pharmaceutical compound and composition

专利摘要:
COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THAT COMPOUND The present invention provides PIK3 protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treating, preventing and / or ameliorating kinase-mediated diseases or disorders with the same .
公开号:BR112013027774B1
申请号:R112013027774-2
申请日:2012-05-04
公开日:2020-11-17
发明作者:Dhanapalan Nagarathnam；Swaroop Kumar V .S. Vakkalanka；Meyyappan Muthuppalaniappan；Srikant Viswanadha；Govindarajulu BABU；Prashant Kashinath Bhavar
申请人:Rhizen Pharmaceuticals S.A.；
IPC主号:

专利说明:

This application claims the benefit of Indian provisional patent applications 1542 / CHE / 2011 of 4 May 2011 and 81 / CHE / 2012 of 9 January 2012, each of which is incorporated herein by reference. FIELD OF THE INVENTION
The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treating, preventing and / or alleviating kinase-mediated diseases or disorders with them. BACKGROUND OF THE INVENTION
In the recent past, major research has been devoted to discovering and understanding the structure and function of enzymes and biomolecules associated with various diseases. An important class of enzymes that has been the subject of extensive research is protein kinase.
In general, protein kinases represent a set of structurally related phosphoryl transferases containing conserved structures and catalytic functions. These enzymes chemically modify proteins by adding phosphate groups (phosphorylation). Phosphorylation involves removing a phosphate group from ATP and covalently attaching it to amino acids that have a free hydroxyl group, such as serine, threonine, or tyrosine. Phosphorylation generally results in a functional change in the target protein (substrate), altering enzymatic activity, cell location or association with other proteins. Up to 30% of all proteins can be modified by kinase activity.
This class of proteins is classified into subgroups, depending on the substrate on which they act, such as tyrosine kinase, serine / teronine kinase, histidine kinase and the like. These proteins can also be classified based on their location on tyrosine kinase receptors (RTKs) or non-tyrosine kinase receptors.
Tyrosine kinase receptors (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular. Tyrosine kinase receptor-mediated signal transduction is typically initiated by an extracellular interaction with a specific growth factor (ligand), followed by dimerization of the receptor, stimulation of the intrinsic activity of the protein tyrosine kinase, and phosphorylation of amino acid residues. The conformational change that followed leads to the formation of complexes with a spectrum of cytoplasmic signaling molecules and facilitates a myriad of responses, such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment.
Protein kinases are known to control a wide variety of biological processes, such as cell survival, growth and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration. In addition to their functions in normal tissues / organs, many protein kinases also perform specialized functions in a number of human diseases, including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when deregulated, can cause tumor formation and growth and contribute to tumor maintenance and progression (Blume-Jensen P et al, Nature 2001, 411 (6835): 355 -365). So far, oncogenic protein kinases are one of the largest and most attractive groups of target proteins for therapeutic intervention and drug development.
Both receptor and non-receptor protein kinases do not prove to be attractive targets for drug discovery as small molecules due to their impact on cell physiology and signaling. Deregulation of protein kinase activity thus leads to changes in cellular responses including the uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is involved in numerous other pathological diseases. These include, among others, immunological disorders, cardiovascular diseases, inflammatory diseases and degenerative diseases.
Modulation (particularly inhibition) of cell proliferation and angiogenesis, the two main cellular processes necessary for tumor growth and survival, is an attractive goal for the development of small molecule drugs (Matter A. Drug Disc Technol 2001, 6, 1005-1024 ). Antiