mg (0.1 mmol) of (S) -5-methyl-2-(1-((5-(1-methyl-1- H -pyrazol-4-yl)-7-((2-(tri-)) silicon alkyl group) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) ethyl) pyrrolo [2,1- f] [1,2,4 Triazine-4( 3H )-one (( S )-5-Methyl-2-(1-((5-(1-methyl-1 H- pyrazol-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) 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 ice water and the product was extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. 48 mg (yield 87%) of the title compound was obtained.

LRMS(m/z): 538(M+1) ⁺

Preparation 50

N -( (S) -1-(4-((3 S ,5 R )-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)-7-((2-(trimethyldecyl)) Oxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine ( N -(( S )-1-(4-((3 S ,5 R )-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)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

48mg (0.09mmol) of (S) - N - (1- (4- chloro-5-methyl-pyrrolo [2,1- f] [1,2,4] triazin-2-yl) ethyl) -5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ] pyrimidin-4-amine (( S )- N -(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5 -(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine), 33 mg ( 0.29 mmol) of (2 S, 6 R) -2,6- dimethyl-piperazine ((2 S, 6 R) -2,6-dimethylpiperazine) and 800μl (4.6mmol) of diisopropylethylamine in The mixture was stirred at room temperature for 30 minutes in 5 ml of acetone. 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 sulfate, filtered and evaporated. The title compound was obtained after EtOAc (EtOAc)

LRMS(m/z): 616(M+1) ⁺

Preparation 51

4-(2-(Dimethylamino)ethoxy)benzaldehyde (4-(2-(Dimethylamino)ethoxy)benzaldehyde)

1.0 g (8.2 mmol) of 4-hydroxybenzaldehyde (purchased from Aldrich ^® , catalog number 144088), 1.77 g (12.3 mmol) of 2-chloro- N , N -dimethylethylamine hydrogen chloride ( 2-chloro- N, N -dimethylethanamine hydrochloride ) ( available from Aldrich ^®, D141208) and potassium carbonate 4.5g (33mmol) catalog number 20ml of DMF was stirred at 80 ℃ 4 hours. The solution was partitioned between water and EtOAc (EtOAc m.

LRMS(m/z): 194(M+1) ⁺

Preparation 52

2-(4-((2 R , 6 S )-2,6-dimethylpiperazin-1-yl)methyl)phenoxy)- N , N -dimethylethylamine (2-( 4-((( 2 R ,6 S )-2,6-Dimethylpiperazin-1-yl)methyl)phenoxy)- N , N -dimethylethanamine)

a) 4-(4-(2-(Dimethylamino)ethoxy)benzyl)-3,5-dimethylpiperazine-1-carboxylic acid (3 R , 5 S )-t-butyl ester ((3 R ,5 S )- Tert -butyl 4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5-dimethylpiperazine-1-carboxylate)

To 250 mg (1.2 mmol) of 3,5-dimethylpiperazine-1-carboxylic acid (3 R , 5 S )-t-butyl ester ((3 R , 5 S )- tert in 10 ml of dichloromethane -butyl 3,5-dimethylpiperazine-1-carboxylate) (available from AK Scientific ^® 166098) and 270 mg (1.4 mmol) of 4-(2-(dimethylamino)ethoxy)benzaldehyde (4-(2- (Dimethylamino)ethoxy)benzaldehyde) 300 mg (1.4 mmol) of sodium triacetoxyborohydride was added to the mixture. The reaction mixture was stirred at 40 ° C overnight, an additional 300 mg of sodium triethoxysulfon borohydride was added, and stirring was continued at 40 ° C for an additional 48 hours. The mixture is then diatomaceous earth (Celite ^®) and filtered, and washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. 146 mg (yield: 32%) ofyield

LRMS(m/z): 392(M+1) ⁺

b) 2-(4-((2 R , 6 S )-2,6-dimethylpiperazin-1-yl)methyl)phenoxy) -N , N -dimethylethylamine dihydrogen (2-(4-((2 R ,6 S )-2,6-Dimethylpiperazin-1-yl)methyl)phenoxy)- N , N -dimethylethanamine dihydrochloride)

146 mg (0.37 mmol) of 4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5-dimethylpiperazine-1-carboxylic acid (3 R , 5 S )- The third butyl ester ((3 R , 5 S )- Tert -butyl 4-(4-(2-(dimethylamino)ethoxy)benzyl)-3,5-dimethylpiperazine-1-carboxylate) was suspended in 5 ml of dioxane In a 4M hydrochloric acid solution. The suspension was stirred for 10 minutes and then 2 ml of water was added. The clarified solution was then stirred at room temperature for 1 hour. The volatiles were then removed under reduced pressure. 136 mg (yield 100%) of title compound as a brown solid.

LRMS(m/z): 292(M+1) ⁺

Preparation 53

(1-(5-Methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid ( S) - (9 H - fluorenyl-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (5-methyl-4-oxo-3,4-dihydropyrrolo [2 , 1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

1.4 g (6.4 mmol) of (S) -2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-4( 3H )- Ketone (( S )-2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one) was dissolved in 12 ml of dichloromethane, and Cool in an ice bath. Then 2.0ml of saturated aqueous sodium bicarbonate was added and 2.0g (7.7mmol) of (9 H - fluorenyl-9-yl) methyl carbon acyl chloride ((9 H -fluoren-9- yl) methyl carbonochloridate). The mixture was stirred at room temperature for 10 minutes and diluted with dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0% to 20% DCM / ethyl acetate, then 100% to recover the remaining starting material) to afford 1.21 g (yield 46%) of white solid. Title compound.

LRMS(m/z): 415(M+1) ⁺

Preparation 54

(1-(3-(2,4-Dimethoxybenzyl)-5-methyl-4-oxooxy-3,4-dihydropyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethyl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (3 -(2,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

a) (1-((2-((2,4-Dimethoxybenzyl)aminecarbamoyl)-3-methyl-1 H -pyrrol-1-yl)amino)-1-yloxy propan-2-yl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1 - ((2 - ((2, 4-dimethoxybenzyl)carbamoyl)-3-methyl-1 H -pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate)

20.4g (65mmol) of (S) -2 - ((( (9 H - fluorenyl-9-yl) methoxy) carbonyl) amino) propanoic acid ((S) -2 - (( ((9 H -fluoren -9-yl)methoxy)carbonyl)amino)propanoic acid) and 13.0 g (68 mmol) of EDC. The HCl was suspended in 300 ml of DMF and stirred at room temperature for 30 minutes. Then 18.1 g (63 mmol) of 1-amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-1) in 145 ml of DMF was added. A solution of Amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into 1000 ml of water and the solid formed was filtered, washed with water and diethyl ether, and then dried in a vacuum oven. The title compound was obtained as a white solid.

LRMS(m/z): 583(M+1) ⁺

b) (1-(3-(2,4-Dimethoxybenzyl)-5-methyl-4-oxooxy-3,4-dihydropyrrolo[2,1- f ][1, 2,4] triazin-2-yl) ethyl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (3-(2,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

10.9 g of the crude product obtained in the preparation of 54a (1-((2-((2,4-dimethoxybenzyl)aminocarbazyl)-3-methyl-1 H -pyrrol-1-yl)amino) ) -1-oxo-2-yl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- ( (2-((2,4-dimethoxybenzyl)carbamoyl)-3-methyl-1 H- pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate) suspended in 450 ml of toluene at 7.5 g The PPTS was heated at 150 ° C for 16 hours in the presence of PPTS using a Dean-Stark head to remove traces of water from the reaction mixture. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to afford 13.1 g of crude product (l-(3-(2,4-dimethoxybenzyl)-5-methyl-4- Oxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -(9H-fluoren-9-yl) ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (3- (2,4-dimethoxybenzyl) -5-methyl-4-oxo-3,4-dihydropyrrolo [2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate), which was used in the next step without any further purification, which was used in the next step without any further purification.

LRMS(m/z): 565(M+1) ⁺

Preparation 55

(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -(9H-茀-9 - yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [2,1- f] [1,2,4] triazin-2- Yl)ethyl)carbamate)

a) (1-(5-Methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino acid (S) - (1- (5 -methyl-4-oxo-3,4-dihydropyrrolo (9 H -Fluoren-9-yl) methyl [- (9H- fluorene-9-yl) methyl ester ((S) 2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

13.1 g of the crude product obtained in the preparation of 54b (1-(3-(2,4-dimethoxybenzyl)-5-methyl-4-oxooxy-3,4-dihydropyrrolo[2] , 1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -(9H-fluoren-9-yl)methyl ester (( S )-(9 H -Fluoren- 9-yl)methyl(1-(3-(2,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2- Yl)ethyl)carbamate) was 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. The solid formed was filtered and washed with EtOAc (EtOAc)

LRMS(m/z): 415(M+1) ⁺

b) (1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -(9H-茀9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [2,1- f] [1,2,4] triazin- 2-yl)ethyl)carbamate)

Preparation of 7.47 g (18 mmol) of (1-(5-methyl-4-oxo-oxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazine- 2- yl) ethyl) carbamate (S) - (9 H - fluorenyl-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (5-methyl-4 -oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate) is 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 aqueous sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulfate. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 433(M+1) ⁺

Preparation 56

(S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2 ,4]triazin-2-yl)ethylamine (( S )-1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine)

a)( (S) -1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][ 2,4] triazin-2-yl) ethyl) carbamate (9H-fluorene-9-yl) methyl ((9 H -Fluoren-9- yl) methyl ((S) -1- (4 -((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

87mg (0.46mmol) of (2 S, 6 R) -2,6- dimethyl-piperazine dihydrochloride ((2 S, 6 R) -2,6-dimethylpiperazine dihydrochloride) was suspended in 10ml of acetone. 250 μl (1.44 mmol) of DIEA was added and the mixture was stirred for 10 minutes. To this mixture, 100 mg (0.23 mmol) of (1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2-) in 2 ml of acetone was added. yl) ethyl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate) solution, and the resulting suspension was stirred at room temperature for 90 minutes. The volatiles were then removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with EtOAc EtOAc m.

LRMS(m/z): 415(M+1) ⁺

b) (S) -1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethylamine (( S )-1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2, 1- f ][1,2,4]triazin-2-yl)ethanamine)

The crude product from the previous step was dissolved in 2 ml of dioxane. 20 μl (23 mmol) of morpholine was added, and the mixture was heated at reflux temperature for 2.5 hours. The volatiles were removed under reduced pressure, the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v formic acid The title compound was obtained as an off-white solid (yield: 44%).

LRMS(m/z): 289(M+1) ⁺

Preparation 57

N - (3- (4- chloro-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) benzene N- (3-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimid in-5-yl)phenyl )methanesulfonamide)

300 mg (0.73 mmol) of 4-chloro-5-iodo-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine (4 -Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidine), 326 mg (1.1 mmol) of N- (3-(4,4) ,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl)methanesulfonamide ( N- (3-(4,4,5,5-tetramethyl-) 1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide) (available from Aldrich ^® , catalog number 63,603-7), 54 mg (0.07 mmol of PdCl ₂ dppf.DCM, 187 mg (0.88 mmol)) of potassium phosphate and 561 μl (4.0 mmol) of triethylamine was suspended in a mixture of 10 ml of tetrahydrofuran and 1 ml of water. The reaction mixture was stirred at reflux temperature under a nitrogen atmosphere for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:

LRMS(m/z): 454(M+1) ⁺

Preparation 58

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)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - Pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide ( N- (3-(4-(( S ))-(4-(( 3S , 5R )) -3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy) )methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide)

26 mg (0.09 mmol) of (S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f] [1,2,4] triazin-2-yl) ethanamine ((S) -1- (4 - ((3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5- Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine), 62 mg (0.14 mmol) of N- (3-(4-chloro-7-((2-(trimethyl))) silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) phenyl) methanesulfonamide Amides (N - (3- (4- Chloro-7- ( (2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide), 42 mg (0.28 mmol) of cesium fluoride and 100 μl (0.57 mmol) of DIEA Suspended in 2 ml of third 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 phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 706(M+1) ⁺

Preparation 59

4-(Hydroxymethyl)benzenesulfonamide

In 80ml of THF 1.0g (4.97mmol) 4-acyl sulfonic acid amine (commercially available from Aldrich ^®, Cat. No. C1,180-4) was cooled in an ice bath under nitrogen atmosphere. Then 20 ml (20 mmol) of 1 M borane solution in THF was added dropwise, and the reaction mixture was stirred at 0 ° C for 30 min and left at room temperature overnight. An additional 20 ml of borane solution was added dropwise at 0 ° C and the mixture was stirred at room temperature for an additional 72 hours. The solution was then cooled to 0 ° C and 50 ml of methanol was added to quench the reaction, followed by the addition of 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 EtOAc EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was treated with dichloromethane, the insoluble solid was filtered and dried in air. The title compound was obtained as a white solid (yield: 95%).

LRMS(m/z): 188(M+1) ⁺

Preparation 60

N -(3-(4-(( S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1 ,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidin-5-yl) phenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) pyrrolo [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] Pyrimidin-5-yl)phenyl)methanesulfonamide)

5-bromo- N -( (S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethyl) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4 amine (5-Bromo- N - (( S) -1- (4 - ((2 S, 6 R) -2,6-dimethylmorpholino) pyrrolo [2,1- f] [1,2,4] triazin- 2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]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 a nitrogen atmosphere. Then N- (3-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)phenyl)methanesulfonamide ( N -(3) was added in sequence. -(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 PdCl ₂ dppf.CH ₂ Cl ₂ (135 mg, 0.16 mmol), and the mixture was heated at 70 ° C overnight. The reaction mixture was poured into aq. EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc

LRMS(m/z): 693(M+1) ⁺

Preparation 61

(2 S ,6 R )-2,6-Dimethyl-1-(methylsulfonyl)piperazine ((2 S ,6 R )-2,6-Dimethyl-1-(methylsulfonyl)piperazine)

a) 3,5-Dimethyl-4-(methylsulfonyl)piperazine-1-carboxylic acid (3 S ,5 R )-T-butyl ester ((3 S ,5 R )- Tert -butyl 3,5-dimethyl-4-(methylsulfonyl)piperazine-1-carboxylate)

500mg (2.33mmol) of 3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) tert-butyl ester ((3 S, 5 R) - tert -butyl 3,5-dimethylpiperazine-1 -carboxylate) (available from AK Scientific ^® 166098) was dissolved in 10 ml of anhydrous dichloromethane. 650 μl (4.7 mmol) of triethylamine and 216 μl (2.8 mmol) of methanesulfonium chloride were added, and the mixture was stirred at room temperature for 3 hours. The organic solution was washed with a 1M aqueous HCl solution, water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was treated with diethyl ether, the insoluble solid was filtered and dried in air. 379 mg (yield 56%) of title compound

LRMS(m/z): 293(M+1) ⁺

b) (2 S, 6 R ) -2,6- dimethyl-1- (sulfonic acyl methyl) piperazine hydrogen chloride ((2 S, 6 R) -2,6-Dimethyl-1- (methylsulfonyl) Piperazine hydrochloride)

379mg (1.3mmol) of 3,5-dimethyl-4- (sulfonic acyl methyl) piperazine-1-carboxylic acid (3 S, 5 R) - tert-butyl ester ((3 S, 5 R) - Tert- butyl 3,5-dimethyl-4-(methylsulfonyl)piperazine-1-carboxylate) was suspended in 5.5 ml of a 4 M hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 249 mg (yield 100%) of the title compound was obtained, m.

LRMS(m/z): 193(M+1) ⁺

Preparation 62

5-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-3-ol (5-(4,4,5,5-Tetramethyl) -1,3,2-dioxaborolan-2-yl)pyridin-3-ol)

a) 5-Bromopyridin-3-ol (5-Bromopyridin-3-ol)

4.0 g (20.6 mmol) of 3-bromo-5-methoxypyridine was 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, every 24 hours. 9 ml of hydrobromic acid. After the reaction was completed, the solution was poured into ice and adjusted to pH = 6 with a concentrated solution of sodium hydroxide. The product was extracted with EtOAc. EtOAc was evaporated. 3.15 g (yield 90%) of title compound as a white solid.

LRMS(m/z): 172,174(M-1) ⁺

b) 5-(4,4,5,5-Tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-3-ol (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, - bis(1,3,2-dioxacyclopentane), 258 mg (0.32 mmol) of PdCl ₂ dppf. DCM, 175 mg (0.32 mmol) of dppf and 930 mg (9.5 mmol) of potassium acetate were suspended in 25 ml of dioxane in a nitrogen atmosphere. The mixture was heated at 90 ° C overnight. The suspension was then filtered and the solvent removed. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 270 mg (yield 39%) of title compound.

LRMS(m/z): 222(M+1) ⁺

Preparation 63

1-((2 S ,6 R )-2,6-dimethylpiperazin-1-yl)ethanone hydrogen chloride (1-((2 S ,6 R )-2,6-Dimethylpiperazin-1-yl) Ethanone hydrochloride)

a) 4- acetyl-3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) - tert-butyl ester ((3 S, 5 R) - Tert -butyl 4-acetyl- 3,5-dimethylpiperazine-1-carboxylate)

100mg (0.47mmol) of 3,5-dimethyl-piperazine-1-carboxylate (3 S, 5 R) - tert-butyl ester ((3 S, 5 R) - tert -butyl 3,5-dimethylpiperazine- 1-carboxylate) (available from AK Scientific ^® 166098) and 156μl (1.1mmol) of triethylamine were dissolved in 3ml of dioxan. A solution of 40 μl (2.8 mmol) of methanesulfonium 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 a 2M aqueous HCl solution, water and brine, dried over magnesium sulfate, filtered and evaporated. Obtained 107 mg (yield: 92%, yield:

LRMS(m/z): 257(M+1) ⁺

b) 1-((2 S ,6 R )-2,6-Dimethylpiperazin-1-yl)ethanone hydrogen chloride (1-((2 S ,6 R )-2,6-Dimethylpiperazin-1- Yl)ethanone hydrochloride)

104mg (0.41mmol) 4-acetyl-3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) - tert-butyl ester ((3 S, 5 R) - Tert -butyl 4-acetyl-3,5-dimethylpiperazine-1-carboxylate) was suspended in 2 ml of a 4 M hydrochloric acid solution in dioxane. The mixture was stirred at room temperature overnight, then the volatiles were removed under reduced pressure. This gave 63 mg (yield: 100%) of the title compound which was used without any further purification.

LRMS(m/z): 157(M+1) ⁺

Preparation 64

4-(2-( (S) -1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid (3 S ,5 R )-t-butyl ester ((3 S ,5 R )- Tert -butyl 4-(2-(( S )-1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile) and 59mg (0.27mmol) of 3,5-dimethyl-piperazine-1-carboxylic acid (3 S, 5 R) - tert-butyl ester ( (3 S ,5 R )- tert -butyl 3,5-dimethylpiperazine-1-carboxylate) (available from AK Scientific ^® 166098) was stirred in a solution of 0.6 ml of methylisobutylcetone at 150 ° C using microwave irradiation. 17 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 sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 8 mg (yield: 17%) of the title compound.

LRMS(m/z): 507(M+1) ⁺

Preparation 65

3-iodo-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)- 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1- f ][1 ,2,4]triazin-2-yl)methyl) -1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

100 mg (0.23 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 (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), 22 mg (0.25 mmol) of piperazine and 120 μl (0.57 mmol) of DIEA in 20 ml of acetone at room temperature 24 hour. The resulting suspension was filtered and washed with EtOAc EtOAcjjjjjjjj

LRMS(m/z): 491(M+1) ⁺

Preparation 66

3-iodo-1-((5-methyl-4-thiomorpholinylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H - Pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-thiomorpholinopyrrolo[2,1- f ][1,2,4]triazin-2-yl )methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

100 mg (0.23 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 (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), 24 μl (0.23 mmol) of thiomorpholine and 120 μl (0.57 mmol) of DIEA in 4 ml of acetone at room temperature Stir for 24 hours. The resulting suspension was filtered and washed with EtOAc EtOAcjHHHHHH

LRMS(m/z): 508(M+1) ⁺

Preparation 67

3-iodo-1-((5-methyl-4-((2-(pyrrol-1-yl)ethyl)amino)pyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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-4-amine)

100 mg (0.23 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 (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), 32 μl (0.27 mmol) of 2-(pyrrol-1-yl)ethylamine and 120 μl (0.57 mmol) of DIEA in The mixture was stirred at room temperature for 24 hours in 4 ml of acetone. An additional 16 μl of the amine was added, and the mixture was stirred at room temperature for 8 hours or more, followed by stirring at 55 ° C for 16 hours. The suspension was cooled, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

LRMS(m/z): 519(M+1) ⁺

Preparation 68

5-(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)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 S , 4 S )-T-butyl ester ((1 S , 4 S )- Tert -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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2 -carboxylate)

a) 5-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1 - f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 S ,4 S )-t-butyl ester ((1 S ,4 S )- Tert -butyl 5-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo [2,1- f ][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- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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), 50 mg (0.25 mmol) of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 S , 4 S )-T-butyl ester ((1 S ,4 S )- tert -butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate) and 120 μl (0.57 mmol) of DIEA in 4 ml Stir in acetone at room temperature for 24 hours. The resulting suspension was filtered and washed with EtOAc EtOAcjjjjjjjj

LRMS(m/z): 603(M+1) ⁺

b) 5-(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)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 S ,4 S )-T-butyl ester ((1 S ,4 S )- Tert -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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane -2-carboxylate)

40 mg (0.07 mmol) of 5-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole [2,1- f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 S ,4 S )- Tert -butyl ester ((1 S , 4 S )- Tert -butyl 5-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)) -5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate), 20 mg (0.13 mmol) (3 -(fluoro-5-hydroxyphenyl)boronic acid and 6 mg (0.007 mmol) of PdCl ₂ dppf. The DCM is suspended in the dioxane. 0.1 ml of a 2 M aqueous sodium carbonate solution was added, and the resulting mixture was heated at 80 ° C for 20 hours under an argon atmosphere. After an excessive amount of boric acid and a catalyst were added twice, 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 sulfate. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc

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- f ][1,2,4]triazin-4-yl)(methyl)amino)propan-1-ol (3-((2-((4-Amino-3-iodo-1 H- pyrazolo[3 ,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)(methyl)amino)propan-1-ol)

75 mg (0.17 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 (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), 23 μl (0.25 mmol) of 3-(methylamino)propan-1-ol and 89 μl (0.51 mmol) of DIEA Stir at room temperature for 24 hours in 4 ml of acetone. The volatiles were removed under reduced br~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

LRMS(m/z): 494(M+1) ⁺

Preparation 70

3-iodo-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholinyl)pyrrolo[2,1- f ][1,2,4]triazine- 2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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 ]pyrimidin-4-amine)

75 mg (0.17 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 (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), 46 mg (0.25 mmol) of 2,2,6,6-tetramethylmorpholine (2,2,6, 6-tetramethylmorpholine and 89 μl (0.51 mmol) of DIEA were stirred at room temperature for 24 hours in 4 ml of acetone. The volatiles were removed under reduced br~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

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- f ][1,2,4]triazin-4-yl)piperidin-4-ol (1-(2-((4-Amino-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-) 1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperidin-4-ol)

75 mg (0.17 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 (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), 23 μl (0.25 mmol) of piperidin-4-ol (piperidin-4-o) and 89 μl (0.51 mmol) The DIEA was stirred at room temperature for 4 hours in 4 ml of acetone. The volatiles were removed under reduced EtOAcqqqqqqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ

LRMS(m/z): 506(M+1) ⁺

Preparation 72

N - (3- (4- chloro-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) - 5- hydroxyphenyl) methanesulfonamide Amides (N - (3- (4- Chloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-5- Yl)-5-hydroxyphenyl)methanesulfonamide)

500mg (1.2mmol) of 4-chloro-5-iodo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine (4 -Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidine), 575 mg (1.8 mmol) of N- (3-hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl)methanesulfonamide ( N- (3-Hydroxy-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide), 92 mg (0.11 mmol) of PdCl ₂ dppf. DCM, 315 mg (1.5 mmol) of potassium phosphate and 1000 μl (7.2 mmol) of triethylamine were suspended in a mixture of 160 ml of tetrahydrofuran and 16 ml of water. The reaction mixture was stirred at reflux temperature under a nitrogen atmosphere for 3 hr. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc EtOAc)

LRMS(m/z): 469(M+1) ⁺

Preparation 73

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)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- (4 - ((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2- (trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

29 mg (0.10 mmol) of (S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f] [1,2,4] triazin-2-yl) ethanamine ((S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl) -5- Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine), 90 mg (0.19 mmol) of N- (3-(4-chloro-7-((2-(trimethyl))) silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- (4- chloro -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide), 50mg (0.33mmol) and cesium fluoride 100 μl (0.57 mmol) of DIEA was suspended in 2 ml of third butanol. The mixture was heated at reflux temperature overnight. An additional 90 mg of chlorine starting material and 100 μl of DIEA were added and the reaction mixture was stirred for more than 4 hours 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 phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 721(M+1) ⁺

Preparation 74

4-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperazin-2-one (4-(2-((4-Amino-3-iodo-1 H- 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- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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), 35 mg (0.35 mmol) of piperazin-2-one (purchased from Aldrich ^® , catalogue No. 641065) and 160 μl (0.91 mmol) of DIEA were stirred at 60 ° C for 24 hours in a mixture of 2 ml of THF and 2 ml of acetone. The reaction mixture was filtered and washed with EtOAc EtOAc. 105 mg (yield 92%) of title compound as a white solid.

LRMS(m/z): 505(M+1) ⁺

Preparation 75

1-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperidine-4-carboxamide (1-(2-((4-Amino-3-iodo-1 H- pyrazolo[3,4- d ]] Pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperidine-4-carboxamide)

100 mg (0.23 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 (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), 45mg (0.35mmol) piperidin-4-2carboxamide (piperidine-4-carboxamide) (available from Aldrich ^® , Catalog No. I1, 790-7) and 160 μl (0.91 mmol) of DIEA were stirred at 60 ° C for 24 hours in a mixture of 3 ml of THF and 3 ml of acetone. The reaction mixture was filtered and washed with EtOAc EtOAc. 115 mg (yield 95%) of title compound as a white solid.

LRMS(m/z): 553(M+1) ⁺

Preparation 76

3-iodo-1-((5-methyl-4-(2-(pyrrol-1-yl)ethoxy)pyrrolo[2,1- f ][1,2,4]triazine-2- Methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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-4-amine)

53 μl (0.45 mmol) of 2-(pyrrol-1-yl)ethanol was dissolved in 2 ml of anhydrous THF. 14 mg (0.35 mmol) of sodium hydride (60% dispersion in mineral oil) was 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- f ][1,2,4]triazine- 2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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), and the resulting reaction mixture was stirred at room temperature overnight, then Place at 60 ° C for 24 hours. An additional 53 μl of a solution of 2-(pyrrol-1-yl)ethanol and 14 mg of sodium hydride was added, and after 4 hours at 60 ° C, the reaction was allowed to reach room temperature. The mixture was filtered, and the filtrate was evaporatedjjjjjjjjj

LRMS(m/z): 520(M+1) ⁺

Preparation 77

4-(2-((4-Amino-3-iodo-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 (4-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4 - d ]pyrimidin-1-yl)methyl)-5-methylpyr rolo[2,1- f ][1,2,4]triazin-4-yl)thiomorpholine 1,1-dioxide)

100 mg (0.23 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 (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), 47 mg (0.35 mmol) of thiomorpholine 1,1-dioxide ( DIEA, purchased from TCI ^® , Cat. No. T2193) and 160 μl (0.91 mmol), was stirred at 50 ° C for 24 hours in a mixture of 3 ml of THF and 3 ml of acetone. An additional 47 mg of amine was added and the reaction was allowed to proceed for more than 16 hours. The reaction mixture was filtered and washed with diethyl ether. Most of the desired product was taken in solution, then the solvent was removed under reduced pressure to give 164 mg of the title compound.

LRMS(m/z): 540(M+1) ⁺

Preparation 78

1-((4-(1,4-diazepan-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-(1,4-Diazepan-1-yl)-5-methylpyrrolo[2 , 1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

100 mg (0.23 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 (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), 28 mg (0.28 mmol) of 1,4-diazepane (1,4-diazepane) (purchased from 1,4-diazepane) Aldrich ^® , Cat. No. H1, 660-4) and 160 μl (0.91 mmol) of DIEA were stirred at room temperature for 40 hours in a mixture of 4 ml of THF and 4 ml of acetone. The reaction mixture was filtered and washed with diethyl ether. Most of the desired product was taken in a solution, and then dissolved under reduced pressure to give 28 mg (yield: 24%) of the title compound.

LRMS(m/z): 505(M+1) ⁺

Preparation 79

5-(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)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester ( Tert -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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate)

a) 5-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1 - f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert -butyl ester ( Tert -butyl 5-(2) -((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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), 110 mg (0.52 mmol) of 2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid Tert -butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (available from J&W Pharmalab ^® , catalog number 65-0429) and 240 μl (0.48 mmol) of DIEA in 5 ml The mixture of THF and 5 ml of acetone was stirred at 60 ° C for 24 hours. The reaction mixture was filtered and the solid was washed with THF. Most of the desired product was in solution, so the solvent was removed under reduced pressure to give 210 mg (yield: 100%) of the title compound.

LRMS(m/z): 617(M+1) ⁺

b) 5-(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)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid III Tert- 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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate)

200 mg (0.32 mmol) of 5-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole [2,1- f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert -butyl ester ( Tert- butyl 5-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][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 ((3-fluoro-) 5-hydroxyphenyl)boronic acid), 26 mg (0.032 mmol) of PdCl ₂ dppf. DCM and 480 μl (0.96 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 15 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. After cooling, the volatiles were evaporated in vacuo tolululululululululululululululululululu

LRMS(m/z): 602(M+1) ⁺

Preparation 80

(S) -4-amino-6-((1-(4-(4-carbamimido-3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)amino)pyrimidine-carbonitrile (( S )-4-Amino-6-((1-(4-(4-formyl-3,5-dimethylphenyl)) -5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 271 mg (1.52 mmol) of (4-methylindolyl-3,5-dimethylphenyl)boronic acid ((4-formyl-3,5) -dimethylphenyl)boronic acid) (available from Combi-blocks ^® , catalog number BB-6256), 62 mg (0.08 mmol) of PdCl ₂ dppf. DCM and 1.14 ml (2.3 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 8.5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. The reaction mixture was filtered through diatomaceous earth (Celite ^®), and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The crude product was first purified by flash chromatography (0% to 16% DCM/MeOH) and then purified by reverse phase chromatography (C-18 cerium oxide from Waters ^® , water / 1:1 acetonitrile - The methanol was purified as a EtOAc (yield: 0.1% vol.).

LRMS(m/z): 427(M+1) ⁺

Preparation 81

Bromo-4-chloro-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine (5-Bromo-4-chloro -7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine)

The title compound following the experimental procedure described in Example 47 by 6.0g (25.8mmol) of 5-bromo-4-chloro -7 H - pyrrolo [2,3- d] pyrimidine (5-bromo-4-chloro -7 H- pyrrolo[2,3- d ]pyrimidine) (available from Aldrich ^® , catalog number 720194) and 5.4 g (32.4 mmol) of (2-(chloromethoxy))ethyl)trimethylnonane preparation. The crude product was treated with hexanes, the residual solid was filtered, washed with more hexanes and dried in air. 6.5 g of the title compound are obtained as white solid. The filtrate was evaporated and the residue was purified EtOAcjjjjjjjj

LRMS(m/z): 362,364(M+1) ⁺

Preparation 82

5-bromo- N -( (S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((2 S, 6 R) -2,6-dimethylmorpholino) -5-methylpyrrolo [2,1- f] [ 1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

a) (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethanamine ((S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) -5-methylpyrrolo [2,1- f] [1, 2,4]triazin-2-yl)ethanamine)

520 mg (1.2 mmol) of (1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - (9H-fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [2,1- f] [1,2, 4]triazin-2-yl)ethyl)carbamate) was dissolved in 36 ml of acetone. Was added 152mg (1.32mmol) of (2 S, 6 R) -2,6- dimethylmorpholine ((2 S, 6 R) -2,6-dimethylmorpholine) and 630μl (3.6mmol) of DIEA, and The mixture was stirred at room temperature for 2.5 hours. The solvent was then removed under reduced pressure and the residue was taken up in 10 mL of dioxane. Was added 691mg (6mmol) of (2 S, 6 R) -2,6- dimethyl morpholine, and the resulting mixture was heated to 100 deg.] C for 1 hour. The volatiles were removed under reduced pressure. EtOAcqqqqqqqq

LRMS(m/z): 290(M+1) ⁺

b) 5-bromo- N -( (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ] pyrimidin-4-amine (5-Bromo- N -(( S )-1-(4-((2 S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

186 mg (0.64 mmol) of (S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethylamine (( S )-1-(4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine) was dissolved in 14 ml of tert-butanol. Was added 466mg (1.28mmol) 5-bromo-4-chloro-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine ( 5-Bromo-4-chloro- 7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidine), 39mg (0.26mmol) of cesium fluoride and 1ml (5.8mmol DIEA, the resulting mixture was stirred at 100 ° C for 48 hours. The solvent was evaporated under reduced pressure. EtOAc m.

LRMS(m/z): 616,618 (M+1) ⁺

Preparation 83

N -( (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2 ,4]triazin-2-yl)ethyl)-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl)ethoxy) A -7 H -pyrrolo[2,3- d ]pyrimidin-4-amine ( N -(( S )-1-(4-(( 2S ,6 R )-2,6-Dimethylmorpholino)-5 -methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethylsilyl) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

29mg (0.05mmol) of 5-bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrole [2,3- d ]pyrimidine-4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2 ,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4- Amine, 20 mg (0.10 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1 H - Pyrazole (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazole) (available from Aldrich ^® , catalog number 595314), 4 mg (0.005 mmol) of PdCl ₂ dppf. DCM and 72 μl (0.14 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. The volatiles were removed and the crude was purified eluting eluting elut elut elut

LRMS(m/z): 618(M+1) ⁺

Preparation 84

N ¹ , N ¹ -dimethyl- N ² -(tetrahydro-2 H -pyran-4-yl)ethane-1,2-diamine ( N ¹ , N ¹ -Dimethyl- N ² -(tetrahydro -2 H -pyran-4-yl)ethane-1,2-diamine)

200 mg (2.0 mmol) of dihydro-2 H -pyran-4(3 H )-one (dihydro-2 H -pyran-4(3 H )-on) was added to 270 μl (2.9) in dichloroethane. mmol) of N ^1, N ¹ - dimethyl-ethane-1,2-diamine ^{(N 1, N 1 -dimethylethane-} 1,2-diamine) was added. The mixture was stirred at room temperature for 1 hour, and then 636 mg (3.0 mmol) of sodium triacetoxyhydroborate was added. The reaction mixture was stirred at room temperature for 60 hours and then diluted with a 10% aqueous ammonium hydroxide solution. The product was extracted with EtOAc (EtOAc)EtOAc. 50 mg (yield 14%) of the title compound as a colourless oil.

LRMS(m/z): 173(M+1) ⁺

Preparation 85

N ¹ -(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl) -N ² , N ² -dimethyl- N ¹ -(tetrahydro-2 H -pyran-4-yl)ethane-1,2 -diamine ( N ¹ -(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-4-yl)- N ² , N ² -dimethyl- N ¹ -(tetrahydro-2 H -pyran-4-yl)ethane-1,2-diamine)

85 mg (0.19 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 (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), 50 mg (0.29 mmol) of N ¹ , N ¹ -dimethyl- N ² -(tetrahydro-2 H - Pyridin-4-yl)ethane-1,2-diamine ( N ¹ , N ¹ -Dimethyl- N ² -(tetrahydro-2 H -pyran-4-yl)ethane-1,2-diamine) and 160 μl (0.91 mmol) of DIEA was stirred at 60 ° C for 24 hours in a mixture of 2 ml of THF and 2 ml of acetone. The reaction mixture was filtered and the solid was washed with THF. Most of the desired product was in solution, so the solvent was removed under reduced pressure to give 94 mg (yield: 85%) of the title compound.

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- N- (piperidin-4-ylmethyl)benzamide (( 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 -(piperidin-4- Ylmethyl)benzamide)

a) 4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-4-yl)-5-methylbenzamideamino)methyl)piperidine-1-carboxylic acid (S) -t-butyl ester (( S )- Tert- butyl 4-((3-(2-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][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 -f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (( 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), 38 mg (0.18 mmol) of 4-(aminomethyl)perazine Butane-1-carboxylic acid tert-butyl ester (available from Maybridge Int. ^® , catalog number KM10802DA), 27 mg (0.14 mmol) of EDC.HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethyl The amine was stirred at room temperature overnight in 4 mL anhydrous dichloromethane. An additional 38 mg of 4-(aminomethyl)piperidine-1-carboxylate was added and the reaction mixture was stirred for an additional 2 hours. It was then diluted with dichloromethane and washed with EtOAc EtOAc (EtOAc m.

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- N- (piperidin-4-ylmethyl)benzamide amine hydrogen chloride (( 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 -(piperidin -4-ylmethyl)benzamide hydrochloride)

To 60 mg (0.10 mmol) of 4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-) in 1 ml of dichloromethane Methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzamideamino)methyl)piperidine-1-carboxylic acid (S) - Third butyl ester (( S )- Tert- butyl 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)piperidine-1-carboxylate) To the solution was added 2 ml of a 4 M hydrochloric acid solution in dioxane. The reaction mixture was stirred at room temperature for 1 hour, then the volatiles were removed under reduced pressure. The crude product was taken up in EtOAc (EtOAc)EtOAc. 45 mg (yield 90%) of the title compound are obtained.

LRMS(m/z): 526(M+1) ⁺

Preparation 87

(1 R ,4 R )-2-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane ((1 R ,4 R )-2-(Methylsulfonyl)-2, 5-diazabicyclo[2.2.1]heptane)

a) 5-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 R ,4 R )-t-butyl ester ((1 R , 4 R )- Tert -butyl 5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate)

To 200 mg (1.0 mmol) of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 R , 4 R )-t-butyl ester ((1 R , 4 R )- tert -butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate) (purchased from Aldrich ^® , catalog number CDS019057) was added 350 μl (2.0 mmol) of DIEA and 120 μl (1.5 mmol). Methane sulfonium chloride. The reaction mixture was stirred at room temperature for 48 hours, then the second addition of the two reagents followed by stirring for more than 4 hours. The volatiles were then removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was washed with EtOAc (EtOAc m.

LRMS(m/z): 277(M+1) ⁺

b) (1 R , 4 R )-2-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane ((1 R ,4 R )-2-(Methylsulfonyl)- 2,5-diazabicyclo[2.2.1]heptane)

225 mg (0.81 mmol) of 5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1 R ,4 R )-t-butyl ester (( 1 R ,4 R )- Tert -butyl 5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate) dissolved in 4 ml of 4M hydrochloric acid in dioxane, solution at room temperature Stir under 2 hours. The volatiles were removed under reduced pressure to give 173 mg (yield: 100%) of

LRMS(m/z): 177(M+1) ⁺

Preparation 88

3-iodo-1-((5-methyl-4-((1 R ,4 R )-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2 -yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3 -Iodo-1-((5-methyl-4-((1 R ,4 R )-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

110 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 (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 ,4 R )-2-(methylsulfonyl)-2, 5-diazabicyclo[2.2.1]heptane hydrogen chloride ((1 R ,4 R )-2-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride) and 220 μl (1.27 mmol) of DIEA The mixture was stirred at 60 ° C for 60 hours in a mixture of 3 ml of THF and 3 ml of acetone. The reaction mixture was filtered and the solid was washed with THF. Most of the desired product was in solution, and therefore, the solvent was removed under reduced pressure to give 195 mg of crude material of the title compound. This crude product was used directly in the next step.

LRMS(m/z): 581(M+1) ⁺

Preparation 89

N - (3- (4 - ( ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [2,1 -f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ 2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- (4 - ((2 S, 6 R -2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl) -7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

100mg (0.16mmol) 5-bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrole [2,3- d ]pyrimidine-4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2 ,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4- Amine, 102 mg (0.33 mmol) of N- (3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl N- (3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide), 14 mg (0.016 mmol) of PdCl ₂ dppf. DCM and 245 μl (0.49 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. It is then necessary to add all reagents a second time and the reaction is stirred at 100 ° C for more than 24 hours. The volatiles were removed, and the crude crystal was purified eluting eluting eluting eluting

LRMS(m/z): 723(M+1) ⁺

Preparation 90

N- (2-hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl) Benzoamide ( N- (2-Hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

a) 4- bromo - N - (2- hydroxyethyl) -2,6-dimethyl-benzoyl amine (4-Bromo- N - (2 -hydroxyethyl) -2,6-dimethylbenzamide)

Add 5 drops of DMF to a suspension of 500 mg (2.2 mmol) of 4-bromo-2,6-dimethylbenzoic acid in 15 ml of dichloromethane. And 320 μl (4.4 mmol) of thionyl chloride. The resulting solution was stirred at reflux temperature for 1 hour, then the volatiles were removed under reduced pressure. The residue was dissolved in 15 ml of THF, and 190 μl (1.1 mmol) of DIEA and 265 μl (4.4 mmol) of 2-aminoethanol were added to the solution. 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 phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut

LRMS(m/z): 272,274(M+1) ⁺

b) N- (2-hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane-2- N- (2-Hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

439mg (1.6mmol) of 4-bromo - N - (2- hydroxyethyl) -2,6-dimethyl-benzoyl amine (4-Bromo- N - (2 -hydroxyethyl) -2,6-dimethylbenzamide) 819 mg (3.2 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxycyclopentaneborane (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)), 132 mg (0.16 mmol) of PdCl ₂ dppf . 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 cooled to room temperature. Suspension was filtered through diatomaceous earth (Celite ^®), and the filtrate was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc

LRMS(m/z): 320(M+1) ⁺

Preparation 91

N -(5-(4-(( (S))- 1-(4-((2 R ,6 S )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1 -f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ 2,3- d] pyrimidin-5-yl) -2-methoxy-3-yl) methanesulfonamide Amides (N - (5- (4 - (((S) -1- (4 - (( 2 R ,6 S )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl) Ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide)

109mg (0.17mmol) 5-bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrole [2,3- d ]pyrimidine-4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2 ,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4- Amine, 102 mg (0.33 mmol) of N- (2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl) Pyridin-3-yl)methanesulfonamide ( N- (2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide ), 14 mg (0.016 mmol) of PdCl ₂ dppf. DCM and 250 μl (0.50 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. The volatiles were removed and the crude was purified eluting eluting elut elut elut elut

LRMS(m/z): 738(M+1) ⁺

Preparation 92

3-iodo-1-((5-methyl-4-(2-morpholinylethoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl -1 H -pyrazolo[3,4- d ]pyrimidine-4-amine (3-Iodo-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)

Add 55.6 μl (0.45 mmol) of 2-morpholinylethanol (available from Aldrich ^® , catalog number H2, 820-3) to 8 mg (0.20 mmol) of sodium hydride (60% in mineral oil) in 2 ml anhydrous THF In the suspension of the dispersion). The mixture was stirred under a nitrogen atmosphere for 30 minutes, and 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4) in 3 ml of THF was added. Triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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). The resulting mixture was stirred at room temperature for 20 hours. Then two additional additions of the reagent were carried out to prepare a solution of 55.6 μl of 2-morpholinylethanol and 8 mg of sodium hydride, and stirred for 30 minutes, and then this solution was added to the reaction mixture. Once the reaction is complete, the solvent is removed under reduced pressure and the residue is taken from EtOAc. The remaining solid was filtered and the filtrate containing the desired material was evaporated in vacuo to afford 190 mg of crude material This crude product 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- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2] , 1- f ][1,2,4]triazin-4-yl)oxy)ethyl)pyrrol-2-one (1-(2-((2-((4-Amino-3-iodo-) 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)

Add 51 μl (0.45 mmol) of 1-(2-hydroxyethyl)pyrrolidin-2-one (purchased from Aldrich ^® , catalog number 33, 047-7) to 2 ml A suspension of 8 mg (0.20 mmol) of sodium hydride (60% dispersion in mineral oil) in anhydrous THF. The mixture was stirred under a nitrogen atmosphere for 30 minutes, and 100 mg (0.23 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4) in 3 ml of THF was added. Triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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). The resulting mixture was stirred at room temperature for 20 hours. Then two additional additions of the reagent were carried out to prepare a solution of 55.6 μl of 2-morpholinylethanol and 8 mg of sodium hydride, and stirred for 30 minutes, and then this solution was added to the reaction mixture. Once the reaction is complete, the solvent is removed under reduced pressure and the residue is taken from EtOAc. The remaining solid was filtered and dried in air to give 103 mg (yield: 85%) of title compound.

LRMS(m/z): 534(M+1) ⁺

Preparation 94

5-(5-Amino-6-methoxypyridin-3-yl) -N -( (S) -1-(4-((2 R ,6 S )-2,6-dimethylmorpholinyl) -5-Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy) Methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (5-(5-Amino-6-methoxypyridin-3-yl)- N -(( S )-1-(4- ((2 R ,6 S )-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

100mg (0.16mmol) 5-bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrole [2,3- d ]pyrimidine-4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2 ,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4- Amine, 82 mg (0.33 mmol) of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine-3 -Amine (2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine), 14 mg (0.016 mmol) of PdCl ₂ dppf. DCM and 245 μl (0.49 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. The volatiles were removed and the crude was purified eluting elut elut elut elut elut elut

LRMS(m/z): 660(M+1) ⁺

Preparation 95

5- (2-Amino-4-yl) -N- ((S) -1- ( 4 - ((2 S, 6 R) -2,6- dimethyl-morpholinyl) pyrrolo [2, 1-f][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine (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- N -( (S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethyl) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4 amine (5-Bromo- N - (( S) -1- (4 - ((2 S, 6 R) -2,6-dimethylmorpholino) pyrrolo [2,1- f] [1,2,4] triazin- 2-yl) ethyl) -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine) (550mg, 0.91mmol) is placed in a sealed tube, In dimethoxyethane (11 ml) and water (1.1 ml) under a nitrogen atmosphere. Then add 4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-2-amine (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 PdCl ₂ dppf.CH ₂ Cl ₂ (40 mg, 0.05 mmol ) and the mixture was heated at 90 ° C overnight. The reaction mixture was cooled to room temperature, ethyl acetate was added, the resulting suspension was filtered through diatomaceous earth (Celite ^®). After evaporation, the crude product was purified by first flash chromatography (0% to 50% petroleum ether / ethyl acetate) and then purified by flash chromatography (0% to 5% DCM / methanol) To give 53 mg (yield 10%) 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 was added 2.46 g (16 mmol) of ethyl piperidine-4-carboxylate (available from Aldrich ^® , catalog number E3, 350-5). 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 diethyl ether. The organic layer was extracted with a 5% aqueous citric acid solution, and then aqueous extracts were basified to pH = 11 with 1M aqueous sodium hydroxide. The product was re-extracted with diethyl ether. EtOAc (EtOAc)

LRMS(m/z): 202(M+1) ⁺

Preparation 97

1-(2-((2-((4-amino-3-iodo-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 ethyl ester (Ethyl 1-(2-((2-((4-amino -3-iodo-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)

Add 540 mg (2.7 mmol) of ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylate to 90 mg (2.3 mg in 20 ml anhydrous THF) Methyl) a suspension of sodium hydride (60% dispersion in mineral oil). The mixture was stirred under a nitrogen atmosphere for 5 minutes, and 400 mg (0.9 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] in 10 ml of THF was added. Triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-Chloro-5-methylpyrrolo[2,1- A suspension of f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine). The resulting mixture was stirred at room temperature for 16 hours. Once the reaction was complete, the suspension was filtered and the solid was washed with THF. The filtrate contained the desired product and evaporated to give 350 mg (yield: 64%) of the title compound.

LRMS(m/z): 606(M+1) ⁺

Preparation 98

N - (4- (4 - ( ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [2,1 -f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ 2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide ( N- (4-(4-(( S ))-(4-(( 2S , 6R )-2, 6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H - Pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide)

76mg (0.12mmol) of 5-bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholin-yl) -5-methyl-pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrole [2,3- d ]pyrimidine-4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2 ,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4- Amine, 92 mg (0.31 mmol) of N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)phenyl)methanesulfonate Amine ( N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide) (available from Combi-blocks ^® , catalog number PN-2165), 30 mg (0.04 mmol) of PdCl ₂ dppf. 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 at 100 ° C for 24 hours under a nitrogen atmosphere. After adding excess equivalents of all reagents, the mixture was heated for an additional 24 hours. It was then allowed to cool to room temperature and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted with EtOAc. EtOAc was evaporated. The crude product was purified by flash chromatography eluting elut elut elut

LRMS(m/z): 707(M+1) ⁺

Preparation 99

(S) -1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl Ethylamine (( S )-1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine)

a) (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) ethyl) -carbamic acid (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4- (2,6-dimethylpyridin-4 -yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

512 mg (1.2 mmol) of (1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - (9H-fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [2,1- f] [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-dioxo Cyclopentane-2-yl)pyridine (2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) (purchased from Combi-blocks ^® , catalog number PN-5673), 95 mg (0.12 mmol) of PdCl ₂ dppf. DCM and 1.75 ml (3.5 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 8.5 ml of dioxin. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth (Celite ^®), the solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 585(M+1) ⁺

b) (S) -1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2 -yl)ethylamine (( S )-1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Ethanamine)

288 mg (0.56 mmol) of (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 2- yl) ethyl) carbamate (S) - (9H- fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4- (2,6 -dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate) and 2.45 ml (28 mmol) of morpholine dissolved in 5 ml of dioxane Stir in the mixture and stir at reflux temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated, the organic phase was washed with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj the mixture fluorene (9-methylene-9 H -fluorene ) - a group -9 H. The crude product was used in the next step without further purification.

LRMS(m/z): 282(M+1) ⁺

Preparation 100

(S) -5-Bromo- N- (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4 Triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (( S )-5-Bromo- N- (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2- Yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -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- f ][1,2,4 Triazin-2-yl)ethylamine (( S )-1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin -2-yl)ethanamine) (see Preparation 99b), 117 mg (0.32 mmol) of 5-bromo-4-chloro-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidine (5-Bromo-4-chloro -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidine), 9.8mg (0.06 mmol) of cesium fluoride and 254 μg (1.46 mmol) of DIEA were dissolved in 3 ml of third butanol and stirred at 130 ° C in a closed vessel overnight. The volatiles were removed under reduced pressure, the residue was partitioned between water and ethyl acetate, and the aqueous phase was basified with saturated sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 609(M+1) ⁺

Preparation 101

(S) - N -(3-(4-((1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides ((S) - N - ( 3- (4 - ((1- (4- (2,6-Dimethylpyridin-4-yl) -5 -methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

83 mg (0.13 mmol) of (S) -5-bromo- N- (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d Pyrimidine-4-amine (( S )-5-Bromo- N- (1-(4-(2,6-dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2, 4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine), 126 mg (0.31 mmol) of N -(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl)methanesulfonamide ( N- (3) -Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide), 31 mg (0.04 mmol) of PdCl ₂ dppf. 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 at 100 ° C for 24 hours under a nitrogen atmosphere. It was then cooled to room temperature and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted with EtOAc. EtOAc was evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut eluting eluting

LRMS(m/z): 714(M+1) ⁺

Preparation 102

3-(2-(1-Aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (S) -Methyl ester(( S )-Methyl 3-(2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

260 mg (0.45 mmol) of (1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - (9H-fluorene-9-yl) methyl ester ((S) - (9 H -Fluoren-9-yl) methyl (1- (4-chloro-5-methylpyrrolo [2,1- f] [1,2, 4]triazin-2-yl)ethyl)carbamate), 250 mg (0.91 mmol) of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentyl boron 2-yl) benzoic acid methyl ester (methyl 3-methyl-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate) ( commercially available from Combi-blocks ^® , catalog number PN-5549), 37 mg (0.05 mmol) of PdCl ₂ dppf. DCM and 680 μl (1.4 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C under a nitrogen atmosphere overnight. The solvent was removed under reduced pressure, the residue was purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1) as a red liquid bank [with 0.1% v / v formic acid buffered ] 0 to 100%) and purification to give 24 mg of (10% yield) of 3 (2- (1 - (( ((9 H - fluorenyl-9-yl) methoxy) carbonyl) amino) ethyl -5-Methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid ( S )-methyl ester (( S )-methyl 3- (2- (1 - ((( (9 H -fluoren-9-yl) methoxy) carbonyl) amino) ethyl) -5-methylpyrrolo [2,1- f] [1,2,4] triazin-4-yl )-5-methylbenzoate)

LRMS(m/z): 547(M+1) ⁺

And 132 mg (yield 90%) of the title compound.

LRMS(m/z): 325(M+1) ⁺

Preparation 103

(S) -3-(2-(1-(5-bromo-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d Pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (( S -3(2-(1-(5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid)

a) 3- (2- (1 - ((5- bromo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidine 4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (S) -A ester ((S) -Methyl 3- (2- (1 - ((5-bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-4- Yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

93 mg (0.29 mmol) of 3-(2-(1-aminoethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-A acid (S) - ester ((S) -Methyl 3- (2- (1-aminoethyl) -5-methylpyrrolo [2,1- f] [1,2,4] triazin-4-yl) - 5-methylbenzoate), 209 mg (0.57 mmol) of 5-bromo-4-chloro-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidine (5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine), 17.5 mg (0.12 mmol) of cesium fluoride And 451 μg (2.58 mmol) of DIEA was dissolved in 3 ml of third butanol and stirred at 100 ° C for 40 hours. The volatiles were removed under reduced pressure. EtOAc m.

LRMS(m/z): 650,652 (M+1) ⁺

b) (S) -3- (2- (1 - ((5- bromo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3 - d ] pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid ( ( S )-3-(2-(1-((5-Bromo-7)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-yl)amino )ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid)

119mg (0.18mmol) 3- (2- (1 - ((5-bromo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3 - d ] pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid ( S) - Methyl ester (( S )-Methyl 3-(2-(1-((5-bromo-7)-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ] Pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate) was dissolved in 5 ml of THF and added to 732 μl ( 0.73 mmol) of 1 M aqueous lithium hydroxide solution. The resulting solution was stirred at room temperature overnight. An additional 730 μl (0.73 mmol) of 1 M aqueous lithium hydroxide solution was added, and the mixture was stirred for 24 hours or more. Then, the diluted hydrochloric acid was added, the product was extracted with ethyl acetate.

LRMS (m/z): 634 (M-1) ^-

Preparation 104

(S) -3-(2-(1-(5-bromo-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidin-4-yl) amino) ethyl) -5-methyl-pyrrolo [2,1- f] [1,2,4] triazin-4-yl) - N - (2- hydroxyethyl) -5-Methylbenzamide (( S )-3-(2-(1-((5)-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -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)

109mg (0.17mmol) of (S) -3- (2- (1 - ((5- bromo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d ]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5- acid ((S) -3- (2- ( 1 - ((5-Bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-4 -yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid), 12 μl (0.20 mmol) of 2-aminoethanol, 39 mg (0.20 mmol) of EDC.HCl, 31 mg (0.20 mmol) of butanol and 59 μl (0.42 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane 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 a further 16 hours, then treated with aqueous sodium bicarbonate solution, the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated. 96 mg (yield 83%) of the title compound was isolated which was pure enough to be used directly in the next step without any additional purification steps.

LRMS(m/z): 679(M+1) ⁺

Preparation 105

(S) -3-(2-(1-((5-(5-Amino-6-methoxypyridin-3-yl)-7-((2-(trimethyldecyl)ethoxy)) Methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine 4-yl) - N - (2- hydroxyethyl) -5-methyl-benzoyl amine ((S) -3- (2- ( 1 - ((5- (5-Amino-6-methoxypyridin- 3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -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)

90mg (0.13mmol) of (S) -3- (2- (1 - ((5- bromo-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d ]pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl) -N- ( 2-(hydroxyethyl)-5-methylbenzimidamide (( S )-3-(2-(1-((5-Bromo-7)((2-(trimethylsilyl)ethoxy)methyl)-7 H ) -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), 66 mg (0.26 mmol) of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane-2-yl Pyridin-3-amine (2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine), 11 mg (0.013 mmol) of PdCl ₂ dppf. DCM and 200 μl (0.40 mmol) of a 2 M aqueous solution of cesium carbonate were stirred at 100 ° C overnight in 10 ml of dioxane in argon atmosphere. The volatiles were removed under reduced pressure and the crude title was purified eluting eluting eluting eluting

LRMS(m/z): 724(M+1) ⁺

Preparation 106

3-((Methylamino)methyl)phenol (3-((Methylamino)methyl)phenol)

1.0 g (8.2 mmol) of 3-hydroxybenzaldehyde (purchased from Aldrich ^® , catalog number H19808) and 1.15 ml of 33% methylamine solution in ethanol (marketed by Fluka ^® , catalog number 65590) Mix and stir at room temperature overnight. The volatiles were removed under reduced pressure and the residue was taken up in 5 ml of ethanol and cooled in ice. 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 phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. 950 mg (yield 84%) of the title compound was obtained.

LRMS(m/z): 138(M+1) ⁺

Preparation 107

2-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)propionic acid (2-(4-Amino-3-iodo-1 H -pyrazolo[3] ,4- d ]pyrimidin-1-yl)propanoic acid)

a) Ethyl 2-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)propanoate (Ethyl 2-(4-amino-3-iodo-1) H -pyrazolo[3,4- d ]pyrimidin-1-yl)propanoate)

2.0 g (7.7 mmol) of 3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (available from Ark Pharm ^® , catalog number AK-32203) and 1.1 g (8.1 mmol) 2-chloro-propionic acid (R) - ethyl ((R) -ethyl 2-chloropropanoate ) ( available from Santai Labs ^®, Cat. No. ADH-2600) was dissolved in 120ml of DMF. 2.1 g (15.3 mmol) of potassium carbonate was 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 taken from water, filtered, washed, washed with water and dried in air stream and then dried at 50 ° C for 2 hours in a vacuum oven. 2.8 g (100% yield) of the title compound are obtained as a racemic mixture of 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 (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- d ]pyrimidin-1-yl)propanoate (Ethyl 2-(4) -amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)propanoate) was 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 crystallised with 2M hydrochloric acid The product was filtered, washed with water and dried first in a stream of air then dried at 50 ° C in a vacuum oven. 1.03 g (yield 79%) of the title compound was obtained.

LRMS(m/z): 332(M+1) ⁺

Preparation 108

1-(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-3-iodo-1 H -pyrazole And [3,4- d ]pyrimidin-4-amine (1-(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)- 3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

a) 1- (2- (4- amino-3-iodo -1 H - pyrazolo [3,4- d] pyrimidin-1-yl) propylamino) - N - (2,4- dimethoxyphenyl Benzyl)-3-methyl-1 H -pyrrole-2-carboxyguanamine (1-(2-(4-Amino-3-iodo-1 H -pyrazolo[3,4-d]pyrimidin-1-yl )propanamido)- N -(2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide)

210 mg (0.67 mmol) of 1-amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-Amino- N- (2, 4-dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide), 267 mg (0.80 mmol) of 2-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidine -1-yl)propionic acid (2-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)propanoic acid), 134 mg (1.1 mmol) of EDC.HCl and 95 mg (1.1 mmol) of butanol was suspended in 4 ml of DMF and stirred at 50 ° C overnight. The mixture was diluted with ethyl acetate. EtOAc (EtOAc)EtOAc. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 110 mg (yield 25%) of the title compound.

LRMS(m/z): 605(M+1) ⁺

b) 2-(1-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one (2-(1-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl )ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

310mg (0.51mmol) of 1- (2- (4-amino-3-iodo -1 H - pyrazolo [3,4- d] pyrimidin-1-yl) propylamino) - N - (2,4- Dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-(2-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin -1-yl) propanamido) - N - (2,4-dimethoxybenzyl) -3-methyl-1 H -pyrrole-2-carboxamide) was suspended in 70ml of toluene. 194 mg (0.77 mmol) of PPTS was added and the resulting mixture was heated at 150 °C for 4 days using a Dean-Stark head to remove traces of water from the reaction mixture. The volatiles were then removed and the residue was taken up in ethyl acetate. EtOAc (EtOAc) The volatiles were removed and the residue was taken &lt 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 EtOAc EtOAc m.

LRMS(m/z): 437(M+1) ⁺

c) 1-(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-3-iodo-1 H - Pyrazolo[3,4- d ]pyrimidin-4-amine (1-(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl )-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine)

230 mg (0.53 mmol) of 2-(1-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)ethyl)-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-4(3 H )-one (2-(1-(4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin -1-yl)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) is suspended in 5 ml of phosphorus oxychloride and Heat at 80 ° C for 1 hour. The volatiles were removed under reduced pressure. The two layers were separated and the organic phase was washed with water and brine, dried over magnesium sulfate. 192 mg (yield 80%) of title compound as a brown solid.

LRMS(m/z): 455(M+1) ⁺

Preparation 109

1-(1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethyl) -3-iodo -1 H - pyrazolo [3,4- d] pyrimidin-4-amine (1- (1- (4 - ( (3 S, 5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazin-2-yl)ethyl)-3-iodo -1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-(1-(4-Chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2 -yl)ethyl)-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine) was suspended in 10 ml of acetone. Was added 117mg (0.63mmol) of (2 S, 6 R) -2,6- dimethyl-piperazine dihydrochloride ((2 S, 6 R) -2,6-dimethylpiperazine dihydrochloride) and 364μl (2.1mmol) of DIEA The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane / methanol. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 52 mg (yield: 23%)

LRMS(m/z): 533(M+1) ⁺

Preparation 110

4-(Sulfamoylamino)benzylamine (4-(Sulfamoylamino)benzylamine)

a) Tert -butyl 4-(sulfamoylaminobenzylbenzylcarbamate)

To the solution was added tert-butyl ester in 2ml of DMA, 196mg (0.88mmol) of 4-aminobenzyl carbamate (tert -butyl 4-aminobenzylcarbamate) (available from Aldrich ^®, Catalog No. 525626) was 204mg (1.76mmol) The amine sulfonium chloride was stirred and the resulting reaction mixture was stirred at room temperature for 64 hours. It was then diluted with ethyl acetate, washed with EtOAc EtOAc.

LRMS (m/z): 300 (M-1) ^-

b) 4-(Sulfamoylamino)benzylamine hydrochloride

80 mg (0.27 mmol) of Tert -butyl 4-(sulfamoylaminobenzylbenzylcarbamate) in 2 ml of 4M hydrochloric acid solution in dioxane Stir at room temperature for 90 minutes. The volatiles were removed under reduced pressure and the residue was taken in diethyl ether and stirring. The insoluble solid was filtered, washed with diethyl ether and dried to give 60 mg (yield 95%) of the title compound.

LRMS(m/z): 202(M+1) ⁺

Preparation 111

N - (3- (aminomethyl) -5-methoxy phenyl) methanesulfonamide Amides (N - (3- (Aminomethyl) -5-methoxyphenyl) methanesulfonamide)

a) 3-Amino-5-methoxybenzonitrile

In 5ml of anhydrous N - methyl-2-pyrrolidone (N -methyl-2-pyrrolidinone) of 500mg (2.47mmol) 3-bromo-5-cyano-methoxyaniline solution and 288mg (3.21mmol) of The cyanocopper was heated at 200 ° C overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (0% to 10%EtOAc)

LRMS(m/z): 149(M+1) ⁺

b) N - (3- cyano-5-methoxyphenyl) methanesulfonamide Amides (N - (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 μl (3.6 mmol) of methanesulfonium chloride was added, and the solution was stirred at room temperature overnight. The mixture was then diluted with EtOAc EtOAc EtOAc EtOAc.

LRMS (m/z): 225 (M-1) ^-

c) N - (3- (aminomethyl) -5-methoxy phenyl) methanesulfonamide Amides (N - (3- (Aminomethyl) -5-methoxyphenyl) methanesulfonamide)

200mg (0.88mmol) of N - (3- cyano-5-methoxyphenyl) methanesulfonamide Amides (N - (3-Cyano- 5-methoxyphenyl) methanesulfonamide), 420mg (1.7mmol) of cobalt (II Chlorohexahydrate and 334 mg (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, the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v formic acid Purify by buffering from 0% to 100%) to give a solid which was taken up in dioxane and stirred at room temperature overnight. The remaining solid was filtered, and the solvent was removed from the filtrate under reduced pressure to give 73 mg (yield 35%) of the title compound.

LRMS(m/z): 231(M+1) ⁺

Preparation 112

N - (4- (aminomethyl) -2-methoxy phenyl) methanesulfonamide Amides (N - (4- (Aminomethyl) -2-methoxyphenyl) methanesulfonamide)

a) 4- amino-3-methoxybenzonitrile (4-Amino-3-methoxybenzonitrile ) in 4ml of anhydrous N - methyl-2-pyrrolidone (N -methyl-2-pyrrolidinone) of 400mg (2.0 A solution of mmol of 4-bromo-2-methoxyaniline was heated with 233 mg (2.6 mmol) of cyanocopper overnight at 150 °C. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (0% to 10%EtOAc)

LRMS(m/z): 149(M+1) ⁺

b) N - (4- cyano-2-methoxyphenyl) methanesulfonamide Amides (N - (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 μl (3.4 mmol) of methanesulfonium chloride was added, and the solution was stirred at room temperature overnight. The mixture was then diluted with EtOAc EtOAc EtOAc EtOAc.

LRMS (m/z): 225 (M-1) ^-

c) N - (4- (aminomethyl) -2-methoxy phenyl) methanesulfonamide Amides (N - (4- (Aminomethyl) -2-methoxyphenyl) methanesulfonamide)

100mg (0.44mmol) of N - (4- cyano-2-methoxyphenyl) methanesulfonamide Amides (N - (4-Cyano- 2-methoxyphenyl) methanesulfonamide), 210mg (0.88mmol) of cobalt (II Chlorohexahydrate 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, the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0% to Purified to give 60 mg (yield: 59%) of the title compound.

LRMS(m/z): 231(M+1) ⁺

Preparation 113

N - (3- (aminomethyl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- (Aminomethyl) -5-hydroxyphenyl) methanesulfonamide)

2.2 ml (2.2 mmol) of 1 M boron tribromide solution in dichloromethane was added dropwise to 100 mg (0.44 mmol) of N- (3-(aminomethyl) in 3 ml of dichloromethane cooled in an ice bath. a solution of N- (3-(Aminomethyl)-5-methoxyphenyl)methanesulfonamide). The resulting mixture was stirred overnight at room temperature and then volatiles were removed, the crude product was directly by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed under reduced pressure [in Purification was carried out to give 29 mg (yield: 31%) of the title compound.

LRMS(m/z): 217(M+1) ⁺

Preparation 114

2-Methyl-4-(4-methylpiperazin-1-yl)-6-(trimethylstannyl)pyrimidine (2-Methyl-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 ^® , 596728) was dissolved in 2 ml of third butanol and 819 μl was added. (7.4 mmol) of 1-methylpiperazine. The reaction mixture was stirred at 100 &lt;0&gt;C over EtOAc. The residue was taken up in ethyl acetate. EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc:

LRMS(m/z): 227(M+1) ⁺

b) 2-Methyl-4-(4-methylpiperazin-1-yl)-6-(trimethylstannyl)pyrimidine (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 (4-Chloro-2-methyl-6-(4-methylpiperazin-1-yl) Pyrimidine), 128 mg (0.1 mmol) of Pd(PPh ₃ ) ₄ and 457 μl (2.2 mmol) of 1,1,1,2,2,2-hexamethyldistanane (1,1,1,2,2 , 2-hexamethyldistannane) was stirred in a sealed tube at 5 ° C in THF under nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature, then filtered through diatomaceous earth (Celite ^®), to give 530mg of crude product which was used without further purification in the next step.

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 (available from Aldrich ^® , catalog number 716588), 124 mg (0.11) Ment) of Pd(PPh ₃ ) ₄ and 703 μl (3.4 mmol) of 1,1,1,2,2,2-hexamethyldistanane (1,1,1,2,2,2-hexamethyldistannane) The mixture was stirred under a nitrogen atmosphere in 5 ml of THF at 100 ° C for 24 hours. The reaction mixture was cooled to room temperature, then filtered through diatomaceous earth (Celite ^®), the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography eluting elut elut elut elut

LRMS(m/z): 316(M+1) ⁺

Preparation 116

(S) -2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid (( S )-2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino) )ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid)

a) 2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2, 4] Triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid (S) -methyl ester (( S )-Methyl 2-(2-(1-((6-amino-5-cyanopyrimidin-) 4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 (Methyl 6- Methyl-2-(trimethylstannyl)pyrimidine-4-carboxylate), 18 mg (0.02 mmol) of Pd(PPh ₃ ) ₄ and 15 mg (0.08 mmol) of copper (I) iodide were stirred at 2 ° C for 3 hours at 100 ° C. . The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (EtOAc: EtOAc: EtOAc: EtOAc)

LRMS(m/z): 445(M+1) ⁺

b) (S) -2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid (( S )-2-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl) )amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid)

35 mg (0.08 mmol) of 2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid (S) -methyl ester (( S )-Methyl 2-(2-(1-((6-amino-) 5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylate) Dissolved in 5 ml of methanol . 281 μl (0.56 mmol) of 2M aqueous sodium hydroxide solution was added, and the resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure. The aqueous solution was then acidified to pH = 3 and the product was extracted with dichloromethane. The combined organic phases were washed with EtOAcqqqqqqm

LRMS (m/z): 429 (M-1) ^-

Preparation 117

N- (3-hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)benzenesulfonate Amine ( N -(3-Hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide)

a) 3- bromo - N - (3- hydroxy-benzyl) -5-methyl-benzenesulfonamide Amides (3-Bromo- N - (3 -hydroxybenzyl) -5-methylbenzenesulfonamide)

500 mg (1.9 mmol) of 3-bromo-5-methylbenzene-1-sulfonyl chloride (available from Aster Astatech ^® , catalog number CL8741) was dissolved in 30 ml In chloroform. 520 μl (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. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 111 mg (yield: 17%) of title compound.

LRMS (m/z): 354,356 (M-1) ^-

b) N- (3-hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)benzene N -(3-Hydroxybenzyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide)

243mg (0.68mmol) 3-bromo - N - (3- hydroxy-benzyl) -5-methyl-benzenesulfonamide Amides (3-Bromo- N - (3 -hydroxybenzyl) -5-methylbenzenesulfonamide), 346mg (1.4mmol 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentane) (4,4 , 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, ₂ -dioxaborolane)), 56 mg (0.07 mmol) of PdCl ₂ dppf. DCM, 38 mg (0.07 mmol) of dppf and 201 mg (2.1 mmol) of potassium acetate were suspended in 10 ml of dioxane in a nitrogen atmosphere. The mixture was heated at 80 ° C overnight. The suspension was then diluted with ethyl acetate, filtered through diatomaceous earth (Celite ^®), the filtrate was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash chromatography (0% to 100% EtOAc/EtOAcEtOAcEtOAc .

LRMS(m/z): 404(M+1) ⁺

Preparation 118

N ¹ , N ¹ -dimethyl- N ² -(4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine ( N ¹ , N ¹ -Dimethyl- N ^2- (4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine)

a) 4-(4-Methylpiperazin-1-yl)benzaldehyde (4-(4-Methylpiperazin-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 at 100 ° C in 10 ml of water overnight. The reaction mixture was diluted with water and the product was extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate. 1.59 g (yield: 97%) of title compound.

LRMS(m/z): 205(M+1) ⁺

b) N ¹ , N ¹ -dimethyl- N ² -(4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine ( N ¹ , N ¹ -Dimethyl - N ² -(4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine)

1.59 g (7.8 mmol) of 4-(4-methylpiperazin-1-yl)benzaldehyde (4-(4-Methylpiperazin-1-yl)benzaldehyde) and 900 μl (8.2 mmol) of N ¹ , N ¹ - Dimethylethane-1,2-diamine ( N ¹ , N ¹ -dimethylethane-1,2-diamine) was stirred in 40 ml of methanol for 30 minutes. The volatiles were then removed under reduced pressure and the residue was taken up in 40 mL methanol. The resulting solution was cooled in an ice bath and 150 mg (4.0 mmol) sodium borohydride was 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 phase was washed with EtOAc (EtOAc m.

LRMS(m/z): 277(M+1) ⁺

Preparation 119

(S) -3-(1-aminoethyl)phenol (( S )-3-(1-Aminoethyl)phenol)

In 12.5ml dichloromethane 250mg (1.65mmol) of (S) -1- (3- methoxyphenyl) ethylamine ((S) -1- (3- methoxyphenyl) ethanamine) ( available from Aldrich ^® , catalog number 727199) The solution was cooled to -78°. 3.3 ml (3.3 mmol) of 1 M boron tribromide solution in dichloromethane was added dropwise, and the resulting reaction mixture was stirred at room temperature for 2 hr. 30 ml of methanol was added to quench the reaction, and then the volatiles were removed under reduced pressure. The title product was obtained as a white solid, which was used in the next step without further purification.

LRMS(m/z): 138(M+1) ⁺

Preparation 120

N , N -Dimethyl-1-(4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine ( N , N -Dimethyl-1-(4-(trimethylstannyl)pyridin- 2-yl)piperidin-4-amine)

a) 1- (4- bromo-2-yl) - N, N - dimethyl-4-amine (1- (4-Bromopyridin-2 -yl) - N, N -dimethylpiperidin-4-amine )

1.00 g (5.7 mmol) of 4-bromo-2-chloropyridine (available from Aldrich ^® , catalog number 646318), 874 μl (6.8 mmol) of N , N -dimethylpiperidin-4-amine and 2.36 g (17 mmol) Potassium carbonate was dissolved in 5 ml of DMSO and heated at 100 ° C overnight. The reaction mixture was poured into water and the product was extracted withEtOAc. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. 1.57 g (yield 92%) of the title compound as a pale yellow oil.

LRMS(m/z): 284,286(M+1) ⁺

b) N , N -Dimethyl-1-(4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine ( N , N -Dimethyl-1-(4-(trimethylstannyl)) Pyridin-2-yl)piperidin-4-amine)

300 mg (1.0 mmol) of 1-(4-bromopyridin-2-yl) -N , N -dimethylpiperidin-4-amine (1-(4-Bromopyridin-2-yl) -N , N- dimethylpiperidin -4-amine), 115 mg (0.10 mmol) of Pd(PPh ₃ ) ₄ and 411 μl (2.0 mmol) of 1,1,1,2,2,2-hexamethyldistanane (1,1,1, 2,2,2-hexamethyldistannane) was stirred in a sealed tube at 7.5 ml of THF at 100 ° C for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then filtered through diatomaceous earth (Celite ^®). The filtrate was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 50% Purified to give 152 mg (yield: 42%)

LRMS(m/z): 369(M+1) ⁺

Preparation 121

N , N , 2-trimethyl-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine- 2-yl)piperidin-4-yl)pyridin-4-amine ( N , N , 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)

a) 2-(1-(4-Bromopyridin-2-yl)piperidin-4-yl) -N , N ,6-trimethylpyridin-4-amine (2-(1-(4-Bromopyridin-) 2-yl)piperidin-4-yl)- N , N ,6-trimethylpyridin-4-amine)

96 mg (0.55 mmol) of 4-bromo-2-fluoropyridine (available from Aldrich ^® , catalog number 722421), 144 mg (0.65 mmol) of N , N , 2-trimethyl-6- in 0.5 ml of DMSO (piperidin-4-yl)pyridin-4-amine ( N , N , 2-trimethyl-6-(piperidin-4-yl)pyridin-4-amine) (available from Asinex ^® , catalog number 27288294) and 226 mg ( A mixture of 1.6 mmol of potassium carbonate 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 sulfate, filtered and evaporated. 131 mg (yield 64%) of the title product was obtained.

LRMS(m/z): 376(M+1) ⁺

b) N , N , 2-trimethyl-6-(1-(4-(4,4,5,5-tetramethyl-2,3,2-dioxacyclopentan-2-yl) Pyridin-2-yl)piperidin-4-yl)pyridin-4-amine ( N , N , 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) -N , N ,6-trimethylpyridin-4-amine (2-(1-( 4-Bromopyridin-2-yl)piperidin-4-yl)- N , N ,6-trimethylpyridin-4-amine), 150 mg (0.59 mmol) of 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentane) (4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane)), 15 mg (0.02 mmol) of PdCl ₂ dppf. DCM and 87 mg (0.9 mmol) of potassium acetate were suspended in 2.5 ml of dioxane in an argon atmosphere. The mixture was heated at 120 ° C for 20 minutes for 3 cycles, after each heating cycle, 15 mg of catalyst was added. Once the reaction was complete, the suspension was washed with water and the filtrate was diluted with DCM, filtered through diatomaceous earth (Celite ^®),. The product was extracted into the aqueous phase, the solution was injected directly into a reverse phase purification system (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / volume Ammonium formate buffering] 0% to 100%) to give 80 mg (yield 54%) of the title compound.

LRMS(m/z): 423(M+1) ⁺

Preparation 122

1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperazine (1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-) 2-yl)piperazine)

a) 1-(4-Bromo-6-methylpyridin-2-yl)-4-methylpiperazine (1-(4-Bromo-6-methylpyridin-2-yl)-4-methylpiperazine)

200 mg (0.97 mmol) of 4-bromo-2-chloro-6-methylpyridine (available from Combi-blocks ^® , catalog number PY-1965), 129 μl (1.2 mmol) of 1-methylpiperazine, 506 μl (2.9 Mmol) of DIEA and 147 mg (0.97 mmol) of cesium fluoride were suspended in 8 ml of third butanol and heated at 100 ° C overnight, then heated at 120 ° C for 4 hours, then heated at 130 ° C for more than 16 hours, and finally resistant The pressure-tight container was heated at 180 ° C for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS (m/z): 270,272 (M+1) ⁺

b) 1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperazine (1-Methyl-4-(6-methyl-4-(trimethylstaunnyl)) Pyridin-2-yl)piperazine)

47 mg (0.17 mmol) of 1-(4-bromo-6-methylpyridin-2-yl)-4-methylpiperazine (1-(4-Bromo-6-methylpyridin-2-yl)-4-methylpiperazine ), 20 mg (0.02 mmol) of Pd(PPh ₃ ) ₄ and 72 μl (0.35 mmol) of 1,1,1,2,2,2-hexamethyldistanane (1,1,1,2,2, 2-hexamethyldistannane) was stirred overnight in a sealed tube at 3O<0> C in THF under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then filtered through diatomaceous earth (Celite ^®). The solvent was removed, and the title compound was crystalljjjjjjjjj

LRMS(m/z): 355(M+1) ⁺

Preparation 123

5-bromo- N -( (S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1 - f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2, 3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl) -5-methylpyrrolo [ 2, 1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4 -amine)

170 mg (0.59 mmol) of (S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f] [1,2,4] triazin-2-yl) ethanamine ((S) -1- (4 - ((3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5- Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethanamine), 290 mg (0.80 mmol) of 5-bromo-4-chloro-7-((2-(trimethyldecyl)alkyl) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine (5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[ 2,3- d ]pyrimidine), 35 mg (0.23 mmol) of cesium fluoride and 0.91 ml (5 mmol) of DIEA were suspended in 10 ml of tert-butanol. The reaction mixture was stirred at 100 ° C for 24 hours. The volatiles were removed under reduced pressure. EtOAcqqqqqqqqq

LRMS(m/z): 615(M+1) ⁺

Preparation 124

5-(2-Aminopyridin-4-yl) -N -( (S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5 -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl) -7 H -pyrrolo[2,3- d ]pyrimidine-4-amine (5-(2-Aminopyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R) )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy) Methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

96 mg (0.16 mmol) of 5-bromo- N -( (S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2, 1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ]pyrimidin-4-amine), 60 mg (0.28 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine- 2-amine (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine) (available from Combi-blocks ^® , catalog number PN-0151), 12 mg (0.014 mmol) of PdCl ₂ dppf. DCM and 225 μl of a 2 M aqueous solution of cesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred at 100 ° C under argon for 16 hours. The solvent was removed and then directly, the crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 1:} 8) and purification to give 70 mg of (65% yield) of a white solid Title compound.

LRMS(m/z): 629(M+1) ⁺

Preparation 125

5- (6-amino-pyridin-3-yl) - N - ((S) -1- (4 - ((3 S, 5 R) -3,5- dimethyl-piperazin-1-yl) -5 -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl) -7 H -pyrrolo[2,3- d ]pyrimidine-4-amine (5-(6-Aminopyridin-3-yl)- N -(( S )-1-(4-((3 S ,5 R) )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy) Methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

40 mg (0.07 mmol) of 5-bromo- N -( (S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ]pyrimidin-4-amine), 36 mg (0.16 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine- 2-amine (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine) (purchased from Fluorochem ^® , catalog number 021607), 6 mg (0.007 mmol) ) PdCl ₂ dppf. DCM and 100 μl of a 2 M aqueous solution of cesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred at 100 ° C under argon for 16 hours. The solvent was removed and then directly, the crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 1:} 8) and purification to give 70 mg of (32% yield) of a white solid Title compound.

LRMS(m/z): 629(M+1) ⁺

Preparation 126

4-Chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine (4-Chloro-2-(methoxymethyl)-5-methylpyrrolo [2,1- f ][1,2,4]triazine)

a) N -(2,4-Dimethoxybenzyl)-1-(2-methoxyethenylamino)-3-methyl-1 H -pyrrole-2-carboxamide ( N -(2) ,4-Dimethoxybenzyl)-1-(2-methoxyacetamido)-3-methyl-1 H -pyrrole-2-carboxamide)

3.8 g (13 mmol) of 1-amino- N- (2,4-dimethoxybenzyl)-3-methyl-1 H -pyrrole-2-carboxamide (1-Amino- N- (2, 4-dimethoxybenzyl)-3-methyl-1 H- pyrrole-2-carboxamide) was dissolved in acetic acid and cooled in an ice bath. 1.3 ml (14.3 mmol) of 2-methoxyethonyl chloride was 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 dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc)

LRMS(m/z): 362(M+1) ⁺

b) 3-(2,4-Dimethoxybenzyl)-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 4(3 H )-keto(3-(2,4-Dimethoxybenzyl)-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one )

3.4 g (9.4 mmol) of N- (2,4-dimethoxybenzyl)-1-(2-methoxyethenylamino)-3-methyl-1 H -pyrrole-2-carboxamide ( N -(2,4-Dimethoxybenzyl)-1-(2-methoxyacetamido)-3-methyl-1 H- pyrrole-2-carboxamide) was suspended in 300 ml of toluene. 4.7 g (19 mmol) of PPTS was added and the resulting mixture was heated at 160 °C for 6 hours using a Dean-Stark head to remove traces of water from the reaction mixture. The volatiles were then removed and the residue was taken up in ethyl acetate then washed with water and brine. The volatiles were removed and the residue was taken up in ethyl acetate. The crude product was purified by flash chromatography eluting elut elut elut elut elut

LRMS(m/z): 344(M+1) ⁺

c) 2-(Methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2-(Methoxymethyl)-5 -methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one)

To 2.7 g (7.9 mmol) of 3-(2,4-dimethoxybenzyl)-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ] in TFA [1,2,4]triazin-4( 3H )-one (3-(2,4-Dimethoxybenzyl)-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4 ]triazin-4(3 H )-one) solution, 24 ml of anisole was added. The reaction mixture was stirred at 80 ° C for 9 hours. The solvent was then removed and the title compound was crystalljjjjjjjjjjjj

LRMS(m/z): 194(M+1) ⁺

d) 4-Chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine (4-Chloro-2-(methoxymethyl)-5 -methylpyrrolo[2,1- f ][1,2,4]triazine)

1.43 g (7.4 mmol) of 2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4( 3H )-one (2- (methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4(3 H )-one) suspended in 24 ml of phosphorus oxychloride and stirred at 80 ° C 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 sodium bicarbonate solution and the layers were separated. The organic solution was washed with water and brine, dried over magnesium sulfate.

LRMS(m/z): 212(M+1) ⁺

Preparation 127

Methyl 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate ( Methyl 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

315 mg (1.5 mmol) of 4-chloro-2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine (4-Chloro-2-( Methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine), 624 mg (2.3 mmol) of 3-methyl-5-(4,4,5,5-tetramethyl-1 Methyl 3,2-dioxocyclopentan-2-yl)benzoate (methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzoate) (purchased from Combi-blocks ^® , catalog number PN-5549), 93 mg (0.11 mmol) of PdCl ₂ dppf. DCM and 1.7 ml (3.4 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. The solvent was removed and the crude was purified EtOAc EtOAcjjjjjj

LRMS(m/z): 326(M+1) ⁺

Preparation 128

3-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]methyltriazin-4-yl)-5-methylbenzoate (Methyl 3-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

a) methyl 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate ( Methyl 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

291 mg (0.89 mmol) of 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-A Methyl 3-(2-(methoxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate) is dissolved in 10 ml of dichloromethane in. The solution was cooled at -78 ° C, then 2.7 ml (2.7 mmol) of 1M boron tribromide solution in dichloromethane was added dropwise. The reaction mixture was stirred at room temperature for 90 minutes and then quenched by the addition of methanol. The volatiles were removed under reduced pressure and the residue was taken up in 20 ml of methanol, and 600 &lt;RTIgt; The solution was stirred at room temperature overnight. The solvent was then removed and the residue was partitioned between ethyl acetate and sat. sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulfate. 228 mg (yield 82%) of the title compound was obtained.

LRMS(m/z): 312(M+1) ⁺

b) 3-methyl-5-(5-methyl-2-((methylsulfonyl)oxy)methyl)pyrrolo[2,1- f ][1,2,4]triazine Methyl 3-methyl-5-(5-methyl-2-((methylsulfonyl)oxy)methyl)pyrrolo[2,1- f ][1,2,4]triazin- 4-yl)benzoate)

To 77 mg (0.25 mmol) of 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl) in anhydrous DCM -5-methyl-methylbenzoate (Methyl 3-(2-(hydroxymethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate) 40 μl (0.28 mmol) of triethylamine and 20 μl of methanesulfonium chloride were added. The reaction mixture was stirred at room temperature for 2 hours. Excess reagent was then added and the mixture was stirred for a further 6 hours. The solution was washed with aq. EtOAc EtOAc.

LRMS(m/z): 390(M+1) ⁺

c) 3-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1 -f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid methyl ester (Methyl 3-(2-((4-amino-3-iodo-1 H -pyrazolo[3, 4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

83.7 mg (0.21 mmol) of 3-methyl-5-(5-methyl-2-((methylsulfonyl)oxy)methyl)pyrrolo[2,1- f ][1,2 ,4]Methyl 3-methyl-5-(5-methyl-2-((methylsulfonyl)oxy)methyl)pyrrolo[2,1- f ][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 dissolved In DMF. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the title compound was crystalljjjjjjjjjj

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- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (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-methylbenzoic acid)

98 mg (0.18 mmol) of 3-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole [2,1- f] [1,2,4] triazin-4-yl) -5-methyl-benzoic acid methyl ester (methyl 3- (2 - (( 4-amino-3-iodo-1 H - Pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate), 42 mg (0.27 mmol) (3-fluoro-5-hydroxyphenyl) boronic acid and 14.7 mg (0.27 mmol) of PdCl ₂ dppf. The DCM was dissolved in 5 ml of ethanol in a sealed reactor. 270 μl (0.54 mmol) of 2M aqueous cesium carbonate solution (0.27 ml, 0.54 mmol) were added, and then the mixture was evaporated from argon and stirred at 80 ° C overnight. The solvent was evaporated and the crude material was partitioned between water and ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid and the product precipitated when it was extracted with dichloromethane. The solid was filtered and dried <RTI ID=0.0>

LRMS(m/z): 523(M-1) ^-

The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to give the main product 3 (2-((4-amino-3(3-fluoro-5-hydroxyphenyl)-1 H -py) Zoxao[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5- Ethyl 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), which was isolated and purified as described in Example 171.

Preparation 130

2- (dimethylamino) - N - (3- hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ) sulfonic ethyl amine (2- (Dimethylamino) - N - (3-hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanesulfonamide)

a) N - (3- bromo-5-hydroxyphenyl) ethylene sulfonamide Amides (N - (3-Bromo- 5-hydroxyphenyl) ethenesulfonamide)

To 13 ml of dichloromethane cooled in an ice bath 465 mg (2.47 mmol) of 3-amino-5-bromophenol and 817 μl (8.2 mmol) of 4-methylmorpholine solution were added dropwise in 7 ml two 387 μl (3.7 mmol) of a solution of 2-chloroethanesulfonyl chloride in methyl chloride. 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 phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. 640 mg (purity: 63%, yield 60%) of crude material was obtained, which was used in the next step without any further purification.

LRMS (m/z): 278,280 (M+1) ⁺

b) N - (3- bromo-5-hydroxyphenyl) -2- (dimethylamino) ethane sulfonamide Amides (N - (3-Bromo- 5-hydroxyphenyl) -2- (dimethylamino) ethanesulfonamide)

The crude product isolated in the preparation of 130a was dissolved in 13 ml of methanol, and 2.9 ml of a 2M dimethylamine solution in tetrahydrofuran 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 phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. This gave 500 mg (yield: 83%, yield 88%) of crude material which was used in the next step without any further purification.

LRMS(m/z): 323,325(M+1) ⁺

c) 2- (dimethylamino) - N - (3- hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethane sulfonic Amides (2- (Dimethylamino) - N - (3-hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolah-2-yl) phenyl) ethanesulfonamide )

335 mg (1.0 mmol) of N- (3-bromo-5-hydroxyphenyl)-2-(dimethylamino)ethanesulfonamide ( N- (3-Bromo-5-hydroxyphenyl)-2-(dimethylamino) Ethylenesulfonamide), 791 mg (3.1 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxe) Pentaborane) (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)), 170 mg (0.21 mmol) PdCl ₂ dppf. DCM and 612 mg (6.2 mmol) of potassium acetate were suspended in 14 ml of dioxane in an argon atmosphere. The mixture was stirred at 100 ° C for 16 hours. The volatiles were removed and the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 200 mg (yield 69%) of title compound as a white solid.

LRMS(m/z): 371(M+1) ⁺

Preparation 131

2- (dimethylamino) - N - (3- (4 - (((S) -1- (4 - ((3 S, 5 R) -3,5- dimethyl-piperazin-1-yl -5-Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy) yl) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) ethane sulfonamide Amides (2- (Dimethylamino) - N - (3- (4 -((( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin -2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)ethanesulfonamide)

50 mg (0.08 mmol) of 5-bromo- N -( (S) -1-(4-(( 3S , 5R )-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d] pyrimidin-4-amine ), 100mg (0.27mmol) of 2- (dimethylamino) - N - (3- hydroxy-5- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) phenyl) ethyl amine sulfonylurea (2- (Dimethylamino) - N - (3-hydroxy-5- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide), 6 mg (0.007 mmol) of PdCl ₂ dppf. DCM and 100 μl of a 2 M aqueous solution of cesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred at 100 ° C for 16 hours under argon. The solvent was then removed and the crude was purified mpqqqqqqqqq

LRMS(m/z): 779(M+1) ⁺

Preparation 132

N ¹ -(4-(4-(Dimethylamino)piperidin-1-yl)benzyl) -N ² , N ² -dimethylethane-1,2-diamine ( N ¹ -(4) -(4-(Dimethylamino)piperidin-1-yl)benzyl)- N ² , N ² -dimethylethane-1,2-diamine)

a) 4-(4-(Dimethylamino)piperidin-1-yl)benzaldehyde (4-(4-(Dimethylamino)piperidin-1-yl)benzaldehyde)

The title compound was obtained according to the experimental procedure of Preparation 118a from 500 mg (4.0 mmol) of 4-fluorobenzaldehyde and 878 mg (6.9 mmol) of N , N - dimethyl-piperidine-4-amine ( Prepared by N , N- dimethylpiperidin-4-amine). 907 mg (yield: 97%) of title compound.

LRMS(m/z): 233(M+1) ⁺

b) N ¹ -(4-(4-(Dimethylamino)piperidin-1-yl)benzyl) -N ² , N ² -dimethylethane-1,2-diamine ( N ¹ - (4-(4-(Dimethylamino)piperidin-1-yl)benzyl)- N ² , N ² -dimethylethane-1,2-diamine)

The title compound was obtained according to the experimental procedure of Preparation 118b from 907 mg ( 3.9 mmol) of 4-(4-(dimethylamino)piperidin-1-yl)benzaldehyde (4-(4-(Dimethylamino)piperidin-1-yl)benzin 1-yl)benzaldehyde) and 451 μl (4.1 mmol) of N ¹ , N ¹ -dimethylethane-1,2-diamine ( N ¹ , N ¹ -dimethylethane-1,2-diamine) were prepared. This gave 1.18 g (yield: 99%) ofyield

LRMS(m/z): 305(M+1) ⁺

Preparation 133

N -( (S) -1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] Pyrimidine-4-amine ( N -(( S )-1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1 ,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

The by-products of the Suzuki reaction as described in Preparation 124, Preparation 125 and Preparation 131 gave the title compound. In some cases, the title compound is the major product of the reaction and is isolated from the crude product of the reaction during the purification of the desired product.

LRMS(m/z): 336(M+1) ⁺

Preparation 134

2-(4-(Dimethylamino)piperidin-1-yl)ethanol(2-(4-(Dimethylamino)piperidin-1-yl)ethanol)

400 mg (3.1 mmol) of N , N -dimethylpiperidine-4-amine ( N , N- dimethylpiperidine-4-amine) was dissolved in acetonitrile. 1.3 g (9.4 mmol) of potassium carbonate and 450 μl (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 a minimum amount of water and a few drops of 1 N NaOH were added to clearly reach an alkaline pH. The aqueous layer was extracted with EtOAc (EtOAc) EtOAc.

LRMS(m/z): 173(M+1) ⁺

Preparation 135

1-((4-(2-(4-(Dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-(2-(4-(Dimethylamino)piperidin)) -1-yl)ethoxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin -4-amine)

Add 45 mg (0.26 mmol) of 2-(4-(Dimethylamino)piperidin-1-yl)ethanol to 2 ml of anhydrous THF. A suspension of 10 mg (0.26 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred under a nitrogen atmosphere for 5 minutes, and 51 mg (0.12 mmol) of 1-((4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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). The resulting mixture was stirred at room temperature for 16 hours. Once the reaction was complete, the suspension was filtered and the solid was washed with THF. The filtrate contained the desired product, which was evaporated to give crystals (yield:

LRMS(m/z): 577(M+1) ⁺

Preparation 136

N- (4-(4-Methylpiperazin-1-yl)benzyl)-2-(pyrrol-1-yl)ethylamine ( N -(4-(4-Methylpiperazin-1-yl)benzyl)- 2-(pyrrolidin-1-yl)ethanamine)

The title compound was subjected to the experimental procedure described in Preparation 118b from 150 mg (0.68 mmol) of 4-(4-methylpiperazin-1-yl)benzaldehyde (4-(4-methylpiperazin-1-yl)benzaldehyde) and 90 μl (0.71 mmol) of 2-(pyrrolidin-1-yl)ethanamine (2-(pyrrolidin-1-yl)ethanamine) was prepared. 207 mg (yield: 100%) ofyield

LRMS(m/z): 303(M+1) ⁺

Preparation 137

N , N -Dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine ( N , N -Dimethyl-1-(6- Methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine)

a) 1-(4-Bromo-6-methylpyridin-2-yl) -N , N -dimethylpiperidin-4-amine (1-(4-Bromo-6-methylpyridin-2-yl)- N , N -dimethylpiperidin-4-amine)

250 mg (1.21 mmol) of 4-bromo-2-chloro-6-methylpyridine (purchased from Combi-blocks ^® , catalog number PY-1965), 186 mg (1.45) Methyl) N , N -dimethylpiperidin-4-amine ( N , N- dimethylpiperidin-4-amine), 633 μl (3.6 mmol) of DIEA and 184 mg (1.21 mmol) of cesium fluoride suspended in 10 ml of the third In butanol, it was heated at 180 ° C in a pressure-tight container overnight. An additional amount of reagent is required every 24 hours until no material remains (additional three times in a row). The solvent was then removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut

LRMS(m/z): 298,300 (M+1) ⁺

b) N , N -Dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine ( N , N -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) -N , N -dimethylpiperidin-4-amine (1-(4-Bromo-6-methylpyridin-2) -yl) -N , N- dimethylpiperidin-4-amine), 97 mg (0.08 mmol) of Pd(PPh ₃ ) ₄ and 346 μl (1.67 mmol) of 1,1,1,2,2,2-hexamethyldi The stannane (1,1,1,2,2,2-hexamethyldistannane) was stirred under a nitrogen atmosphere in a sealed tube of 36 ml of THF at 100 ° C overnight. The reaction mixture was cooled to room temperature, then filtered through (Celite ^®). The solvent was removed, and the title compound was crystalljjjjjjjjj

LRMS(m/z): 383(M+1) ⁺

Preparation 138

N , N -Dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-2-yl)per Acridine-4-amine ( N , N -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-bromopyridin-2-yl) -N , N -dimethylpiperidin-4-amine (1-(4-Bromopyridin-2-yl) -N , N- dimethylpiperidin -4-amine), 460 mg (1.8 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis (1,3,2-di Oxycyclopentane borane) (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)), 60 mg (0.07 mmol) ) PdCl ₂ dppf. DCM and 440 mg (4.5 mmol) of potassium acetate were suspended in 15 ml of dioxane in an argon atmosphere. The mixture was heated at 80 ° C for 16 hours. All reagents were added to more equivalents and the mixture was heated for an additional 4 hours at 80 °C. Once the reaction was complete, the suspension was diluted with diethyl ether, filtered through diatomaceous earth (Celite ^®) and the volatiles were removed. The residue was treated with hexanes and stirred vigorously for 1 hour. The remaining solid, which was mainly contained in the residue, was filtered, and the solvent was removed to give 490 mg (yield: 99%) 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) -N -( (S) -1-(4-(( 3S , 5R )-3) ,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-(2 - (alkyl trimethyl silicon) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5- (2- (4- (Dimethylamino ) piperidin-1-yl )pyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ] [1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

100 mg (0.16 mmol) of 5-bromo- N -( (S) -1-(4-(( 3S , 5R )-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ]pyrimidin-4-amine), 159 mg (0.48 mmol) of N , N -dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Cyclopentane-2-yl)pyridin-2-yl)piperidin-4-amine ( N , N -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 PdCl ₂ dppf. DCM and 400 μl of a 2 M aqueous solution of cesium carbonate were dissolved in 6 ml of dioxane. The mixture was stirred at 100 ° C under argon for 20 hours. The solvent was removed and then directly, the crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 1:} 8) and purified to give a solid which was dissolved in DCM line, and with The 1N aqueous sodium hydroxide solution was washed three times, and washed with water and brine. The organic solution was dried over magnesium sulfate, filtered and evaporated. Finally, the obtained solid by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) of Purification to give 50 mg (yield: 42%)

LRMS(m/z): 740(M+1) ⁺

Preparation 140

5-(2-(Dimethylamino)pyridin-4-yl) -N -( (S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazine-1 -yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy) Methyl)-7 H -pyrrolo[2,3- d ]pyrimin-4-amine (5-(2-(Dimethylamino)pyridin-4-yl)- N -(( S )-1-(4) -((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

100 mg (0.16 mmol) of 5-bromo- N -( (S) -1-(4-(( 3S , 5R )-3,5-dimethylpiperazin-1-yl)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5-Bromo- N - (( S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d ]pyrimidin-4-amine), 121 mg (0.48 mmol) of N , N -dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentyl boron Alkyl-2-ylpyridin-2-amine ( N , N- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine), 21 mg (0.025 mmol) of PdCl ₂ dppf. DCM and 410 μl of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C under argon for 18 hours. The solvent was then removed, the crude product was first purified directly by flash chromatography (0% to 10% DCM / methanol) and then purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / The acetonitrile was purified as a dying liquid [0% to 100% of a volume of vol.

LRMS(m/z): 657(M+1) ⁺

Preparation 141

1-(3-Aminopropyl) -N , N -dimethylpiperidin-4-amine (1-(3-Aminopropyl) -N , N- dimethylpiperidin-4-amine)

a) 3-(4-(Dimethylamino)piperidin-1-yl)propanenitrile (3-(4-(Dimethylamino)piperidin-1-yl)propanenitrile)

500 mg (3.9 mmol) of N , N -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 was added, and the reaction mixture was stirred at room temperature overnight and then placed at 50 ° C for 5 hours. The reaction mixture was passed through diatomaceous earth (Celite ^®) and filtered, and the volatiles were then evaporated under reduced pressure. 700 mg (100% yield) of the title compound are obtained.

LRMS(m/z): 182(M+1) ⁺

b) 1-(3-Aminopropyl) -N , N -dimethylpiperidin-4-amine (1-(3-Aminopropyl) -N , N- dimethylpiperidin-4-amine)

440 mg (11.6 mmol) of lithium aluminium hydride in 18 ml of anhydrous THF was degassed with nitrogen. 5 ml of anhydrous 700 mg (3.86 mmol) of 3-(4-(Dimethylamino)piperidin-1-yl)propanenitrile solution was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. To quench the reaction, water was added and 3ml 3ml of 2N sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 2 hours and then filtered through diatomaceous earth (Celite ^®) and the solvent removed. The residue was taken up in EtOAc (EtOAc)EtOAc.

LRMS(m/z): 186(M+1) ⁺

Preparation 142

1-(3-Aminopropyl) -N , N -dimethylpiperidin-4-amine (1-(3-Aminopropyl) -N , N- dimethylpiperidin-4-amine)

a) 3-((3-(Dimethylamino)propyl)(methyl)amino)propanenitrile (3-((3-(Dimethylamino)propyl)(methyl)amino)propahenitrile)

350 mg of (80% yield) of the title compound is prepared following the experimental procedure as described in 141a, a 300mg (2.6mmol) of ^{N 1, N 1, N 3} - trimethyl-1,3-diamine (N ¹ , N ¹ , N ³ -trimethylpropane-1,3-diamine) and 247 μl (2.84 mmol) of 3-bromopropanenitrile.

LRMS(m/z): 170(M+1) ⁺

b) N ¹ -(3-aminopropyl)- N ¹ , N ³ , N ³ -trimethylpropane-1,3-diamine ( N ¹ -(3-Aminopropyl)- N ¹ , N ³ , N ³ -trimethylpropane-1,3-diamine)

250 mg (yield 69%) of the title compound eluted from 350 mg (2.1 mmol) of 3-((3-(dimethylamino)propyl)(methyl)amino)propanonitrile as described in Preparation 141b. (3-((3-(Dimethylamino)propyl)(methyl)amino)propanenitrile)).

LRMS(m/z): 174(M+1) ⁺

Preparation 143

3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazine-4- yl) -5-methyl-benzoic acid (S) - ester ((S) -Methyl 3- (2- (1 - ((6-amino-5-cyanopyrimidin-4-yl) amino) ethyl) pyrrolo [2 ,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate)

(S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Benzonitrile ((S ) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][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 PdCl ₂ dppf were added. .CH ₂ Cl ₂ and 4.1 ml (8.2 mmol) of a 2 M solution of cesium carbonate. The mixture was subjected to three vacuum-argon cycles, followed by stirring at 100 ° C overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over sodium sulfate. The crude product was purified by flash chromatography eluting elut elut elut elut elut

LRMS(m/z): 429(M+1) ⁺

Preparation 144

(S) -4-amino-6-((1-(4-(4-carbamimido-3,5-dimethylphenyl)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-(4-formyl-3,5-dimethylphenyl)pyrrolo[2 , 1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

(S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Formonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][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), PdCl ₂ dppf. CH ₂ Cl ₂ (52 mg, 0.06 mmol) and 2M EtOAc (0.64 mL, 1.28 mmol). The mixture was subjected to three vacuum-argon cycles, followed by stirring at 100 ° C overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc:EtOAc

LRMS(m/z): 413(M+1) ⁺

Preparation 145

(1-(4-Actyloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -benzyl ester (( S )-Benzyl(1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

a) (1-((2-Aminomethyl)-1 H -pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamic acid (S) -benzyl ester (( S )- Benzyl(1-((2-carbamoyl-1 H -pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate)

The 10.4g (83mmol) 1-amino -1 H - pyrrole-2carboxamide (1-amino-1 H -pyrrole -2-carboxamide) were added to 100ml of dichloromethane and 19.4g in 100ml of DMF (86 mmol) of (S) -2 - (((benzyloxy) carbonyl) amino) propanoic acid ((S) -2 - (( (benzyloxy) carbonyl) amino) propanoic acid), 34.9g (91mmol) of HATU And a mixture of 16.3 ml (173 mmol) of DIEA. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjj .

LRMS(m/z): 331(M+1) ⁺

b) (1-(4-Sideoxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) - Benzyl ester (( S )-Benzyl(1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate)

Pyridinium p-toluenesulfonate (4.28 g, 17 mmol) was added to (1-((2-aminocarbamimidino-1 H -pyrrol-1-yl)amino) in anhydrous toluene (80 ml) -1- oxo-2-yl) carbamate (S) - benzyl ester ((S) -Benzyl (1 - ((2-carbamoyl-1 H -pyrrol-1-yl) amino) -1-oxopropan -2-yl)carbamate) (4.08 g, 12 mmol) and a stirred mixture of 4 Å molecular sieves (small amount). The resulting mixture was heated under reflux with Dean-Stark for 15 hours. The solvent was then removed under reduced pressure. The obtained solid was treated with water (100 ml) and then extracted three times with ethyl acetate (100 ml). The insoluble white solid was filtered off and dried in a vacuum oven at 50 ° C to give 1.93 g (yield 54%) of the title compound. The ethyl acetate extract was dried over sodium sulfate, filtered and solvent was evaporated to yield 1.92 g (yield: 53%) of white solid. Total amount: 3.85 g (quantitative yield).

LRMS(m/z): 313(M+1) ⁺

Preparation 146

5-bromo- N -( (S) -1-(4-(( 2S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2, 4] triazin-2-yl) ethyl) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4 amine (5-Bromo- N - (( S) -1- (4 - ((2 S, 6 R) -2,6-dimethylmorpholino) pyrrolo [2,1- f] [1,2,4] triazin- 2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

a)( (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2,4]triazine 2-yl) ethyl) carbamate (benzyl ((S) -1- ( 4 - ((2 S, 6 R) -2,6-dimethylmorpholino) pyrrolo [2,1- f] [1, 2,4]triazin-2-yl)ethyl)carbamate)

(1-(4-Actyloxy-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamic acid (S) -benzyl ester (( S )-Benzyl(1-(4-oxo-3,4-dihydropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)carbamate) (1.0g, 3.2mmol) And (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.7 g, 3.8 mmol) was dissolved in THF ( 100ml). The mixture is heated to preferably dissolve. When cooled to room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (1,8-diazabiciclo[5.4.0]undec-7-eno) was added, followed by a few minutes was added (2 R, 6 S) -2,6- dimethylmorpholine ((2 R, 6 S) -2,6-dimethylmorpholine) (0.75ml, 4.8mmol). The mixture was stirred at room temperature overnight. Tetrahydrofuran was concentrated under reduced pressure. Then ethyl acetate was added and the organic phase was washed sequentially with water and brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 410(M+1) ⁺

b) (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2,4]triazine- 2- yl) ethanamine ((S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) pyrrolo [2,1- f] [1,2,4] triazin-2- Yl)ethanamine)

( (S) -1-(4-((2 S ,6 R )-2,6-Dimethylmorpholinyl)pyrrolo[2,1- f ][1,2,4]triazine-2 - yl) ethyl) carbamate (benzyl ((S) -1- ( 4 - ((2 S, 6 R) -2,6-dimethylmorpholino) pyrrolo [2,1- f] [1,2, 4] Triazin-2-yl)ethyl)carbamate) (1.39 g, 3.3 mmol) and 10% by weight (130 mg) of palladium on carbon were degassed in ethanol (130 ml) and the hydrogen balloon was loaded. The reaction mixture was stirred at room temperature for 4 hours. The mixture was then filtered on a pad of celite. The solvent was removed to give 948 mg (yield: 100%)

LRMS(m/z): 276(M+1) ⁺

c) 5- bromo - N - ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholinyl) pyrrolo [2,1- f] [1, 2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine- 4-amine (5-Bromo- N -(( S )-1-(4-(( 2S ,6 R )-2,6-dimethylmorpholino)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine)

(S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)pyrrolo[2,1- f ][1,2,4]triazine-2- Ethylamine (( S )-1-(4-(( 2S ,6 R )-2,6-Dimethylmorpholino)pyrrolo[2,1- f ][1,2,4]triazin-2-yl) Ethanamine) (720 mg, 2.6 mmol), 5-bromo-4-chloro-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ] pyrimidine (5-Bromo-4-chloro -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidine) (1.42g, 3.9mmol), diisopropylethylamine Amine (3.2 ml, 17 mmol) and cesium 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 (100ml) and 4% aqueous NaHCO ₃ (50ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0% to 100% petroleum ether / ethyl acetate) to afford 976 mg (yield: 62%) as a yellow solid.

LRMS(m/z): 602,604(M+1) ⁺

Example 1

4-(((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazine- 4-(yl)oxy)methyl)piperidine-1-carboxylic acid (S)-t-butyl ester (( S )- Tert- butyl 4-(((2-(1-((6-amino-5) -cyanopyrimidin-4-yk)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy)methyl)piperidine-1-carboxylate)

239 mg (1.11 mmol) of tert -butyl 4-(hydroxymethyl)piperidine-1-carboxylate (available from Aldrich ^® , catalog number 556017) was added. To a 27 mg (0.68 mmol) sodium hydride suspension (60% dispersion in mineral oil) in 2 ml anhydrous THF. The mixture was stirred under a nitrogen atmosphere for 15 minutes, and 175 mg (0.56 mmol) of (S) -4-amino-6-((1-(4-chloropyrrolo[2,1- f ]] in 3 ml of THF was added. [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) solution. 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 crystalljjjjjjjjjjjjj The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 133 mg (yield: 49%) of white title product. Purity: 98.5%.

LRMS(m/z): 494(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.00 (s, 1H), 7.90 (dd, 1H), 7.39 (d, 1H), 7.32 (s, 2H), 6.80 (ddd, 2H), 5.35-5.22 (m, 1H), 4.48-4.24 (m, 2H), 4.05-3.86 (m, 2H), 2.84-2.56 (m, 2H), 1.97 (s, 1H), 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 (( 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 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-carboxylic acid (S)-t-butyl ester (( 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) The 6.3 ml of 4 M hydrogen chloride solution in the oxygen sputum was stirred for 3 hours until all the starting materials were consumed. The volatiles were then removed under reduced pressure and the residue was partitioned between sat. After a second extraction with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. 100 mg (yield 100%) of the title product as a white solid was isolated. Purity: 98.6%.

LRMS(m/z): 394(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.00 (s, 1H), 7.90 (dd, 1H), 7.48- 7.17 (m, 3H), 6.79 (ddd, 2H), 5.36-5.21 (m, 1H), 4.36 ( Ddd, 2H), 2.94 (d, 2H), 2.48-2.37 (m, 2H), 1.95-1.80 (m, 1H), 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-f][1,2,4 Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-((tetrahydro-2 H- pyran-4-yl))) Methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to the experimental procedure as described in Example 1 from 62 mg (0.20 mmol) of (S) -4-amino-6-((1-(4-chloropyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 46 mg (0.40 mmol) of (tetrahydro-2 H -pyran-4-yl)methanol ((tetrahydro-2 H - Prepared by pyran-4-yl)methanol). The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 %) was purified, and the purified by prep HPLC (Symmetry Prep ^® C ₁₈ column, from 45% B to 75% B in a / liquid mixing punch the bank B, 20 min gradient). This gave 2.0 mg (yield 3%) of title compound as 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-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)

45 mg (0.11 mmol) of (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-(piperidin-4-ylmethoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) was dissolved in dichloromethane (5 ml). 32 μl (0.23 mmol) of triethylamine was added and the solution was cooled in an ice bath. Then 10 μl (0.13 mmol) of methanesulfonium chloride was 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 dichloromethane. The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 99.4%.

LRMS(m/z): 472(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.67 (dd, 1H), 6.81 (dd, 1H), 6.74 (dd, 1H), 6.43 (d, 1H), 5.45-5.33 (m, 1H), 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-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)

45 mg (0.11 mmol) of (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-(piperidin-4-ylmethoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 21 mg (0.14 mmol) of sodium iodide, 13 μl (0.14 mmol) of 2-bromopropane and 38 mg (0.27 mmol) Potassium carbonate was suspended in acetonitrile (10 ml). The mixture was stirred at reflux temperature overnight. An excess of 400 μl of 2-bromopropane and 5 ml of acetone were added as a cosolvent, and the reaction mixture was further refluxed for 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 sulfate. The crude product containing the title product was obtained as a minor constituent, and by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% The volume/volume ammonium acetate buffer] 0% to 100%) was purified to give 4 mg (yield 8%) of white title compound. Purity: 79%.

LRMS(m/z): 436(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 7.99 (s, 1H), 7.90 (dd, 1H), 7.38 (d, 1H), 7.31 (s, 2H), 6.93-6.66 (m, 2H), 5.44-5.12 ( m, 1H), 3.54-3.37 (m, 2H), 2.76 (d, 2H), 2.65 (dd, 1H), 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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine -5-carbonitrile (( S )-4-Amino-6-((1-(4-isopropoxypyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile)

23 mg (yield 59%) of the title compound were obtained as a by-product in the experimental procedure described in Example 5. Purity: 96.2%.

LRMS(m/z): 339(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.00 (s, 1H), 7.88 (t, 1H), 7.39-7.24 (m, 2H), 6.79-6.74 (m, 2H), 5.61-5.43 (m, 1H), 5.35-5.18(m,1H), 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-f][1 , 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-((tetrahydro-2) H- pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to the experimental procedure as described in Example 1 from 310 mg (0.79 mmol) of (S) -4-amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f] ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 183 mg (1.58 mmol) of (tetrahydro-2 H -pyran-4-yl) Prepared by methanol ((tetrahydro-2 H -pyran-4-yl)methanol). The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (0% to 100%). Purity: 93.2%.

LRMS (m/z): 473,475 (M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 7.99 (s, 1H), 7.93 (d, 1H), 7.37 (s, 1H), 7.29 (s, 2H), 6.91 (d, 1H), 5.33-5.17 (m, 1H), 4.39 (tt, 2H), 3.87 (d, 2H), 2.12-1.97 (m, 1H), 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-f][1,2,4]triazin-5-carbonitrile (( S )-2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)) Ethyl)-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4) -((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 25mg ( 0.21 mmol) of zinc dinitrate and 12 mg (0.010 mmol) of Pd(PPh ₃ ) _{4 were} suspended in 2 ml of DMF. The mixture was stirred at 120 ° C under a nitrogen atmosphere overnight. The reaction mixture was partitioned between water and dichloromethane, and a small portion of methanol was added to separate the layers. The organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - Methanol was purified as a bankwash [buffered with 0.1% volume/volume ammonium formate] 0% to 100%). The product thus obtained was treated with diethyl ether and EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Purity: 95.8%.

LRMS(m/z): 420(M+1) ⁺

¹ H NMR (400 MHz, DMSO) δ 8.07 (d, 1H), 7.78 (s, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 7.30 (s, 2H), 5.42-5.24 (m, 1H), 4.55-4.37 (m, 2H), 3.87 (d, 2H), 2.13-1.98 (m, 1H), 1.72-1.61 (m, 2H), 1.57 (d, 3H), 1.46-1.26 (m, 2H)

Example 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 (( S )-4-Amino-6-((1-(5-methyl-4-((tetrahydro-) 2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4) -((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 155 μl ( 0.14 mmol) of 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborolane (2,4,6-trimethyl-1,3,5, 2,4,6-trioxatriborinane) (available from Aldrich ^® , catalog number 323136), 5.20 mg (0.006 mmol) of PdCl ₂ dppf. DCM and 53 mg (0.38 mmol) of potassium carbonate were suspended in 1.5 ml of 1,2-dimethoxyethane. The mixture was heated at 120 ° C for 30 minutes under microwave atmosphere using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane and the layers were separated. The organic solution was washed with water and brine, dried over magnesium sulfate. The crude product was first purified by flash chromatography (0% to 5% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - Methanol was purified as a spurt [0% to 100% of a volume of vol. Purity: 97.4%.

LRMS(m/z): 409(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.00 (s, 1H), 7.74 (d, 1H), 7.36-7.23 (m, 3H), 6.58 (d, 1H), 5.31-5.14 (m, 1H), 4.49- 4.23(m,2H), 3.87(d,2H), 2.42(s,3H),2.12-1.98(m,1H), 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-f][1,2,4]3 Pyridazin-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)

100 mg (0.25 mmol) of (S) -4-amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl) Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f ][1,2,4]triazin -2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 84 μl (0.76 mmol) of 1-methylpiperazine were dissolved in 5 ml of THF and stirred at 70 ° C for 1 hour (until the reaction was completed). The volatiles were removed under reduced pressure and the residue was dissolved in 2M hydrochloric acid. The solution was washed twice with dichloromethane and then basified with 8M sodium hydroxide. The product was extracted twice with aqueous dichloromethane. 79 mg (yield 68%) of the title product as a white solid was isolated. Purity: 98.8%.

LRMS(m/z): 457,459(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.02 (s, 1H), 7.82 (d, 1H), 7.30 (s, 2H), 7.16 (d, 1H), 6.88 (d, 1H), 5.28-5.07 (m, 1H), 3.76-3.52 (m, 4H), 2.48-2.42 (m, 4H), 2.21 (s, 3H), 1.50 (d, 3H)

Example 11

4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-bromopyrrolo[2,1-f][1,2,4] ( S )-T-butyl ester of triazin-4-yl)oxy)piperidine-1-carboxylic acid (( 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)

The title compound was subjected to the experimental procedure as described in Example 1, from 641 mg (1.63 mmol) of (S) -4-amino-6-((1-(5-bromo-4-chloropyrrolo[2,1- f] ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 984 mg (4.88 mmol) of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( tert- butyl 4-hydroxypiperidine-1-carboxylate) (available from Aldrich ^® , catalog number 495484). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 209 mg (yield: 23%) Purity: 95.7%.

LRMS(m/z): 558,560(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.20 (s, 1H), 7.57 (d, 1H), 6.74 (d, 1H), 6.29 (d, 1H), 5.73-5.59 (m, 1H), 5.40-5.31 ( m,1H), 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-f] [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-((( Tetrahydro-2 H -pyran-4-yl)methyl)amino)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound following the experimental procedure described in Example 10, a 26mg (0.066mmol) of (S) -4- amino-6 - ((l- (5-bromo-4-chloro-pyrrolo [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-bromo-4-chloropyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 12 μl (0.11 mmol) of (tetrahydro-2 H -pyran-4-yl) Prepared by (tetrahydro-2 H- pyran-4-yl)methanamine (purchased from Acros ^® , Cat. No. 38521). 11 mg (yield 64%) of title compound as white solid. Purity: 94.2%.

LRMS(m/z): 472,474(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.43 (d, 1H), 6.72 (t, 1H), 6.60 (d, 1H), 5.29 (s, 2H), 5.27-5.14 (m, 1H), 4.09-3.88 (m, 2H), 3.72-3.50 (m, 2H), 3.48-3.34 (m, 2H), 2.05-1.89 (m, 1H), 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-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)

The title compound was subjected to an experimental procedure as described in Example 9 from 40 mg (0.087 mmol) of (S)-4-amino-6-((1-(5-bromo-4-(4-methylpiperazine)-1 -yl)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) Prepared by 16 mg (0.13 mmol) of 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborolane. The crude product was first purified by reverse chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified, and then purified by preparative HPLC (Symmetry Prep ^® C18 column, mixing from 5% B to 40% B A/B burrow, 15 minute gradient) to give 7 mg (yield 20) %) 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-f][1,2,4]triazine-2- 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)

In the experimental procedure described in Example 13, as a by-product, 10 mg (yield 30%) of the title compound was obtained. Purity: 99.1%.

LRMS(m/z): 379(M+1) ⁺

Example 15

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-carboxylic acid (S) - tert-butyl ester ((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)

The title compound was subjected to the experimental procedure described in Example 9 from 70 mg (0.13 mmol) of 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-carboxylic acid (S)-t-butyl ester (( 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) and 53 μl (0.38 mmol) of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane And prepared. 54 mg (yield 87%) of title compound Purity: 100%.

LRMS(m/z): 494(M+1) ⁺

Example 16

(S)-4-amino-6-((1-(5-methyl-4-(piperidin-4-yloxy)pyrrolo[2,1-f][1,2,4]triazine -2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

The title compound was subjected to the experimental procedure as described in Example 2 from &lt;RTI ID=0.0&gt; -5-Methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)piperidine-1-carboxylic acid (S)-t-butyl ester (( S ) - Tert- butyl 4-((2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin Prepared by -4-yl)oxy)piperidine-1-carboxylate). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol [unbuffered] as a red liquid bank 0 to 100%) and purified to give 52mg ( Yield 54%) of the title compound 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-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[2,1- f ][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-f][1, 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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), 21 mg (0.14 mmol) of sodium iodide, 26 μl (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 at 140 ° C for 2 hours using microwave irradiation. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol [unbuffered] as a red liquid bank 0 to 100%) and purified to give 22mg ( Yield 74%) of the title compound as a white solid. Purity: 98.1%.

LRMS(m/z): 436(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.01 (s, 1H), 7.74 (d, 1H), 7.30 (s, 2H), 7.22 (d, 1H), 6.58 (d, 1H), 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-f][1,2 ,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol (( 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)

55 mg (0.11 mmol) of (S) -5-iodo- N ⁴ -(1-(5-methyl-4-(4-methylpiperazin-1-yl)pyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine (( S )-5-Iodo- N ⁴ -(1-(5-methyl-4-(4-methylpiperazin) -1-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine), 26 mg (0.17 mmol) of 3-fluoro-5- (3-fluoro-5-hydroxyphenyl) boronic acid (purchased from Combi-blocks ^® , catalog number BB-2773) and 10.0 mg (0.011 mmol) of PdCl ₂ dppf. The DCM was suspended in 5 ml of dioxane. 167 μl (0.33 mmol) of 2M aqueous sodium carbonate solution was added, and the reaction mixture was stirred at 100 ° C under argon overnight. Another equivalent of boric acid and catalyst was added and the reaction was maintained at 100 ° C until the starting material was consumed. The solvent was then removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The two layers were separated, the organic solution was washed with water and brine, dried over magnesium sulfate. The crude product was first purified by flash chromatography (3% to 10% DCM / methanol) and then by a preparative HPLC (Symmetry Prep ^® C ₁₈ column, from 5% B to 44% B in A / The mixture was purified by EtOAc (EtOAc) eluting 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- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol (( S )-3-(4-Amino-6-((1- (5-methyl-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5 -yl)-5-fluorophenol)

The title compound was subjected to the experimental procedure as described in Example 18 from 135 mg (0.27 mmol) of (S) -5-iodo- N ⁴ -(1-(5-methyl-4-((tetrahydro-2 H - Pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)pyrimidine-4,6-diamine (( S )- 5-Iodo- N ⁴ -(1-(5-methyl-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1 - f ][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 by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 50 mg (yield: 38%) 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]triazine-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)

The title compound was subjected to 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- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 34 mg (2.03 mmol) of resorcinol were prepared. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 23 mg (yield: 38%) Purity: 98.5%.

LRMS(m/z): 403(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.61 (d, 1H), 7.32 (t, 1H), 6.98 (dd, 1H), 6.87 (dd, 1H), 6.77 (dd, 1H) , 6.60 (d, 1H), 6.25 (d, 1H), 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-f][1,2,4]3 Pyridazin-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)

a) ( S )-4-Amino-6-((1-(4-((3-((t-butyldimethyl)alkyl)oxy)benzyl)oxy)-5-methylpyrrole And [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4) -((3-(( tert- butyldimethylsilyl)oxy)benzyl)oxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile )

72 mg (0.30 mmol) of (3-(( tert- butyldimethylsilyl)oxy)phenyl)methanol) was added to 2 ml of anhydrous THF A suspension of 7 mg (0.18 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred under a nitrogen atmosphere for 30 minutes, and 50 mg (0.15 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 (( S )-4-Amino-6-((1-(4-chloro-) 5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile). The resulting mixture was stirred at room temperature for 3 hours until the starting material was consumed. The reaction mixture was partitioned between EtOAc EtOAc m. The crude product was purified by flash chromatography (0% to 100% hexanes / ethyl acetate) to afford 35 mg (yield 43%) of ( S )-4-amino-6- ((1-) 4-((3((t-butyldimethyl)alkyl)oxy)benzyl)oxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazine- 2-(ethyl)amino)pyrimidine-5-carbonitrile(( S )-4-amino-6-((1-(4-((3-(( tert )))))) 5-methylpyrrolo[2,1- f ][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-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)

35 mg (0.07 mmol) of ( S )-4-amino-6-((1-(4-(3-((tert-butyldimethyl)alkyl)oxy)benzyl)oxy)-5 -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-amino-6-(( 1-(4-(( tert- butyldimethylsilyl)oxy)benzyl)oxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine -5-carbonitrile was dissolved in 2 ml of anhydrous THF, and 73 μl (0.07 mmol) of tetrabutylammonium fluoride in THF was added. The mixture was stirred at room temperature for 2 hours and then partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 20 mg (yield: 73%) Purity: 99.5%.

LRMS(m/z): 417(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.52 (d, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 7.01 (s, 1H), 6.83 (dd, 1H) , 6.49 (d, 1H), 6.36 (d, 1H), 5.79 (d, 1H), 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-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)

In the experimental procedure of Example 21a, the title compound (14 mg) was obtained. Purity: 97.9%.

LRMS(m/z): 417(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.16 (s, 1H), 7.62 (d, 1H), 7.45 (t, 1H), 7.34 (d, 1H), 7.10 (dd, 1H), 6.61 (dd, 1H) , 6.01(d,1H), 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-f][1,2,4]triazine-2- 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)

50 mg (0.15 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 PdCl ₂ dppf. DCM and 48 mg (0.45 mmol) of sodium carbonate were suspended in 2 ml of dioxane. The mixture was stirred at 100 ° C under a nitrogen atmosphere overnight. An additional 32 mg of boric acid, 24 mg of palladium catalyst and 50 mg of sodium carbonate were added and the reaction was heated for an additional 24 hours until most of the starting material was consumed. The reaction mixture was then diluted with EtOAc EtOAc. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purification and purification by flash chromatography (0% to 10% EtOAc /MeOH) Purity: 98.9%.

LRMS(m/z): 387(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.80 (d, 1H), 7.36 (t, 1H), 7.28-7.27 (m, 1H), 7.22-7.14 (m, 1H), 7.02 ( Ddd, 1H), 6.97 (d, 1H), 6.79-6.71 (m, 1H), 5.53-5.38 (m, 1H), 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-f][1,2,4]triazine-2- 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)

50 mg (0.15 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 PdCl ₂ dppf. DCM and 228 μl (0.46 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 2 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. The reaction mixture was then diluted with EtOAc EtOAc. The crude product was first by reverse-phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as bank red liquid [with 0.1% v / v ammonium formate buffered] 0% to 100 Purification, and purification by flash chromatography (0% to 10% DCMMeOH) to afford 30 mg (yield: 51%) Purity: 99.7%.

LRMS(m/z): 387(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.78 (d, 1H), 7.59 (d, 2H), 6.94 (d, 2H), 6.72 (s, 1H), 6.66 (d, 1H) , 6.09 (s, 1H), 5.56-5.42 (m, 1H), 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-f][1,2,4]triazine- 2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1-((4-((tetrahydro-2)) H -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)

45 mg (0.088 mmol) 3-iodo-1-((4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((4-((tetrahydro-2 H- 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 Methyl) (3-fluoro-5-hydroxyphenyl) boronic acid, 3.6 mg (0.045 mmol) of PdCl ₂ dppf. DCM and 88 μl (0.18 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 100 ° C for 40 hours under an argon atmosphere. The reaction mixture was then diluted with EtOAc EtOAc. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 6 mg (yield: 14%) Purity: 97%.

LRMS(m/z): 491(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.20 (s, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 6.94-6.74 (m, 4H), 6.63 (d, 1H), 5.52 (s, 2H), 4.11 (d, 2H), 3.74 (d, 2H), 3.21-3.02 (m, 3H), 1.76 (s, 1H), 1.35 (d, 2H), 1.19-1.00 (m, 2H)

Example 26

(S)-4-amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl Amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-(3-hydroxyphenoxy)pyrrolo[2,1- f ][1,2,4]triazin-2 -yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to the experimental procedure as described in Example 20 from 45 mg (0.12 mmol) of (S) -4-amino-6-((1-(4-chloropyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 68 mg (0.62 mmol) of resorcinol. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 41 mg (yield: 82%) of the title compound. Purity: 96%.

LRMS(m/z): 389(M+1) ⁺

¹ H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 8. s (s, 1H), 7.94 (s, 1H), 7.37-7.16 (m, 4H), 6.92 (s, 1H), 6.89 (s, 1H), 6.71 (s, 1H), 6.69 (s, 2H), 5.24 - 5.01 (m, 1H), 1.46 (d, 3H)

Example 27

3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl) -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

The title compound was subjected to an experimental procedure as described in Example 25 from 50 mg (0.12 mmol) of 1-((4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl) Methyl)-3-iodo-1 H -pyrazolo[3,4-d]pyrimidin-4-amine (1-((4-Chloropyrrolo[2,1- f ][1,2,4]triazin- 2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4-d]pyrimidin-4-amine) and 75 mg (0.48 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid (3 -fluoro-5-hydroxyphenyl)boronic acid). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 9 mg (yield 19%) of the title compound. Purity: 100%.

LRMS(m/z): 487(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.35 (s, 1H), 10.20 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.33 (s, 1H), 7.24-7.16 (m, 2H), 7.11 (d, 1H), 6.96-6.77 (m, 4H), 6.65 (d, 1H), 5.74 (s, 2H)

Example 28

4-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazine- 2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-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)

45 mg (0.088 mmol) 3-iodo-1-((4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((4-((tetrahydro-2 H- 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 Methyl) (3-fluoro-4-hydroxyphenyl) boronic acid (available from Apollo Scientific ^® , catalog number PC1628), 3.6 mg (0.045 mmol) PdCl ₂ dppf. DCM and 7 mg (0.18 mmol) of sodium hydroxide were mixed together in 2 ml of DMF. The mixture was stirred at 120 ° C for 40 hours under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc EtOAc. The crude product was purified by prep HPLC (Symmetry Prep ^® C ₁₈ column, from A 40% B to 85% B / B of the bank were mixed punch 12 min gradient) to afford to give 1.8mg (yield 4% ) 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-f][1, 2,4]triazin-4-yl)-2-hydroxybenzamide (( 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)

The title compound was subjected to the experimental procedure as described in Example 24 from &lt; RTI ID=0.0&gt;&gt;&gt;&gt; f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 36 mg (0.20 mmol) of (4-aminoformamido-3-hydroxyphenyl) Prepared by boric acid ⁶ ((4-carbamoyl-3-hydroxyphenyl) boronic acid ⁶ ). The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (0% to 100%). Purity: 96.7%.

LRMS(m/z): 430(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 12.28 (s, 1H), 8.21 (s, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.17 (dd, 1H), 6.75 (d, 1H) , 6.56 (d, 1H), 5.57-5.45 (m, 1H), 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-f][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-(2-hydroxyphenyl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to the experimental procedure as 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 39 mg (0.20 mmol) of 2-(4,4,5,5-four Methyl-1,3,2-dioxaborolan-2-yl)phenol (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) Prepared from Aldrich ^® , catalog number 522554). After 2 h the reaction was complete, the crude product was isolated by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / Purification by volume of ammonium formate buffer [0% to 100%) afforded 18 mg (yield: 53%) of title compound. Purity: 100%.

LRMS(m/z): 387(M+1) ⁺

¹ H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8. s (s, 1H), 7.96 (d, 1H), 7.46-7.22 (m, 5H), 7.02-6.90 (m, 2H), 6.76 ( s, 1H), 5.45-5.27 (m, 1H), 1.94 (s, 3H), 1.57 (d, 3H)

Example 31

(S)-4-amino-6-((1-(4-(3-aminophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) was dissolved in 2 ml of dioxane. 50 mg (0.46 mmol) of 3-aminophenol and 137 μl (0.27 mmol) of 2M aqueous cesium carbonate solution were added, and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was partitioned between EtOAc EtOAc m. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 14 mg (yield: 37%) of the title compound. Purity: 96%.

LRMS(m/z): 402(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 7.95 (s, 1H), 7.85 (d, 1H), 7.36-7.16 (m, 3H), 7.03 (t, 1H), 6.68 (d, 1H), 6.49-6.43 ( m, 2H), 6.39 (d, 1H), 5.28 (s, 2H), 5.07 (m, 1H), 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 (( 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 subjected to the experimental procedure as 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 (( 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) Prepared by (3-hydroxy-5-(trifluoromethyl)phenyl) boronic acid (purchased from Combi-blocks ^® , Cat. No. BB-5075). After 2 h the reaction was complete, the crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v formic acid Purification by ammonium buffering, 0% to 100%). Purity: 100%.

LRMS(m/z): 455(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.62 (s, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 7.46 (d, 1H), 7.42-7.16 (m, 5H), 6.88 (s, 1H), 5.42-5.32 (m, 1H), 2.03 (s, 3H), 1.58 (d, 3H)

Example 33

(S)-4-amino-6-((1-(4-(3,5-dihydroxyphenoxy)-5-methylpyrrolo[2,1-f][1,2,4]3 Pyrazin-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)

The title compound was subjected to 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- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 57 mg (0.46 mmol) of benzene-1,3,5-triol were prepared. The reaction was stirred at room temperature and then refluxed until most of the starting material was consumed. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 17 mg (yield: 44%) of the title compound. Purity: 96%.

LRMS(m/z): 419(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 9.57 (s, 2H), 7.95 (s, 1H), 7.84 (d, 1H), 7.35-7.18 (m, 3H), 6.68 (s, 1H), 6.16 (s, 3H), 5.07 (s, 1H), 1.44 (d, 3H)

Example 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-methoxy-3-yl) methanesulfonamide Amides ((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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 72 mg (0.22 mmol) of N- (2-methoxy-5-(4,4,5,5-tetramethyl-1,3) , 2-dioxocyclopentan-2-yl)pyridin-3-yl)methanesulfonamide, 6.4 mg (0.01 mmol) of PdCl ₂ (PPh ₃ ) ₂ and 120 μl (0.22 mmol) of 2 M sodium carbonate aqueous solution Dissolved in 2 ml of 1,2-dimethoxyethane. The mixture was stirred at 70 ° C for 5 hours under a nitrogen atmosphere. The volatiles were removed under reduced pressure. EtOAc EtOAc m. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 9 mg (yield 20%) of the title compound. Purity: 95%.

LRMS(m/z): 495(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.16 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.68-7.38 (m, 2H), 7.30 (s, 1H), 6.85 (s, 1H), 5.44-5.28 (m, 1H), 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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

The title compound obtained as a by-product from the reaction described in Example 34 was isolated 5 mg (yield: 14%) purity: 96%.

LRMS(m/z): 403(M+1) ⁺

Example 36

(S)-4-amino-6-((1-(4-(5-hydroxypyridin-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine -2-yl)ethyl)amino)pyrimidine-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)

The title compound was subjected to the experimental procedure as described in Example 24 from 50 mg (0.15 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 42 mg (0.30 mmol) of (5-hydroxypyridin-3-yl)boronic acid) ((5-hydroxypyridin-3-yl)boronic acid) (purchased from Anichem ^® , catalog number NP2179). After 2 h the reaction was complete, the crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 8:} 1) and purified to give 24 mg of (41% yield) of The title compound is a pale yellow solid. Purity: 97.7%.

LRMS(m/z): 388(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.38 (s, 1H), 8.36-8.24 (m, 2H), 8.07 (d, 1H), 8.00 (s, 1H), 7.49-7.38 (m, 2H), 7.30 ( s, 2H), 6.88 (d, 1H), 5.45-5.29 (m, 1H), 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 (( 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 subjected to 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- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 76 mg (0.54 mmol) of 5(hydroxymethyl)benzene-1,3-di Prepared by an alcohol (5-(hydroxymethyl)benzene-1,3-diol). The reaction was stirred at room temperature and then refluxed until most of the starting material was consumed. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (1% to vol.). Purity: 100%.

LRMS(m/z): 433(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.16 (s, 1H), 7.61 (d, 1H), 6.88 (s, 1H), 6.80-6.70 (m, 2H), 6.59 (dd, 1H), 6.15 (d, 1H), 5.55 (s, 2H), 5.38-5.22 (m, 1H), 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 -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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 82 mg (0.45 mmol) of 3-((2-(dimethylamino)ethyl)amino)phenol ⁴ (3-((2-) Dimethylamino)ethyl)amino)phenol ⁴ ) and 25 mg (0.18 mmol) of potassium carbonate were stirred in 2 ml of 3,3-dimethylbutan-2-one (3,3-dimethylbutan-2-one) at reflux temperature for 2 hours. . The reaction mixture was partitioned between water and ethyl acetate. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (2% to vol.). Purity: 100%.

LRMS(m/z): 473(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.15 (s, 1H), 7.61 (d, 1H), 7.23 (t, 1H), 6.61-6.52 (m, 3H), 6.47 (t, 1H), 6.19 (d, 1H), 5.46 (s, 2H), 5.33-5.19 (m, 1H), 4.48 (s, 1H), 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 -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[2,1- 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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 82 mg (0.45 mmol) of 3-((2-(dimethylamino)ethyl)amino)phenol ⁴ (3-((2-) Dimethylamino)ethyl)amino)phenol ⁴ ) was heated at 150 ° C for 20 minutes in 0.5 ml of acetone using microwave irradiation. The reaction mixture was partitioned between water and ethyl acetate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 20 mg (yield: 46%) Purity: 98.4%.

LRMS(m/z): 473(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.50 (d, 1H), 7.10 (t, 1H), 6.69 (s, 1H), 6.62 (d, 1H), 6.58 (d, 1H) , 6.53 (d, 1H), 6.28 (d, 1H), 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 (( 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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( 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 (3-(piperazin-1-ylmethyl)phenol) Dichlorohydrate (available from ChemBridge ^® , catalog number 4039846) and 38 μl (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. EtOAc (EtOAc)EtOAc. 35 mg (yield 79%) of the title compound as a white solid. Purity: 99.2%.

LRMS(m/z): 485(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 9.32 (s, 1H), 8.03 (s, 1H), 7.65 (d, 1H), 7.31 (s, 2H), 7.17-7.00 (m, 2H), 6.83-6.69 ( m, 2H), 6.64 (d, 1H), 6.54 (d, 1H), 5.24 - 4.97 (m, 1H), 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-hydroxyphenyl)-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)

The title compound was subjected to the experimental procedure as described in Example 24, from 70 mg (0.21 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 77 mg (0.44 mmol) of (3,5-difluoro-4-hydroxybenzene) Prepared by (3,5-difluoro-4-hydroxyphenyl) boronic acid (purchased from Combi-Blocks ^® , Cat. No. BB-1093). After 16 hours the reaction was complete, the crude product was first isolated by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / Purification by volume of ammonium formate buffer] 0% to 100%), then purified by flash chromatography (0% to 12% DCM/MeOH) to give 25 mg (yield: 28%) . Purity: 100%.

LRMS(m/z): 423(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.90 (s, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.45-7.39 (m, 3H), 7.31 (s, 1H), 6.86 (s, 1H), 5.41-5.28 (m, 1H), 2.13 (s, 3H), 1.57 (d, 3H)

Example 42

3-(4-Amino-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

94 mg (0.18 mmol) of 3-iodo-1-((4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]3 Pyrazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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) ( 3-fluoro-5-hydroxyphenyl) boronic acid, 30 mg (0.04 mmol) of PdCl ₂ dppf. DCM and 443 μl (0.89 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc EtOAc. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purification, and purification by flash chromatography (0% to EtOAc EtOAc) Purity: 99%.

LRMS(m/z): 517(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.19 (s, 1H), 8.25 (s, 1H), 7.63 (s, 1H), 6.91 (s, 1H), 6.84 (d, 1H), 6.65 (d, 1H) , 6.52 (s, 1H), 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]triazine -2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 in a closed vessel at 100 ° C for 16 hours. The volatiles were removed under reduced pressure, the residue was untreated first by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% by volume Purification by flash chromatography (0% to 100%), followed by flash chromatography (0% to 12% DCM/MeOH) to afford 17 mg (yield 46%) of . Purity: 100%.

LRMS(m/z): 402(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 9.43 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.61 (d, 1H), 7.41-7.03 (m, 6H), 6.60-6.40 ( m, 2H), 5.26-5.08 (m, 1H), 2.60 (s, 3H), 1.52 (d, 3H)

Example 44

(S)-4-amino-6-((1-(4-(3-fluoro-5-hydroxyphenyl)-5-methylpyrrolo[2,1-f][1,2,4]3 Pyrazin-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)

The title compound was subjected to the experimental procedure as 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 29 mg (0.18 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid ( (3-fluoro-5-hydroxyphenyl)boronic acid) (purchased from Combi-Blocks ^® , catalog number BB-2773). After 16 hours the reaction was complete and the crude product was purified by flash chromatography (0% to 16% DCM/MeOH) and then purified by reverse phase chromatography (C-18 cerium oxide from Waters ^® , water / 1:1 acetonitrile-methanol was purified as a dying solution [0% to 100% in 0.1% volume/volume ammonium acetate buffer) to give 2 mg (yield 5%) of the title compound. Purity: 89%.

LRMS(m/z): 405(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.38 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.44 (d, 1H), 7.31 (s, 2H), 6.95-6.83 (m, 3H), 6.79 (d, 1H), 5.45-5.27 (m, 1H), 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-f][1,2, 4]triazin-2-yl)methyl)-1H-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)

92 mg (0.18 mmol) of 3-iodo-1-((5-methyl-4-((tetrahydro-2 H -pyran-4-yl)methoxy)pyrrolo[2,1- f ][ 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-hydroxyl) Phenyl)boronic acid, 29 mg (0.04 mmol) of PdCl ₂ dppf. DCM and 441 μl (0.88 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc EtOAc. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purification, and purification by flash chromatography (0% to EtOAc EtOAc) Purity: 96%.

LRMS(m/z): 505(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.19 (s, 1H), 8.27 (s, 1H), 7.76 (s, 1H), 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, 1H), 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-f][1,2,4]triazine-2- Methyl)-1H-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]tri azin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-3-yl)-5- Fluorophenol)

The title compound following the experimental procedure described in Example 45 from 101mg (0.23mmol) 1 - ((4-chloro-5-methyl-pyrrolo [2,1- f] [1,2,4] triazine -2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (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) and 177 mg (1.14 mmol) of 3-fluoro-5 Prepared by (3-fluoro-5-hydroxyphenyl) boronic acid. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purification to give 18 mg (yield: 16%) Purity: 95.9%.

LRMS(m/z): 501(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.26 (s, 1H), 8.04 (d, 1H), 6.94-6.72 (m, 7H), 6.66 (d, 1H), 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-f][1 ,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

The title compound was subjected to the experimental procedure as described in Example 24 from &lt; RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 110 mg (0.61 mmol) of (4-methoxy-3,5-di) Prepared by (4-methoxy-3,5-dimethylphenyl) boronic acid (purchased from Aldrich ^® , catalog number 598062). After 16 hours the reaction was complete, the crude product was first isolated by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / Purification by volume of ammonium formate buffer] 0% to 100%), then purified by flash chromatography (0% to 16% DCM /MeOH) to afford 85 mg (yield 65%) of the title compound. Purity: 100%.

LRMS(m/z): 429(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.02 (s, 2H), 7.57-7.20 (m, 5H), 6.85 (s, 1H), 5.34 (s, 1H), 3.74 (s, 3H), 2.32 (s, 6H), 2.09 (s, 3H), 1.58 (d, 3H)

Example 48

3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2, 4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1-((4- ((2 S ,6 R )-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-tluorophenol)

The title compound was subjected to an experimental procedure as described in Example 45 from 102 mg (0.20 mmol) of 1-((4-(( 2S ,6 R )-2,6-dimethylmorpholine)-5-methyl. Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine ( 1-((4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3- Iodo-1 H- pyrazolo [3,4- d ]pyrimidin-4-amine) and 94 mg (0.39 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid were prepared. After 2 hours the completion of the reaction, the crude product was isolated by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / volume Purified by ammonium formate buffering] 0% to 100%). The product obtained after purification was recrystallized from hot isopropyl ether, and the precipitated white solid was filtered and dried in vacuo to give 25 mg (yield: 25%) of the title compound. Purity: 96.1%.

LRMS(m/z): 504(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.20 (s, 1H), 8.27 (s, 1H), 7.66 (d, 1H), 6.89 (s, 1H), 6.82 (d, 1H), 6.65 (d, 1H) , 6.54 (d, 1H), 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-f][1,2 ,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

60 mg (0.14 mmol) of (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 was dissolved in 2 ml of dichloromethane. 420 μl (0.42 mmol) of a commercially available 1 M boron tribromide solution in dichloromethane was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride. EtOAc (EtOAc m. 55 mg (yield 95%) of the pure product was isolated. Purity: 95%.

LRMS(m/z): 415(M+1) ⁺

¹ H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8. s (s, 1H), 7.78 (d, 1H), 7.43 - 7.27 (m, 4H), 6.82 (d, 1H), 5.36-5.26 ( m,1H), 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)-N-cyclopropyl-5-hydroxybenzamide (( 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)

The title compound was subjected to the experimental procedure as 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 115 mg (0.18 mmol) of N -cyclopropyl-3-hydroxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)benzamide ( N- Cyclopropyl-3-hydroxy-5-(4,4, Prepared by 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide). After 40 hours to complete the reaction, the crude product was isolated by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / volume Purification with ammonium formate buffer] 0% to 100%) gave 8 mg (yield: 18%) 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-methyl) Pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-( 4-((2-(dimethylamino)ethyl)(3-fluoro-5-methoxyphenyl)amino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino) Pyrimidine-5-carbonitrile)

The title compound following the experimental procedure of Example 39 from 100 mg (0.30 mmol) of (S) -4- amino-6 - ((1- (4-Chloro-5-methyl-pyrrolo [2,1- f] [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2 , 1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 129 mg (0.61 mmol) of N ¹ -(3-fluoro-5-methoxyphenyl) ) - N ^2, N ² - dimethyl-ethane-1,2-diamine ^{4 (N 1 - (3-} fluoro-5-methoxyphenyl) - N 2, N 2 -dimethylethane-1,2-diamine 4) And prepared. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purification to give 88 mg (yield: 57%) Purity: 100%.

LRMS(m/z): 505(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.39 (s, 2H), 8.21 (s, 1H), 7.57 (d, 1H), 6.79 (d, 1H), 6.53-6.34 (m, 4H), 5.57 (s, 2H), 5.46-5.33 (m, 1H), 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-morpholinylethyl)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-morpholinoethyl)amino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to 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 (( 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)phenol Prepared by ⁴ (3-((2-morpholinoethyl)amino)phenol ⁴ )). The reaction was completed after microwave irradiation at 150 ° C for 40 minutes and microwave irradiation at 160 ° C for 2 hours. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 16 mg (yield: 34%) Purity: 95.2%.

LRMS(m/z): 515(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.39 (s, 2H), 8.21 (s, 1H), 7.57 (d, 1H), 6.79 (d, 1H), 6.53-6.34 (m, 4H), 5.57 (s, 2H), 5.46-5.33 (m, 1H), 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)-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 (( 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)

The title compound was subjected to the experimental procedure as 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 73 mg (0.23 mmol) of N- (3-hydroxy-5-(4,4) ,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)phenyl)methanesulfonamide ( N- (3-Hydroxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide). The reaction was completed in 16 hours, and the isolated crude product was purified by flash chromatography (0% to 100% hexane/ethyl acetate) and then purified by reverse phase chromatography (C-18 Waters ^®, water / 1 from: 1 acetonitrile - methanol as punch bank liquid [with 0.1% v / v ammonium formate buffered] 0 to 100%) and purified to give 4mg (9% yield) of the title compound. Purity: 100%.

LRMS(m/z): 480(M+1) ⁺

^{1 H NMR (400MHz, CDCl3 /} MeOD) δ 8.30 (s, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 6.94-6.89 (m, 1H), 6.87 (t, 1H), 6.81- 6.76 (m, 1H), 6.68 (d, 1H), 5.47-5.28 (m, 1H), 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][1,2,4 Triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

27 mg (0.05 mmol) of 3-iodo-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-4-amine (3-Iodo-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-4-amine) , 15 mg (0.10 mmol) of (3-fluoro-5-hydroxyphenyl) boronic acid, 4 mg (0.01 mmol) of PdCl ₂ dppf. DCM and 74 μl (0.15 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere until the starting material was consumed. The reaction mixture was then diluted with ethyl acetate and extracted twice with 2M hydrochloric acid. The aqueous solution was adjusted to pH = 9 with 8M sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesium sulfate. The crude product is purified by prep HPLC (Symmetry Prep ^® C ₁₈ column, from 5% B to 60% B in A / liquid mixing punch the bank B, 20 min gradient). 8 mg (yield 31%) of title compound 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-f][ 1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1- ((4-((2-(dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H - Pyrazolo[3,4- d ]pyrimidin-3-yl)-5-fluorophenol)

The title compound was subjected to an experimental procedure as described in Example 45 from 50 mg (0.09 mmol) of 3-((2-((4-amino-3-iodo- 1H -pyrazolo[3,4- d ]] -1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)(2-(dimethylamino)ethyl)amino) It was prepared by phenol and 27 mg (0.17 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol [unbuffered] as a red liquid bank 0 to 100%) and purified to afford 8mg ( Yield 16%) of the title compound as a white solid. Purity: 96.5%.

LRMS(m/z): 569(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.19 (s, 1H), 9.50 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.66 (d, 1H), 7.10 (t, 1H) , 6.90 (s, 1H), 6.83 (d, 1H), 6.65 (d, 1H), 6.57 (d, 2H), 6.48 (s, 1H), 6.37 (s, 1H), 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-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-fluoro-5-hydroxyphenyl)amino)-5-methylpyrrolo[2,1- f ][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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6 -((1-(4-(dimethylamino)ethyl)(3-fluoro-5-methoxyphenyl)amino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2- Yl)ethyl)amino)pyrimidine-5-carbonitrile) was dissolved in 2 ml of dichloromethane. 464 μl (0.46 mmol) of a commercially available 1 M boron tribromide solution in dichloromethane was added, and the mixture was stirred at room temperature for 40 hours. The solid formed was filtered and washed with dichloromethane, and by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% Purification by volume/volume ammonium sulphate buffer [0% to 100%) gave 26 mg (yield: 34%) of title compound as 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)phenyl)-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-methylp yrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to the experimental procedure as 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][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-dioxacyclopentan-2-yl)phenol (2-(2-Hydroxypropan-2-yl)-4-( Prepared by 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol). After 16 hours the reaction was complete, the crude product was first purified by flash chromatography (0% to 16% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water /1:1 acetonitrile-methanol was purified as a dying solution [0% to 100% by volume of 0.1% by volume of ammonium formate) to give 10 mg (yield 25%) of the title compound. Purity: 100%.

LRMS(m/z): 445(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 9.35 (s, 1H), 8.21 (s, 1H), 7.77 (d, 1H), 7.54 (dd, 1H), 7.47 (d, 1H), 7.01 (t, 1H) , 6.75-6.64 (m, 2H), 5.56-5.40 (m, 1H), 5.26 (s, 2H), 2.58 (s, 1H), 2.18 (s, 3H), 1.75 (d, 6H), 1.65 (d , 3H)

Example 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-methoxy-3-yl) -4-methoxy-benzenesulfonamide Amides ((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-methoxybenzenesulfonami de)

The title compound was subjected to the experimental procedure as described in Example 24, from 70 mg (0.21 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), and 199 mg (0.43 mmol) of 4-methoxy- N- (2-A) Oxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridin-3-yl)benzenesulfonamide (4-Methoxy) - N - (2-methoxy- 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide) was prepared. After 16 hours the reaction was complete and the crude product isolated was purified by flash chromatography (0% to 16% DCM/MeOH) and then purified by reverse phase chromatography (C-18 cerium oxide from Waters ^® , water / 1:1 acetonitrile-methanol was purified as a dying solution [0% to 100% in 0.1% volume/volume ammonium acetate buffer) to give 48 mg (yield 36%) of the title compound. Purity: 94.8%.

LRMS(m/z): 588(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.19 (d, 2H), 8.03 (s, 1H), 7.86-7.72 (m, 3H), 7.26 (s, 1H), 7.09 (s, 1H), 6.93 (d, 2H), 6.74 (s, 1H), 6.43 (d, 1H), 5.57-5.46 (m, 1H), 5.41 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 2.15 (s) , 3H), 1.67(s, 3H)

Example 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-hydroxy-pyridin-3-yl) -4-methoxy-benzenesulfonamide Amides ((S) - N - ( 5- (2- (1- ((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrol o[2,1- f ][1,2,4]triazin-4-yl)-2-hydroxypyridin-3- Yl)-4-methoxybenzenesulfonamide)

45 mg (0.7 mmol) of (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-methoxy-3-yl) -4-methoxy-benzenesulfonamide Amides ((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) was dissolved in 1.5 ml of dichloromethane. 218 μl (0.22 mmol) of a commercially available 1 M boron tribromide solution in dichloromethane was added, and the mixture was stirred at room temperature overnight in a sealed vessel. The reaction mixture was diluted with methylene chloride. The obtained mixture was washed with sodium hydrogen sulfate, water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 91%.

LRMS(m/z): 573(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.23 (s, 1H), 7.92-7.74 (m, 4H), 7.67 (s, 1H), 6.91 (d, 2H), 6.77 (s, 1H), 6.66 (d, 1H), 5.77 (s, 2H), 5.47-5.33 (m, 1H), 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-f][1,2,4 Triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

The title compound was subjected to the experimental procedure as described in Example 24 from 90 mg (0.17 mmol) of 2-(4-(2-(4-amino-3-iodo-1 H -pyrazolo[3,4- d] Pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperazin-1-yl)ethanol (2-( 4-(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2, 4] triazin-4-yl) piperazin-1-yl)ethanol), and 79 mg (0.51 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid were prepared. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 30 mg (yield: 32%) Purity: 100%.

LRMS(m/z): 565(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.25 (s, 1H), 8.19 (s, 1H), 7.61 (d, 1H), 6.93-6.88 (m, 1H), 6.88-6.79 (m, 1H), 6.65 ( Dt, 1H), 6.54-6.49 (m, 1H), 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 (( 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 following the experimental procedure of Example 39 from 100 mg (0.30 mmol) of (S) -4- amino-6- (l- (4-chloro-5-methyl-pyrrolo [1,2- f] [ 1,2,4]triazin-2-yl)ethylaminopyrimidine-5-carbonitrile (( S )-4-amino-6-(1-(4-chloro-5-methylpyrrolo[1,2- f] [1,2,4] triazin-2 -yl) ethylamino) pyrimidine-5-carbonitrile) and 80mg (0.61mmol) of 3-methoxy - N - methylaniline (3-methoxy- N -methylaniline) And prepared. The reaction was completed after heating at 120 ° C for 20 minutes under microwave irradiation. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purification to give 93 mg (yield: 62%) 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-f][1,2,4 Triazin-2-yl)methyl)-1H-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)

The title compound was subjected to an experimental procedure as described in Example 24 from 63 mg (0.11 mmol) of 3-iodo-1-((5-methyl-4-(4-(methylsulfonyl)piperazin-1-) Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3- Iodo-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-4-amine) and 50 mg (0.32 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid. The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 95%.

LRMS(m/z): 553(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.19 (s, 1H), 8.27 (s, 1H), 7.66 (d, 1H), 6.91 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H) , 6.56 (d, 1H), 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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

83 mg (0.19 mmol) of (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 (( 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) was dissolved in 2.7 ml of dichloromethane. 580 μl (0.57 mmol) of a commercially available 1 M boron tribromide solution in dichloromethane was added, and the mixture was stirred at room temperature overnight in a sealed vessel. The precipitated solid was collected by filtration, washed several times with dichloromethane, and dried under air flow. 73 mg (yield 93%) of title compound as a pale yellow solid. Purity: 100%.

LRMS(m/z): 416(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 8.21 (s, 1H), 8.05 (s, 1H), 7.92 (s, 2H), 7.65 (d, 1H), 7.15 (t, 1H), 6.67-6.57 (m, 2H), 6.53 (t, 1H), 6.38 (dd, 1H), 5.33-5.23 (m, 1H), 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-f][1,2 ,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

The title compound was subjected to an experimental procedure as described in Example 24 from 90 mg (0.18 mmol) of N ¹ -(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidine. -1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl) -N ¹ , N ² , N ² -trimethyl Alkane-1,2-diamine ( N ¹ -(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2 , 1- f ][1,2,4]triazin-4-yl)- N ¹ , N ² , N ² -trimethylethane-1,2-diamine) and 83 mg (0.53 mmol) of 3-fluoro-5- Prepared with hydroxyphenyl)boronic acid. The crude product was first purified by flash chromatography (0% to 100% DCM to DCM / methanol _{/ NH 3, 100: 1:} 8) and then purified by reverse phase chromatography (C-18 commercially available silicon dioxide Purified from Waters ^® , water / 1:1 acetonitrile-methanol as a bankwash [0% to 100% in 0.1% volume / volume ammonium formate buffer) to give a white solid title of 7 mg (yield 8%) Compound. Purity: 100%.

LRMS(m/z): 491(M+1) ⁺

^{1 H NMR (400MHz, DMSO)} δ 10.17 (s, 1H), 8.25 (s, 1H), 7.60 (s, 1H), 6.89 (s, 1H), 6.83 (d, 1H), 6.65 (d, 1H) , 6.50 (s, 1H), 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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

25 mg (0.04 mmol) of (S) -4-amino-6-((2-(3-(benzyloxy)phenyl)-1-(4-(4-isopropyl-1-yl)-5) -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-(( 2-(3-(benzyloxy)phenyl)-1-(4-(4-isopropylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl )amino)pyrimidine-5-carbonitrile) was 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 was added and the mixture was stirred under a hydrogen atmosphere (60 psi) for 40 hours. The catalyst was then removed by filtration and the volatiles were evaporated under reduced pressure. The crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3 (100: 8:} 1)), to yield 9 mg of the title compound (42% yield) of.

LRMS(m/z): 513(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.19 (s, 1H), 7.46 (d, 1H), 7.03 (t, 1H), 6.64 (d, 1H), 6.61-6.49 (m, 3H), 6.45 (s, 1H), 5.55-5.41 (m, 1H), 5.32 (s, 2H), 3.64 (d, 4H), 3.23 (ddd, 2H), 2.81-2.70 (m, 1H), 2.64 (s, 4H), 2.43 (s, 3H), 1.09 (d, 6H)

Example 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 (4-Amino-6-((( S )-1-(4-(( 3S ) 5 R )-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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 17 mg (0.15 mmol) of (2 R ,6 S )-2,6-dimethylpiperazine dihydrogen chloride ((2 R ,6 S ) -2,6-dimethylpiperazine dihydrochloride) and 52 μl (0.30 mmol) of diisopropylethylamine were stirred at room temperature overnight in 2 ml of acetone. The volatiles were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 100: 8:} 1) and purified to give 25mg (82% yield) of the title compound as a white solid. Purity: 98.2%.

LRMS(m/z): 407(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.53 (d, 1H), 6.64 (d, 1H), 6.48 (d, 1H), 5.35 (s, 2H), 5.29-5.16 (m, 1H), 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-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)

The title compound was subjected to 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 (( S )-4-Amino-6-((1-(4-chloro-5-) Methylpyrrolo[2,1- f ][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-dioxacyclopentan-2-yl)pyridine (2,6-dimethyl-4-(4,4,5,5-tetramethyl-) Prepared by 1,3,2-dioxaborolan-2-yl)pyridine) (available from Combi-blocks ^® , catalog number PN-5673). The reaction overnight, the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 Purification to afford 23 mg (yield: 63%) Purity: 100%.

LRMS(m/z): 400(M+1) ⁺

¹ H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.82 (d, 1H), 7.23-7.21 (m, 2H), 6.76 (s, 1H), 6.47 (d, 1H), 5.62. m,1H), 5.27(s,2H), 2.09(s,3H),1.66(d,3H),1.25(s,6H)

Example 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 (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 26 mg (0.11 mmol) of 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (purchased from ChemBridge ^® , Cat. No. 4010589) and 48 μl (0.28 mmol) of diisopropylethylamine 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 sulfate. 30 mg (yield 71%) of title compound as white solid. Purity: 95.0%.

LRMS(m/z): 461(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.22 (s, 1H), 7.49 (s, 1H), 6.76 (d, 1H), 6.46 (s, 1H), 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-f][ 1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]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)

23 mg (0.07 mmol) of (S) -4-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl) Amino)-7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile (( S )-4-((1-(4-Chloro-5-methylpyrrolo[2,1- f ][1 , 2,4]triazin-2-yl)ethyl)amino)-7 H- pyrrolo[2,3- d ]pyrimidine-5-carbonitrile) and 24 mg (0.13 mmol) of 3-((2-(dimethyl)) The amino)ethyl)amino)phenol ^{4 was} heated in a solution of microwaves in 0.4 ml of acetone at 150 ° C for 20 minutes. The solvent was removed, the crude product was first purified by flash chromatography (5% to 20% DCM / methanol) under reduced pressure, and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, Water/1:1 acetonitrile-methanol was purified as a scouring solution [0% to 100% in 0.1% volume/volume ammonium acetate buffer) to give 6 mg (yield: 17%) of the title compound. Purity: 94%.

LRMS(m/z): 497(M+1) ⁺

^{1 H NMR (400MHz, dmso)} δ 12.81 (s, 1H), 9.54 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 7.14 (t, 1H) , 6.73-6.45(m,4H), 6.38(s,1H),5.45-5.25(m,1H), 4.37-4.14(m,1H),4.14-3.90(m,1H),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-f][1,2,4]triazine- 2-(yl)ethyl)amino)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)

20 mg (0.06 mmol) of (S) -4-amino-6-((1-(5-methyl-4-vinylpyrrolo[2,1- f ][1,2,4]triazine-2 -yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5-methyl-4-vinylpyrrolo[2,1- f ][1,2,4 ]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) was dissolved in 5 ml of ethanol under an inert atmosphere. 15 μl (0.11 mmol) of triethylamine and 50 μl (0.58 mmol) of morpholine were added, and the resulting solution was stirred at reflux temperature for 4 hours. The volatiles were then removed under reduced pressure to give &lt Purity: 96.4%.

LRMS(m/z): 408(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.64 (d, 1H), 6.65 (d, 1H), 6.60 (d, 1H), 5.39 (t, 1H), 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,5R)-4-(2-(benzyloxy)ethyl)-3,5-dimethylpiperazin-1- 5-(methylpyrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile

(4-Amino-6 - ( ((S) -1- (4 - ((3 S, 5 R) -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)

50 mg (0.15 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile), 45mg (0.18mmol) of (2 S, 6 R) -1- (2- ( benzyloxy) ethyl) -2,6- (-1- -2,6-dimethylpiperazine (2 S , 6 R) (2- (Benzyloxy) ethyl)) and at 79μl (0.45mmol) of diisopropylethylamine in 5ml of acetone at room temperature methylpiperazine Stir 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 sulfate, filtered and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut Purity: 98%.

LRMS(m/z): 541(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.51 (d, 1H), 7.32 (d, 5H), 6.66 (d, 1H), 6.46 (d, 1H), 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-f][1 , 2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1-( (4-((3 S ,5 R )-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)

The title compound following the experimental procedure as described in Example 25 from 79 mg (0.15 mmol) of 1 - ((4 - (( 3 S, 5 R) -3,5- dimethyl-piperazin-1-yl) - 5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)oxy)methyl)-3-iodo-1 H -pyrazolo[3,4- d ] pyrimidin-4-amine (1 - ((4 - ( (3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2,1- f] [1,2,4] Triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine) and 48 mg (0.31 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid Prepared at 80 ° C overnight. An additional 30 mg of boric acid must be added and the reaction is completed after 6 hours at 80 °C. The crude product was first purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 100: 1:} 8) and then purified by reverse phase chromatography (C-18 commercially available silicon dioxide Purified from Waters ^® , water / 1:1 acetonitrile-methanol as a bank (buffered with 0.1% v/v ammonium acetate buffer) 0% to 100%) to give 36 mg (yield 47%) of white solid title Compound. Purity: 97%.

LRMS(m/z): 503(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.44 (s, 1H), 7.48 (d, 1H), 6.97-6.84 (m, 2H), 6.63 (d, 1H), 6.43 (d, 1H), 5.58 (s, 1H), 5.55 (s, 1H), 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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

The title compound was subjected to the experimental procedure as described in Example 71 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 8.8 μl (0.11 mmol) of 2-(methylamino)ethanol (2-( Prepared by methylamino)ethanol). The crude oil obtained was stirred with hexanes, and the precipitated white solid was filtered and dried with air. 35 mg (100% yield) of the title compound are obtained. Purity: 96%.

LRMS(m/z): 368(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.20 (s, 1H), 7.53 (d, 1H), 6.55 (d, 1H), 6.48 (d, 1H), 5.27 (s, 2H), 5.24-5.16 (m, 1H), 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-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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 32 mg (0.18 mmol) of 3-((2-methoxyethyl)amino)phenol (3-((2-methoxyethyl)amino)phenol) It was heated at 150 ° C for 30 minutes in 0.5 ml of acetone using microwave irradiation. The reaction mixture was partitioned between EtOAc EtOAc m. The crude product was first purified by flash chromatography (0% to 16% DCM/MeOH) and then purified by reverse phase chromatography (C-18 cerium oxide from Waters ^® , water / 1:1 acetonitrile - Methanol was purified as a dike solution [0% to 100% in 0.1% volume/volume ammonium formate buffer) and finally prepared by preparative HPLC (Symmetry Prep ^® C ₁₈ column from 55% A to 55% B) The A/B emulsified liquid was mixed and purified by a 32-minute isocratic gradient to give 2.1 mg (yield 5%) of the title compound. Purity: 100%.

LRMS(m/z): 460(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.49 (s, 1H), 7.13 (t, 1H), 6.81-6.68 (m, 2H), 6.61 (dd, 2H), 6.28 (s, 1H), 5.38 (s, 2H), 5.34-5.25 (m, 1H), 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-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)

The title compound was subjected to the experimental procedure as described in Example 71 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 16 μl (0.11 mmol) of N ,1-dimethylpiperidin-4-amine ( N , 1-dimethylpiperidin-4-amine) (available from Aldrich ^® , Cat. No. 22, 140-6). The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 100%. LRMS(m/z): 421 (M+1) ^{+ 1} H NMR (400 MHz, cdCl3) δ 8.20 (s, 1H), 7.48 (d, 1H), 6.60 (d, 1H), 6.44 (d, 1H) , 5.34 (s, 2H), 5.27-5.11 (m, 1H), 4.30 (t, 1H), 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,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 (4-Amino-6-((( S )-) 1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)-2 -(3-hydroxyphenyl)ethyl)amino)pyrimidine-5-carbonitrile)

The title compound was subjected to an experimental procedure as described in Example 65 from 30 mg (0.09 mmol) of 4-amino-6-(( (S) -2-(3-(benzyloxy)phenyl)-1-(4) -((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- yl) ethyl) amino) pyrimidine-5-carbonitrile (4-amino-6 - ( ((S) -2- (3- (benzyloxy) phenyl) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile). The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 26 mg (yield: 32%) of the title compound. Purity: 98%.

LRMS(m/z): 499(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.44 (s, 1H), 7.48 (d, 1H), 6.97-6.84 (m, 2H), 6.63 (d, 1H), 6.43 (d, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-hydroxybenzamide (( 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)

21 mg (0.05 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-hydroxybenzoic acid (( 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), 11 mg (0.06 mmol) of EDC. HCl and 6.6 mg (0.05 mmol) of butanol were dissolved in 0.2 ml of DMF and stirred for 15 minutes. Then add 22 μl (0.20 mmol) of 4-methylmorpholine and 5.3 μl (0.05 mmol) of N ¹ , N ¹ -dimethylethane-1,2-diamine ( N ¹ , N ^{1 -dimethylethane-1,2-diamine)} (available from Aldrich ^®, Catalog No. D158003), and the reaction mixture was stirred at room temperature for 48 hours. Then an excess of 22 μl (0.20 mmol) of 4-methylmorpholine and 5.3 μl (0.05 mmol) of N ¹ , N ¹ -dimethylethane-1,2-diamine ( N ¹ , N ¹ -dimethylethane-) were added. 1,2-diamine), and the mixture was stirred for more than 24 hours. The reaction mixture was then partitioned between water and ethyl acetate. EtOAc EtOAc. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 %) and then purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 100: 8:} 1) and purified to give the title compound 19mg (yield 15%). Purity: 96%.

LRMS(m/z): 501(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.31 (s, 1H) , 6.95 (d, 1H), 6.75 (s, 1H), 5.61 (s, 2H), 5.42 (d, 1H), 4.20 (dd, 1H), 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((1S,2S)-2-(methylamino)cyclohexyl)amino)pyrrolo[2,1 -f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (4-Amino-6-((( S )-1-(5-methyl-4-) (methyl(( S , 2S )-2-(methylamino)cyclohexyl)amino)pyrrolo[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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 26 mg (0.18 mmol) of (1 S , 2 S )- N ¹ , N ² -dimethylcyclohexane-1,2-diamine ((1 S , 2 S )- N ¹ , N ² -dimethylcyclohexane-1,2-diamine) (available from Aldrich ^® , catalog number 669660) and 80 μl (0.46 mmol) of diisopropylethylamine in 5 ml of acetone Stir at room temperature overnight. An excess of 26 mg of diamine and 240 μl of diisopropylethylamine were added and the mixture was stirred at room temperature for a further 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 sulfate, filtered and evaporated. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 %) and then purified by flash chromatography (100% DCM to 10% DCM / methanol _{/ NH 3, 100: 8:} 1) and purified to give 3mg (5% yield) of the title compound. Purity: 94%. LRMS(m/z): 435(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.48 (s, 1H), 6.60 (d, 1H), 6.44 (s, 1H), 5.31 (s, 2H), 5.24-5.14 (m, 1H), 4.12 (s, 1H), 3.13 (s, 3H), 2.64 (s, 1H), 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-f][1,2,4]triazin-2-yl) Ethyl)amino)pyrimidine-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)

9 mg of the title compound was obtained and isolated as a by-product in the experimental procedure described in Example 78. Purity: 94%.

LRMS(m/z): 338(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.49 (d, 1H), 6.86 (d, 1H), 6.45 (d, 1H), 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 (( 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 subjected to the experimental procedure as described in Example 71 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 10.6 μl (0.11 mmol) of 3-(methylamino)propan-1-ol Prepared by (3-(methylamino)propan-1-ol). The reaction mixture was stirred at room temperature overnight, the crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% volume / Purification by volume of ammonium formate buffer [0% to 100%) gave 23 mg (yield: 67%) Purity: 100%.

LRMS(m/z): 382(M+1) ⁺

¹ H NMR (400 MHz, cdcl3) δ 8.21 (s, 1H), 7.51 (d, 1H), 6.79 (d, 1H), 6.46 (d, 1H), 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,5R)-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-5-methylpyrrole And [2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol ( 3- (4-Amino-1 - ((4 - ((3 S, 5 R) -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)

The title compound was subjected to an experimental procedure as described in Example 45 from 20 mg (0.03 mmol) of 1-((4-(( 3S ,5 R )-3,5-dimethyl-4-(methylsulfonium) Piperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazole And [3,4- d ]pyrimidin-4-amine, and 11 mg (0.07 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid were prepared. After 16 hours of reaction, an additional 10 mg of boric acid and 5 mg of palladium catalyst were added, and the mixture was stirred at 100 ° C for more than 48 hours. The crude product was purified by flash chromatography eluting elut elut elut elut Purity: 95%.

LRMS(m/z): 581(M+1) ⁺

Example 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 (( 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)

The title compound was subjected to an experimental procedure as described in Example 71 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 7 μl (0.08 mmol) of N ¹ -methylethane-1,2-diamine Prepared by ( N ¹ -methylethane-1,2-diamine). The reaction mixture was stirred at room temperature overnight, the crude product was first purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 100: 8:} 1) and then purified by prep of HPLC (Symmetry Prep ^® C ₁₈ column, from 5% B to 40% B in a / liquid mixing red bank B, 14 min gradient) to afford to give 4mg (13% yield) of the title compound as a white solid. Purity: 100%.

LRMS(m/z): 367(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.50 (d, 1H), 6.77 (d, 1H), 6.50-6.42 (m, 1H), 5.29 (s, 2H), 5.25-5.12 ( m,1H),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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

6 mg of the title compound was obtained and isolated as a by-product in the experimental procedure described in Example 82. Purity: 98%.

LRMS(m/z): 367(M+1) ⁺

¹ H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.36 (d, 1H), 6.88 (d, 1H), 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-f] [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 35 μl (0.30 mmol) of N ¹ , N ¹ , N ² -trimethylethane-1,2-diamine ( N ¹ , N ¹ , N ² -trimethylethane-1,2-diamine) was stirred at 55 ° C for 2 hours in 0.6 ml of acetone. 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 sulfate, filtered and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut Purity: 100%.

LRMS(m/z): 395(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.49 (d, 1H), 6.67 (d, 1H), 6.44 (d, 1H), 5.33 (s, 2H), 5.28-5.11 (m, 1H), 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

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-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( N -(( S )-1-(4-((3 S ,5 R )-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)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

63 mg (0.1 mmol) of 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)-7-((2-(3) Methyl decyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine ( N -(( S )-1-(4-((3 S ,5 R) )-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)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine) was treated with 1.5 ml of trifluoroacetic acid and the mixture was Stir at room temperature for 30 minutes. The volatiles were then removed under reduced pressure and the residue was taken &lt The solution was stirred at room temperature for 30 minutes, then the volatiles were evaporated under reduced vacuo. The organic layer was washed with water and brine, dried over magnesium sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 11 mg (yield: 24%) Purity: 92%.

LRMS(m/z): 486(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 10.99 (s, 1H), 8.33 (s, 1H), 7.76 (s, 1H), 7.57 (d, 1H), 7.53 (s, 1H), 6.96 (s, 1H) , 6.52 (d, 1H), 6.45 (d, 1H), 5.34 (m, 1H), 4.15 (br.s, 1H), 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 4-Amino-6-((( S )-1-(4-(( 3S ,5 R )-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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 43 mg (0.15 mmol) of 2-(4-((2 R ,6 S )-2,6-dimethylpiperazin-1- Methyl)phenoxy) -N , N -dimethylethylamine (2-(4-((2 R ,6 S )-2,6-Dimethylpiperazin-1-yl)methyl)phenoxy)- N , N-dimethyletha namine) (dihydrochloride) and 85 μl (0.49 mmol) of DIEA were stirred at room temperature overnight in 4 ml of acetone. 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 sulfate. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium hydroxide buffered] 0% to 100 Purification to give 11 mg (yield: 14%) Purity: 100%.

LRMS(m/z): 584(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.42 (s, 1H), 8.19 (s, 1H), 7.49 (d, 1H), 7.29 (d, 2H), 6.84 (d, 2H), 6.64 (d, 1H) , 6.45 (d, 1H), 5.45 (s, 2H), 5.30-5.11 (m, 1H), 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

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 ( N - (3- (4 - (( (S) -1- (4 - ((3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2,1- f] [1 ,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide)

28 mg (0.04 mmol) of N- (3-(4-(( S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5) -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy) A yl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) phenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- (4 - (( 3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-(( 2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-5-yl) phenyl) methanesulfonamide) treated with 1.0ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes . The volatiles were then removed under reduced pressure and the residue dissolved in 2 mL methanol and &lt;1&gt; The solution was stirred at room temperature for 30 min. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium hydroxide buffered] 0% to 100 Purification to give 13 mg (yield: 52%) Purity: 92%.

LRMS(m/z): 575(M+1) ⁺

¹ H NMR (400 MHz, CD3 OD) δ 8.19 (s, 1H), 7.43 (t, 1H), 7.39 (d, 1H), 7.38-7.34 (m, 1H), 7.34-7.26 (m, 2H), 7.14 ( s, 1H), 6.51 (dd, 1H), 5.21 (q, 1H), 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

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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonamide ( N - (3- (4-Amino- 1 - ((4 - ((3 S, 5 R) -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)

The title compound was obtained according to the procedure from Example 45 from 50 mg (0.10 mmol) of 1-((4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)oxy)methyl)-3-iodo-1 H -pyrazolo[3,4- d ] pyrimidin-4-amine (1 - ((4 - ( (3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2,1- f] [1,2,4] Triazin-2-yl)methyl)-3-iodo-1 H- pyrazolo[3,4- d ]pyrimidin-4-amine) and 75 mg (0.24 mmol) of N- (3-hydroxy-5-(4,4) ,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)phenyl)methanesulfonamide ( N- (3-Hydroxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide). After the reaction at 100 ℃ 16 hours, the reaction mixture was passed through diatomaceous earth (Celite ^®) and filtered, and the solvent removed to give the crude product is extracted, it first by reverse phase chromatography (C-18 silicon dioxide available from Waters ^® , water / 1:1 acetonitrile-methanol was purified as a dyke solution [0% to 100% in 0.1% volume / volume ammonium formate buffer], and then subjected to second reverse phase chromatography (C-18 dioxide) Purified from Waters ^® , water / 1:1 acetonitrile-methanol as a bankwash [buffered with 0.1% volume / volume ammonium hydroxide] 0% to 100%) to give 7mg (yield 13%) White solid the title compound. 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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (4-Amino-6-((( S )-) 1-(4-((3 R ,5 S )-3,5-dimethyl-4-(methylsulfonyl)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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile), 21mg (0.11mmol) of (2 S, 6 R) -2,6- dimethyl-1- (sulfonic acyl methyl) piperazine hydrogen chloride ((2 S, 6 R) -2,6-Dimethyl-1- (methylsulfonyl) piperazine hydrochloride) and 64μl (0.37mmol) of DIEA in 3ml of acetone was stirred overnight at room temperature. 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 sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 100%.

LRMS(m/z): 485(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.56 (d, 1H), 6.58 (d, 1H), 6.50 (d, 1H), 5.35 (s, 2H), 5.29-5.18 (m, 1H), 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,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol (5-(4-Amino-1-( (4-((3 S ,5 R )-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)

The title compound was subjected to an experimental procedure as described in Example 45 from 50 mg (0.10 mmol) of 1-((4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)- 5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)oxy)methyl)-3-iodo-1 H -pyrazolo[3,4- d ] pyrimidin-4-amine (1 - ((4 - ( (3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2,1- f] [1,2,4] Triazi n-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine) and 43 mg (0.19 mmol) of 5-(4,4,5,5-tetra Methyl-1,3,2-dioxocyclopentan-2-yl)pyridin-3-ol (5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) ) prepared by pyridin-3-ol). After the reaction at 100 ℃ 16 hours, the reaction mixture was passed through diatomaceous earth (Celite ^®) and filtered, and the solvent removed to give the crude product is extracted, it first by reverse phase chromatography (C-18 silicon dioxide available from Waters ^® , water / 1:1 acetonitrile-methanol was purified as a dyke solution [0% to 100% in 0.1% volume / volume ammonium formate buffer], and then subjected to second reverse phase chromatography (C-18 dioxide) Purchased from Waters ^® , water / 1:1 acetonitrile-methanol as a bankwash [buffered with 0.1% volume / volume ammonium hydroxide] 0% to 100%), and finally by preparative HPLC (Symmetry Prep ^® C ₁₈ column, purified from 5% B to 35% B of A/B broth, 15 min. gradient, to give 8 mg (yield: 17%) of white title compound. Purity: 99%.

LRMS(m/z): 486(M+1) ⁺

¹ H NMR (400 MHz, CD 3 OD) d 8.50 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.21 (d, 1H), 7.56 (d, 1H), 7.53 (dd, 1H) , 6.55 (d, 1H), 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-((3R,5S)-4-Ethyl)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2, 1-f] [1,2,4] triazin-2-yl) ethyl) amino) -6-amino-5-carbonitrile (4 - (((S) -1- (4 - ((3 R ,5 S )-4-Acetyl-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile), 29mg (0.18mmol) of 1 - ((2 S, 6 R) -2,6- dimethyl-piperazin-1-yl) ethanone hydrogen chloride (1 - ((2 S, 6 R) -2,6-Dimethylpiperazin-1-yl) ethanonehydrochloride) and 64μl (0.37mmol) of DIEA in 2ml of acetone was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was washed with EtOAcq. Purity: 98%.

LRMS(m/z): 449(M+1) ⁺

¹ H NMR (400 MHz, cdcl 3 ) δ 8.21 (s, 1H), 7.56 (d, 1H), 6.60 (d, 1H), 6.49 (dd, 1H), 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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

The title compound was subjected to the experimental procedure as described in Example 71 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 (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo) [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 12 μl (0.11 mmol) of N ¹ -methylpropane-1,3-diamine ( N ¹ -methylpropane-1,3-diamine) was prepared. The reaction mixture was stirred at room temperature overnight, the crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [0.1% by volume / volume ammonium formate buffer] 0% to 100%) and purified by flash chromatography (100% DCM to 100% DCM / methanol / NH ₃ , 100: 8: 1), then prepared by type HPLC (Symmetry Prep ^® C ₁₈ column, from 5% B to 45% B in a / liquid mixing punch the bank B, 15 min gradient) and purified to afford 3mg (10% yield) of the title compound. Purity: 100%.

LRMS(m/z): 381(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.22 (s, 1H), 7.37 (d, 1H), 6.75 (d, 1H), 6.37 (s, 1H), 5.32 (s, 2H), 5.23-5.12 (m, 1H), 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-f][1,2, 4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

3 mg of the title compound was obtained and isolated as a by-product in the experimental procedure described in Example 92. Purity: 100%.

LRMS(m/z): 381(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.57 (s, 1H), 8.19 (s, 1H), 7.36 (d, 1H), 6.78 (d, 1H), 6.69 (s, 1H), 6.36 (d, 1H) , 5.53 (s, 2H), 5.27-5.05 (m, 1H), 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,6R)-2,6-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-(( 2S ) 6 R )-2,6-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile)

8 mg (0.016 mmol) of 4-(2-( (S) -1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 - f ][1,2,4]triazin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid (3 S ,5 R )-t-butyl ester ((3 S ,5 R )- Tert -butyl 4-(2-(( S )-1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-4-yl)-3,5-dimethylpiperazine-1-carboxylate) was dissolved in 0.2 ml of 4 M hydrogen chloride solution in dioxane. The mixture was stirred at room temperature for 2 hours and then the volatiles were removed under reduced pressure. 5 mg (yield 78%) of the title compound are obtained. Purity: 100%.

LRMS(m/z): 407(M+1) ⁺

^{1 H NMR (400MHz, CD3OD)} δ 8.17 (s, 1H), 7.72 (d, 1H), 6.69 (s, 1H), 5.51-5.33 (m, 1H), 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-f][1,2,4]triazin-2-yl)) -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1-((5-methyl-4-(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)

The title compound was subjected to an experimental procedure as described in Example 45, from 130 mg (0.27 mmol) of 3-iodo-1-((5-methyl-4-(piperazin-1-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl) -4-(piperazin-1-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine And 82 mg (0.52 mmol) of (3-fluoro-5-hydroxyphenyl) boronic acid were prepared. After the reaction at 80 ℃ 20 hours, the reaction mixture was passed through diatomaceous earth (Celite ^®) and filtered, and the filtrate was washed with ethyl acetate, dried over sodium sulfate and the solvent was removed. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) is purified, then After the second reverse phase chromatography under the same conditions, 6 mg (yield: 6%) Purity: 98%.

LRMS(m/z): 475(M+1) ⁺

¹ H RMN: (DMSO-d6, 400 MHZ) δ 8.24 (1H, s), 8.19 (1H, s), 7.60 (1H, d); 6.89-6.88 (1H, m), 6.82 (1H, ddd), 6.64 (1H, dt), 6.53 (1H, 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-thiomorpholinylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4-Amino-1-((5-methyl-4-thiomorpholinopyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-3-yl)-5-fluorophenol)

The title compound was subjected to the experimental procedure as described in Example 45 from 118 mg (0.23 mmol) of 3-iodo-1-((5-methyl-4-thiomorpholinylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-) Thiomorpholinopyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine) and 85mg (0.55mmol) (3 -Fluoro-5-hydroxyphenyl)boronic acid. After the reaction at 80 ℃ 20 hours, the reaction mixture was passed through diatomaceous earth (Celite ^®) and filtered, and the filtrate was washed with ethyl acetate solution was dried over sodium sulfate and the solvent removed under reduced pressure. The crude product by reverse phase chromatography and purified by (C-18 silicon dioxide available as red liquid bank [with 0.1% v / v formic acid buffered] 0 to 100% from Waters ^®, water / acetonitrile), in the warp After the second reverse phase chromatography of the same conditions, 9 mg (yield: 7%) Purity: 97%.

LRMS(m/z): 492(M+1) ⁺

¹ H RMN (DMSO-d6, 500 MHZ) δ 10.15 (1H, brs), 8.25 (1H, s), 7.63 (1H, d), 6.89-6.88 (1H, m), 6.83 (1H, ddd), 6.64 ( 1H, dt), 6.53 (1H, 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 (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)

The title compound was subjected to an experimental procedure as described in Example 45, from 90 mg (0.17 mmol) of 3-iodo-1-((5-methyl-4-((2-(pyrrole-1-yl)ethyl)amino) Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-) 1-((5-methyl-4-((2-(pyrrolidin-1-yl)ethyl)amino)pyrrolo[2,1- f ][1,2,4]tri azin-2-yl)methyl)- 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine) and 40 mg (0.26 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid preparation. After reacting at 80 ° C for 20 hours, an excess of boric acid and a catalyst were added, and the reaction was heated at 80 ° C for 60 hours or more. The reaction mixture through diatomaceous earth (Celite ^®) and filtered, and the filtrate was washed with ethyl acetate solution was dried over sodium sulfate and the solvent removed under reduced pressure. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 5 mg (yield 6%) of white solid (formate) title compound. Purity: 99%.

LRMS(m/z): 503(M+1) ⁺

¹ H RMN: (DMSO-d6, 500 MHZ) δ 10.16 (1H, brs), 8.24 (1H, s), 8.14 (1H, s), 7.46 (1H, d), 6.97 (1H, t), 6.89-6.88 (1H, dd), 6.82 (1H, ddd), 6.64 (1H, dt), 6.37 (1H, 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-1H-pyrazol-5-yl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 -dioxocyclopentan-2-yl)-1 H -pyrazole (1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrazole) (available from Combi-blocks ^® , catalog number PN-6021), 20 mg (0.02 mmol) PdCl ₂ dppf. DCM and 183 μl (0.37 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 90 ° C for 4 hours under an argon atmosphere. After cooling, the reaction mixture was filtered through a layer of diatomaceous earth (Celite ^®), and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (0% to 10%EtOAc) elute Purity: 100%.

LRMS(m/z): 389(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 6.47-6.22 (m, 2H), 5.63-5.43 (m, 1H), 5.32 ( s, 2H), 3.94 (s, 3H), 2.36 (s, 3H), 2.23 (s, 3H), 1.65 (d, 3H)

Example 99

4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] ( S )-methyl ester of triazin-4-yl)-2,6-dimethylbenzoic acid (( 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)

250 mg (0.76 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 316 mg (1.52 mmol) (4-(methoxycarbonyl)-3,5-dimethylphenyl)boronic acid ((4-(methoxycarbonyl)) -3,5-dimethylphenyl)boronic acid) (available from Combi-blocks ^® , catalog number FA-1919), 62 mg (0.08 mmol) of PdCl ₂ dppf. DCM and 1.14 ml (2.3 mmol) of a 2M aqueous solution of cesium carbonate were dissolved in 8.5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate. EtOAc m. The crude product was directly by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purification to give 223 mg (yield: 64%) of title compound. Purity: 100%.

LRMS(m/z): 348(M+1) ⁺

Example 100

3-(1-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)methyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(1- ((4-((1 S ,4 S )-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)

16 mg (27 mmol) of 5-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)) 5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Acid (1 S , 4 S )-T-butyl ester ((1 S , 4 S )- Tert -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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2. 1] Heptane-2-carboxylate) was stirred at room temperature for 2 hours in 0.5 ml of a 4 M hydrochloric acid solution in dioxane. The resulting suspension was diluted with EtOAc (EtOAc)EtOAc. Purity: 99%.

LRMS(m/z): 487(M+1) ⁺

¹ H RMN: (DMSO-d6, 400 MHZ) δ 10.29 (1H, brs), 9.43 (1H, brs), 8.58 (1H, brs), 8.46 (1H, s), 7.65 (1H, d), 6.91-6.89 (1H, m), 6.69 (1H, dt), 6.54 (1H, d), 5.50 (1H, d), 5.38 (1H, d), 4.54 (1H, s), 4.33 (1H, s), 3.95 ( 1H, d), 3.69 (1H, d), 3.10 (1H, m), 2.92 (1H, m), 2.35 (3H, s), 2.07 (1H, d), 1.82 (1H, d)

Example 101

3-(4-Amino-1-((4-((3-hydroxypropyl))(methyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazine -2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

66 mg (0.13 mmol) of 3-((2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole And [2,1- f ][1,2,4]triazin-4-yl)(methyl)amino)propan-1-ol (3-((2-((4-Amino-3-iodo-) 1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][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 PdCl ₂ dppf. DCM and 133 μl (0.26 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 4 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate. EtOAc m. The crude product was purified by flash chromatography (0% to 10%EtOAc) Purity: 99%.

LRMS(m/z): 478(M+1) ⁺

^{1 H NMR (500MHz, DMSO-} d6) δ 10.16 (s, 1H), 8.25 (s, 1H), 7.57 (d, 1H), 6.90-6.88 (m, 1H), 6.85-6.81 (m, 1H), 6.64 (dt, 1H), 6.48 (d, 1H), 5.37 (s, 1H), 4.37 (t, 1H), 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-tetramethylmorpholinyl)pyrrolo[2,1-f][1,2,4] Triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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 ]pyrimidin- 3-yl)-5-fluorophenol)

63 mg (0.12 mmol) 3-iodo-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholinyl)pyrrolo[2,1- f ][1,2, 4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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 ]pyrimidin-4-amine), 35mg (0.22 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 12 mg (0.015 mmol) of PdCl ₂ dppf. DCM and 150 μl (0.29 mmol) of 2 M aqueous cesium carbonate solution were dissolved in 4 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate. EtOAc m. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1 Purified as a bankwash [15% to 50% in 0.1% by volume/volume formic acid) to give 9 mg (yield 15%) of the title compound. Purity: 99%.

LRMS(m/z): 532(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.20 (s, 1H), 8.25 (s, 1H), 7.65 (d, 1H), 6.88-6.84 (m, 1H), 6.81-6.75 (m, 1H), 6.64 (dt, 1H), 6.53 (d, 1H), 5.38 (s, 2H), 3.37 (s, 3H), 2.38 (s, 3H), 0.91 (s, 12H)

Example 103

3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] ( 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)

440 mg (1.3 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 739 mg (2.7 mmol) of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di Methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate) (purchased from methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate) Combi-blocks ^® , catalog number PN-5549), 84 mg (0.10 mmol) of PdCl ₂ dppf. DCM and 2 ml (2.0 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 15 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the crude product was purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile ( 1:1) Purified as a scouring solution [0% to 100% by volume of 0.1% by volume of formic acid) to give 372 mg (yield: 63%) of the title compound. Purity: 99%.

LRMS(m/z): 443(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.07 (d, 1H), 8.04-7.97 (m, 3H), 7.78 (s, 1H), 7.43 (d, 1H), 7.29 (s, 2H), 6.90- 6.84(m,1H), 5.37(q,1H), 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-f][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

157 mg (0.47 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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-dioxo 5-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (purchased from Milestone ^® , catalogue No. 8C-0165), 40 mg (0.049 mmol) of PdCl ₂ dppf. DCM and 720 μl (1.4 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the crude product was purified by flash chromatography eluting eluting eluting Purity: 96%.

LRMS(m/z): 412(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 7.43 (d, 1H), 7.37-7.32 (m, 2H), 7.29 ( s, 1H), 6.88 (d, 1H), 5.37 (p, 1H), 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-f][1, 2,4]triazin-4-yl)-5-methylbenzoic acid (( 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)

480 mg (1.1 mmol) of 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 (S)-methyl ester (( 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) was dissolved in 20 ml of THF. 4.4 ml (0.44 mmol) of 1 M aqueous lithium hydroxide solution 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 cerium oxide from Waters ^® , water / acetonitrile (1:1) as a levee solution [with 0.1% volume/volume formic acid buffer]0 Purification to give 350 mg (yield: 75%) of title compound. Purity: 100%.

LRMS (m/z): 427 (M-1) ^-

¹ H NMR (400 MHz, DMSO-d6) δ 8.06 (d, 1H), 8. s (s, 1H), 7.78 (s, 2H), 7.73 (s, 1H), 7.43 (d, 1H), 7.28 (s, 2H), 6.87 (d, 1H), 5.38 (p, 1H), 2.48 (s, 3H), 2.02 (s, 3H), 1.59 (d, 3H)

Example 106

1-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-A Pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperidin-4-ol (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)

86 mg (0.17 mmol) of 1-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole [2,1- f ][1,2,4]triazin-4-yl)piperidin-4-ol (1-(2-((4-Amino-3-iodo-1 H- pyrazolo[3, 4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperidin-4-ol), 40 mg (0.25 mmol) ( 3-fluoro-5-hydroxyphenyl) boronic acid, 13 mg (0.016 mmol) of PdCl ₂ dppf. DCM and 250 μl (0.48 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. After cooling, the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate. EtOAc m. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 98%.

LRMS(m/z): 490(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.18 (s, 1H), 8.25 (s, 1H), 7.59 (d, 1H), 6.93-6.85 (m, 1H), 6.87-6.80 (m, 1H), 6.65 (dt, 1H), 6.51 (d, 1H), 5.41 (s, 2H), 4.71 (d, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl)-5-methylbenzamide (( 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-methylbenzamide)

50 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 (( 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), ¹⁶ μl (0.14 mmol) of N ¹ , N ¹ -dimethyl Ethyl 1,2-diamine ( N ¹ , N ¹ -dimethylethane-1,2-diamine), 27 mg (0.14 mmol) of EDC. HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethylamine were stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (EtOAc m. Purity: 96%.

LRMS(m/z): 499(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.47 (t, 1H), 8.06 (d, 1H), 8.01 (s, 1H), 7.91 (d, 2H), 7.63 (s, 1H), 7.41 (d, 1H), 7.28 (s, 2H), 6.87 (dd, 1H), 5.38 (p, 1H), 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)-N-(2-hydroxyethyl)-5-methylbenzamide (( 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)

50 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 (( 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), 9 μl (0.14 mmol) of 2-aminoethanol (2-aminoethanol) ), 27mg (0.14mmol) of EDC. HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethylamine were stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (EtOAc m. Purity: 95%.

LRMS(m/z): 472(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.56-8.43 (m, 1H), 8.06 (d, 1H), 8.01 (d, 1H), 7.97-7.88 (m, 2H), 7.63 (dt, 1H), 7.44-7.37 (m, 1H), 7.28 (s, 2H), 6.87 (dd, 1H), 5.38 (p, 1H), 4.69 (t, 1H), 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-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) and 32 mg (0.27 mmol) of ( 2R ,6 S )-2,6-dimethylmorpholine ((2 R ,6 S )-2 , 6-dimethylmorpholine) was stirred at 55 ° C in 1 ml of acetone 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 sulfate, filtered and evaporated. 29 mg (yield 78%) of the title compound was obtained without any purification. Purity: 100%.

LRMS(m/z): 408(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.53 (d, 1H), 6.66 (d, 1H), 6.48 (d, 1H), 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

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)methanesulfonate Amides (N - (3- (4 - (((S) -1- (4 - ((3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

34 mg (0.05 mmol) of N- (3-(4-(( S) -1-(4-(( 3S ,5 R )-3,5-dimethylpiperazin-1-yl)-5) -Methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy) A yl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- ( 4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)- 7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide) with 1.0ml of trifluoroacetic acid, and the mixture Stir at room temperature for 30 minutes. The volatiles were then removed under reduced pressure and the residue dissolved in 1 mL MeOH and &lt 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 sulfate, filtered and evaporated. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium hydroxide buffered] 0% to Purified by 100%), then purified by preparative HPLC (Symmetry Prep ^® C18 column, mixing from 20% B to 60% B A/B burrowing solution, 20 min gradient) to give 3 mg Rate 11%) of the title compound. Purity: 98%.

LRMS(m/z): 592(M+1) ⁺

Example 111

4-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-one (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)

100 mg (0.20 mmol) of 4-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole [2,1- f ][1,2,4]triazin-4-yl)piperazin-2-one (4-(2-((4-Amino-3-iodo-1 H- pyrazolo[3, 4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperazin-2-one), 62 mg (0.40 mmol) ( 3-fluoro-5-hydroxyphenyl) boronic acid, 16 mg (0.020 mmol) of PdCl ₂ dppf. DCM and 300 μl (0.60 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. After cooling, the volatiles were removed under reduced pressure. EtOAcjjjjjjjj Purity: 99%.

LRMS(m/z): 489(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.15 (1H, s), 8.23 (1H, s), 7.98 (1H, s), 7.65 (1H, d), 6.88 (1H, t,), 6.85-6.82 (1H, m), 6.65-6.61 (1H, m), 6.54 (1H, 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-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)piperidine-4-carboxamide (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)

110 mg (0.21 mmol) of 1-(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-4-yl)piperidine-4-carboxamide (1-(2-((4-Amino-3-iodo-1 H -pyrazolo[3 , 4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperidine-4-carboxamide), 62 mg (0.40 mmol) (3-fluoro-5-hydroxyphenyl) boronic acid, 16 mg (0.020 mmol) of PdCl ₂ dppf. DCM and 300 μl (0.60 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were removed under reduced pressure. EtOAcjjjjjjj Purity: 99%.

LRMS(m/z): 517(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.13 (1H, s), 8.23 (1H, s), 7.58 (1H, d), 7.26 (1H, s), 6.88 (1H, s), 6.82 (1H, d), 6.77 (1H, s), 6.63 (1H, dd), 6.50 (1H, d), 5.40 (2H, s), 3.86 (2H, d), 2.92-2.87 (2H, m), 2.34 (3H) , s), 2.33-2.28 (1H, 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][1,2,4]3 Pyrazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-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)

50 mg (0.10 mmol) 3-iodo-1-((5-methyl-4-(2-(pyrrol-1-yl)ethoxy)pyrrolo[2,1- f ][1,2,4] Triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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-4-amine), 31 mg ( 0.20 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 5 mg (0.010 mmol) of PdCl ₂ dppf. DCM and 150 μl (0.30 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles, the crude product was first purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90 1::} 8) was removed under reduced pressure and then purified by reverse phase Chromatography (C-18 cerium oxide was purchased from Waters ^® , water / acetonitrile (1:1) as a scouring solution [0% to 100% in 0.1% volume/volume formate buffer) to obtain 23 mg (yield 45%) of the title compound. Purity: 99%.

LRMS(m/z): 504(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.24 (1H, s), 7.73 (1H, d), 6.88 (1H, s), 6.81 (1H, d), 6.63 (1H, d), 6.57 (1H, d), 5.49 (2H, s), 4.35 (2H, t), 2.83-2.77 (1H, q), 2.59 (2H, d), 2.36 (3H, s), 2.31 (4H, brs), 1.55 (4H ,brs),1.06(1H,t)

Example 114

4-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)thiomorpholine 1,1-dioxide (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)

In Preparation 77, 164 mg of crude product was obtained containing imp. 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)thiomorpholine 1,1-dioxide (4-(2-((4-Amino) -3-iodo-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), 93 mg (0.60 mmol) of (3-fluoro-5-hydroxyphenyl) boronic acid, 24 mg (0.03 mmol) of PdCl ₂ dppf. DCM and 450 μl (0.90 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were evaporated <RTI ID=0.0> Purity: 97%.

LRMS(m/z): 524(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.14 (1H, s), 8.24 (1H, s), 7.70 (1H, d), 6.89-6.87 (1H, m), 6.84 (1H, dd), 6.63 ( 1H, dt), 6.57 (1H, d), 5.46 (2H, s), 3.80 (4H, brs), 3.07 (4H, brs), 2.37 (3H, s)

Example 115

3-(1-((4-(1,4-diazepan-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-2 -yl)methyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

70 mg (0.14 mmol) of 1-((4-(1,4-diazepan-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]3 Pyrazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-(1,4-Diazepan-1-yl)) -5-methylpyrrolo[2,1- f ][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, 11 mg (0.013 mmol) of PdCl ₂ dppf. DCM and 210 μl (0.42 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. After cooling, the volatiles were removed under reduced pressure and the crude product was first purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 1:} 8) and then purified by crystallization in acetonitrile To give 23 mg (yield: 34%) of the title compound. Purity: 95%.

LRMS(m/z): 489(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.27 (1H, brs), 8.25 (1H, s), 7.62 (1H, s), 6.92 (1H, s), 6.82 (1H, d), 6.64 (1H, d), 6.50 (1H, 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-f][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 26 mg (0.11 mmol) of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di Oxocyclopentan-2-yl)-phenol (3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) (available from Combi-blocks ^® , catalog number PN-5985), 15 mg (0.02 mmol) of PdCl ₂ dppf. DCM and 137 μl (0.27 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 80 ° C for 4 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with dioxan, and through diatomaceous earth (Celite ^®) and filtered, is first purified by flash chromatography (0% to 10% DCM / methanol) removing the solvent, the crude product And then by reverse phase chromatography (C-18 ruthenium dioxide purchased from Waters ^® , water / 1:1 acetonitrile - methanol as a dyke solution [with 0.1% volume / volume ammonium formate buffer] 0% to 100% Purified to give 5 mg (yield: 14%) Purity: 96%.

LRMS(m/z): 401(M+1) ⁺

Example 117

3-(1-((4-((1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)methyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol)

100 mg (0.17 mmol) of 5-(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)-2,5-diazabicyclo[2.2.2]octane-2- Tert- 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 ][1,2,4]triazin-4-yl)-2,5-diazabicyclo[2.2.2]octan e-2-carboxylate) suspended in dioxane In 5 ml of 4M hydrochloric acid solution. The resulting mixture was stirred at room temperature for 1 hour. The suspension was filtered, and the solid was washed with EtOAc (EtOAc)EtOAc.

LRMS(m/z): 501(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.30 (1H, brs), 9.35 (1H, brs), 9.13 (1H, brs), 8.47 (1H, s), 7.65 (1H, d), 6.89-6.87 ( 1H, m), 6.84 (1H, dt), 6.69 (1H, dt), 6.54 (1H, d), 5.44 (2H, s), 4.20 (1H, brs), 4.02 (1H, d), 3.76 (1H) , d), 3.72 (1H, brs), 3.28 (1H, m), 3.13 (1H, 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-f][1, 2,4]triazin-4-yl)-N-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5-methylbenzamide (( S )-3- (2-((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)

50 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 (( 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), 25 mg (0.15 mmol) of 2-((5-aminopentyl) ()(5-aminopentyl(methyl)amino)ethanol) (prepared according to the experimental procedure described in PCT Int. Appl. WO2010069504), 27 mg (0.14 mmol) of EDC . HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethylamine were stirred at room temperature under 2 ml of anhydrous dichloromethane overnight. The reaction mixture was treated with water, the organic layer was separated, washed with water, sat. sodium hydrogen carbonate, saturated sodium carbonate and brine, then dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1) as a red liquid bank [with 0.1% v / v formic acid buffered] 0 to 100%) Purification was carried out to provide 10 mg (yield 15%) of the title compound.

LRMS(m/z): 501(M+1) ⁺

¹ H NMR (400 MHz, Chloroform-d) δ 8.22 (d, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.81 (d, 1H), 7.57 (d, 1H), 7.14 (d, 1H), 7.06 (t, 1H), 6.76 (dd, 1H), 5.47-5.35 (m, 1H), 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-methylpiperazin-1-yl)pyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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-Dioxylcycloborane-2-yl)pyridin-2-yl)piperazine (1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-2-yl)pipera zine) (available from Combi-blocks ^® , catalog number PN-8651), 5 mg (0.004 mmol) of Pd(PPh3)4 and 137 μl (0.27 mmol) of 2M sodium carbonate aqueous solution Dissolved in 1 ml of dioxane. The mixture was stirred at 90 ° C under argon overnight. An excess of the same amount of all reagents was added and the reaction was carried out at 90 ° C for more than 24 hours. 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 sulfate. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purified, and then purified by preparative HPLC (Symmetry Prep ^® C ₁₈ column, mixing from 5% B to 53% B A/B burrow, 16 minute isocratic gradient) to give 14 mg (yield 11%) of the title compound as a yellow solid. Purity: 100%.

LRMS(m/z): 470(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.33 (d, 1H), 8.20 (s, 1H), 7.81 (d, 1H), 6.88 (s, 1H), 6.83 (d, 1H), 6.75 (s, 1H) , 6.50 (d, 1H), 5.60-5.43 (m, 1H), 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-f] [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

156 mg (0.37 mmol) of (S) -4-amino-6-((1-(4-(4-carbamimido-3,5-dimethylphenyl)-5-methylpyrrolo[2, 1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-carbonitrile (( S )-4-Amino-6-((1-(4-(4-formyl-) 3,5-dimethylphenyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) was suspended in 4 ml of methanol. Then 11 mg (0.29 mmol) of sodium borohydride were added and the resulting suspension was stirred at room temperature overnight. Sodium borohydride was continuously added until the reaction was completed. A saturated aqueous solution of sodium carbonate was added and the product was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 100%.

LRMS(m/z): 429(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.21 (s, 1H), 7.78 (d, 1H), 7.36 (s, 2H), 6.72 (d, 1H), 6.63 (d, 1H), 5.60-5.42 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-5-methyl-N-(4-aminesulfonylbenzyl)benzamide (( 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)

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 (( 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)benzene 4-(aminomethyl)benzenesulfonamide hydrochloride (purchased from Sigma ^® , Cat. No. A-2134), 28 mg (0.14 mmol) of EDC. HCl, 22 mg (0.14 mmol) of butanol and 42 μl (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane at room temperature overnight. The volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 95%.

LRMS(m/z): 598(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.21 (t, 1H), 8.07 (d, 1H), 8.03-7.95 (m, 3H), 7.85-7.75 (m, 2H), 7.67 (td, 1H), 7.56-7.47 (m, 2H), 7.43 (d, 1H), 7.30 (s, 4H), 6.87 (dd, 1H), 5.38 (p, 1H), 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)-N-(3-hydroxybenzyl)-5-methylbenzamide (( 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)

50 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 (( 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), 19 mg (0.15 mmol) of 3-(aminomethyl)phenol (3-(aminomethyl)phenol) (available from Apollo Scientific ^® , catalog number OR14753), 27 mg (0.14 mmol) of EDC. HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane at room temperature overnight. The volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 98%.

LRMS(m/z): 535(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.30 (s, 1H), 9.08 (t, 1H), 8.06 (d, 1H), 8.03-7.92 (m, 3H), 7.66 (s, 1H), 7.43 ( d, 1H), 7.29 (s, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 6.76-6.68 (m, 2H), 6.62 (dt, 1H), 5.37 (p, 1H), 4.41 (d, 2H), 2.48 (s, 3H), 2.01 (s, 3H), 1.59 (d, 3H)

Example 123

3-(4-Amino-1-((5S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2] octyl- 2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 5-fluorophenol (3-(4-Amino-1-((5 S ,4 S )-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)

To 25 mg (0.05 mmol) of 3(1-((4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)methyl)-4-amino- 1H- pyrazolo[3,4- d ]pyrimidin-3-yl)-5-fluorophenol hydrogen chloride (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 hydrochloride) In a solution of 6 ml of a 1:1 mixture of THF and dichloromethane, 1 ml of dichloro is added at 0 ° C. 4 μl (0.05 mmol) of methanesulfonium chloride solution in methane and 10 μl (0.06 mmol) of DIEA. The mixture was stirred at 0 ° C for 5 hours and then a second addition of the two reagents was required. The reaction was then 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 (EtOAc EtOAc) Purity: 98%.

LRMS(m/z): 580(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.15 (1H, s), 8.23 (1H, s), 7.61 (1H, d), 6.89-6.87 (1H, m), 6.82 (1H, ddd), 6.63 ( 1H, dt), 6.50 (1H, d), 5.38 (2H, d), 4.26 (1H, brs), 3.94-3.88 (2H, m), 3.67 (1H, dd), 3.45 (1H, d), 3.24 (1H, dd), 2.85 (3H, s), 2.38 (3H, s), 1.90-1.80 (2H, m), 1.64-1.55 (2H, m)

Example 124

N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4 Triazin-2-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( N- ( ( S )-1-(4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl) -5-(1-methyl-1 H -pyrazol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

35 mg (0.057 mmol) of N -( (S) -1-(4-((2 S ,6 R )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1 H -pyrazol-4-yl)-7-((2-(trimethyldecyl) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine ( 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)-7- ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine) treated with 1.0ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The volatiles were then removed under reduced pressure and the residue was dissolved in 1M EtOAc. 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 (EtOAc:EtOAc) Purity: 96%.

LRMS(m/z): 488(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.71 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, 1H), 7.61 (s, 1H), 7.10 (d, 1H), 6.58 (d, 1H), 6.21 (d, 1H), 5.20 (p, 1H), 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-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-( 4-Amino-1-((4-((2-(dimethylamino)ethyl)(tetrahydro-2 H -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)

90 mg (0.16 mmol) of N ¹ -(2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrole And [2,1- f ][1,2,4]triazin-4-yl) -N ² , N ² -dimethyl- N ¹ -(tetrahydro-2 H -pyran-4-yl) Ethane-1,2-diamine ( N ¹ -(2-((4-Amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-4-yl)- N ² , N ² -dimethyl- N ¹ -(tetrahydro-2 H -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 PdCl ₂ dppf. DCM and 225 μl (0.45 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C for 24 hours under an argon atmosphere. After cooling, the volatiles were evaporated under reduced EtOAcqqqqqqqqq Purity: 98%.

LRMS(m/z): 561(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.16 (1H, brs), 8.23 (1H, s), 7.81 (1H, brs), 7.67 (1H, d), 6.87-6.85 (1H, m), 6.79 ( 1H, dd), 6.62 (1H, dt), 6.57 (1H, d), 5.40 (2H, s), 3.97-3.90 (1H, 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-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzamide (( S )-3 -(2-((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)

To 43 mg (0.08 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-methyl- N- (piperidin-4-ylmethyl)benzamide amine hydrogen chloride (( 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 - (piperidin-4-ylmethyl)benzamide hydrochloride) and 32 μl (0.18 mmol) of DIEA in 5 ml of THF solution, 8 μl (0.11 mmol) of methanesulfonium chloride was added at 0 °C. The reaction mixture was stirred at 0 ° C for 1 hour and the volatiles were evaporated under reduced pressure. The crude product was purified by flash chromatography (EtOAc:EtOAc)

LRMS(m/z): 604(M+1) ⁺

¹ H NMR (400 MHz, DMSO-d6) δ 8.61 (t, 1 H), 8.07 (d, 1H), 8.1 (s, 1H), 7.93 (d, 2H), 7.64 (d, 1H), 7.47-7. m, 1H), 7.29 (s, 1H), 6.91-6.82 (m, 1H), 5.37 (p, 1H), 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-((5R,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane -2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) -5-fluorophenol (3-(4-Amino-1-((5 R ,4 R )-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-3-yl)-5-fluorophenol)

88 the crude product was obtained, containing 3-iodo-1 as a main component - ((5-methyl -4 - ((1 R, 4 R) -5- ( methyl acyl sulfo) -2,5 -diazabicyclo[2.2.1]hept-2-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[ 3,4- d ]pyrimidin-4-amine (3-Iodo-1-((5-methyl-4-((1 R ,4 R )-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine), 100mg (0.64 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 25 mg (0.031 mmol) of PdCl ₂ dppf. DCM and 500 μl (1.0 mmol) of 2 M aqueous cesium carbonate solution were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C for 20 hours under an argon atmosphere. After cooling, the volatiles were removed under reduced pressure and the crude was purified by flash chromatography (0% to 10% DCM / methanol) and then purified by reverse phase chromatography (C-18 Waters ^®, water / acetonitrile (1: 1) as a red bank liquid [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 23mg (16% yield two steps) of the title compound. Purity: 97%.

LRMS(m/z): 566(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.15 (1H, brs), 8.26 (1H, s), 7.62 (1H, d), 6.91-6.89 (1H, m), 6.87-6.83 (1H, m), 6.66-6.62 (1H, m), 6.51 (1H, d), 5.39 (2H, dd), 4.56 (1H, s), 4.40 (1H, s), 3.93 (1H, dd), 3.45 (1H, d) , 3.17 (1H, d), 3.09 (1H, dd), 2.89 (3H, s), 2.37 (3H, s), 1.89 (1H, d), 1.79 (1H, d)

Example 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)propanamine (( 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 )propanamide)

30 mg (0.19 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][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 (( S )-2-amino -3- (4-hydroxyphenyl) propanamide) ( available from Aldrich ^®, Cat. No. T3879) was stirred at 2ml acetone 50 ℃ 16 hours. Then 2 ml of THF was added and the mixture was stirred at 50 ° C for more than 16 hours. Finally, 3 ml of DMSO was added, and the resulting solution was stirred at 70 ° C for 20 hours and at room temperature for 60 hours or more. The volatiles were removed under reduced pressure and the residue was taken with water. The solid formed was filtered and washed with water. The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 96%.

LRMS(m/z): 473(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.09 (s, 1H), 7.32 (d, 1H), 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

N-(3-(4-((S))-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f ][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide N - (3- (4 - ( ((S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) -5-methylpyrrolo [2,1- f] [1,2, 4]triazin-2-yl)ethyl)amino)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

The title compound following the experimental procedure described in Example 124 from 60mg (0.08mmol) of N - (3- (4 - ( ((S) -1- (4 - ((2 S, 6 R) -2, 6-Dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2- silicon alkyl trimethyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides (N - (3- ( 4-((( S )-1-(4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2- yl) ethyl) amino) -7 - ((2- (trimethylsilyl) ethoxy) prepared methyl) -7 H -pyrrolo [2,3- d ] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide). The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1 Purified as a scouring solution [0% to 100% in 0.1% by volume/volume formic acid) to give 12 mg (yield: 26%) of title compound. Purity: 95%.

LRMS(m/z): 593(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.81 (d, 1H), 8.17 (s, 1H), 7.53 (d, 1H), 7.18 (d, 1H), 6.88-6.68 (m, 2H), 6.60 ( t,1H), 6.53 (d, 1H), 6.16 (d, 1H), 5.28-5.06 (m, 1H), 3.85-3.71 (m, 2H), 3.65-3.51 (m, 2H), 2.91 (s, 3H), 2.76-2.61 (m, 1H), 2.61-2.50 (m, 1H), 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)ethyl)-5-methylpyrrolo[2,1-f][1, 2,4]triazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 58 mg (0.18 mmol) of N- (2-hydroxyethyl)-2,6-dimethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)benzamide ( N -(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 PdCl ₂ dppf. DCM and 137 μl (0.27 mmol) of 2M aqueous sodium carbonate solution were dissolved in 2 ml of dioxane. The mixture was stirred at 100 ° C under an argon atmosphere overnight. The reaction mixture was filtered through diatomaceous earth (Celite ^®), filtered and washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was first purified by flash chromatography (0% to 10% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a dying liquid [0% to 100% of a volume of vol. Purity: 96%.

LRMS(m/z): 486(M+1) ⁺

¹ H NMR (400 MHz, cdCl3) δ 8.22 (s, 1H), 7.79 (d, 1H), 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

N-(5-(4-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-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 Amides (N - (5- (4 - (((S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) -5-methylpyrrolo [2,1- f] [1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide)

The title compound following the experimental procedure described in Example 124 from 85mg (0.12mmol) of N - (5- (4 - ( ((S) -1- (4 - ((2 R, 6 S) -2, 6-Dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2- silicon alkyl trimethyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxy-3-yl) methanesulfonamide Amides (N - (5- (4 - (( (S) -1- (4 - ((2 R, 6 S) -2,6-Dimethylmorpholino) -5-methylpyrrolo [2,1- f] [1,2,4 ]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methoxypyridin-3- Prepared by yl)methanesulfonamide). The crude product was purified by flash chromatography (EtOAc:EtOAc: Purity: 99%.

LRMS(m/z): 608(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.97-11.92 (m, 1H), 8.21 (s, 1H), 8.11 (d, 1H), 7.75 (d, 1H), 7.55 (d, 1H), 7.30 ( d, 1H), 6.55 (d, 1H), 5.98 (d, 1H), 5.17 (p, 1H), 3.98 (s, 3H), 3.85-3.71 (m, 2H), 3.68-3.54 (m, 2H) , 2.98 (s, 3H), 2.64 (dd, 1H), 2.61-2.53 (m, 1H), 2.37 (s, 3H), 1.48 (d, 3H), 1.08 (dd, 6H)

Example 132

3-(4-Amino-1-((5-methyl-4-(2-morpholinylethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl) )methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

The crude product of Preparation 92 contains, as a main component, 3-iodo-1-((5-methyl-4-(2-morpholinylethoxy)pyrrolo[2,1- f ][1,2,4 Triazin-2-yl)methyl)-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (3-Iodo-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), 82 mg (0.53 mmol) (3 -(fluoro-5-hydroxyphenyl)boronic acid, 29 mg (0.036 mmol) of PdCl ₂ dppf. DCM and 524 μl (1.10 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of ethanol. The mixture was stirred at 80 ° C for 16 hours under an argon atmosphere. After cooling, the volatiles were evaporated in vacuo tolululululululululululululululululululu Purity: 98%.

LRMS(m/z): 520(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.18 (s, 1H), 8.26 (s, 1H), 7.75 (d, 1H), 6.93-6.87 (m, 1H), 6.87-6.80 (m, 1H), 6.65 (dt, 1H), 6.59 (d, 1H), 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-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)) 5-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl)pyrrolidin-2-one (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)

100 mg (0.19 mmol) of 1-(2-((2-(4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-) Methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy)ethyl)pyrrol-2-one (1-(2-((2-((4- Amino-3-iodo-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), 44 mg (0.28 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 15 mg (0.018 mmol) of PdCl ₂ dppf. DCM and 281 μl (0.56 mmol) of 2M aqueous cesium carbonate solution were dissolved in 5 ml of ethanol. The mixture was stirred at 80 ° C for 16 hours under an argon atmosphere. After cooling, the volatiles were evaporated under reduced EtOAcqqqqqqqq Purity: 98%.

LRMS(m/z): 518(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.18 (s, 1H), 8.27 (s, 1H), 7.74 (d, 1H), 6.92-6.88 (m, 1H), 6.87-6.81 (m, 1H), 6.65 (dt, 1H), 6.58 (dd, 1H), 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-f] [1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

60 mg (0.15 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 was dissolved in 2 ml of acetone, and 15 μl (0.17 mmol) of 3-bromopropan-1-ol, 30 mg (0.22) was added. Methyl) potassium carbonate and 7 mg (0.04 mmol) of potassium iodide. The resulting mixture was stirred at 50 ° C for 5 hours. Then all reagents were added a second time 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 phase was washed with aq. The crude product was purified by EtOAc EtOAc (EtOAc) Purity: 99%.

LRMS(m/z): 470(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.07 (1H, d), 7.98 (1H, s), 7.67-7.64 (2H, m), 7.51-7.50 (1H, m), 7.39 (1H, d), 7.27 (2H, brs), 6.87 (1H, d), 5.36 (1H, q), 4.54 (1H, 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)-N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)- 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5- (5-Amino-6-methoxypyridin-3-yl)- N -(( S )-1-(4-((2 S ,6 R )-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

The title compound was subjected to an experimental procedure as described in Example 124 from 43 mg (0.07 mmol) of 5-(5-amino-6-methoxypyridin-3-yl) -N -( (S) -1-(4) -((2 R ,6 S )-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) yl) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5- (5-Amino-6 -methoxypyridin-3-yl)- N -(( S )-1-(4-((2 R ,6 S )-2,6-dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2 , 4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine). The crude product was first purified by flash chromatography (0% to 5% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1 Purified as a dike solution [0% to 100% in 0.1% volume/volume formate buffer), and finally by preparative HPLC (Symmetry Prep ^® C ₁₈ column, from 40% B to 80% B) The A/B broth was mixed and purified by a 20-minute gradient to give 8 mg (yield 23%) of the title compound. Purity: 100%.

LRMS(m/z): 530(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.25 (s, 1H), 7.70 (d, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.08 (d, 1H), 7.00 (d, 1H) , 6.48 (s, 1H), 5.29-5.18 (m, 1H), 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

N-(3-(4-Amino-1-((4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-hydroxyphenyl)methanesulfonamide ( N -(3) -(4-Amino-1-((4-(( 2S ,6 R )-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)

The title compound was subjected to an experimental procedure as described in Example 45 from 65 mg (0.11 mmol) of 1-((4-(( 2S ,6 R )-2,6-dimethylmorpholine)-5-methyl Pyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine ( 1-((4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][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 N- (3-hydroxy-5-(4,4,5,5-tetramethyl-1, Prepared by 3,2-dioxacyclopentan-2-yl)phenyl)methanesulfonamide. After reacting at 100 ° C for 1 hour, the reaction mixture was filtered through Celite ^{® to} remove the solvent. After extraction, the crude product was obtained by flash chromatography (0% to 25% DCM / methanol) Purification afforded 23 mg (yield: 32%) Purity: 100%.

LRMS(m/z): 580(M+1) ⁺

^{1 H NMR (400MHz, dmso)} δ 9.87 (s, 1H), 9.81 (s, 1H), 8.26 (s, 1H), 7.66 (d, 1H), 6.94 (s, 1H), 6.77 (s, 2H) , 6.54 (d, 1H), 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-methyl Pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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 was dissolved in 2 ml of acetone, and 26 mg (0.10 mmol) of 1-(bromomethyl)-4-(A) was added. sulfo acyl) benzene (1- (bromomethyl) -4- (methylsulfonyl ) benzene) ( available from Acros ^®, catalog number 357580025), 19mg (0.14mmol) of potassium carbonate and 3.4 mg (0.02 mmol) of potassium iodide. The resulting mixture was stirred at 50 ° C for 5 hours. All reagents were then added a second time and the mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the crude material was purified eluting eluting eluting The solid obtained was triturated with hexane to give 20 mg (yield: 35%) of pure title compound. Purity: 98%.

LRMS(m/z): 581(M+1) ⁺

¹ H NMR (400 MHz, dmso) δ 8.07 (1H, d), 8.00 (1H, s), 7.95 (2H, d), 7.81 (1H, s), 7.76-7.74 (3H, m), 7.64-7.62 ( 1H, m), 7.39 (1H, d), 7.27 (1H, brs), 6.86 (1H, d), 5.39 (2H, s), 5.38-5.35 (1H, m), 3.90 (1H, 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-f][1, 2,4]triazin-4-yl)-5-methyl-N-(4-(methylsulfonylamino)benzyl)benzamide (( 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)

50 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 (( 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), 28 mg (0.14 mmol) of N- (4-(aminocarbamate) N- (4-(aminomethyl)phenyl)methanesulfonamide hydrochloride (purchased from ABCR ^® , Cat. No. AB233719), 27 mg (0.14 mmol) of EDC. HCl, 22 mg (0.14 mmol) of butanol and 41 μl (0.29 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane and a few drops of DMF at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc m. Purity: 99%.

LRMS(m/z): 612(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.64 (s, 1H), 9.09 (t, 1H), 8.06 (d, 1H), 8.00 (s, 1H), 7.99-7.92 (m, 2H), 7.67- 7.62 (m, 1H), 7.43 (d, 1H), 7.33-7.25 (m, 3H), 7.20-7.11 (m, 2H), 6.87 (dd, 2H), 5.37 (p, 1H), 4.44 (d, 2H), 2.94 (s, 3H), 2.47 (s, 3H), 2.01 (s, 3H), 1.59 (d, 3H)

Example 139

4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1, 2,4]triazin-4-yl)-5-methylbenzimidino)methyl)benzoic acid (S)-methyl ester (( 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)

150 mg (0.35 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 (( 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), 85 mg (0.42 mmol) of 4-(aminomethyl)benzene Methyl 4-(aminomethyl)benzoate hydrochloride (available from Aldrich ^® , catalog number 47,999-3), 81 mg (0.42 mmol) of EDC. HCl, 65 mg (0.42 mmol) of butanol and 122 μl (0.87 mmol) of triethylamine in 4 ml of anhydrous dichloromethane and a few drops of DMF were stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (EtOAc m.) Purity: 98%.

LRMS(m/z): 677(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.22 (t, 1H), 8.06 (d, 1H), 8.00 (s, 1H), 8.00-7.96 (m, 2H), 7.95-7.93 (m, 1H), 7.93-7.91 (m, 1H), 7.68-7.66 (m, 1H), 7.48-7.44 (m, 2H), 7.43 (d, 1H), 7.29 (bs, 1H), 6.87 (dd, 1H), 5.37 ( p,1H), 4.57(d,1H), 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-f][1, 2,4]triazin-4-yl)-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-5-methylbenzamide (( 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)

30 mg (0.07 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 (( 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), 17 mg (0.07 mmol) of 4-(aminomethyl)- 4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol dihydrochloride hydrate (purchased from Aldrich ^® , Catalog No. 28,709-1), 16 mg (0.08 mmol) of EDC. HCl, 13 mg (0.42 mmol) of butanol and 24 μl (0.40 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane and a few drops of DMF at room temperature for 5 hours. The reaction mixture was diluted with EtOAc EtOAc m. Purity: 98%.

LRMS(m/z): 580(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.96 (s, 1H), 9.33 (t, 1H), 8.06 (d, 1H), 8.00 (s, 1H), 7.99-7.94 (m, 2H), 7.93 ( s, 1H), 7.68-7.66 (m, 1H), 7.42 (d, 1H), 7.28 (bs, 1H), 6.87 (dd, 1H), 5.37 (p, 1H), 5.19 (t, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-hydroxyphenyl)-5-methylbenzamide (( 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)

60 mg (0.14 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 (( 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), 18 mg (0.16 mmol) of 3-aminophenol (3-aminophenol) ), 64 mg (0.17 mmol) of HATU and 29 μl (0.17 mmol) of triethylamine were stirred in 4 ml of anhydrous dichloromethane and a few drops of DMF at room temperature for 4 hours. An additional 12 mg of 3-aminophenol was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc m.) The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 97%.

LRMS(m/z): 520(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.18 (s, 1H), 9.43 (s, 1H), 8.08 (d, 1H), 8.04-8.02 (m, 1H), 8.01 (s, 1H), 8.01- 7.99 (m, 1H), 7.70-7.68 (m, 1H), 7.44 (d, 1H), 7.36 (t, 1H), 7.29 (bs, 2H), 7.15 (dt, 1H), 7.11 (t, 1H) , 6.88 (dd, 1H), 6.51 (ddd, 1H), 5.39 (p, 1H), 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-methylbenzimidino)methyl)benzoic acid (( 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 4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 -f][1,2,4]triazin-4-yl)-5-methylbenzimidino)methyl)benzoic acid (S)-methyl ester (( S )-Methyl 4-((3) -(2-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)- 5-methylbenzamido)methyl)benzoate) was dissolved in 5 ml of THF, and 800 μl (0.8 mmol) of a 1 M aqueous lithium hydroxide solution was added. The resulting solution was stirred at room temperature overnight, then the volatiles were removed under reduced pressure. The residue was dissolved in water and the solution was acidified with 2M hydrochloric acid until precipitation 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. Purity: 96%.

LRMS (m/z): 560 (M-1) ^-

^{1 H NMR (400MHz, DMSO-} d6) δ 9.18 (1H, brs), 8.04 (1H, d), 7.98-7.95 (3H, m), 7.88 (2H, d), 7.65 (1H, s), 7.41 ( 3H, d), 7.27 (1H, brs), 6.86 (1H, s), 5.35 (1H, q), 4.54 (2H, d), 2.46 (3H, s), 2.00 (3H, s), 1.57 (3H) , d)

Example 143

1-(2-((2-(4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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 ethyl ester (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)

120 mg (0.20 mmol) of 1-(2-((2-((4-amino-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl)methyl)-5-) Ethyl methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylate (Ethyl 1-(2-((2) -((4-amino-3-iodo-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), 62 mg (0.40 mmol) of (3-fluoro-5-hydroxyphenyl)boronic acid, 16 mg (0.02 mmol) of PdCl ₂ dppf. DCM and 300 μl (0.60 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 10 ml of dioxane. The mixture was stirred at 100 ° C for 16 hours under an argon atmosphere. After cooling, the volatiles were evaporated in vacuo tolulululululululululululululululululu Purity: 99%.

LRMS(m/z): 591(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 10.16 (1H, s), 8.24 (1H, s), 7.73 (1H, s), 6.87 (1H, s), 6.81 (2H, d), 6.63 (1H, d), 6.57 (1H, s), 5.48 (2H, s), 4.32 (2H, s), 4.01 (2H, d), 2.64 (2H, s), 2.36 (3H, s), 2.16 (1H, brs ), 1.90 (2H, t), 1.67 (2H, d), 1.45-1.59 (2H, m), 1.16.12.12 (3H, m)

Example 144

N-(4-(4-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f ][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide ( N- (4) -(4-(( S )-1-(4-((2 S ,6 R )-2,6-Dimethylmorpholino)-5-methylpyrrolo[2,1- f ][1,2,4]triazin- 2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide)

The title compound was obtained according to the experimental procedure of Example 124, from the crude product (yield: 73) of Preparation 98, which contains N- (4-(( ()))) 2 S ,6 R )-2,6-Dimethylmorpholinyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino ) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) phenyl) methanesulfonamide Amides (N - (4- (4 - (( (S) -1- (4 - ((2 S, 6 R) -2,6-Dimethylmorpholino) -5-methylpyrrolo [2,1- f] [1,2,4 [Triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide). The crude product was first purified by flash chromatography (0% to 15% DCM / isopropanol), and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1 :1) Purified as a dike solution [0% to 100% in 0.1% volume/volume formate buffer), and finally by preparative HPLC (Symmetry Prep ^® C ₁₈ column, from 40% B to 80%) The A/B broth of B was mixed and purified by a 20 minute gradient to give 1 mg (yield 23%) of the title compound. Purity: 97%.

LRMS(m/z): 577(M+1) ⁺

Example 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 (( S )- N -(3-(4-((1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide)

The title compound was obtained according to the experimental procedure from Example 124 from 42 mg (0.06 mmol) of (S) - N - (3-(4-(4-(4-(2,6-dimethylpyridine-4-) 5-(methylpyrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)) oxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -5-hydroxyphenyl) methanesulfonamide Amides ((S) - N - ( 3- (4- ( (1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]tria zin-2-yl)ethyl)amino)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonamide). The crude product was first purified by flash chromatography (0% to 15% DCM / isopropanol), and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1 :1) Purified as a dike solution [0% to 100% in 0.1% volume/volume formate buffer), and finally by preparative HPLC (Symmetry Prep ^® C ₁₈ column, from 5% B to 95%) The A/B emulsion of B was mixed and purified by a 12-minute gradient to give 10 mg (yield 29%) of the title compound. Purity: 98%.

LRMS(m/z): 585(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 9.40 (s, 2H), 8.36 (s, 1H), 7.80 (d, 1H), 7.13 (s, 1H), 7.01 (d, 1H), 6.82 (d, 2H) , 6.73 (d, 1H), 6.63 (s, 1H), 6.41 (d, 1H), 5.65-5.46 (m, 2H), 2.96 (s, 3H), 2.62 (d, 3H), 2.02 (s, 3H) ), 1.25 (s, 6H)

Example 146

3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] (S)-3-Aminophenyl 3-(3-(1-(1-(6-amino-5-cyanopyrimidin-4) -yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzoate)

6 mg (yield 9%) of the title compound was obtained and isolated as a by-product in the experimental procedure described in Example 141. Purity: 95%.

LRMS(m/z): 520(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.13 (s, 2H), 8.08 (d, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.45 (d, 1H), 7.29 (bs, 2H), 7.07 (t, 1H), 6.89 (d, 1H), 6.49 (dd, 1H), 6.44 (t, 1H), 6.37 (dd, 1H), 5.39 (p, 1H), 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-f][1,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzamide Indoleamine (( S )-3-(2-(1-((5-(5-Amino-6-methoxypyridin-3-yl)-7 H- 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)

The title compound following the experimental procedure described in Example 124 from 31mg (0.043mmol) of (S) -3- (2- (1 - ((5- (5- amino-6-methoxy-3-yl -7-((2-(Trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)ethyl)-5- methyl-pyrrolo [2,1- f] [1,2,4] triazin-4-yl) - N - (2- hydroxyethyl) -5-methyl-benzoyl amine ((S) -3 -(2-((5-(5-Amino-6-methoxypyridin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -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) is prepared. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 95%.

LRMS(m/z): 593(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.83 (s, 1H), 8.51 (t, 1H), 8.20 (s, 1H), 7.94 (d, 1H), 7.92-7.87 (m, 2H), 7.59- 7.52 (m, 3H), 7.19 (d, 1H), 7.04 (d, 1H), 6.91-6.85 (m, 1H), 6.24 (d, 1H), 5.40 (q, 1H), 5.08 (s, 2H) , 4.70 (t, 1H), 3.88 (s, 3H), 3.57-3.44 (m, 2H), 3.42-3.32 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-N,5-dimethylbenzamide (( 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)

30 mg (0.07 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 (( 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), 15 mg (0.11 mmol) of 3-((methylamino) Methyl)phenol (3-((Methylamino)methyl)phenol), 16mg (0.08mmol) EDC. HCl, 13 mg (0.42 mmol) of butanol and 24 μl (0.40 mmol) of triethylamine were stirred at room temperature overnight in a mixture of 2 ml of anhydrous dichloromethane and DMF. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. This solution was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 97%.

LRMS(m/z): 548(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.40 (s, 1H), 8.05 (bs, 1H), 8.00 (s, 1H), 7.61-7.51 (m, 1H), 7.48 (s, 1H), 7.46- 7.37 (m, 2H), 7.29 (bs, 2H), 7.20-7.07 (m, 1H), 6.86 (bs, 1H), 6.77-6.72 (m, 1H), 6.69-6.55 (m, 2H), 5.41 5.27 (m, 1H), 4.60 (bs, 1H), 4.44 (bs, 1H), 2.87 (bs, 3H), 2.01 (bs 3H), 1.58 (d, 3H)

Example 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4) -Amino-1-(( R )-1-(4-((3 S ,5 R )-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)

52mg (0.10mmol) of racemic 1- (1- (4 - (( 3 S, 5 R) -3,5- dimethyl-piperazin-1-yl) -5-methyl-pyrrolo [2, 1- f ][1,2,4]triazin-2-yl)ethyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-(1- (4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][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 PdCl ₂ dppf. DCM and 147 μl (0.30 mmol) of 2M aqueous sodium carbonate solution were dissolved in 5 ml of dioxane. The mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. Excess reagent and catalyst were added and the reaction was stirred at 80 ° C for an additional 24 hours. The reaction mixture through diatomaceous earth (Celite ^®) and filtered, washed with water and brine and the organic solution was washed with ethyl acetate was filtered, the filtered, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol _{/ NH 3, 90: 1:} 8) was purified to give the outer 34mg (yield 67%) of the racemic mixture. The two palm isomers were separated by palm-prepared HPLC (Daicel Chiralpack IC ^® C ₁₈ column, heptanol/ethanol/diethylamine (93:7:0.5) running on a 40-minute isocratic gradient). To give 15 mg of the title compound as a white solid. Purity: 100%.

LRMS(m/z): 517(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.45 (s, 1H), 7.52 (d, 1H), 6.98-6.80 (m, 2H), 6.63 (d, 1H), 6.44 (d, 1H), 6.13 (q, 1H), 5.56 (s, 2H), 4.18 (d, 1H), 4.01 (br s, 1H), 3.85 (d, 1H), 3.53-3.42 (m, 1H), 2.94-2.81 (m, 1H), 2.81-2.70 (m, 1H), 2.70-2.56 (m, 1H), 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][1,2,4]triazin-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4) -Amino-1-(( S )-1-(4-((3 S ,5 R )-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)

15 mg of the title compound as a white solid was isolated from the preparative HPLC as described in Example 149 (the second peak was washed). 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-f][1,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylic acid (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)

15 mg (0.025 mmol) of 1-(2-((2-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1) -yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylic acid ethyl ester ( 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) was dissolved in 1 ml of THF and 100 μl (0.1 mmol) of 1 M lithium hydroxide was added. Aqueous solution. The resulting solution was stirred at room temperature overnight, then an additional 100 μl of lithium hydroxide solution was 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, the solution was washed with diethyl ether and acidified with 1M hydrochloric acid until a precipitate appeared. The solid was filtered, washed with water and dried. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 2.3 mg (yield 64%) of the title compound. Purity: 98%.

LRMS (m/z): 560 (M-1) ^-

^{1 H NMR (400MHz, DMSO-} d6) δ 11.5 (1H, brs), 8.25 (1H, s), 8.23 (1H, brs), 7.73 (1H, d), 6.90-6.89 (1H, m), 6.81 ( 1H, dt), 6.62 (1H, 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 (1H, 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-f][1, 2,4]triazin-4-yl)-N-(4-((2-hydroxyethyl)aminecarbamimidyl)benzyl)-5-methylbenzamide (( 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)

50 mg (0.09 mmol) of (S)-4-((3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl))amino)ethyl)-5-methylpyrrole [2,1-f][1,2,4]triazin-4-yl)-5-methylbenzimidino)methyl)benzoic acid (( 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), 8.2 μl (0.13 mmol) of 2-aminoethanol, 21 mg (0.11 mmol) of EDC. HCl, 16 mg (0.12 mmol) of butanol and 31 μl (0.22 mmol) of triethylamine were stirred at room temperature in 5 ml of dichloromethane. The second addition of the reagent was completed and the solution was stirred at 50 ° C for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc m.) The crude product was stirred in acetonitrile and the insoluble solid was filtered and dried in air flow and dried at 45 ° C in a vacuum oven. 20 mg (yield 37%) of the title compound was obtained. Purity: 95%.

LRMS(m/z): 605(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.16 (1H, br s), 8.34 (1H, t), 8.05 (1H, d), 7.98 (2H, d), 7.95 (1H, s), 7.79 (2H , d), 7.65 (1H, s), 7.40 (1H, d), 7.36 (2H, d), 7.27 (1H, br s), 6.85 (1H, d), 5.36 (1H, q), 4.68 (1H , 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-f][1, 2,4]triazin-4-yl)-5-methyl-N-(4-(aminosulfonylamino)benzyl)benzamide (( 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)

60 mg (0.14 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 (( 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), 33 mg (0.17 mmol) of EDC. HCl and 26 mg (0.17 mmol) of butanol were stirred at room temperature for 90 minutes in 2 ml of DMF. Then add 88 μl (0.63 mmol) of triethylamine and 4-(Sulfamoylamino)benzylamine hydrochloride in 2 ml of DMF, and stir the reaction mixture at room temperature. overnight. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 95%.

LRMS(m/z): 612(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.38 (s, 1H), 9.07 (t, 1H), 8.06 (d, 1H), 8.00 (s, 1H), 7.96 (d, 2H), 7.65 (s, 1H), 7.43 (d, 1H), 7.29 (s, 2H), 7.22 (d, 2H), 7.11 (d, 2H), 7.02 (s, 2H), 6.89-6.85 (m, 1H), 5.36 (q) , 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-methoxy-5-(methylsulfonylamino)benzyl)-5-methylbenzamide (( S )-3- (2-((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)

37 mg (0.09 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 (( 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), 30 mg (0.13 mmol) of N- (3-(aminocarbamate) N- (3-(Aminomethyl)-5-methoxyphenyl)methanesulfonamide, 21 mg (0.11 mmol) of EDC. HCl, 16 mg (0.12 mmol) of butanol and 31 μl (0.22 mmol) of triethylamine were stirred at room temperature overnight in 2 ml of DMF. The second addition of the reagent was completed and the solution was stirred at room temperature for more than 90 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was first purified by flash chromatography (0% to 15% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile (1: 1 Purified as a scouring solution [0% to 100% in 0.1% by volume/volume formic acid) to give 13 mg (yield 24%) of the title compound. Purity: 99%.

LRMS(m/z): 640(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.12 (1H, brs), 8.06 (1H, d), 8.00 (1H, s), 7.96 (2H, d), 7.66 (1H, s), 7.42 (1H, d), 7.29 (2H, brs), 6.87 (1H, d), 6.76 (1H, s), 6.64 (2H, dd), 5.35 (1H, 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

3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] ( S )-Methyl 3-(4-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)) Ethyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-cyanobenzoate)

572 mg (1.7 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 549 mg (1.9 mmol) of 3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-di Methyl 3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate) (purchased from methyl 3-cyano-5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Combi-blocks ^® , Cat. No. PN-5521), 100 mg (0.09 mmol) of Pd(PPh ₃ ) ₄ and 553 mg (5.2 mmol) of sodium carbonate were suspended in 11.5 ml of dioxane. The mixture was stirred at 90 ° C under argon overnight. An additional 200 mg of catalyst was added every 24 hours until no starting material was detected (two additional additions, 64 hours of reaction). After cooling, the mixture was filtered through diatomaceous earth (Celite ^®), filtered and washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 116 mg (yield 15%) of the title compound. Purity: 100%.

LRMS(m/z): 454(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.56 (s, 1H), 8.50 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.87 (d, 1H), 6.80 (d, 1H) , 6.37 (d, 1H), 5.63-5.47 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-5-cyanobenzoic acid (( 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)

100 mg (0.22 mmol) of 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 (S)-methyl ester (( 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) was dissolved in 2.7 ml of THF. 1.10 ml (1.1 mmol) of 1 M aqueous lithium hydroxide solution was added, and the resulting solution was stirred at room temperature overnight. An additional 1.10 ml of lithium hydroxide was added, and the resulting mixture was stirred at room temperature for 3 hours and further stirred at 50 ° C for 2 hours. The volatiles were then evaporated and the residue was crystallised eluted with dil. The combined organic extracts were washed with EtOAcq. Purity: 94%.

LRMS (m/z): 438 (M-1) ^-

^{1 H NMR (400MHz, dmso)} δ 8.49 (s, 1H), 8.44 (s, 1H), 8.42 (s, 1H), 8.11 (d, 1H), 7.99 (s, 1H), 7.50 (d, 1H) , 7.30 (s, 2H), 6.90 (s, 1H), 5.48-5.28 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-methoxy-4-(methylsulfonylamino)benzyl)-5-methylbenzamide (( S )-3- (2-((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)

69 mg (0.16 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 (( 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), 56 mg (0.24 mmol) of N- (4-(aminocarbamate) N- (4-(Aminomethyl)-2-methoxyphenyl)methanesulfonamide, 37 mg (0.19 mmol) of EDC. HCl, 30 mg (0.19 mmol) of butanol and 56 μl (0.4 mmol) of triethylamine were stirred at room temperature overnight in 3 ml of DMF. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 95%.

LRMS(m/z): 641(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.11 (1H, m), 8.83 (1H, brs), 8.06 (1H, s), 8.00 (1H, s), 7.99 (1H, m), 7.96 (1H, m), 7.66 (1H, s), 7.42 (1H, d), 7.28 (1H, brs), 7.19 (1H, d), 7.04 (1H, s), 6.88 (2H, d), 5.37 (1H, 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-N-(4-aminesulfonylbenzyl)benzamide (( 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)

54 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-cyanobenzoic acid (( 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), 35 mg (0.16 mmol) of 4-(aminomethyl)benzene 4-(aminomethylbenzenesulfonamide), 28 mg (0.15 mmol) of EDC. HCl, 20 mg (0.15 mmol) of butanol and 54 μl (0.31 mmol) of DIEA were stirred at room temperature overnight in 4 ml of dichloromethane. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was purified by flash chromatography eluting elut elut elut Purity: 95%.

LRMS(m/z): 608(M+1) ⁺

^{1 H NMR (400MHz, dmso)} δ 9.43 (t, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.11 (d, 1H), 7.98 (s, 1H) , 7.76 (d, 2H), 7.50 (d, 2H), 7.45 (d, 1H), 7.37-7.19 (m, 4H), 6.90 (d, 1H), 5.48-5.29 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-hydroxy-5-(methylsulfonylamino)benzyl)-5-methylbenzamide (( 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-methylbe nzamide)

33 mg (0.08 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 (( 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), 18 mg (0.09 mmol) of EDC. HCl and 14 mg (0.09 mmol) of butanol were stirred at room temperature for 1 hour in 2 ml of dichloromethane. Next, 25 mg (0.12 mmol) of N- (3-(aminomethyl)-5-hydroxyphenyl)methanesulfonamide ( N- (3-(Aminomethyl)) in 2 ml of dichloromethane and 1 ml of DMF mixture was added. -5-hydroxyphenyl)methanesulfonamide) solution. The resulting solution was stirred at room temperature overnight. The volatiles were removed, the crude product was purified by flash chromatography (0% to 10% DCM / methanol) under reduced pressure, and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^® The water/acetonitrile was purified as a scouring solution [0% to 100% in 0.1% by volume/volume formic acid) to give 22 mg (yield 45%) of the title compound. Purity: 99%.

LRMS(m/z): 627(M+1) ⁺

^{1 H NMR (400MHz, dmso)} δ 9.57 (1H, s), 9.47 (1H, s), 9.08 (1H, m), 8.05 (1H, d), 8.0 (1H, s), 7.97 (2H, d) , 7.65 (1H, s), 7.42 (1H, d), 7.28 (1H, s), 6.87 (1H, d), 6.60 (1H, s), 6.56 (1H, s), 6.46 (1H, s), 5.37 (1H, 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-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 (( 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)

108 mg (0.15 mmol) of 2-methyl-4-(4-methylpiperazin-1-yl)-6-(trimethylstannyl)pyrimidine (the crude product obtained in the preparation of 114b), 50 mg (0.15 mmol) (S) -4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl) Amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2- Yl)ethyl)amino)pyrimidine-5-carbonitrile), 18 mg (0.02 mmol) of Pd(PPh ₃ ) ₄ and 15 mg (0.08 mmol) of copper (I) iodide suspended in 2 ml of DMF and placed in a sealed tube Heat at 100 ° C overnight. After cooling, the mixture was filtered through diatomaceous earth (Celite ^®), filtered and washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0 to 100% Purified to give 28 mg (yield: 38%) of the title compound. Purity: 100%.

LRMS(m/z): 485(M+1) ⁺

^{1 H NMR (400MHz, dmso)} δ 8.04 (d, 1H), 7.98 (s, 1H), 7.42 (d, 1H), 7.28 (s, 2H), 6.95 (s, 1H), 6.84 (d, 1H) , 5.40-5.27 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-6-methyl-N-(4-aminesulfonylbenzyl)pyrimidine-4-carboxamide (( 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)

10 mg (0.02 mmol) of (S) -2-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1 - f ][1,2,4]triazin-4-yl)-6-methylpyrimidine-4-carboxylic acid, 5 mg (0.03 mmol) of EDC. HCl, 4 mg (0.03 mmol) of butanol and 10 μl (0.06 mmol) of DIEA were stirred at room temperature for 30 minutes in 2 ml of dichloromethane. Then, 7 mg (0.03 mmol) of 4-(aminomethyl)benzenesulfonamide hydrochloride was added, and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc m. The crude product was purified by flash chromatography (0% to 10%EtOAc) Purity: 96%.

LRMS(m/z): 599(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.64 (t, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.86 (d, 3H), 7.49 (d, 2H), 6.79 (s, 1H) , 6.48 (d, 1H), 5.54-5.46 (m, 1H), 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-f][1, 2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5-methylbenzenesulfonamide (( 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)

50 mg (0.15 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)am ino)pyrimidine-5-carbonitrile), 74 mg (0.18 mmol) of N- (3-hydroxybenzyl)-3-methyl-5-(4,4,5,5- Tetramethyl-1,3,2-dioxocyclopentan-2-yl)benzenesulfonamide ( N- (3-Hydroxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzenesulfonamide), 12 mg (0.01 mmol) of PdCl ₂ dppf. DCM and 228 mg (0.46 mmol) of a 2 M aqueous solution of cesium carbonate were suspended in 5 ml of dioxane. The mixture was stirred at 100 ° C overnight under an argon atmosphere. After cooling, the mixture was diluted with ethyl acetate and filtered through diatomaceous earth (Celite ^®), filtered and washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was first purified by flash chromatography (0% to 15% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - Methanol was purified as a scouring solution [0% to 100% in 0.1% by volume/volume of ammonium formate) to give 34 mg (yield 39%) of the title compound. Purity: 95%.

LRMS(m/z): 570(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.92 (s, 1H), 7.86 (d, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.05 (t, 1H) , 6.89 (br s, 1H), 6.79 (s, 1H), 6.76-6.65 (m, 2H), 6.60 (d, 1H), 6.35 (s, 1H), 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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

30 mg (0.09 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 38 mg (0.14 mmol) of N ¹ , N ¹ -dimethyl- N ² -(4-(4-methylpiperazin-1-yl) Benzyl)ethane-1,2-diamine ( N ¹ , N ¹ -Dimethyl- N ² -(4-(4-methylpiperazin-1-yl)benzyl)ethane-1,2-diamine) and 48 μl ( 0.28 mmol) of DIEA was 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 dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (100% DCM to 100% DCM / methanol / NH ₃₎ was purified by flash chromatography to give 20mg (39% yield) of the title compound as a white solid. Purity: 100%.

LRMS(m/z): 569(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.52 (d, 1H), 7.10 (d, 2H), 6.87 (d, 2H), 6.65 (d, 1H), 6.45 (d, 1H) , 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-f][1, 2,4]triazin-4-yl)-N-((S)-1-(3-hydroxyphenyl)ethyl)-5-methylbenzamide (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)

35 mg (0.08 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 (( 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), 18 mg (0.09 mmol) of EDC. HCl and 15 mg (0.10 mmol) of butanol were stirred in 2 ml of DMF at room temperature for 1 hour. Then, 44 mg (0.33 mmol) of a solution of (S) -3-(1-aminoethyl)phenol (( 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 phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc: Purity: 97%.

LRMS(m/z): 548(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.29 (s, 1H), 8.83 (d, 1H), 8.06 (d, 1H), 8.04-7.89 (m, 3H), 7.64 (s, 1H), 7.42 ( d,1H), 7.29(s,2H), 7.10(t,1H), 6.87(d,1H),6.84-6.74(m,2H),6.66-6.57(m,1H),5.38(q,1H) , 5.10 (q, 1H), 2.47 (s, 3H), 2.00 (s, 3H), 1.59 (d, 3H), 1.44 (d, 3H)

Example 165

3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] ( S )-4-Aminosulfonylbenzyl ester of triazin-4-yl)-5-methylbenzoate (( 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)

40 mg (0.09 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 (( 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), 22 mg (0.11 mmol) of EDC. HCl and 17 mg (0.13 mmol) of butanol were stirred at room temperature for 1 hour in 4 ml of DMF. Then 52 mg (0.27 mmol) of 4-(hydroxymethyl)benzenesulfonamide and 13 μl (0.09 mmol) of triethylamine in 2 ml of DMF were added. The resulting solution was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc:EtOAc) Purity: 96%.

LRMS(m/z): 598(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.11-8.02 (m, 3H), 8.00 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.69- 7.62 (m, 2H), 7.43 (d, 1H), 7.37 (s, 2H), 7.33-7.25 (m, 1H), 6.88 (dd, 1H), 5.46 (s, 2H), 5.42-5.30 (m, 1H), 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][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

100 mg (0.30 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 112 mg (0.30 mmol) of N , N -dimethyl-1-(4-(trimethylstannyl)pyridin-2-yl) Piperidine-4-amine ( N , N- Dimethyl-1-(4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine), 35 mg (0.03 mmol) of Pd(PPh ₃ ) ₄ and 29 mg (0.15 The mmol of copper (I) iodide was suspended in 4 ml of dioxane and heated overnight at 100 ° C in a sealed tube under argon atmosphere. After cooling, the mixture was diluted with ethyl acetate, and through diatomaceous earth (Celite ^®) and filtered, and the filter was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 100%.

LRMS(m/z): 498(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.32 (d, 1H), 8.21 (s, 1H), 7.80 (d, 1H), 6.87 (s, 1H), 6.78 (d, 1H), 6.74 (d, 1H) , 6.48 (d, 1H), 5.58-5.44 (m, 1H), 5.29 (s, 2H), 4.43 (d, 2H), 2.92 (t, 2H), 2.50-2.37 (m, 1H), 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-(dimethylamino))-6-methylpyridin-2-yl)piperidin-1-yl) Pyridin-4-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )- 4-Amino-6-((1-(4-(2-(4-(4-(dimethylamino)-6-methylpyridin-2-yl)piperidin-1-yl)pyridin-4-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]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 77 mg (0.18 mmol) of N , N ,2-trimethyl-6-(1-(4-(4,4,5,5-) Tetramethyl-1,3,2-dioxocyclopentan-2-yl)pyridin-2-yl)piperidin-4-yl)pyridin-4-amine ( N , N , 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 PdCl ₂ dppf. DCM and 137 mg (0.27 mmol) of 2M aqueous sodium carbonate solution were suspended in 4 ml of dioxane. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. After cooling, the mixture was filtered through diatomaceous earth and the solvent was removed (Celite ^®). The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 100%.

LRMS(m/z): 589(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.33 (d, 1H), 8.20 (s, 1H), 7.80 (d, 1H), 6.88 (s, 1H), 6.77 (d, 1H), 6.74 (s, 1H) , 6.47 (d, 1H), 6.25 (s, 1H), 6.22 (s, 1H), 5.60-5.43 (m, 1H), 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-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(5- Methyl-4-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-yl)pyrrolo[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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 43 mg (0.12 mmol) of 1-methyl-4-(6-methyl-4-(trimethylstannyl)pyridine-2- Piperazine (1-Methyl-4-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperazine), 14 mg (0.01 mmol) of Pd(PPh ₃ ) ₄ and 12 mg (0.06 mmol) of iodine Copper (I) was suspended in 4 ml of dioxane and heated overnight at 100 ° C in a sealed tube under a nitrogen atmosphere. After cooling, the mixture was filtered through diatomaceous earth (Celite ^®), and the solvent removed under reduced pressure. The crude product was first purified by flash chromatography (0% to 15% DCM / methanol) and then by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - The methanol was purified as a EtOAc (yield: EtOAc: EtOAc: EtOAc) Purity: 99%.

LRMS(m/z): 484(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.20 (s, 1H), 7.79 (d, 1H), 6.73 (d, 1H), 6.69 (s, 1H), 6.65 (s, 1H), 6.51 (d, 1H) , 5.60-5.43 (m, 1H), 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)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5-(2- Aminopyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

The title compound was obtained according to the experimental procedure from Example 124 from 70 mg (0.11 mmol) of 5-(2-aminopyridin-4-yl) -N -( (S) -1-(4-(( 3S ) 5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)- 7-((2-(Trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (5-(2-Aminopyridin-4-yl) - N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4] Prepared by triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine). The crude product was taken up in ethyl acetate. EtOAc (EtOAc m. Purity: 95%.

LRMS(m/z): 499(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.93 (1H, s), 8.18 (1H, s), 7.95 (1H, d), 7.53 (1H, d), 7.31 (1H, d), 6.62 (1H, Dd), 6.53-6.50 (1H, m), 6.22 (1H, d), 5.97 (1H, s), 5.15 (1H, 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)-N-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5-(6- Aminopyridin-3-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

The title compound following the experimental procedure described in Example 124 from 70mg (0.11mmol) of 5- (6-amino-pyridin-3-yl) - N - ((S) -1- (4 - ((3 S, 5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)- 7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5- (6-aminopyridin-3 -yl) - N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4] triazin-2-yl) ethyl) -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine) is prepared. The crude product was taken up in ethyl acetate. EtOAc (EtOAc)EtOAc. The crude product was purified by prep HPLC (Symmetry Prep ^® C ₁₈ column, from A 5% B to 25% B / liquid mixing red bank B, 8 min gradient) to afford to give 3mg (5% yield) The title compound. Purity: 99%.

LRMS(m/z): 499(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 9.68 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.63 (dd, 1H), 7.47 (d, 1H), 6.96 (s, 1H) , 6.61 (d, 1H), 6.44 (d, 1H), 6.20 (d, 1H), 5.42-5.23 (m, 1H), 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

3-(2-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-A Ethyl 3-(2-(]4-amino-3-(3) 3-pyrido[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzoate -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)

25 mg (yield 26%) of the title compound was obtained as a by-product in the experimental procedure described in Preparation 129. The product was isolated as a white solid which was purified by flash chromatography (0% to 20% DCM/MeOH). Purity: 97%.

LRMS(m/z): 553(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.26 (s, 1H), 8.05 (d, 1H), 7.99- 7.95 (m, 1H), 7.95-7.91 (m, 1H), 7.72-7.67 (m, 1H ), 6.92-6.90 (m, 2H), 6.90-6.87 (m, 2H), 6.88-6.81 (m, 1H), 6.65 (m, 1H), 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-d]pyrimidin-1-yl)methyl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzimidamide (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)

To 52 mg (0.01 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H -pyrazolo[3,4- d ]pyrimidine) in DCM -1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (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-methylbenzoic acid), adding 0.07 ml (0.01 mmol) of 2-aminoethanol and 23 mg (0.01 mmol) of EDC. HCl, 16 mg (0.01 mmol) of butanol and 0.4 ml (0.03 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 3 hours and then an additional amount of reagent was added. The solution was stirred at room temperature overnight, then transferred to a sep. funnel and washed with saturated aqueous sodium bicarbonate and then washed with 5% EtOAc. The organic phase was dried with EtOAc EtOAc m. Purity: 98%.

LRMS(m/z): 568(M+1) ⁺

^{1 H NMR (400MHz, Methanol-} d4) δ 8.29 (s, 1H), 7.92-7.90 (m, 2H), 7.82 (d, 1H), 7.64-7.59 (m, 1H), 6.99-6.98 (m, 1H ), 6.93 (ddd, 1H), 6.84-6.78 (m, 1H), 6.67 (dt, 1H), 5.76 (s, 2H), 5.51 (s, 1H), 3.73 (t, 2H), 3.53 (t, 2H), 2.52 (s, 3H), 2.06 (s, 3H)

Example 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) ethane sulfonamide Amides (2- (Dimethylamino) - N - (3- (4 - (((S) -1- (4 - ((3 S, 5 R) -3,5 -dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5 -yl)-5-hydroxyphenyl)ethanesulfonamide)

The title compound following the experimental procedure described in Example 124 from 18mg (0.02mmol) of 2- (dimethylamino) - N - (3- (4 - (((S) -1- (4 - (( 3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl) Amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-5-hydroxyphenyl ) ethane sulfonamide Amides (2- (Dimethylamino) - N - (3- (4 - (((S) -1- (4 - ((3 S, 5 R) -3,5-dimethylpiperazin-1-yl )-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2 , 3- d ]pyrimidin-5-yl)-5-hydroxyphenyl)ethanesulfonamide). The crude product was directly by purified by reverse phase chromatography (C-18 silicon dioxide available as red liquid bank [with 0.1% v / v formic acid buffered] 0 to 100% from Waters ^®, water / acetonitrile) to 4 mg (25% yield) of the title compound are obtained. Purity: 96%.

LRMS(m/z): 648(M+1) ⁺

^{1 H NMR (400MHz, Methanol-} d4) δ 8.20 (1H, s), 7.56 (1H, d), 7.13 (1H, s), 6.87-6.85 (1H, m), 6.76-6.75 (1H, m), 6.73-6.72(1H, m), 6.58(1H,d), 5.25(1H,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))piperidin-1-yl)benzyl) Amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4- Amino-6-((1-(4-(dimethylamino)piperidin-1-yl)benzyl)amino)-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- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 56 mg (0.18 mmol) of N ¹ -(4-(4-(dimethylamino)piperidin-1-yl)benzyl) -N ^2, N ² - dimethyl-ethane-1,2-diamine ^{(N 1 - (4- (4-} (dimethylamino) piperidin-1-yl) benzyl) - N 2, N 2 -dimethylethane-1,2 -diamine) and 64 μl (0.37 mmol) of DIEA were stirred at room temperature overnight in 3 ml of acetone. The volatiles were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (100% DCM to 100% DCM / methanol / NH _3), to afford 38 mg (52% yield) of the title compound as a white solid. Purity: 99%.

LRMS(m/z): 597(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.21 (s, 1H), 7.52 (d, 1H), 7.08 (d, 2H), 6.87 (d, 2H), 6.66 (d, 1H), 6.45 (d, 1H) , 5.30 (s, 2H), 5.27-5.16 (m, 1H), 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, 1H), 2.16 (s, 6H), 1.92 (d, 2H), 1.55 (t, 3H)

Example 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 ( N -(( S )-1-(4-((3 S ,5) R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

The title compound following the experimental procedure described in Example 124 from 47mg (0.06mmol) of N - ((S) -1- ( 4 - ((3 S, 5 R) -3,5- dimethyl-piperazine -1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)) Ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine ( N -(( S )-1-(4-((3 S ,5 R )-3,5 -Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine). The crude product was directly by purified by reverse phase chromatography (C-18 silicon dioxide available as red liquid bank [with 0.1% v / v formic acid buffered] 0 to 100% from Waters ^®, water / acetonitrile) to 15 mg (yield 61%) of the title compound was obtained. Purity: 99%.

LRMS(m/z): 406(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 11.46 (1H, s), 8.17 (1H, s), 8.03 (1H, s), 7.62 (1H, d), 7.47 (1H, d), 7.07 (1H, Dd), 6.68 (1H, dd), 6.52 (1H, d), 5.31 (1H, 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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 (0.11 mmol) of 1-((4-(2-(4-(dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1- f ][ 1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine (1-((4-(2-) 4-(Dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)methyl)-3-iodo-1 H -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 PdCl ₂ dppf. DCM and 200 μl (0.40 mmol) of a 2 M aqueous solution of cesium carbonate were dissolved in 5 ml of dioxane. The mixture was stirred at 100 ° C for 16 hours under an argon atmosphere. The reaction mixture was filtered through diatomaceous earth (Celite ^®), the filtrate was washed with ethyl acetate, and the solvent removed from the organic solution. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 18 mg of oil which was treated with hexanes and sonicated until solids formed. The solid was filtered and dried in vacuo to give 13 mg (yield 20%) Purity: 98%.

LRMS(m/z): 562(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.24 (1H, s), 8.20 (1H, s), 7.73 (1H, d), 6.88 (1H, s), 6.81 (1H, d), 6.63 (1H, d), 6.57 (1H, d), 5.48 (2H, s), 4.33 (2H, t), 2.71 (1H, d), 2.48-2.43 (2H, m), 2.36 (3H, s), 2.19 (6H) , s), 2.11-2.06 (1H, 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-) Ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino- 6-((1-(5-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)

40 mg (0.12 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 55 mg (0.18 mmol) of N- (4-(4-methylpiperazin-1-yl)benzyl)-2-(pyrrole-1) - yl) ethanamine (N - (4- (4- methylpiperazin-1-yl) benzyl) -2- (pyrrolidin-1-yl) ethanamine) and 64μl (0.37mmol) of DIEA in 3ml of acetone was stirred overnight at room temperature . 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 sulfate, filtered and evaporated. The crude product ₍₃ 100% 100% DCM to DCM / methanol / NH) was purified by flash chromatography to give 57 mg of the title compound as an off-white solid (79% yield) of. Purity: 100%.

LRMS(m/z): 595(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.45 (s, 1H), 8.19 (s, 1H), 7.58 (d, 1H), 6.98 (d, 2H), 6.82 (d, 2H), 6.54 (d, 1H) , 6.51 (d, 1H), 5.50 (s, 2H), 5.33-5.21 (m, 1H), 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)piperidin-1-yl)-6-methylpyridin-4-yl)-5-) Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

50 mg (0.15 mmol) of (S) -4-amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazine-2- Ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino-6-((1-(4-chloro-5-methylpyrrolo[2,1- f ][1,2,4] Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile), 73 mg (0.15 mmol) of N , N -dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridine -2-yl)piperidin-4-amine ( N , N- Dimethyl-1-(6-methyl-4-(trimethylstannyl)pyridin-2-yl)piperidin-4-amine), 18 mg (0.02 mmol) of Pd (PPh ₃ ) ₄ and 15 mg (0.08 mmol) of copper (I) iodide were stirred in 2 ml of dioxane in 100 ° C overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was first purified by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / 1: 1 acetonitrile - methanol as a red liquid bank [with 0.1% v / v ammonium formate buffered] 0% to 100 Purified, and then purified by preparative HPLC (Symmetry Prep ^® C ₁₈ column, mixing from 15% B to 95% B A/B burrow, 20 minute gradient) to give 4 mg 5%) of the title compound as an off-white solid. Purity: 99%.

LRMS(m/z): 512(M+1) ⁺

Example 179

5-(2-Aminopyridin-4-yl)-N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5-(2-Aminopyridin-4-yl) -N -(( S )-1-(4-((2 S ,6 R )-2,6-dimethylmorpholino)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)- 7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

Trifluoroacetic acid (2ml) and a solution of 5- (2-amino-4-yl) -N- ((S) -1- ( 4 - ((2 S, 6 R) -2,6- dimethylmorpholine Phenidopyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (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) (53 mg, 0.08 mmol) was stirred at room temperature for 1.5 hours. The trifluoroacetic acid was then removed under reduced pressure. The residue obtained was dissolved in 0.5 ml of methanol, and 2 ml of a 7M ammonia solution 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) The aqueous phase was extracted again with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate The crude product was purified by flash chromatography eluting elut elut elut elut elut Purity: 97%.

LRMS(m/z): 485(M+1) ⁺

^{1 H NMR (500MHz, CDCl3)} δ 1.30 (6H, m), 1.66 (3H, d), 2.82 (1H, m), 2.92 (1H, m), 3.72 (2H, m), 4.63 (2H, m) , 4.73 (2H, br s), 5.40 (1H, m), 6.52 (1H, d), 6.69 (2H, m), 6.77 (1H, s), 6.93 (1H, d), 7.22 (1H, s) , 7.59 (1H, s), 8.18 (1H, d), 8.47 (1H, s), 10.60 (1H, br s)

Example 180

(1-(2-((2-)(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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-methylpiperazine- 1-(1)2-(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)

10 mg (0.017 mmol) of 1-(2-((2-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1) -yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl)piperidine-4-carboxylic acid (1- (2-((2-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 μl (0.03 mmol) of 1-methylpiperazine and 7 mg ( 0.018 mmol) of HATU was suspended in 2 ml of dichloromethane. 6 μl (0.03 mmol) of DIEA was added, and the resulting solution was stirred at room temperature for 4 hours. All reagents were added to another equivalent and stirring was continued for more than 72 hours. The reaction mixture was then diluted with EtOAc EtOAc m. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 3 mg (yield 26%) as the title compound of the diformiate salt.

LRMS(m/z): 644(M+1) ⁺

^{1 H NMR (400MHz, Methanol-} d4) δ 8.40 (s, 2H), 7.63 (d, 1H), 7.06-7.03 (m, 1H), 6.99 (ddd, 1H), 6.75 (dt, 1H), 6.61 ( Dd,1H), 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,1H),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)-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 (5-(2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3 - d ]pyrimidin-4-amine)

The title compound following the experimental procedure described in Example 124 from 45mg (0.06mmol) 5- (2- (4- (dimethylamino) piperidin-1-yl) pyridin-4-yl) - N - ( (S) -1-(4-((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1, 2,4]triazin-2-yl)ethyl)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidine- 4-(2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3 ,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- Prepared by 7 H -pyrrolo[2,3- d ]pyrimidin-4-amine). 27 mg (yield 73%) of the title compound are obtained. Purity: 100%.

LRMS(m/z): 610(M+1) ⁺

^{1 H NMR (400MHz, CD3OD)} δ 8.25 (s, 1H), 8.16 (d, 1H), 7.45 (d, 1H), 7.33 (s, 1H), 6.88 (dd, 1H), 6.82 (s, 1H) , 6.55 (d, 1H), 5.18 (q, 1H), 4.33 (d, 1H), 4.11 (d, 1H), 3.86 (d, 1H), 3.77 (d, 1H), 3.01-2.91 (m, 1H) ), 2.90-2.76 (m, 1H), 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)-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 ( 5-(2-(Dimethylamino)pyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo [2,1- f ][1,2,4]triazin-2-yl)ethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

The title compound was subjected to an experimental procedure as described in Example 124 from 43 mg (0.07 mmol) of 5-(2-(dimethylamino)pyridin-4-yl) -N -( (S) -1-(4- ((3 S ,5 R )-3,5-Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl ) ethyl) -7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (5- (2- ( Dimethylamino)pyridin-4-yl)- N -(( S )-1-(4-((3 S ,5 R )-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f [[,2,4]triazin-2-yl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-amine) . 25 mg (72% yield) of the title compound are obtained. Purity: 99%.

LRMS(m/z): 526(M+1) ⁺

^{1 H NMR (400MHz, CD3OD)} δ 8.24 (s, 1H), 8.11 (d, 1H), 7.42 (d, 1H), 7.31 (s, 1H), 6.82-6.79 (m, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 5.20 (q, 1H), 3.89-3.84 (m, 1H), 3.70 (d, 1H), 3.06-2.92 (m, 1H), 2.92-2.78 (m, 7H) , 2.67-2.54 (m, 1H), 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-A Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-(4-(dimethylamino)piperidin-1-yl)propyl)- 5-(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-(4-(dimethylamino)piperidin-1-yl)propyl)-5-methylbenzamide)

To 50 mg (0.10 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H -pyrazolo[3,4- d ) in 5 ml of DCM Pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (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-methylbenzoic acid), 27 mg (0.14 mmol) of 1-(3-aminopropyl) -N , N -dimethylpiperidin-4- Amine (1-(3-Aminopropyl)- N , N -dimethylpiperidin-4-amine), 27 mg (0.14 mmol) of EDC. HCl, 19 mg (0.14 mmol) of butanol and 40 μl (0.3 mmol) of triethylamine. The reaction mixture was stirred at room temperature overnight and then at 50 ° C for 3 hours. The volatiles were then removed under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 9 mg (yield 14%) of the title compound (diformate). Purity: 98%.

LRMS(m/z): 693(M+1) ⁺

^{1 H NMR (400MHz, cdcl3)} δ 8.43 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.78 (d, 1H) , 7.55 (s, 1H), 7.20 (s, 1H), 6.88-6.78 (m, 1H), 6.73 (d, 1H), 6.72-6.64 (m, 1H), 5.77 (s, 2H), 3.61-3.51 (m, 2H), 3.15 (d, 2H), 2.89-2.74 (m, 1H), 2.72-2.56 (m, 2H), 2.47 (s, 3H), 2.39 (s, 6H), 2.22-2.11 (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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-((3-(dimethylamino)propyl)(methyl)amino)propyl 5-(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)

To 50 mg (0.10 mmol) of 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1 H -pyrazolo[3,4- d ) in 5 ml of DCM Pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (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-methylbenzoic acid), adding 25 mg (0.14 mmol) of N ¹ -(3-aminopropyl)- N ¹ , N ³ , N ³ -trimethyl Propane-1,3-diamine ( N ¹ -(3-Aminopropyl)- N ¹ , N ³ , N ³ -trimethylpropane-1,3-diamine), 27 mg (0.14 mmol) of EDC. HCl, 19 mg (0.14 mmol) of butanol and 40 μl (0.3 mmol) of triethylamine. The reaction mixture was stirred at room temperature overnight and then stirred at 50 ° C for 3 hours. The volatiles were then removed under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product by reverse phase chromatography (C-18 silicon dioxide available from Waters ^®, water / acetonitrile as the bank was washed [with 0.1% v / v formic acid buffered] 0 to 100%) and purified to give 8 mg (yield 12%) of the title compound (diformate salt). Purity: 96%.

LRMS(m/z): 681(M+1) ⁺

^{1 H NMR (400MHz, CDCl3)} δ 8.43-8.35 (m, 2H), 8.29 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.76 (d, 1H), 7.48 (s, 1H), 7.17-7.15 (m, 1H), 6.85-6.79 (m, 1H), 6.69 (dd, 1H), 6.64 (dt, 1H), 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-f][1,2,4] ( S )-3-yl)-5-methylbenzoic acid (( 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)

2M aqueous lithium hydroxide solution (4 ml, 8 mmol) was added to a stirred suspension of 3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl) in tetrahydrofuran) Pyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoic acid (S) -methyl ester (( S )-Methyl 3-(2-(1- ((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1- f ][1,2,4]triazin-4-yl)-5-methylbenzoate) (85mg, 0.2mmol) The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed in vacuo then water (15 mL) was added to the residue and the solution was acidified to pH 6 with acetic acid. The obtained yellow solid was filtered, washed with water and purified by preparative HPLC to afford 50 mg (yield: 61%) of the title compound. Purity: 100%.

LRMS(m/z): 415(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.46 (s, 1H), 8.18 (m, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 8.0 (s, 1H), 7.57 (d, 1H), 7.32 (br s, 2H), 7.16 (m, 1H), 7.10 (m, 1H), 5.46 (m, 1H), 2.54-2.49 (methyl peak is masked by DMSO, 3H), 1.64 (d, 3H)

Example 186

(S)-3-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4] Pyrazin-4-yl)-N-(2-hydroxyethyl)-5-methylbenzimidamide (( 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)

Triethylamine (130 μl, 0.93 mmol) was added to a stirred mixture of (S)-3-(2-(1-(6-amino-5-cyano) in dimethylformamide at 0 to 5 °C Pyrimidin-4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzoic acid (( 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) (200mg, 0.48mmol), N- ( 3- dimethylaminopropyl) -N'- ethylcarbodiimide chloride (N- (3-dimethylaminopropyl) - N '-ethylcarbodiimide hydrochloride) (140mg, 0.73mmol And 1-Hydroxybenzotriazole hydrate (98 mg, 0.72 mmol). The reaction mixture was stirred at 0 to 5 &lt;0&gt;C for 1 h then ethanolamine (31 mg, 0.5 mmol) was evaporated. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give EtOAc (md. Purity: 100%.

LRMS(m/z): 458(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.64 (t, 1H), 8.35 (s, 1H), 8.19 (m, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.56 (d, 1H), 7.34 (br s, 2H), 7.24 (dd, 1H), 7.11 (m, 1H), 5.49-5.42 (m, 1H), 4.79 (t, 1H), 3.57 ( m, 2H), 3.39 (m, 2H, masked by the peak of water), 2.52 (s, 3H, masked 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] Pyridazin-4-yl)-5-methyl-N-(4-aminesulfonylbenzyl)benzamide (( 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 subjected to the experimental procedure as described in Example 186 from (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 (( 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) (200 mg, 0.48 mmol) and 4-(aminomethyl)benzene Prepared by sulfonamide (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 (yield 32%) Yellow solid title compound. Purity: 100%.

LRMS(m/z): 583(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 9.30 (t, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 8.02 (m, 2H), 7.81 (m, 2H), 7.54 (m, 3H), 7.32-724 (m, 5H), 7.11 (m, 1H), 5.50 (m, 1H), 4.60 (d, 2H), 2.5 (s, 3H, masked by DMSO peak ),1.66(d,3H)

Example 188

(S)-4-amino-6-((1-(4-(2,6-dimethylpyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( 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)

(S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Formonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (200 mg, 0.63 mmol) was dissolved in dioxane (4 ml). 2,6-Dimethylpyridin-4-ylboronic acid (140 mg, 0.93 mmol), bis(diphenylphosphino)ferrocene-palladium (2,6-Dimethylpyridin-4-yl)boronic acid (140 mg, 0.93 mmol) II) Dichlorophosphino ferrocene-palladium (II) dichloride chrome complex (52 mg, 0.06 mmol) and 2 M cesium carbonate solution (0.64 ml, 1.28 mmol). The mixture was subjected to three vacuum-argon cycles and then stirred at 100 ° C overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over sodium sulfate. The residue was purified by flash chromatography (EtOAc:EtOAc) The solid appeared as a mixture of the desired product and triphenylphosphine oxide by LCMS. The solid was triturated with EtOAc (EtOAc) (EtOAc) Purity: 98%.

LRMS(m/z): 386(M+1) ⁺

¹ H-NMR (400 MHz, CDCl 3 ) δ 8.24 (s, 1H), 7.78 (s, 1H), 7.77 (br s, 2H), 7.11-7.06 (m, 2H), 6.59 (d, 1H), 5.64 5.57 (m, 1H), 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 (( 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 (S) -4-amino-6-((1-(4-(4-carbyl)-3,5) in THF (4 ml) and methanol (2 ml) -Dimethylphenyl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (( S )-4-Amino- 6-((1-(4-(4-formyl-3,5-dimethylphenyl)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (100 mg, 0.24 mmol) in a stirred solution and stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL). The mixture was extracted with EtOAc (3×EtOAc)EtOAc. The solvent was removed in vacuo to leave a yellow solid which was purified by flash chromatography (0% to 100% pet. . Purity: 99%.

LRMS(m/z): 415(M+1) ⁺

¹ H-NMR (400 MHz, CDCl 3 + a few drops of CD 3 OD) δ 8.11 (s, 1H), 7.81 (m, 1H), 7.71 (s, 2H), 7.02 (dd, 1H), 6.91 (m, 1H), 5.49 ( m,1H), 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]3 Pyrazin-4-yl)-N-(2-hydroxyethyl)-2,6-dimethylbenzamide (( 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)

(S) -4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Formonitrile (( S )-4-Amino-6-((1-(4-chloropyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (120 mg, 0.38 mmol) was dissolved in dioxane (4 ml). Addition of N- (2-hydroxyethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl ) N- (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(II) dichloromethane chloride complex (31 mg, 0.038 mmol) and 2M cesium carbonate solution (0.38 ml, 0.76 mmol). The mixture was subjected to three vacuum-argon cycles and 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 sulfate. The residue was purified by preparative HPLC to afford 49 mg (yield: 27%) Purity: 98%.

LRMS(m/z): 472(M+1) ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ 8.43 (t, 1H), 8.17 (m, 1H), 8.02 (s, 1H), 7.81 (s, 2H), 7.50 (d, 1H), 7.35 (br s , 2H), 7.23 (dd, 1H), 7.09 (m, 1H), 5.47-5.40 (m, 1H), 4.74 (t, 1H), 3.56 (m, 2H), 3.3 (m, 2H, by water Peak cover), 2.35 (s, 6H), 1.65 (d, 3H)

Example 191

N-(3-(4-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)pyrrolo[2,1-f][1,2 ,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide ( N- (3-(4-( (( S )-1-(4-((2 S ,6 R )-2,6-Dimethylmorpholino)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino) -7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide)

Trifluoroacetic acid (2ml) and a solution of N - (3- (4 - ( ((S) -1- (4 - ((2 S, 6 R) -2,6- dimethyl-morpholinyl) pyrrolo [ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H - - pyrrolo [2,3- d] pyrimidin-5-yl) phenyl) methanesulfonamide Amides (N - (3- (4 - (((S) -1- (4 - ((2 S, 6 R -2,6-dimethylmorpholino)pyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)methanesulfonamide) (200 mg, 0.28 mmol) was stirred at room temperature for 1.5 hours. The trifluoroacetic acid was then removed under reduced pressure. The mixture obtained was then diluted in 5 ml of methanol and 2.6 ml of a 7 M ammonia solution in methanol was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue obtained was crystalljjjjjjjjj The aqueous phase was extracted again with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate The crude product was purified by flash chromatography eluting elut elut elut elut Purity: 95%.

LRMS(m/z): 562(M+1) ⁺

^{1 H NMR (500MHz, CDCl3)} δ 1.26 (6H, dd), 1.61 (3H, d), 2.76 (1H, m), 2.87 (1H, m), 3.02 (3H, s), 3.67 (2H, m) , 4.58 (2H, m), 5.34 (1H, m), 6.49 (1H, d), 6.62 (1H, dd), 6.66 (1H, dd), 7.10 (1H, s), 7.37-7.56 (4H, m ), 7.86 (1H, br s), 8.43 (1H, s), 10.81 (1H, br s)

According to the methods and procedures described above, the methods described in Schemes 1 to 6 and the above examples, the following compounds were obtained.

Example 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)-1H-indol-6-yl ) methanesulfonamide Amides (N - (4- (4 - (((S) -1- (4 - ((3 S, 5 R) -3,5-Dimethylpiperazin-1-yl) -5-methylpyrrolo [2 , 1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-1 H -indol-6-yl) Methanesulfamide)

Example 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[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl)methanesulfonamide (( S )- N -(4-(4-((1-(4-(2,6-Dimethylpyridin-4-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2 -yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-1 H -indol-6-yl)methanesulfamide)

Example 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)-1H-indol-6-yl)methanesulfonamide (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)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-1 H -indol-6-yl)methanesulfamide)

Example 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 (( 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)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine)

Example 196

(S)-3-(4-(4-((1-(4-(methylamino))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)-1H-pyrazole-1 -( S )-3-(4-(4-(4-(4-(2-(4-(Dimethylamino)piperidin-1-yl)ethoxy)-5-methylpyrrolo[ 2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-1 H -pyrazol-1-yl )propan-1-ol)

Example 197

(S)-1-(5-(4-((1-(4-(4-(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)-2-methoxypyridine -3-yl)urea(( S )-1-(5-(4-(4-(4-(4-(4-(4-())))))) 1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methoxypyridin-3-yl)urea)

Example 198

N ¹ -(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)-N ^2, N ² - dimethyl-ethane-1,2-diamine ^{(N 1 - (4- (4} - (((S) -1- (4 - ((3 S, 5 R) -3,5 -Dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-5 -yl)pyridin-2-yl)- N ² , N ² -dimethylethane-1,2-diamine)

Example 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] Pyrimidine-4-amine ( N -(( S )-1-(4-((3 S ,5 R )-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)-7 H -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-A Pyryrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(1-(3-(dimethylamino)propyl)piperidin-4-yl)- 5-(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)

Example 201

3-(4-Amino-1-((4-(2-(dimethylamino)propyl))(methyl)amino)ethoxy)-5-methylpyrrolo[2,1 -f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4- Amino-1-((4-(2-(3-(dimethylamino)propyl)(methyl)amino)ethoxy)-5-met hylpyrrolo[2,1- f ][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-(methylamino)methyl)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2, 1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (3-(4) -Amino-1-((4-(2-(4-(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)

Example 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

Example 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

Example 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol (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)

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 (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]triazine- 2-yl)methyl)-1H-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)-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 (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 (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 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)

Reference material

The following experimental procedure described in Preparation ^1: Simmen, Kenneth Alan; Lin, Tse-I; Lenz, Oliver; Surleraux, Dominique Louis Nestor Ghislain; Raboisson, Pierre Jean-Marie Bernard, PCT Int.Appl (2006) WO2006035061...

² The following steps of preparation are described in: PCT Int. Appl., 2010151735.

The following experimental procedures for the preparation of ^{3 are} described in: Ohta, T.; Fukuda, T.; Ishibashi, F., Iwao, MJ Org. Chem., 2009, 74, 8143-8153.

The following experimental procedures for the preparation of ^{4 are} described in: Mazaro, G. et al., Green Chem., 2009, 11, 774-776.

The following experimental procedures for the preparation of ^{5 are} described in: Wu, Y.-C., J. Am. Chem. Soc., 2008, 130(22), 7148-7152.

The following steps for the preparation of ⁶ are described in: PCT Int. Appl., 2012064973.

Pharmacological activity

Enzyme inhibition assay of PI3Kα, β, δ and γ

Compound in its inhibition PI3Kα (PI3Ka), PI3Kβ (PI3Kb ), ability PI3Kδ (PI3Kd) and PI3Kγ (PI3Kg), the detection is based on the use of PI3K HTRF ^TM (Millipore (Millipore) Company, catalog # 33-017) cells without Screening.

PI-3 enzyme HTRF kit (No. # 33-037) and different PI3K recombinant isomers (No. # 14-602, No. 14-603, No. 14-604, No. 15-558 for α, β, δ, respectively γ) was purchased from Millipore (characterized in insect cells). ATP is purchased from Sigma Aldrich (No. # A7699).

The compound was preincubated with the enzyme for 30 minutes before starting the catalytic reaction. [PIP2] is used for its Km constant. [ATP] The amount of all isomers for technical reasons was 15 μM (depending on the Km value of the isomers varying between 10 and 20 μM). The detection time and [enzyme] are optimized in a linear range. Stop using the detection mixture as a PI-3 enzyme kit designated by Millipore.

Final test condition

The reaction time and enzyme concentration in the assay will be based on each batch.

All experiments were performed using IDBS's Activity Base software and a four-parameter logarithmic equation.

The results are shown in Table 1.

As can be seen from Table 1, the compound of formula (I) is a potent inhibitor of phosphoinositide 3-enzyme delta (PI3kd). Preferred compounds of the invention have an inhibitory effect on PI3Kd (as defined above) having less than 10 [mu]M (10,000 nM), preferably less than 1 [mu]M (1,000 nM), even more preferably less than 0.2 [mu]M (200 nM), optimally IC ₅₀ values of less than 0.05 μM (50 nM).

The invention also relates to a compound of the invention as described herein for use in the therapeutic use of a human or animal body. The compounds of the invention intended for pharmaceutical use may be used as crystalline or amorphous products, or mixtures thereof. For example, they can be obtained by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying as solid plugs, powders or films. Microwave or radio frequency drying can be used for this purpose.

combination

The compounds of formula (I) as defined herein may also be combined with other active compounds useful for the treatment of pathological conditions or diseases which are readily ameliorated by the inhibition of phosphoinositide 3-kinase (PI3Ks).

Combinations of the invention may optionally comprise one or more additional active substances which are known to be useful in the treatment of respiratory diseases, allergic diseases, inflammatory reactions or autoimmune mediated diseases. (inflammatory or autoimmune-mediated diseases), dysfunctional and neurological disorders and pain, cardiovascular diseases, viral infections, metabolic/endocrine dysfunction (metabolism/endocrine) Function disorders), bone marrow and organ transplant rejection, myelo-dysplastic syndrome, myeloproliferative disorders (MPDs), cancer and hematological malignancies (cancer and Hematologic malignancies), leukemia, lymphomas, and solid tumors.

In particular, the combinations of the invention may optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases such as leukemia, lymphomas and solid tumors. )); transplant rejection; bone marrow transplantation applications (eg, graft-versus-host disease); autoimmune diseases (eg rheumatoid arthritis, multiple sclerosis) ), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia (autoimmune hemolytic anemia), type I diabetes, cutaneous vasculitis, cutaneous lupus Erythematosus), dermatomyositis, and vesicular disease including but not limited to pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa ( Blistering diseases)); respiratory inflammatory diseases (eg, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis) Sarcoidosis)); skin inflammatory diseases (such as atopic dermatitis, contact dermatitis, eczema or psoriasis); pre-cancerous and malignant skin diseases (premalignant and malignant) Skin conditions) (eg basal cell carcinoma (BCC), squamous cell carcinoma (SCC)) or actinic keratosis (AK); neurological disorders and pain (eg rheumatoid) Arthritis (rheumatoid arthritis) or osteoarthritis (osteoarthritis), low back pain, general inflammatory pain, inflammatory neuropathic pain Athic pain), trigeminal neuralgia or pain associated with central pain.

Preferably, the combination of the invention optionally comprises one or more additional active substances which are known to be useful in the treatment of neoplastic 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 1 diabetes, cutaneous vasculitis, erythema Lupus erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullous pemphigoid and Blistering diseases of epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis ), sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cells Basal cell carcinoma, squamous cell carcinoma, and actinic keratosis.

Compound as defined above combination of the invention comprises (I); and (ii) another compound selected from the group consisting of: adenosine A _2A agonist (Adenoside A _2A agonist), an agent for treating cardiovascular disease An agent for treating diabetes, an agent for treating liver disease, an anti-allergic agent, an anti-cholinergic agent, an anti-inflammatory agent, an anti-infective agent, a β2-adrenergic agonist (β2-adrenergic agonist) Inhibitors of chemoattractant receptor homologous molecules (CRTH2), chemotherapeutic agents, corticosteroids, IKKβ/IKBKB (IkB kinase β or IKK2) inhibitors expressed on TH ₂ cells , immunosuppressant, Janus kinase (JAK) inhibitor, localized p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitor, small intestinal phosphodiesterase (PHO) IV inhibitors and spleen tyrosine kinase (Syk) inhibitors are used simultaneously, separately or sequentially in the treatment of human or animal body.

In a particular embodiment, the composition of the invention optionally comprises one or more additional active substances selected from the group consisting of: a) a Dyhydrofolate reductase inhibitor such as methyl folate (Methotrexate) or CH -1504; b) Dihydroorotate dehydrogenase (DHODH) inhibitors, such as leflunomide, teriflunomide, or international patent application number WO2008/077639 and WO2009/ a compound as described in 021696; c) an immunomodulator such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; d) DNA synthesis and repair Inhibitors, such as Mitoxantrone or Cladribine; e) immunosuppressive agents, such as Imuran (azathioprine) or Purinethol (6- Hydrogenthiopurine or 6-MP); f) anti-α 4 integrin antibody, such as Natalizumab (Tysabri); g) α 4 integrin antagonist, such as R- 1295, TBC-4746, CDP-323, ELND-002, Fiatgrast or TMC-2003; h) Adrenal cortex (C) Orticoids) and glucocorticoids, such as prednisone or methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide (ciclesonide) or beta-metasone; i) fumarate, such as BG-12; j) anti-tumor necrosis factor-alpha (anti-TNF-α) Individual antibodies such as Infliximab, Adalimumab or Certolizumab pegol; k) Soluble Tumor Necrosis Factor-α (TNF-α) Receptor Antagonists (Antagonists), such as etanercept; l) anti-CD20 (lymphocyte protein) monoclonal antibodies, such as rituximab (Rituximab), okrezumab (Ocrelizumab), ovalimumab (Ofatumumab) or TRU-015; m) monoclonal antibodies against CD52 (lymphocyte protein), such as alemtuzumab; a) anti-CD25 (lymphocyte protein), such as daclizumab ;o) anti-CD88 (lymphocyte protein), such as eculizumab or pexilizumab; p) anti-interleukin 6 receptor (Ant) i-Interleukin 6 Receptor) (IL-6R), such as tocilizumab; q) anti-interleukin 12 receptor (IL-12R) / interleukin 23 receptor (IL-23R), such as Ute 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 agonism Agents such as Santix; u) Chemokine CCR1 antagonists such as MLN-3897 or PS-031291; v) Chemokine CCR2 antagonists such as INCB-8696; w) Necrosis factor-κB (NF) -κB or an NFKB) activation inhibitor, such as sulfasalazine (sulfasalazine), iguratimod (iguratimod) or MLN-0415; x) adenosine A _2A agonist (adenosine A _2A agonists), such as ATL-313 , ATL-146e, CGS-21680, Regadenoson or UK-432,097; y sphingosine-1 (S1P) phosphate receptor agonist, such as fingolimod ), BAF-312 or ACT128800; z) sphingosine-1 (S1P) Lyase inhibitors, such as LX2931; aa) Spleen tyrosine kinase (Syk) inhibitors, such as R-112; bb) protease inhibitor (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 (a molecule with dual activity: beta-adrenergic agonist and muscarinic receptor antagonist); ff) histamine 1 (H1) receptor antagonists, such as azelastine or ebastine; gg) Cysteinyl leukotriene (CysLT) receptor antagonists, such as Meng Montelukast; hh) mast cell stabilizers, such as nedocromil or chromoglycate; ii) 5-lipoxygenase-activating protein (FLAP) inhibition Agents such as MK886 or BAY X 1005; jj) 5-lipoxygenase (5-LO) inhibitors, such as WY-50295T; kk) chemoattractant receptors expressed on TH ₂ cells Source molecule (CRTH2) inhibitors, such as OC-459, AZD-1981, ACT-129968, QAV-680; ll) vitamin D derivatives, such as 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, apribicoxib, celecoxib, cimicoxib, deracoxib , etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 or valdecoxib (valdecoxib); nn) anti-allergic agent; oo) antiviral agent; pp) phosphodiesterase (PDE) III inhibitor; qq) phosphodiesterase (PDE) IV inhibitor, such as roflus Roflumilast or GRC-4039; rr) diphosphatase (PDE) III/IV inhibitor; ss) xanthine derivative such as theophylline or theobromin e); tt) p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitors, such as ARRY-797; uu) mitotically activated extracellular signal-regulated kinase kinase (MEK) inhibitors, such as ARRY-142886 or ARRY-438162; vv) Janus kinase (JAK) inhibitors, such as tofacitinib from Pfizer (formerly known as tassocitinib or CP-690, 550), and from English Incyte's INCB-18424;ww) interferon contains interferon beta 1a, such as Avonex from Biogen Idec and CilnoVex from CinnaGen (CinnoVex) ) and Rebif from EMD Serono, as well as interferon beta 1b, such as Betaferon from Schering and Bethel from Berex Betaseron; xx) interferon alpha, such as Sumiferon MP; yy) Epidermal Growth Factor Receptor (EGFR) inhibitors, such as erlotinib, trastuzumab Resistance (Trastuzumab), Herceptin, Avastin, Platins (cisplatin, carboplatin (cisplatin, ca Rboplatin)) or temozolomide (zz) anti-tumor agents, such as docetaxel, estramustine, anthracyc lines, (doxorubicin) (Adriamycin)), epirubicin (Ellence) and liposomal doxorubicin (Doxil), taxane (taxane) (docetaxel (taxotere) (Taxotere)), paclitaxel (Taxol) and protein-bound Pacific paclitaxel (Abraxane), Cyclophosphamide (Cytoxan), and Capec Capecitabine (Xeloda), 5 fluorouracil (5 FU), Gemcitabine (Gemzar) or Vinorelbine (Navelbine) Specific examples of suitable corticosteroids and glucocorticoids that can be combined with the PI3K inhibitors of the invention are prednisolone, methylprednisolone, dexamethasone. , dexamethasone cipecilate, naflocort, difluxate (d Eflazacort), halopedone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, acetone Fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitate (dexamethasone) Palmitoate), tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, sulfophane Methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butbutocort (butixocort) Propionate), RPR-106541, deprodone propionate, fluticasone propionate, furan Fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, strong Prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, dipropionic acid Betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate, and hydrocortisone probutate.

Specific examples of suitable Syk enzyme inhibitors that can be combined with the PI3K inhibitors of the invention are fosfamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel), R-112 (from Rigel), piceatannol, 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)phenylamino]pyrimidine-5-carboxamide , R-091 (from Rigel), 6-[5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4 -Dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-one benzenesulfonate (R-406 from Rigel), 1-(2,4,6-trihydroxyl) Phenyl)-2-(4-methoxyphenyl)ethan-1-one, N-[4-[6-(cyclobutylamino)-9H-indol-2-ylamino]phenyl]-N -methylacetamide (QAB-205 from Novartis), 2-[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine-5-dihydrochloride Aminoamino]pyridine-3-carboxamide (BAY-61-3606 from Bayer) and AVE-0950 (from Sanofi-Aventis).

Specific examples of suitable M3 antagonists (anticholinergic agents) which may be combined with the PI3K inhibitors of the invention are tiotropium salts, oxitropium salts, flutropium salts, Ipratropium salt, glycopyrronium salt, trastium salt, zamifenacin, revatropate, espatropate, bromine Darotropium bromide, CI-923, NPC-14695, BEA-2108, 3-[2-hydroxy-2,2-bis(2-thienyl)ethyloxy]-1-(3- Phenoxypropyl)-1-azaindole bicyclo[2.2.2]octane salt (3-[2-Hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane salts) (especially aclidinium salt, more preferably adiponium bromide), 1-(2-phenylethyl)-3-(9H-dibenzopiperine) Meryl-9-ylcarbonyloxy)-1-azaindole bicyclic [2.2.2] Octane salt (1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts), 2-oxy-1,2, 3,4-tetrahydroquinazoline-3-carboxylic acid internal-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (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-mercaptopiperazin-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-phenylacetamidamine (N-[1-(6-Aminopyridin-2-ylmethyl)piperidin -4-yl]-2(R)-[3,3-difluoro-1(R)-cyclopentyl]-2-hydroxy-2-phenylacetamide) (J-104135), 2(R)-cyclopentyl-2 -hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamidamine (2(R)-Cyclopentyl-2-hydroxy-N-[1- [4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide)(J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[1-(4-methyl-3) -pentenyl)-4-piperidinyl]-2-phenylacetamidamine (2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl ]-2-phenylacetamide) (J-104129), 1-[4-(2-Amine B) Piperidin-1-yl]-2(R)-[3,3-difluorocyclopenta-1(R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634 ), N-[N-[2-[N-[1-(cyclohexylmethyl)piperidin-3(R)-ylmethyl]amine-carbamoyl]ethyl]amine-methylmethyl) -3,3,3-triphenylpropanamide (Banyu CPTP), 2(R)-cyclopentyl-2-hydroxy-2-phenylacetic acid 4-(3-azabicyclo[3.1.0] 3-yl)-2-butynyl ester ((Ranbaxy 364057), iodide 3(R)-[4,4-bis(4-fluorophenyl)-2-oxyimidazolidine-1-yl]- 1-methyl-1-[2-oxy-2-(3-thienyl)ethyl]pyrrolidinium (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-methylpiperidine Pyridin-3(S)-yl]-N-[N-[4-(isopropoxycarbonyl)phenyl]aminecarbamyl]-L-tyramine amine, UCB-101333, Merck OrM3, 7-endo-(2-hydroxy-2,2-diphenyl Ethyl ethoxy)-9,9-dimethyl-3-oxa-9-azaindole tricyclo[3.3.1.0(2,4)]decane salt, iodide 3(R)-[4, 4-Bis(4-fluorophenyl)-2-oxyimidazolidin-1-yl]-1-methyl-1-(2-phenylethyl)pyrrolidinium, bromination from Novartis (412682) -4-[2-[hydroxy-2,2-(dithien-2-yl)ethyloxy]-1-methyl-1-(2-phenoxyethyl)piperidinium, 7-( 2,2-Diphenylpropenyloxy)-7,9,9-trimethyl-3-oxa-9-azinium tricyclo[3.3.1.0*2,4*]decane salt, 7- Hydroxy-7,9,9-trimethyl-3-oxa-9-azinium tricyclo[3.3.1.0*2,4*]decane 9-methyl-9H-indole-9-carboxylate , all of which are in the form of racemates, enantiomers, diastereomers and mixtures thereof, and as the case may be pharmacologically relevant The acid addition salt form. Among the salts, chlorides, bromides, iodides and methanesulfonates are preferred.

Specific examples of suitable beta adrenergic agonists (beta 2 agonists) which may be combined with the PI3K inhibitors of the invention are terbutaline sulphate, eformoterol fumarate ), formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, dopexamine, Metaproterolol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, salbutamol sulfate (albuterol sulphate) ), salbutamol sulphate, salmefamol, salmeterol xinafoate, carmoterol hydrochloride, hydrochloric acid (R)-salbutamol ((R)-albuterol Hydrochloride), Levalbuterol hydrochloride, Levosalbutamol hydrochloride, (-)-salbutamol ((-)-Salbutamol hydrochl Oride), formoterol, tartaric acid (R,R)-formoterol ((R,R)-Formoterol Tartrate), Arformoterol tartrate, sulfonterol, Bedordrine 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-(1H-benzimidazol-1-yl)-1,1-dimethylpropylamino]-1 -hydroxyethyl]-2-(4-methoxydecylamino)phenol, 1-[2H-5-hydroxy-3-oxy-4H-1,4-benzoxazine-8-yl] -2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxy- 4H-1,4-benzoxazine-8-yl]-2-[3-(4-dimethoxyphenyl)-2-methyl-2-propane Amino]ethanol, 1-[2H-5-hydroxy-3-oxy-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butoxyhexyl)- 2-Methyl-2-propylamino]ethanol, KUL-1248, HOKU-81, SM-110444, RP-58802B, LAS100977 (abediterol) and PCT Patent Application No. WO 2007/ Compounds described in No. 124898, WO 2006/122788 A1, WO 2008/046598, WO 2008095720, WO 2009/068177, and WO 2010/072354.

A specific example of a suitable anti-allergic agent that can be combined with a PI3K inhibitor of the invention is an antihistamine (e.g., Methapyrilene, Mequitazine, Azelastine hydrochloride, A Acrivastine, Emedastine difumarate, Emedastine fumarate, Lola Lyatadine, Cyproheptadine hydrochloride, Diphenhydramine hydrochloride, Doxepin hydrochloride, Promethazine hydrochloride, Levocabastine hydrochloride ), Desloratadine, Cinnarizine, Setastine hydrochloride, Mizolastine, Ebastine, Cetirizine hydrochloride Hydrochloride), Epinastine hydrochloride, Olopatadine hydrochloride, Bepotastine besilate, Triprolidine hydrochloride, fumaric acid Rupatadine fumarate, Fexofenadine hydrochloride, Levocetirizine dihydrochloride, Ketotifen, azacitidine maleate Azatadine maleate), Dimethindene maleate, Clemastine fumarate, Aka Set (Alcaftadine), Bilasiting (Bilastine), given his horse cutting hydrochloride (Vapitadine hydrochloride), AZD-1744, GSK-1004723D, GSK-835726, or SUN-1334H.

Specific examples of suitable phosphodiesterase IV (PDE IV) inhibitors which can be combined with the PI3K inhibitors of the invention are benafentrine dimaleate, etazolate, and Denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tyrost (tipelukast), tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, liralast ( Lirimilast), Roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R )-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5-di Chloro-4-pyridyl)-2-[1-(4-fluoroindolyl)-5-hydroxy-1H-indol-3-yl]-2-oxoethylamine (GSK-842470), 9- (2-fluoroindolyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-dichloro-4-pyridyl)-8-methoxy Quinoline-5-formamide (D-4418), 3-[3-(cyclopentyloxy)-4-methoxyindolyl]-6-(ethylamino)-8-isopropyl- 3H-indole hydrochloride (V-11294A), 6-[3-(N,N-dimethylaminecarbamimidino)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)pyridine-2(1H)-one (T-440), (-)-trans-2-[3'-[3-(N-cyclopropylaminecarbamidine) 4-yloxy-1,4-dihydro-1,8-naphthyridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid, MK-0873, CDC-801, UK-500001, BLX-914, 2-methoxycarbonyl-4-cyano-4-(3-cyclopropyl Methoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl) ring Hex-1-ol, 5(S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylindolyl)piperidin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22 (Supp. 45): Abstract 2557) and PCT Patent Application No. WO 03/097613, WO 2004/058729, WO 2005/049581, Compounds as claimed in WO 2005/123693, WO 2005/123692 and WO 2010/069504.

Specific examples of suitable immunosuppressive agents which can be combined with the PI3K inhibitors of the invention are picemolimus, tacrolimus, cyclosporine A, leflunomide ( Leflunomide), teriflunomide, vadofludimus, laquinimod (laquinimod), methotrexate, 5-fluorouracil (5-FU), anti-TNF agent, and PCT patent application No. WO 2008/077639, WO 2009/021696, WO Compounds described in 2009/153043 and WO2010083975 (especially those selected from the group consisting of amino(iso)nicotinic acid derivatives: 2-(3'-ethoxylated) Keto-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid, 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino) An alkali acid and 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; and a derivative selected from the group consisting of azabiphenylaminobenzoic acid : 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-infective agents which can be combined with the PI3K inhibitors of the invention are aclarubicin, actinomycin D, amrubicin, liposome anthracycline (annamycin), adhamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin ), galarubicin, idarubicin, mitomycin C, mupiricin, nemorubicin, neocarcinomatin ), peplomycin, pirarubicin, rebeccamycin, retapamulin, stimalamer, streptozocin, pentrebi Valrubicin, zinostatin, amphotericin B, bifonazole, caspofungin, clotrimazole, echinocandin B (echinocandin B), econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, posaconazole (posaconazole), ravconazole, terbinafine, tioconazole, voriconazole, and combinations thereof.

A particularly preferred combination according to the invention comprises 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 salt, glycopyrronium salt, 3-[2-hydroxy-2,2-bis(2- Thienyl)ethoxycarbonyl]-1-(3-phenoxypropyl)-1-indolizine bicyclo[2.2.2]octane salt (especially adipic ammonium salt, preferably adenosine bromide , 1-(2-Phenylethyl)-3-(9H-dibenzopyran-9-ylcarbonyloxy)-1-indolylbicyclo[2.2.2]octane salt, formoterol , salmeterol, indacaterol, cammotrol, LAS 100977 (abbidite), PCT patent application No. WO 2008/077639, WO 2009/021696, WO 2009/153043 and The compound described in WO 2010/083975 (particularly an amine (iso) nicotinic acid derivative selected from the group consisting of 2-(3'-ethoxy-3-(trifluoromethoxy) Biphenyl-4-ylamino)nicotinic acid, 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamine a nicotinic acid and 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; and an azabiphenylene benzoic acid derivative selected from the group consisting of :5-Cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid, 5-cyclopropyl-2-((2-(2-(3) Fluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid and 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzene Formic acid), mesalazine, cetirizine, lorazidine, ebastine, desloratadine, fexofenadine, urastatin, levocabastine, olopatadine, montan Russell, Peak Morimose, Tacrolimus, Mopirixine, ritamamol, clotrimazole, ketoconazole and terbinafine.

The compounds and combinations of the formula (I) of the present invention are useful for treating respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; dysfunction and neurological disorders; cardiovascular diseases; viral infections; metabolic/endocrine dysfunction Neurological disorders and pain; bone marrow and organ transplant rejection; myelodysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; Leukemia; lymphoma and solid tumors, where the use of PI3K inhibitors is expected to have beneficial effects, such as leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's Disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, type 1 diabetes, cutaneous vasculitis, erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullae Type of pemphigus and epidermal blistering vesicular disease, asthma, chronic obstructive pulmonary disease, pouch Fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma, and actinic keratosis .

In particular, pathological symptoms or diseases are selected from leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic erythema Lupus, autoimmune hemolytic anemia, type 1 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 may be administered together in the same pharmaceutical composition, or in separate compositions intended to be separated by the same or different routes, simultaneously, Accompanyed or sequentially.

It is envisaged that all active agents will be administered simultaneously, or in close proximity. Alternatively, one or both active agents can be administered in the morning while another (other) active agent is administered later in the day. Or in another embodiment, one or two active agents can be administered twice a day, while another (other) active agent is administered once a day, while one of the twice daily doses occurs simultaneously, or separately. Preferably at least two, and more preferably all of the active agents will be administered together at the same time. Preferably at least two, and more preferably all of the active agents will be applied as a blend.

The invention also relates to a combination of a compound of the invention and one or more other therapeutic agents for the treatment of pathological conditions or diseases which are readily ameliorated by inhibition of phosphoinositide 3-kinase (PI3K), particularly Pathological symptoms or diseases are selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; dysfunction and neurological disorders and pain; cardiovascular diseases; viral infections; metabolic/endocrine dysfunction; bone marrow and organs Transplant rejection; myelodysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; leukemia; lymphoma and solid tumors; In particular, the pathological symptoms or diseases are selected from leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, whole body erythema Lupus, autoimmune hemolytic anemia, type 1 diabetes, cutaneous vasculitis, skin erythematous wolf Dermatomyositis, including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermoid vesicular blisters, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibers , 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 compound of the invention in combination with one or more other therapeutic agents for the manufacture of a formulation or medicament for the treatment of the disease.

The present invention also provides a method of treating pathological symptoms or diseases which are easily ameliorated by inhibiting phosphoinositide 3-kinase (PI3Ks), particularly wherein the pathological symptoms or diseases are selected from respiratory diseases; allergic diseases; inflammatory reactions Or autoimmune-mediated diseases; dysfunction and neurological disorders and pain; cardiovascular disease; viral infection; metabolic/endocrine dysfunction; bone marrow and organ transplant rejection; myelodysplastic syndrome; myeloproliferative disorders (MPD, such as Acute polycythemia, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; leukemia; lymphoma and solid tumors; more particularly where pathological symptoms or diseases are selected from leukemia, lymphoma and entities Tumor, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, type 1 diabetes, skin Vasculitis, erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, bullous type Blisters, 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.

Depending on the nature of the condition to be treated, the active compound of the combination of the invention may be administered by any suitable route, for example, orally (in syrup, lozenge, capsule, buccal, controlled release formulation, rapid dissolution) Formulations, etc.); topical (in the form of a cream, ointment, lotion, nasal spray or aerosol); by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by inhalation (in Dry powder, solution, dispersion, etc.).

The active compound in the composition, that is, the combination of the formula (I) of the present invention The active compounds which may be employed in the same pharmaceutical compositions or in separate compositions which are intended to be administered separately, simultaneously, concomitantly or sequentially by the same or different routes may be co-administered in the same pharmaceutical composition.

An embodiment of the invention consists of a kit of dispensing parts comprising an imidazole pyridine derivative of the invention and for simultaneous, parallel, separate or sequential combination with another active compound suitable for the treatment of the following diseases Instructions: respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; dysfunction and neurological disorders and pain; cardiovascular disease; viral infection; metabolic/endocrine dysfunction; bone marrow and organ transplant rejection; Adverse syndromes; myeloproliferative disorders (MPDs, such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; leukemia; lymphomas and solid tumors; more particularly pathological symptoms Or the disease is selected from leukemia, lymphoma and solid tumor, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune Hemolytic anemia, type 1 diabetes, cutaneous vasculitis, erythematous lupus Dermatomyositis, including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermoid vesicular blisters, 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 embodiment of the invention consists of a package comprising an imidazole pyridine derivative of the invention and another active compound suitable for the treatment of a respiratory disease; an allergic disease; an inflammatory response or an autoimmune mediated disease; Dysfunction and neurological disorders and pain; cardiovascular disease; viral infection; metabolic/endocrine dysfunction; bone marrow and organ transplant rejection; myelodysplastic syndrome; Sexual disorders (MPDs, such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; leukemia; lymphomas and solid tumors; more particularly where pathological symptoms or diseases are selected Leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, Type 1 diabetes, cutaneous vasculitis, erythematous lupus erythematosus, dermatomyositis, blistering, asthma, chronic obstructive, including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermal blistering Lung disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and light Keratosis.

Pharmaceutical Compositions

The pharmaceutical compositions according to the invention comprise a compound of the invention, together with a pharmaceutically acceptable diluent or carrier.

The term "pharmaceutical composition" as used herein refers to one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt, solvate, oxynitride, stereoisomer thereof, A deuterated derivative or prodrug thereof, in admixture with other chemical ingredients, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to the organism.

As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

The invention further provides a pharmaceutical composition comprising a compound of the invention And a pharmaceutically acceptable diluent or carrier, and one or more additional therapeutic agents for treating pathological conditions or diseases which are readily ameliorated by inhibition of phosphoinositide 3-kinase (PI3Ks) as previously described.

The present invention is also directed to a pharmaceutical composition of the present invention for treating pathological symptoms or diseases which are easily ameliorated by inhibiting phosphoinositide 3-kinase (PI3Ks), particularly wherein the pathological condition or disease is selected from the respiratory tract Disease; allergic disease; inflammatory response or autoimmune-mediated disease; dysfunction and neurological disorders and pain; cardiovascular disease; viral infection; metabolic/endocrine dysfunction; bone marrow and organ transplant rejection; myelodysplastic syndrome; Myeloproliferative disorders (MPDs, such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancies; leukemia; lymphomas and solid tumors; more particularly pathological symptoms or disease systems Selected from leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic Anemia, type 1 diabetes, cutaneous vasculitis, erythematosus, dermatomyositis, including but not limited to vulgaris Pemphigus, bullous pemphigoid and epidermoid vesicular blister, 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 the treatment of said disease.

The present invention also provides a method of treating pathological symptoms or diseases which are easily ameliorated by inhibiting phosphoinositide 3-kinase (PI3Ks), particularly wherein the pathological symptoms or diseases are selected from respiratory diseases; allergic diseases; inflammatory reactions Or autoimmune-mediated diseases; dysfunction and neurological disorders and pain; cardiovascular disease; viral sensation Dyeing; metabolic/endocrine dysfunction; bone marrow and organ transplant rejection; myelodysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or myelofibrosis); cancer and hematological malignancy Disease; leukemia; lymphoma and solid tumor; more particularly where the pathological symptoms or diseases are selected from leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, type 1 diabetes, cutaneous vasculitis, erythematous lupus erythematosus, dermatomyositis, including but not limited to pemphigus vulgaris, Blister-type pemphigus and epidermal blistering vesicular disease, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic skin Inflammation, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma, and actinic keratosis.

The invention also provides a pharmaceutical composition comprising at least a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether it is intended to be further diluted prior to administration. Preferably, the compositions are formulated in a form suitable for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be readily apparent to those of ordinary skill in the art. The compositions and methods for their preparation can be found, for example, in Lei Mingdeng: Science and Practice in Medicine, 21st Edition, Lin Pinka Williams & Wilkin, Philadelphia, Pa, 2001 (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 compounds or salts of such compounds to form the compositions of the present invention are well known per se, and the actual excipients employed will depend, in particular, on the intended method of administration of the compositions. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Other suitable carriers for formulating the compounds of the 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 can be administered orally (peroral administration; per os (Latin)). Oral administration involves swallowing so that the compound is absorbed from the digestive tract and transmitted to the liver via the portal circulation (the first metabolism of the liver) and eventually into the gastrointestinal (GI) tract.

Compositions for oral administration may be in the form of lozenges, retarded tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalers or liquid preparations, such as mixtures, solutions , elixirs, syrups or suspensions, all containing a compound of the invention; the formulation can be prepared by methods well known in the art. The active ingredient can also be presented in the form of a bolus, an electuary or a paste.

When the composition is in the form of a lozenge, any of the pharmaceutical carriers conventionally used in the preparation of solid formulations may be employed. Examples of the carrier include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose, and sucrose.

Tablets may be compressed or molded by one or more accessory ingredients as appropriate Prepared by system. The compressed lozenge can be in a free-flowing form such as a powder or a mixture of a binder, a lubricant, an inert diluent, a lubricanting agent, a surfactant or a dispersing agent, as appropriate in a suitable machine. The active ingredient of the granule is prepared.

Molded lozenges can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The lozenges may optionally be coated or scored and may be formulated to provide relief or controlled release of the active ingredient therein.

The dosage of the tablet may range from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, the tablet usually contains a disintegrant. Examples of the disintegrant include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose. Sodium), crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, low-carbon alkyl substituted hydroxypropyl fiber Lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. In general, the disintegrant will comprise from 1% to 25% by weight, preferably from 5% to 20% by weight of the dosage form.

Adhesives are commonly used to impart adhesive qualities to lozenge formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxyl Propyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrate, etc.), mannitol, xylitol, dextrose, sucrose (sucrose), Sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, as well as slip agents such as ceria and talc. When present, the amount of surfactant is typically from 0.2% to 5% by weight of the tablet, and the slip agent is typically from 0.2% to 1% by weight of the tablet.

Tablets also typically contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and magnesium stearate and sodium lauryl sulfate ( A mixture of sodium lauryl sulphate). The lubricant is usually present in an amount of from 0.25% to 10% by weight, preferably from 0.5% to 3% by weight of the tablet. Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

Exemplary lozenges contain up to about 80% by weight of the drug, from about 10% to about 90% by weight of the binder, from about 0% to about 85% by weight of the diluent, from about 2% to about 10% by weight of the disintegrant, and about From 0.25 wt% to about 10 wt% lubricant. The tablet blend can be compressed directly or by a roll to form a tablet. Alternatively, portions of the tablet blend or blend may be wet granulated, dry granulated or melt granulated, melt condensed or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; or encapsulated.

The formulation of lozenges is discussed in detail in "Pharmaceutical Formulations: Lozenges, Volume 1," by H. Lieberman and L. Rahman, Marcel Decker, New York, 1980 ("Pharmaceutical Dosage Forms: Tablets" , Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980).

When the composition is in the form of a capsule, any conventional encapsulation is suitable, for example in The above carrier is used in hard gelatin capsules. When the composition is in the form of a soft gelatin capsule, any pharmaceutical carrier conventionally used in the preparation of dispersions or suspensions, such as aqueous gum, cellulose, silicate or oil, may be considered and incorporated into soft gelatin. In the capsule.

Solid formulations for oral administration can be formulated for direct and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release techniques, such as high energy dispersions and osmotic and coated particles, can be found in Verma et al., Online Medical Technology, 25(2), 1-14 (2001) (Verma et al, Pharmaceutical Technology On -line, 25(2), 1-14 (2001)). The use of chewing ingots to achieve controlled release is described in WO 00/35298. The disclosure of the references is hereby incorporated by reference in its entirety.

Liquid formulations comprise suspensions, solutions, syrups and elixirs. The formulation may be used as a filler in soft or hard capsules and usually comprises a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and/or Suspending agent. The solution can be an aqueous solution of a soluble salt, or other derivative of the active compound, and, for example, sucrose used to form a syrup. The suspension may comprise the insoluble active compound of the invention, or a pharmaceutically acceptable salt thereof, and water, as well as a suspending or flavouring agent. Liquid formulations can also be prepared by reconstituting, for example, a solid from a sachet.

Ii) Oral mucosal administration

The compounds of the invention may also be administered via the oral mucosa. In the oral mucosal cavity, drug delivery is divided into three categories: (a) sublingual delivery, which is a comprehensive delivery of the drug through the mucosa in the inner layer of the oral cavity, and (b) transgraft transmission, which is via the face. The mucosa (buccal mucosa) of the buccal layer is administered drug, and (c) is delivered locally, which is the delivery of the drug into the oral cavity.

Pharmaceutical products intended to be administered via the oral mucosa can be designed using mucoadhesives, fast dissolving lozenges, and solid mouth-containing formulations formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxypropylcellulose, Polyvinyl pyrrolidone, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyisobutylene or polyisoprene; and enhanced oral mucosal penetration Agents such as butanol, butyric acid, propranolol, sodium lauryl sulphate and other enhancers are formulated together.

Iii) Inhaled administration

The compounds of the invention may also be administered by inhalation by inhalation of a powder inhaler, usually in the form of a dry powder (in the form of a separate mixture, for example in the form of a dry blend blended with lactose; or in the form of mixed component particles, for example with a phospholipid Phospholipidylcholine phospholipids mixed; or in the form of an aerosol spray from a pressurized container, pump, sprinkler, nebulizer (preferably a nebulizer using electrohydrodynamic forces to produce a fine mist) or nebulizer Inhalation administration, 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 comprise a bioadhesive such as chitosan or cyclodextrin.

The dry powder composition for local delivery to the lung by inhalation may, for example, be provided in capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator, or in a blister such as laminated aluminum foil. Formulations typically comprise a powder mix for inhalation of a compound of the invention with a suitable powder base (carrier material) such as lactose or starch. Lactose is preferably used. Each capsule or cartridge can usually contain between 0.001 and 50 mg, preferably Between 0.01 and 5 mg of the active ingredient or equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient can be provided without excipients.

The package of the formulation may be adapted for delivery in unit dose or multiple doses. In the case of multiple dose delivery, the formulation may be pre-metered or metered at the time of use. Thus, dry powder inhalers are divided into three groups: (a) a single dose, (b) multiple unit doses, and (c) multiple dose devices.

For the first type of inhaler, a single dose has been weighed by the manufacturer into a small container of mostly hard gelatin capsules. The capsule must be taken from a separate box or container and inserted into the receptacle area of the inhaler. Next, the capsule must be opened or perforated with a needle or cutting blade to pass a portion of the inspiratory flow through the capsule to entrain the powder or to expel the powder from the capsule via the opening during the inhalation by means of centrifugal force. After inhalation, the venting capsule must be removed from the inhaler again. In most cases, the inhaler must be disassembled to insert and remove the capsule, which can be a difficult and cumbersome operation for some patients.

Other disadvantages associated with the use of hard gelatin capsules for inhalation of powders are (a) poor effect of preventing moisture uptake from ambient air, and (b) problems with opening or opening after the capsule has been previously exposed to extreme relative humidity, This results in breaks or dents, and (c) the possibility of inhaling the capsule fragments. Furthermore, for many capsule inhalers, incomplete drainage has been reported (e.g., Nielsen et al., 1997).

Some capsule inhalers have cassettes from which individual capsules can be transferred to the receiving chamber for opening and venting in the receiving chamber as described in WO 92/03175. Other capsule inhalers have a rotating cassette containing a capsule chamber that can be lined up with the air line for dose discharge (e.g., WO 91/02558 and GB 2242134). It comprises a multi-unit dose inhaler, as well as blister inhalers having a limited number of unit dose supplies on the disc or on the strip.

The blister inhaler provides better medicinal repellency than the capsule inhaler. The powder is obtained by perforating the lid and the bulb foil, or by stripping the foil. When a blister strip is used instead of a disc, the number of doses can be increased, but replacing the empty strip is inconvenient for the patient. Thus, the device is typically discarded with the incorporated dosage system, including technical equipment for transporting the strip and opening the blister pocket.

Multi-dose inhalers do not contain pre-measured amounts of powder formulations. It consists of a relatively large container and a measuring principle that must be operated by the patient. The container carries multiple doses that are individually separated from a large volume of powder by volumetric displacement. There are various dose measuring configurations, including a rotatable film (eg, EP0069715) or a disk (eg, GB 2041763; EP 0424790; DE 4239402 and EP 0674533), a rotatable cylinder (eg, EP 0166294; GB 2165159 and WO 92/09322) and A rotatable frustum (e.g., WO 92/00771), all having a cavity that must be filled with powder from the container. Other multi-dose devices have measuring slides (e.g., US 5201308 and WO 97/00703) or measuring columns having local or circumferential pockets for displacing a particular volume of powder from the container into the transfer chamber or air duct Plugs (for example EP 0505321, WO 92/04068 and WO 92/04928), or measuring slides, such as Genuair® (formerly known as Novolizer SD2FL), which are described in the following numbered patent applications: WO97/000703, WO03 /000325 and WO2006/008027.

Reproducible dose measurement is a major concern for multi-dose inhaler devices.

Since the filled dose measuring cup or cavity is mostly affected by gravity, the powder formulation must exhibit good and stable flow properties.

For reloading single dose and multiple unit dose inhalers, dose measurement The accuracy and reproducibility can be guaranteed by the manufacturer. Multi-dose inhalers, on the other hand, can contain a much higher number of doses, while the number of prime doses is typically lower.

Because the inspiratory flow in a multi-dose device typically passes straight through the dose measurement cavity, and because the heavy and rigid dose measurement system of the multi-dose inhaler is not agitated by this inspiratory flow, the powder material is only entrained by the cavity and Very little deagglomeration during discharge.

Therefore, a separate disintegration member is required. However, in practice, it is not always part of the design of the inhaler. Since the number of doses in the multi-dose device is high, it is necessary to minimize the amount of powder adhering to the inner wall of the air duct and the deagglomerating member, and/or it is necessary to periodically clean the portion without affecting the residual dose in the device. . Some multi-dose inhalers have disposable drug containers that can be replaced after a prescribed number of doses have been taken (e.g., WO 97/000703). For the semi-permanent multi-dose inhaler with the disposable drug container, the requirement to prevent drug accumulation is even more stringent.

In addition to administration via a dry powder inhaler, the compositions of the invention may also be administered via a propellant gas or an aerosol operated by means of a so-called nebulizer, the solution of the pharmacologically active substance being passed through a nebulizer under high pressure. Spray to produce an aerosol of respirable particles. The advantage of the atomizer is that the use of propellant gas can be completely dispensed with. The nebulizer is described in, for example, PCT Patent Application No. WO 91/14,468, the disclosure of which is incorporated herein by reference.

Spray compositions for topical delivery to the lung by inhalation may, for example, be formulated as an aqueous solution or suspension, or an aerosol delivered from a pressurized pack such as a metered dose inhaler using a suitable liquefied propellant. An aerosol composition suitable for inhalation can be Suspension or solution, and usually containing the active ingredient and a suitable propellant, such as fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof, especially hydrofluorocarbons such as dichlorodifluoromethane, trichlorofluoromethane, Dichlorotetrafluoroethane, 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 can also be used as a propellant.

The aerosol composition may be free of excipients or, where appropriate, other formulation excipients well known in the art, such as surfactants (e.g., oleic acid or lecithin) and cosolvents (e.g., ethanol). The pressurized formulation will typically be maintained in a canister (e.g., an aluminum can) that is closed with a valve (e.g., a metering valve) and mated to an actuator having a mouthpiece.

The agent administered by inhalation desirably has a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually from 1 to 10 μm, preferably from 2 to 5 μm. When inhaled to reach the small air tube, particles larger than 20 μm are usually too large. To achieve the particle size, the size of the particles of the active ingredient produced can be reduced by conventional means, such as by micron sizing. The desired portion can be separated by air classification or sieving. Preferably, the particles will be crystalline.

High dose reproducibility with micron sized powders is difficult because of its poor flow and extreme tendency to cohesive. To improve the efficacy of the dry powder composition, the particles should be larger in the inhaler but smaller when discharged into the respiratory tract. Therefore, excipients such as lactose or glucose are usually employed. Within the present invention, the particle size of the excipient will generally be much larger than the inhaled medicament. When the excipient is lactose, it will usually be in the form of milled lactose, preferably crystalline monohydrated lactose.

The pressurized aerosol composition will typically be filled into a canister equipped with a valve, particularly a metering valve. The can is painted with plastic material, such as W096/32150 The fluorocarbon polymer. The canister will be fitted to an actuator suitable for buccal delivery.

Iv) Nasal mucosal administration

The compounds of the invention may also be administered via the nasal mucosa.

Typical compositions for administration via nasal mucosa are typically administered by metered atomizing spray pumps and, where appropriate, in combination with conventional excipients such as buffers, antimicrobials, tonicity modifiers and viscosity modifiers. An inert vehicle such as a solution or suspension in water.

v) Parenteral Administration

The compounds of the invention may also be administered directly into the bloodstream, muscles or viscera. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedle) syringes, needle-free injectors, and infusion technique equipment.

The parenteral formulation is typically an aqueous solution which may contain excipients such as salts, carbohydrates and buffers (preferably having a pH of from 3 to 9), but for some applications it may be more suitable for formulation into sterile A non-aqueous solution or a dry form intended to be used in combination with a suitable vehicle such as sterile, pyrogen-free water.

Preparation of parenteral formulations, for example by lyophilization under sterile conditions, can be readily accomplished using standard pharmaceutical techniques well known to those of ordinary skill in the art. The solubility of the compounds of the invention for the preparation of parenteral solutions can be increased by the use of suitable formulation techniques, such as incorporation of solubility enhancers.

Formulations for parenteral administration can be formulated for immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Therefore, the present invention combines The article can be formulated as a solid, semi-solid or solution-soluble liquid for administration in the form of an implantable drug reservoir to provide improved 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 to the skin or mucosal surface, i.e., dermally/transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, powders. Tablets, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white paraffin, glycerin, polyethylene glycol, and propylene glycol. Infiltration enhancers can be incorporated; see, for example, Finney and Morgan Journal of Medical Sciences, 88 (10), 955-958 (October 1999) (J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999)). Other topical administration methods include delivery by electroporation, iontophoresis, ultrasonic drug penetration therapy, ultrasonic electroosmosis, and microneedle or needle-free injection.

Formulations for topical administration may be formulated for immediate and/or improved release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

Vii) Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa is a traditional suppository base, but various alternatives can be used where appropriate. Formulations for transrectal/vaginal administration may be formulated for immediate and/or modified release. Improved release Formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

Viii) Ocular Administration

The compounds of the invention may also be administered directly to the eye or ear, usually in the form of drops in micronized suspensions or solutions in isotonic, pH adjusted sterile physiological saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg, gel-absorbent sponges, collagen), and non-biodegradable (eg, polyoxygen) implants, powders , lenses and granule or vesicle systems, such as lipid vesicles (niosomes) or liposomes. a polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, For example, gelan gum can be incorporated with a preservative such as benzalkonium chloride. The formulation can also be delivered by iontophoresis.

Formulations for transocular/urine administration can be formulated for immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release or programmed release.

Ix) Other technologies

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol to improve solubility, dissolution rate, taste, bioavailability And/or stability for use in any of the above modes of administration.

The amount of active compound administered will depend on the individual being treated, the severity of the condition or disease, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. However, the effective dose is usually from 0.01 to 3000 mg, more preferably from 0.5 to 1000 mg per day. The active ingredient or equivalent amount of the pharmaceutically acceptable salt thereof. The daily dose can be administered one or more times per day, preferably one to four treatments.

Preferably, the pharmaceutical composition of the present invention is formulated in a form suitable for oral, inhalation or topical administration, and particularly preferably administered orally or by inhalation.

The pharmaceutical formulation is preferably presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art.

Preferably, the composition is in unit dosage form, such as a lozenge, capsule or metered aerosol dose, such that the patient can administer a single dose.

The amount of each active agent required to achieve a therapeutic effect will, of course, vary depending upon the particular active agent, the route of administration, the individual being treated, and the particular disorder or disease being treated.

The following formulation forms are cited as examples of formulations:

Formulation instance

Formulation Example 1 (oral suspension)

Formulation Example 2 (hard gelatin capsule for oral administration)

Formulation Example 3 (gelatin cartridge for inhalation)

Formulation Example 4 (for formulations using dry powder inhaler (DPI) inhalation)

Formulation Example 5 (Preparation for a Dose Inhaler (MDI))

Do not affect, alter, alter or modify the compound, combination or group of medicines Modifications of the basic aspects of the compositions are within the scope of the invention.

Claims (22)

a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a nitrogen-oxide, or an isotope-labeled derivative: Wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -( CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-(CH ₂ ) _0-3 -yl, -O- (CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 -N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group, a-(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R a chain group in the group ^c or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c ; wherein R ^a and R ^b each independently represent hydrogen a linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group; and wherein (*) represents a linkage a point to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and at least one selected from the group consisting of a monocyclic or bicyclic 5- to 7-membered heterocyclic group of a hetero atom of oxygen, sulfur or nitrogen; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from halogen Atom, hydroxyl, cyano, -NH ₂ group, -CHF Substituted by one or more substituents of a ₂ , -CF ₃ - or straight or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or a -CR ₆ group; R ₁ represents a straight or branched chain C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ hydroxyalkyl, -(CH ₂ ) _0-3 N(R ^d )R ^e group, straight or branched C ₁ -C _{a 6} haloalkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, a heteroaryl group of 5 to 14 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, Or a monocyclic or bicyclic 5- to 14-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ - a C ₄ alkyl group; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C _1- C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _1-3 CN , -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) , -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 CN group, -C(O)-O- (straight chain or branched chain) C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C _{1 )} -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 - (monocyclic or bicyclic 5- to 9-membered heterocyclic) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O) -(CH ₂ ) _0-3 - (a 5- to 7-membered heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _0-3 - NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(benzene Base group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (mixed from 5 to 7 members of at least one hetero atom selected from oxygen, sulfur and nitrogen) Aryl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (monocyclic or bicyclic 5 member containing at least one hetero atom selected from oxygen, sulfur and nitrogen) To a heterocyclic group of 9 members, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH _{2 2-6} -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R _{8 , -NR 7 -S (O) 2} (CH 2) 0-3 R 8 _{groups, -S (O) 2 (CH} 2) 0-3 R 8 _{groups, -S (O) 2 (CH} 2) 0- ₃ NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 - (including at least one choice a 5- to 7-membered heteroaryl) group of a hetero atom of oxygen, sulfur, and nitrogen, -(CH ₂ ) _0-3 - (monocyclic or bicyclic ring containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen) 5- to 7-membered heterocyclyl), -(CH ₂ ) _0-3 -(phenyl) or -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) Substituted by one or more substituents of the group; wherein each phenyl, heteroaryl and heterocyclic group is unsubstituted or selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group , linear or branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -C(O)- O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C _1- C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S ( O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ ) _0-3-- (5 comprises at least one selected from oxygen, sulfur and nitrogen heteroatoms atoms to seven heteroaryl) group with one or more substituents; wherein heteroaryl is unsubstituted based Or substituted with one or more substituents selected from a linear or branched C ₁ -C ₃ alkyl group or a -(CH ₂ ) _0-3 NR ^f R ^g group; wherein R ^f and R ^g are respectively Independently representing hydrogen, a straight or branched C ₁ -C ₄ alkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group; R ₂ and R ₃ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group , cyano, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl , C ₁ -C ₄ alkoxy, -NH ₂ , -N(CH ₃ )H or -N(CH ₃ ) ₂ group; R ₄ represents a hydrogen atom, a straight or branched C ₁ -C ₄ Alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 -S-(CH _{2 0-3} -(phenyl), -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 - (containing at least one hetero atom selected from oxygen, sulfur and nitrogen from 5 to 7 members) miscellaneous _{Yl), - (CH 2) 0-3} -O- (CH 2) 0-3 - ( _{phenyl), - (CH 2) 0-3} -O- (CH 2) 0-3 - ( comprising at least one 5 to 7 heteroaryls of a hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 - (including at least one selected a heteroaryl group of 5 to 7 members of a hetero atom of oxygen, sulfur and nitrogen, wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear chain or One or more substituents of a branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group Substituted; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group, a straight Chain or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _1-3 -O- (straight Chain or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -OC(O)- (linear or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _{0 -3} -C(O)O-(linear or branched C ₁ -C ₄ alkyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group or -(CH ₂ ) _0-3 -C (O) OH group; R ₇ and R ₈ each independently represent a hydrogen atom, a straight-chain Branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, or phenyl, wherein phenyl Is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ Substituted by one or more substituents of -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy; R ₅ represents formula (II-1), (II-2), (II-3), (II- 4), (II-5), (II-6) or (II-7) groups: Wherein: (*) represents the point of attachment of R ₅ to bind to a carbon atom of R ₄ and R ₅ and the point of attachment to the pyrrole triazinyl; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0- 3-} NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S(O ) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazinyl) Substituted by one or more substituents; wherein the piperidinyl or piperazinyl group is Substituted, or selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R 'represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or 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 ₁ -C ₄ alkyl group; L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O)-yl, -C(O) a chain group in the -O- group or -(CH ₂ ) _1-4 group. The compound of claim 1, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, (CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-( CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 - N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(* a -(CH ₂ ) _0-3 -R ^c group or a -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c group; Wherein R ^a and R ^b each independently represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (a straight or branched C ₁ -C ₄ alkane) And (wherein (*) represents a point of attachment to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, 5 to 7 comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen a heteroaryl group, a monocyclic or bicyclic 5-membered to 7-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein a cycloalkyl group, a phenyl group, a heteroaryl group and a heterocyclic group Unsubstituted or selected Substituted from one or more substituents of 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 ₁ -C ₄ alkyl group; X represents nitrogen Atom or -CR ₆ group; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _0-3 N(R ^d ) a R ^e group, a linear or branched C ₁ -C ₆ haloalkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, containing at least one selected from the group consisting of oxygen and sulfur a heteroaryl group of 5 to 7 members of a hetero atom of nitrogen or a heterocyclic group of 5 to 9 members having at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein R ^d and R ^e each independently represents hydrogen or a linear or branched C ₁ -C ₄ alkyl group; and wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 - O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH _{2 2-4} -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C (O)-(CH ₂ ) _1-3 CN group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C (O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 - (phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 - (including at least one selected from the group consisting of oxygen, a monocyclic or bicyclic 5- to 9-membered heterocyclic group of a hetero atom of sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur, and nitrogen Heteroaryl) group of 5 to 7 members of the atom, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) , -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (a 5- to 7-membered heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _0-3 -NR ₇ ( CH ₂ ) _0-3 - (monocyclic or bicyclic 5- to 9-membered heterocyclic) group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _{0- 3-} NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ , -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 - (heteroaryl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen) a group, -(CH ₂ ) _0-3 - (monocyclic or bicyclic 5-membered to 7-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _0- Substituted by one or more substituents of _3- (phenyl) or -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl); wherein each phenyl, heteroaryl And heterocyclic groups are unsubstituted or selected from hydroxy, straight or branched C ₁ -C ₄ alkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C _4- alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 N R ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -( CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or -(CH ₂ ) _0-3 - (containing at least one hetero atom selected from oxygen, sulfur and nitrogen to 5 members Substituted by one or more substituents of a 7 membered heteroaryl) group; wherein the heteroaryl is unsubstituted or is selected from a linear or branched C ₁ -C ₃ alkyl or —CH ₂ ) _0-3 NR ^f R ^g group substituted by one or more substituents; and wherein R ^f and R ^g each independently represent hydrogen, straight or branched C ₁ -C ₄ alkyl or straight chain or Branched C ₁ -C ₄ hydroxyalkyl; 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 ₁ -C ₄ alkyl group, C ₁ -C _4- haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ group, -N(CH ₃ )H Or a -N(CH ₃ ) ₂ group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ -Hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -S-( CH _{2) 0-3} - (comprising at least one 5 hetero atoms from oxygen, sulfur and nitrogen to 7-membered _{heteroaryl), - (CH 2) 0-3} -O- (CH 2) 0-3 - ( phenyl), - (CH _{2) 0-3} -O-(CH ₂ ) _0-3 - (having at least one heteroaryl group of 5 to 7 members selected from hetero atoms of oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 - ( Phenyl), -(CH ₂ ) _0-3 - (having at least one heteroaryl group of 5 to 7 members selected from hetero atoms of oxygen, sulfur and nitrogen), wherein the phenyl group and the heteroaryl group are not Substituted, or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxy group Substituted by one or more substituents of an alkyl group or a C ₁ -C ₄ alkoxy group; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, C _1- C ₄ alkoxy, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _1-3 -O- (straight or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -OC(O)- (straight chain or Branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -C(O)O- (straight or branched C ₁ -C ₄ alkyl), -C(O)-( CH _{2) 0-3} -NR ₇ R ₈ group, or _{- (CH 2) 0-3 -C (} O) OH ; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl a C ₃ -C ₇ cycloalkyl group or a phenyl group, wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, C Substituted with one or more substituents of ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy; R ₅ represents formula (II-1) , (II-2), (II-5), (II-6) or (II-7) groups: Wherein: (*) represent R ₅ to bind to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14 , and R ₁₅ , Z and L are as defined in item 1 of the scope of the patent application. The compound of claim 1, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, - (CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-( CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 - a chain group in the N(R ^a )R ^b group or the -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; wherein R ^a and R ^b independently represent Hydrogen, linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group; and wherein (*) represents a point of attachment of a nitrogen atom to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, comprising at least a heterocyclic group of 5 to 7 members of a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein the cycloalkyl group, the phenyl group, the heteroaryl group and the heterocyclic group are unsubstituted or selected from a halogen atom Substituted by one or more substituents of a hydroxyl group, a cyano group, a -NH ₂ group, a -CHF ₂ group, a -CF ₃ group or a linear or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or - CR ₆ group; R ₁ substituting A straight-chain or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ hydroxyalkyl group, a linear or branched C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl An alkyl group, a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or comprising at least one selected from the group consisting of oxygen, sulfur and nitrogen a heterocyclic group of 5 to 7 members of a hetero atom; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyanogen Base, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, - (CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-( CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ a group of -(CH ₂ ) _0-3 - (a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3 - (including at least a heterocyclic group of 5 to 7 members of a hetero atom selected from oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -(phenyl) group or -(CH ₂ ) _0-3 -O- (CH ₂ ) _0-3 -(phenyl) group; wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group or Substituting one or more substituents of -(CH ₂ ) _0-3 -O-(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 , cyano, straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl , C ₁ -C ₄ alkoxy, -NH ₂ , -N(CH ₃ )H or -N(CH ₃ ) ₂ group; R ₄ represents a hydrogen atom, a straight or branched C ₁ -C ₄ Alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 -S-(CH _{2 0-3} -(phenyl), -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 - (containing at least one hetero atom selected from oxygen, sulfur and nitrogen from 5 to 7 members) Heteroaryl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur and nitrogen 5 to 7 heteroaryl of a hetero atom), -(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen, sulfur and nitrogen a heteroaryl group of 5 to 7 members of the atom, wherein the phenyl and heteroaryl groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ Substituted by one or more substituents of an alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₆ represents a hydrogen atom a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ - C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _1-3 -O- (straight or branched C ₁ - C ₄ alkyl), -(CH ₂ ) _0-3 -OC(O)-(linear or branched C ₁ -C ₄ alkyl), -(CH ₂ ) _0-3 -C(O)O - (linear or branched C ₁ -C ₄ alkyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group or -(CH ₂ ) _0-3 -C(O) OH group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C _{a 4-} alkyl, C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group or a phenyl group, wherein the phenyl group is unsubstituted, Or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or Substituted by one or more substituents of a C ₁ -C ₄ alkoxy group; R ₅ represents a formula (II-1), (II-2), (II-3), (II-4), (II-5) a group of (II-6) or (II-7): Wherein: (*) represents the point of attachment of R ₅ to bind to a carbon atom of R ₄ and R ₅ and the point of attachment to the pyrrole triazinyl; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -NH ₂ group, -(CH ₂ ) _0-3 -C(O)OH group, -(CH ₂ ) _0-3 NR'-S(O) _{2 is} substituted with one or more substituents of the R"group; wherein R' represents a hydrogen atom or a straight or branched C ₁ -C ₃ , and wherein R" represents a linear or branched C ₁ -C ₃ alkyl group or a phenyl group, wherein the phenyl group is unsubstituted or is selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ Substituted by one or more substituents of an alkyl group; The direct bond of the table is either selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH- group, -NH-C(O)- A chain group in the group -OC(O)- group, -C(O)-O- group or -(CH ₂ ) _1-4 group. The compound of claim 3, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, - (CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-( CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 - a chain group in the N(R ^a )R ^b group or the -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; wherein R ^a and R ^b independently represent a hydrogen, linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkane) group; and wherein (*) represents nitrogen a point of attachment of an atom to R ₁ ; R ^c represents a C ₃ -C ₁₀ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, comprising at least one a heterocyclic group of 5 to 7 members of a hetero atom selected from oxygen, sulfur and nitrogen; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, Substituted by one or more substituents of a hydroxy group, a cyano group, a -NH ₂ group, a -CHF ₂ group, a -CF ₃ group or a linear or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or -CR _6-yl; R ₁ representatives Chain or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ hydroxyalkyl group, a linear or branched C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl a C ₃ -C ₁₀ cycloalkenyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or comprising at least one selected from the group consisting of oxygen, sulfur and nitrogen. a heterocyclic group of 5 to 7 members of a hetero atom, wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, and a cyano group. , straight or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -( CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, - C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH _{2 ) 0-3} -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group , -(CH ₂ ) _0-3 - (a 5- to 7-membered heteroaryl group containing at least one hetero atom selected from oxygen, sulfur, and nitrogen), -(CH ₂ ) _0-3 - (including at least one a heterocyclic group of 5 to 7 members of a hetero atom selected from oxygen, sulfur and nitrogen, -(CH ₂ ) _0-3 -(phenyl) group or -(CH ₂ ) _0-3 -O- ( CH ₂ ) _0-3 - substituted by one or more substituents of a (phenyl) group; wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a straight chain or a branched chain Substituting one or more substituents of a C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group; R ₂ and R ₃ are independently Representing a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxyalkyl group ; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ Cycloalkyl, -(CH ₂ ) _0-3 -S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl Or -(CH ₂ ) _0-3 -(phenyl); wherein the phenyl group is unsubstituted or is selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ Substituted with one or more substituents of -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy; R ₆ a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group or a phenyl group, wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ Substituted with one or more substituents of a C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group; R ₅ represents a chemical formula (II-1), a group of (II-5) or (II-7): Wherein; (*) represent R ₅ to bind to the point of attachment carbon atom of R ₄ and R ₅ to pyrrolo point of attachment triazine _{group; R 9, R 10, R} 11, R 12, R 13, R 14, R ₁₅ , Z and L are as defined in item 1 of the scope of the patent application. The compound of claim 1 or 2, wherein R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, (CH ₂ ) _0-3 N(R ^d )R ^e group, C ₃ -C ₇ cycloalkyl group, phenyl group containing at least one hetero atom selected from oxygen, sulfur and nitrogen, 5 to 7 members of heteroaryl a monocyclic or bicyclic 5- to 9-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ -C ₄ alkyl; and wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or are selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O- (CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ , -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O) group, -C(O)-( CH _{2) 0-3} - (linear or branched The C ₁ -C ₄ alkyl) group, -C (O) - (CH 2) 0-3 - ( phenyl) group, -C (O) -O- (CH 2) 0-3 - ( phenyl a group, -C(O)-(CH ₂ ) _0-3 - (monocyclic or bicyclic 5-membered to 9-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C (O)-(CH ₂ ) _0-3 - (heteroaryl group of 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH ₂ ) _{0 -3} -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (5 to 7 containing at least one hetero atom selected from oxygen, sulfur and nitrogen) Heteroaryl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (monocyclic ring containing at least one hetero atom selected from oxygen, sulfur and nitrogen or Heterocyclic 5-membered to 5-membered heterocyclyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ -, -C(O)-(CH ₂ ) _0-3 -NR ₇ - (CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 - NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ ( CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 - ( a 5- to 7-membered heteroaryl) group containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen, -(CH ₂ ) _0-3 - (containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen) Monocyclic or bicyclic 5- to 7-membered heterocyclyl), -(CH ₂ ) _0-3 -(phenyl)yl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 - Substituted by one or more substituents of a (phenyl) group; wherein each phenyl, heteroaryl and heterocyclic group is unsubstituted or selected from a hydroxy, straight or branched C ₁ - C ₄ alkyl, linear or branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -C (O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 -(linear or Branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, - S(O) ₂ (CH ₂ ) _0-3 (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O ^{_{- (CH 2) 2-4 -NR f}} R g or a group - (CH _{2) 0-3} - (5 comprising at least one hetero atoms selected from oxygen, sulfur and nitrogen to 7-membered hetero aryl group) With one or more substituents; wherein the heteroaryl system is unsubstituted, or is selected from linear or branched C ₁ -C ₃ alkyl or ^{_{- (CH 2) 0-3 NR f}} R Substituted by one or more substituents of the ^g group; and wherein R ^f and R ^g each independently represent hydrogen, straight or branched C ₁ -C ₄ alkyl or straight or branched C ₁ -C ₄ Hydroxyalkyl. A compound according to any one of the preceding claims, wherein R ₂ represents a hydrogen atom, a halogen atom or a linear or branched C ₁ -C ₄ alkyl group. A compound according to any one of the preceding claims, wherein R ₃ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, Or a linear or branched C ₁ -C ₄ hydroxyalkyl group. The compound of any one of clauses 1 to 5, wherein R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, -(CH ₂ ) _0-3 - S-(CH ₂ ) _0-3 -(phenyl), -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl), or -(CH ₂ ) _0-3 -( Phenyl); wherein the phenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a straight Substitution of one or more substituents of a chain or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group. A compound according to any one of the preceding claims, wherein R ₆ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, Or a linear or branched C ₁ -C ₄ hydroxyalkyl group. The compound of any one of claims 1 to 3 and 5 to 9, wherein R ₅ represents a chemical formula (II-1), (II-2), (II-5) , (II-6) or (II-7) groups: Wherein: (*) represent R ₅ to bind to the connection point of the carbon atoms of R ₄ and R ₅ to pyrrolo triazinyl point of _{attachment; R 9, R 10, R} 11, R 12, R 13, R 14, R ₁₅ , Z and L are as defined in item 1 of the scope of the patent application. The compound of claim 1, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, (CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-( CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 - N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C(O)-N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N(* a -(CH ₂ ) _0-3 -R ^c group or a -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 -R ^c group; Wherein R ^a and R ^b each independently represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (a straight or branched C ₁ -C ₄ alkane) And (wherein (*) represents a point of attachment to R ₁ ; R ^c represents a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, comprising at least one a monocyclic or bicyclic 5- to 7-membered heterocyclic group of a hetero atom selected from oxygen, sulfur and nitrogen; wherein the phenyl, heteroaryl, and heterocyclic groups are unsubstituted or selected from a halogen atom Hydroxyl, cyano Substituted by one or more substituents of a -NH ₂ group, a -CHF ₂ group, a -CF ₃ group or a linear or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or a -CR ₆ group: R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, a -(CH ₂ ) _0-3 N(R ^d )R ^e group, C ₃ a C ₇ cycloalkyl group, a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or a single atom comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen a heterocyclic group of 5 or 9 members; wherein R ^d and R ^e each independently represent hydrogen or a linear or branched C ₁ -C ₄ alkyl group; and wherein cycloalkyl, phenyl, heteroaryl And the heterocyclic group are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear chain Or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -( CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O- (straight or branched) C ₁ - C ₄ alkyl) group, -C(O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkane) Base, -C(O)-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O )-(CH ₂ ) _0-3 - (monocyclic or bicyclic 5-membered to 9-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -C(O)-(CH _{2 ) 0-3} - (5 to 7 membered heteroaryl) containing at least one hetero atom selected from oxygen, sulfur and nitrogen, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH (C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (a heteroaryl group of 5 to 7 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen) , -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 - (monocyclic or bicyclic 5 to 9 members containing at least one hetero atom selected from oxygen, sulfur and nitrogen) Heterocyclyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, - NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ -yl, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 - (containing at least one selected from the group consisting of oxygen and sulfur And a heteroaryl group of 5 to 7 members of the hetero atom of nitrogen, -(CH ₂ ) _0-3 - (monocyclic or bicyclic 5 to 7 containing at least one hetero atom selected from oxygen, sulfur and nitrogen) Or a heterocyclic group, a -(CH ₂ ) _0-3 -(phenyl) group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl) group Substituted by a plurality of substituents; wherein each phenyl, heteroaryl and heterocyclic group is unsubstituted or selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group, a straight chain or Branched C ₁ -C ₄ hydroxyalkyl, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O- (straight Chain or branched C ₁ -C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ Alkyl) group, -C(O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH _{2 0-3} (linear or branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ ( CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g or a group - (CH _{2) 0-3} - ( Substituting one or more substituents of a 5- to 7-membered heteroaryl) group containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen; wherein the heteroaryl group is unsubstituted or selected from Substituting one or more substituents of a linear or branched C ₁ -C ₃ alkyl group or a -(CH ₂ ) _0-3 NR ^f R ^g group; and wherein R ^f and R ^g each independently represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group or a linear or branched C ₁ -C ₄ hydroxyalkyl group; R ₂ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; ₃ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 - ( Phenyl); wherein the phenyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₄ alkyl group; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxyalkyl group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl, linear or branched C ₁ -C ₃ hydroxyalkyl, C ₃ -C ₇ cycloalkyl Group, or phenyl; wherein the phenyl is unsubstituted lines, or selected from linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, linear or branched C Substituted by one or more substituents of ₁ -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxy; R ₅ represents formula (II-1), (II-2), (II-5), (II -6) or (II-7) groups: Wherein: (*) represents the point of attachment of R ₅ to bind to a carbon atom of R ₄ and R ₅ and the point of attachment to the pyrrole triazinyl; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, -O-(linear or branched C ₁ -C ₃ alkyl) group , -(CH ₂ ) _0-3 -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _{0- 3-} NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, or -(CH ₂ ) _0-3 NR'-S(O ) ₂ (CH ₂ ) _0-3 R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) or -(CH ₂ ) _0-3 -(piperazinyl) Substituted by one or more substituents; wherein the piperidinyl or piperazinyl group is unsubstituted Substituted or substituted with one or more substituents selected from a linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 NR'R"group; and wherein R' represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or 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 ₁ -C ₄ alkyl group; L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, -S-(CH ₂ ) _0-3 -, -C(O)-NH-yl, -NH-C(O)-yl, -OC(O)-yl, -C(O) a chain group in the -O- group or -(CH ₂ ) _1-4 group. The compound of claim 11, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(* )-(CH ₂ ) _2-4 -N(R ^a )R ^b group, -(CH ₂ ) _0-3 -NR ^a -CH[C(*)H ₂ ]-(CH ₂ ) _0-3 -C (O)-N(R ^a )R ^b group, -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _2-4 N(R ^a )R ^b group, -( CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group or -(CH ₂ ) _0-3 -N[C(*)H ₂ ]-(CH ₂ ) _0-3 ^a linking group in the -R ^c group; wherein R ^a and R ^b each independently represent hydrogen, a straight or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (straight chain Or a branched C ₁ -C ₄ alkyl) group; and wherein (*) represents a point of attachment to R ₁ ; R ^c represents a group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen Heterocyclic group; X represents a -CR ₆ group; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, -(CH ₂ ) _{0- 3} N(R ^d )R ^e group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,4-nitrothiamethane 1,4-azathianyl group, thiomorpholinyl 1,1-dioxide group, 2,5-diazabicyclo[2.2.1]heptane-2- (2,5-diazabicyclo[2.2.1]heptan-2-yl group), 2,5-diazabicyclo[2.2.1]oct-2-yl (2,5-diazabicyclo[2.2.1]octan -2-yl group), pyrrolidin-2-one group, or pyrrolidinyl; wherein R ^d and R ^e each independently represent hydrogen or a straight or branched C ₁ - C ₄ alkyl; and wherein cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,4-nitrogen heterocycle Hexyl (1,4-azathianyl), thiomorpholinyl 1,1-dioxide, 2,5-diazabicyclo[2.2.1]heptane-2- (2,5-diazabicyclo[2.2.1]heptan-2-yl), 2,5-diazabicyclo[2.2.1]oct-2-yl (2,5-diazabicyclo[2.2.1]octan- 2-yl), pyrrolidin-2-one or pyrrolidinyl is unsubstituted or is selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C _{a 1-} C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -OR ₇ group, -(CH ₂ ) _0-3 -O- (straight or branched) C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, - (CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C( O)-OH group, -C(O) group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C(O)- (CH ₂ ) _0-3 -(phenyl) group, -C(O)-O-(CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 - (piperazinyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ [CH(C ₁ -C ₂ alkyl)] _0-3 -(phenyl) group, -C(O) -(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -( Piperidinyl), -C(O)-(CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(pyridyl)yl, -C(O)-(CH ₂ ) _0-3 - NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-6 -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ -(CH ₂ ) _1-6 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, - S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 NR ₇ R ₈ group, -S(O) ₂ CH ₂ ) _0-3 -NR ₇ (CH ₂ ) _0-3 -(phenyl) group, -(CH ₂ ) _0-3 -(pyrrolidinyl)yl, -(CH ₂ ) _0-3 -(piperazinyl)yl, -(CH ₂ ) _0-3 -(piperidinyl)yl, -(CH ₂ ) _0- Substituted by one or more substituents of _3- (phenyl) or -(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -(phenyl); wherein each phenyl, pyridyl a pyrrolidinyl, piperazinyl or piperidinyl group which is unsubstituted or selected from a hydroxy, straight or branched C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₄ Hydroxyalkyl, -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group, -C(O)-O- (straight or branched C ₁ - C ₄ alkyl) group, -C(O)-OH group, -C(O)-(CH ₂ ) _0-3 - (linear or branched C ₁ -C ₄ alkyl) group, -C ( O)-(CH ₂ ) _0-3 NR ^f R ^g group, -(CH ₂ ) _0-3 N(R ^f )R ^g group, -S(O) ₂ (CH ₂ ) _0-3 (straight chain or Branched C ₁ -C ₄ alkyl) group, -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 NR ^f R ^g group, -NR ^f -S(O) ₂ (CH ₂ ) _0-3 R ^g group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ^f R ^g group or - Substituting one or more substituents of (CH ₂ ) _0-3 -(pyridyl) group; wherein the pyridyl group is unsubstituted or is selected from a linear or branched C ₁ -C ₃ alkyl group Or -(CH ₂ ) _0-3 NR Substituting one or more substituents of the ^f R ^g group; and wherein R ^f and R ^g each independently represent hydrogen, a straight or branched C ₁ -C ₄ alkyl group or a straight or branched C ₁ - C ₄ hydroxyalkyl; R ₂ represents a hydrogen atom; R ₃ represents a hydrogen atom; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 -(benzene Wherein the phenyl group is unsubstituted or substituted by one or more hydroxyl groups; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a linear or branched C ₁ -C ₃ alkane; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a linear or branched C ₁ -C ₃ hydroxyalkyl group, a C ₃ -C ₄ naphthenic group; a phenyl group, wherein the phenyl group is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups; and R ₅ represents a chemical formula (II-1), (II-2), Groups of II-5), (II-6) or (II-7): Wherein: (*) represent R ₅ to bind to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, a -NH ₂ group, or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group, a pyridyl group, a pyrazolyl group, Or a fluorenyl group; wherein the phenyl, pyridyl, pyrazolyl, or anthracenyl group is unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl, straight or branched C ₁ -C ₄ hydroxyalkyl, —O—(linear or branched C ₁ -C ₃ alkyl) group, —(CH ₂ ) _{0 -3} -C(O)-(CH ₂ ) _0-3 -NR'R" group, -(CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -NR'-(CH ₂ ) _1-6 -NR'R" group, -(CH ₂ ) _0-3 -C(O)OH group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _{0- 3} R" group, -(CH ₂ ) _0-3 NR'-S(O) ₂ (CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 NR'-C(O)( One or more substituents of CH ₂ ) _0-3 NR'R" group, -(CH ₂ ) _0-3 -(piperidinyl) group or -(CH ₂ ) _0-3 -(piperazinyl) group Substituted; wherein the piperidinyl or piperazinyl group is not Substituted or selected from linear or branched C ₁ -C ₄ alkyl or - a (CH _{2) 0-3} NR'R "group one or more substituents; and wherein R 'represents hydrogen An atomic or linear or branched C ₁ -C ₃ alkyl group, and wherein R" represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group or a phenyl group, wherein the phenyl group is unsubstituted Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl group; L represents a direct bond. The compound of claim 3, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -S-(CH ₂ ) _0-3 -yl, - (CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -(CH ₂ ) _0-3 -NR ^a -C(O)-( CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _2-4 - a chain group in the N(R ^a )R ^b group or the -(CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; wherein R ^a and R ^b independently represent Hydrogen, linear or branched C ₁ -C ₄ alkyl or -(CH ₂ ) _0-3 -O- (linear or branched C ₁ -C ₄ alkyl) group; and wherein (*) represents a point of attachment of a nitrogen atom to R ₁ ; R ^c represents a phenyl group, a heteroaryl group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and at least one selected from the group consisting of oxygen, sulfur and nitrogen. a heterocyclic group of 5 to 7 members of a hetero atom; wherein the phenyl, heteroaryl and heterocyclic groups are unsubstituted or selected from a halogen atom, a hydroxyl group, a cyano group, a -NH ₂ group, -CHF Substituted by one or more substituents of a ₂ , -CF ₃ - or straight or branched C ₁ -C ₄ alkyl group; X represents a nitrogen atom or a -CR ₆ group; R ₁ represents a straight or branched chain C ₁ -C ₆ alkyl a linear or branched C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a heterocyclic group of 5 to 7 members containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen a 5- to 7-membered heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the cycloalkyl group, the phenyl group, the heteroaryl group, and the heterocyclic group are unsubstituted, Or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group, C ₃ - C ₄ cycloalkyl, -(CH ₂ ) _0-3 -O-(linear or branched C ₁ -C ₄ alkyl) group, -(CH ₂ ) _0-3 -O-(CH ₂ ) _{2 -4} -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH-(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O )-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _0-3 -NR ₇ R ₈ group, -C(O)-(CH _{2 0-3} -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -(CH ₂ ) _0-3 - (5- to 7-membered heterocyclic group containing at least one hetero atom selected from oxygen, sulfur and nitrogen), -(CH ₂ ) _0-3-- (phenyl) group, or _{- (CH 2) 0-3 -O- (} CH 2) 0-3 - ( phenyl) group, one or more take The substituent group; wherein said phenyl is unsubstituted based, or selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl or - (CH _{2) 0-3} -O -(CH ₂ ) _2-4 -NR _{7 is} substituted with one or more substituents of the R ₈ group; R ₂ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₃ represents a hydrogen atom or a linear or branched C ₁ -C ₄ alkyl group; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 -(phenyl); The phenyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₄ alkyl group; R ₆ represents a hydrogen atom or a halogen atom. a hydroxy, cyano, straight or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, or a linear or branched C ₁ -C ₄ hydroxyalkyl group; R ₇ and R ₈ Respectively independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, or a phenyl group, wherein the phenyl group is unsubstituted or selected from a linear chain Or one or more substitutions of a branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a linear or branched C ₁ -C ₄ hydroxyalkyl group or a C ₁ -C ₄ alkoxy group Substituted by R ₅ represents a group of the formula (II-1), (II-5) or (II-7): Wherein: (*) represents the point of attachment of R ₅ to bind to a carbon atom of R ₄ and R ₅ and the point of attachment to the pyrrole triazinyl; the Z represents a nitrogen atom or a -CH _{group; R 9, R 11, R} 13, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a cyano group, an —NH ₂ group or a linear or branched C ₁ -C ₄ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group or include at least one selected a heteroaryl group of 5 to 9 members of a hetero atom of oxygen, sulfur, and nitrogen; wherein the phenyl group and the heteroaryl group are unsubstituted or selected from a halogen atom, a hydroxyl group, a linear or branched C Substituted with one or more substituents of ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, or a linear or branched C ₁ -C ₄ hydroxyalkyl group; L represents a direct bond or is selected from -O-(CH ₂ ) _0-3 -, S-(CH ₂ ) _0-3 -, -C(O)-NH- group, -NH-C(O)- group, -OC(O)- group a chain group in the -C(O)-O- group or the -(CH ₂ ) _1-4 group. The compound of claim 13, wherein: W represents a direct bond or is selected from the group consisting of -O-(CH ₂ ) _0-3 -yl, -(CH ₂ ) _1-4 -yl, -(CH ₂ ) _0-3 -NR ^a -(CH ₂ ) _0-3 -yl, -O-(CH ₂ ) _2-4 -N(*)R ^a group, -(CH ₂ ) _0-3 -N(* a -(CH ₂ ) _2-4- N(R ^a )R ^b group or a - (CH ₂ ) _0-3 -N(*)-(CH ₂ ) _0-3 -R ^c group; Wherein R ^a and R ^b each independently represent a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group or -(CH ₂ ) _0-3 -O- (straight or branched C ₁ -C ₄ And (wherein (*) represents a point of attachment of a nitrogen atom to R ₁ ; R ^c represents a heterocyclic group of 5 to 7 members comprising at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen; X represents -CR ₆ base; R ₁ represents a linear or branched C ₁ -C ₆ alkyl group, a linear or branched C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group, Piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl; wherein cycloalkyl, phenyl, pyridyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl or pyrrolidinyl system is unsubstituted, or is selected from a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl A straight-chain or branched C ₁ -C ₄ hydroxyalkyl, C ₃ -C _{4 cycloalkyl, - (CH 2) 0-3 -O-} ( linear or branched C ₁ -C ₄ alkyl) , -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group, -(CH ₂ ) _0-3 NR ₇ R ₈ group, -(CH ₂ ) _0-3 NH -(CH ₂ ) _2-4 NR ₇ R ₈ group, -C(O)-O-(linear or branched C ₁ -C ₄ alkyl) group, -C(O)-(CH ₂ ) _{0 -3} -NR ₇ R ₈ group, -C(O)-(CH ₂ ) _0-3 -NR ₇ -(CH ₂ ) _2-4 -NR ₇ R ₈ group, -NR ₇ -S(O) ₂ ( CH ₂ ) _0-3 R ₈ group, -S(O) ₂ (CH ₂ ) _0-3 R ₈ group, -(CH ₂ ) _0-3 -(pyrrolidinyl) group, -(CH ₂ ) _{0- 3} - (phenyl) group, or _{- (CH 2) 0-3 -O- (} CH 2) 0-3 - a (phenyl) group substituted with one or more substituents; wherein said phenyl is based Unsubstituted, or selected from a hydroxy, linear or branched C ₁ -C ₄ alkyl group or a -(CH ₂ ) _0-3 -O-(CH ₂ ) _2-4 -NR ₇ R ₈ group Substituted by one or more substituents; R ₂ represents a hydrogen atom; R ₃ represents a hydrogen atom; R ₄ represents a hydrogen atom, a linear or branched C ₁ -C ₄ alkyl group, or -(CH ₂ ) _0-3 -(phenyl); wherein the phenyl group is unsubstituted or substituted by one or more hydroxyl groups; R ₆ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a linear or branched C ₁ -C ₃ alkyl group; R ₇ and R ₈ each independently represent a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₃ -C ₄ cycloalkyl group, or a phenyl group in which the phenyl group is unsubstituted or substituted by one or more C ₁ -C ₄ alkoxy groups; and R ₅ represents a chemical formula (II-1), (II-5) or (II-7) ) group: Wherein: (*) represent R ₅ to bind to a carbon atom of R ₄ is the point of attachment and R ₅ to pyrrolo point of attachment triazinyl; the Z represents a nitrogen _{atom; R 9, R 11, R} 13, R 14 and R ₁₅ independently represents a hydrogen atom, a cyano group, an -NH ₂ group or a linear or branched C ₁ -C ₃ alkyl group; R ₁₀ and R ₁₂ each independently represent a phenyl group; wherein the phenyl group is unsubstituted Or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, or a linear or branched C ₁ -C ₃ alkyl group; L represents a direct bond. The compound according to claim 1, which is one of the following: 1. 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-carboxylic acid (S)-t-butyl ester; (S)-4-amino-6-((1-(4-(piperidin-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-Bromo-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazine- 2-(yl)ethyl)amino)pyrimidine-5-carbonitrile; 8. (S)-2-(1-((6-amino-5-cyanide) Pyrimidin-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- Benzonitrile; 11. 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-carboxylic acid (S)-t-butyl ester; 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; ((2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4] Pyrazin-4-yl)oxy) Piperidine-1-carboxylic acid (S)-t-butyl ester; 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) (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[2,1-f][1,2,4 Triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-fluorophenol; 20. (S)-4-amino-6-((1-(4-(3-hydroxyphenoxy) 5-(methylpyrolo[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-methylpyrrole [2,1-f][1,2,4]triazin-2-yl)ethyl)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- Benzonitrile; 25. 3-(4-Amino-1-((4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrrolo[2,1-f][1,2, 4] triazin-2-yl)methyl)-1H-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)- 1H-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)-1H-pyrazolo[3,4-d]pyrimidin-3- (2-)2-fluorophenol; 29. (S)-4-(2-(1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrole [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- Nitrile; 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-(hydroxyl)) 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-methylpyridyl) [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]triazine- 2-(yl)ethyl)amino)pyrimidine-5-carbonitrile; 40. (S)-4-Amino-6-((1-(4-(4-(3-hydroxybenzyl))piperazin-1- (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]triazine-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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; (S)-4-Amino-6-((1-(4-((3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]3 (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) A -1H-pyrazole [3,4-d]pyrimidin-3-yl)-5-fluorophenol; 46. 3-(4-Amino-1-((4-(3-fluoro-5-hydroxyphenyl)-5-methyl) Pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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-Dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-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))) -fluoro-5-methoxyphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Benzonitrile; 52. (S)-4-Amino-6-((1-(4-(3-hydroxyphenyl)(2-morpholinylethyl)amino)-5-methylpyrrolo[2 ,1-f][1,2,4 Triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 53. (S)-N-(3-(2-(1-((6-Amino-5-cyanopyrimidine-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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 55. 3-(4-amino-1-((4) -((2-(Dimethylamino)ethyl)(3-hydroxyphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl )methyl)-1H-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]triazine-2- (ethyl)amino)pyrimidine-5-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-hydroxyl Pyridin-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)-1H-pyrazolo[3,4-d]pyrimidin-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)-1H-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]triazine-2 -yl)methyl)-1H-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) ammonia 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) (amino)pyrimidine-5-carbonitrile; 68. (S)-4-amino-6-((1-(5-methyl-4-(4-(pyrrolidin-1-ylmethyl))piperidine -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[2,1-f][1,2,4]triazine -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]triazine -2-yl)methyl)-1H-pyrazole And [3,4-d]pyrimidin-3-yl)-5-fluorophenol; 73. (S)-4-amino-6-((1-(4-((2-hydroxyethyl))) 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) ((1S,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)))) 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)-1H-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]triazine- 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]triazine-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-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine; 86. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(4-(2) -(dimethylamino)B Benzyl)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl Amino)pyrimidine-5-carbonitrile; 87. N-(3-(4-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazin-1-) 5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)phenyl)methanesulfonamide; 88. N-(3-(4-S)-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl) -5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) -5-hydroxyphenyl)methanesulfonamide; 89. 4-amino-6-(((S)-1-(4-((3R,5S)-3,5-dimethyl-4-(A) Sulfosyl)piperazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Nitrile; 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-ol; 91. 4-(( (S)-1-(4-((3R,5S)-4-Ethyl-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-A Pyrrolo[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-- 3-pyrido[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[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4 -d]pyrimidin-3-yl)-5-fluorophenol; 96. 3-(4-Amino-1-((5-methyl-4-thiomorpholinylpyrrolo[2,1-f][ 1,2,4]triazin-2-yl)methyl)-1H-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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 98. (S)-4-amino-6-((1-(4-(1, 3-Dimethyl-1H-pyrazol-5-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile; 99. 4-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)-2 , 6-dimethylbenzoic acid (S)-methyl ester; 100. 3-(1-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2- -5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-4-amino-1H-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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 102. 3 -(4-Amino-1-((5-methyl-4-(2,2,6,6-tetramethylmorpholinyl)pyrrolo[2,1-f][1,2,4]3 Pyrazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 103. 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 (S)-methyl ester; 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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5- Methylpyrrole [2,1 -f][1,2,4]triazin-4-yl)piperidin-4-ol; 107. (S)-3-(2-(1-((6-Amino-5-cyanopyrimidine)- 4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(2-(dimethylamino)ethyl (5)-Methylbenzamide; 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-dimethylmorpholinyl)-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-hydroxy)) Phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-4 -yl)piperazin-2-one; 112. 1-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine -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)-1H-pyrazolo[3 4-(4-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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-1H-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-((1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl) -5-Methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine- 3-yl)-5-fluorophenol; 118. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methyl Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(5-((2-hydroxyethyl)(methyl)amino)pentyl)-5-A Benzobenzamide; 119. (S)-4-Amino-6-((1-(5-methyl-4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl) Pyrrolo[2,1-f][1,2,4] (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-aminesulfonylbenzyl)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-methylbenzimidamide; 123. 3-(4-Amino-1-((5S,4S)-5-(methylsulfonyl) -2,5-diazabicyclo[2.2.2]oct-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H- Pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 124. N-((S)-1-(4-((2S,6R)-2,6-dimethyl Morpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-5-(1-methyl-1H-pyrazole-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)-1H-pyrazole And [3,4-d] Pyridin-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-((1R,4R)-5-(methylsulfonyl)-2,5- Diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-5-fluorophenol; 128. (S)-2-((2-((S)-1-((6-Amino-5-cyanopyrimidine-4-) 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-dimethylmorpholinyl)-5-methylpyrrolo[2, 1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-hydroxyphenyl)methanesulfonate Indoleamine; 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-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4] Pyrazin-2-yl)ethyl)amino)-7H-pyridyl And [2,3-d]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide; 132. 3-(4-amino-1-((5-methyl-4) -(2-morpholinylethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidin-3-yl)-5-fluorophenol; 133. 1-(2-((2-((4-amino-5-hydroxyphenyl))-1H-pyrazolo[3] ,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl)pyrrolidine -2-ketone; 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-methoxypyridine-3 -yl)-N-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-5-methylpyrrolo[2,1-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-dimethylmorpholinyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl) -1H-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]3 Pyrazin-2-yl) Amino)pyrimidine-5-carbonitrile; 138. (S)-3-(2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methyl Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methyl-N-(4-(methylsulfonylamino)benzyl)benzamide; 139. 4-((3-(2-(1-(6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-5-methylbenzimidino)methyl)benzoic acid (S)-methyl ester; 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]triazine-4- -N-(3-hydroxyphenyl)-5-methylbenzamide; 142. (S)-4-((3-(2-(1-((6-amino-5-cyano)) Pyrimidin-4-yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-5-methylbenzimidino) Methyl)benzoic acid; 143. 1-(2-((2-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine) -1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl) Ethyl piperidine-4-carboxylate; 144. N-(4-(4-((S)-1-(4-((2S,6R)-2,6-dimethylmorpholinyl)-) 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. 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 (S)-3-aminophenyl ester; 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)-1H-pyridyl Zoxa[3,4-d] Pyrimidin-3-yl)-5-fluorophenol; 150. 3-(4-Amino-1-((S)-1-(4-((3S,5R)-3,5-dimethylpiperazine- 1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine- 3-yl)-5-fluorophenol; 151. 1-(2-((2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-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)aminecarbamimidyl)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-(aminosulfonylamino)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-(methylsulfonylamino)benzyl)-5-methylbenzimidamide; 155. 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 (S)-A 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-cyanopyrimidine-4-) Amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-methoxy-4-(methyl) Sulfhydrylamino)benzyl)-5-methylbenzimidamide; 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-aminesulfonylbenzyl)benzene Methionine; 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-(methylsulfonylamino)benzyl)-5-methylbenzimidamide; 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)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-6- --N-(4-Aminesulfonylbenzyl)pyrimidine-4-carboxamide; 162. (S)-3-(2-(1-((6-Amino-5-cyanopyrimidine-4) -yl)amino)ethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(3-hydroxybenzyl)-5- Benzene sulfonamide; 163. (S)-4-Amino-6-((1-(4-((2-(dimethylamino)ethyl))) 4-(4-methylpiperazine-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. 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 (S)-4-amine sulfonylbenzyl ester; 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)) Pyridin-1-yl)pyridin-4-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5- Nitrile; 168. (S)-4-Amino-6-((1-(5-methyl-4-(2-methyl-6-(4-methylpiperazin-1-yl)pyridine) 4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 169. 5-(2-Aminopyridine- 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[2,1-f][ 1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 171. 3-(2-((4-amino-3-) 3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2 , 4] triazin-4-yl)-5-methylbenzoic acid ethyl ester; 172. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyridyl) Zoxao[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-( 2-hydroxyethyl)-5-methylbenzimidamide; 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)-1H-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] 5-(2-aminopyridin-4-yl)-N-((S)-1-(4-((2S,6R) -2,6-Dimethylmorpholinyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine; 180. (1-(2-((2-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d Pyrimidine-1-yl)methyl) -5-Methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)ethyl)piperidin-4-yl)(4-methylpiperazine-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[2,1-f][1,2,4]triazin-2-yl) -7H-pyrrolo[2,3-d]pyrimidine-4-amine; 183. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyridyl) Zoxao[3,4-d]pyrimidin-1-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-( 3-(4-(Dimethylamino)piperidin-1-yl)propyl)-5-methylbenzamide; 184. 3-(2-((4-amino-3-(3-fluoro)) -5-hydroxyphenyl)-1H-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]triazine-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-methylbenzimidamide; 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-aminesulfonate Benzyl)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-dimethylmorpholinyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H -pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide; 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]pyrimidine -5-yl)-1H-indol-6-yl)methanesulfonamide; 193. (S)-N-(4-(4-((1-(4-(2,6-dimethylpyridine) 4-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d] Pyrimidin-5-yl)-1H-indol-6-yl)methanesulfonamide; 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)-1H-indol-6-yl)methanesulfonamide; 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[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)propan-1-ol; 197. (S)-1-(5-(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)-2-methoxypyridin-3-yl) Urea; 198. N1-(4-(4-((S))-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-methylpyrrole And [2,1- f ][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-N2,N2-di Methyl ethane-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)pyridine-4- -7H-pyrrolo[2,3-d]pyrimidin-4-amine; 200. 3-(2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyridyl) Zoxao[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-methylbenzimidamide; 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)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 202. 3-(4-amino-1-((4-(2-(4-(4-) (Dimethylamino)methyl)piperidin-1-yl)ethoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl -1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol; 203. 3-(4-amino-1-((4-(3-(4-)) -amino)piperidin-1-yl)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)methyl)-1H-pyrazole And [3,4-d]pyrimidine-3- -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)-1H-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)-1H-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)-1H-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)-1H-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] Benz-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; 209. 4-amino-6-(((S)-1-(4-((3S,5R)-4-(3-hydroxyl) Benzyl)-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-(dimethylamino)ethoxy)benzyl)-3,5-dimethylperidyl) Pyrazin-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; or pharmaceutically thereof Acceptable salts, or nitrogen-oxides, or isotopically-labeled derivatives. The compound according to any one of claims 1 to 15 is for use in the treatment of a pathological condition or disease which is easily improved by inhibiting phosphoinositide 3-kinase (PI3K). The compound of claim 16, wherein the pathological symptom or disease is selected from the group consisting of a respiratory disease, an allergic disease, an inflammatory response or an autoimmune mediated disease, a dysfunction, a neurological disorder and pain, and a cardiovascular disease. , viral infections, metabolic/endocrine dysfunction, neurological disorders and pain, bone marrow and organ transplant rejection, myelodysplastic syndromes, myeloproliferative disorders (MPDs), cancer and hematological malignancies, leukemias, lymphomas and solid tumors. The compound according to claim 16 or 17, wherein the pathological symptom or disease is selected from the group consisting of leukemia, lymphoma and solid tumor, rheumatoid arthritis, multiple sclerosis, muscular atrophic spinal cord side Somatostatosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, type 1 diabetes, cutaneous vasculitis, erythematosus, dermatomyositis, including but not limited to vulgaris Pemphigus, bullous pemphigoid and epidermoid vesicular blister, asthma, chronic obstructive pulmonary disease, cystic fibrosis, Primary pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma, and actinic keratosis. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15 in combination with a pharmaceutically acceptable diluent or carrier. Use of a compound as defined in any one of claims 1 to 15 for the manufacture of a pathological symptom as defined in any one of claims 16 to 18 or The drug of the disease. A method of treating an individual suffering from a pathological condition or disease as defined in any one of claims 16 to 18, the method comprising administering to the individual a therapeutically effective amount as in claim 1 A compound as defined in any one of the fifteenth or a pharmaceutical composition as defined in claim 19. 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 adenosine A _2A Adenoside A _2A agonist, an agent for treating cardiovascular diseases, an agent for treating diabetes, an agent for treating liver disease, an anti-allergic agent, an anti-cholinergic agent, an anti-inflammatory agent Agent, anti-infective agent, β2-adrenergic agonist, inhibitor of chemoattractant receptor homologous molecule (CRTH2) expressed on TH ₂ cells, chemotherapy Agent, corticosteroid, IKKβ/IKBKB (IkB kinase β or IKK2) inhibitor, immunosuppressant, Janus kinase (JAK) inhibitor, localized p38 mitogen-activated protein kinase (p38 Mitogen- Activated Protein Kinase, p38 MAPK) inhibitor, phosphodiesterase (PDE) IV inhibitor, and spleen tyrosine kinase (Syk) inhibitor for simultaneous treatment in human or animal body, Use separately or sequentially.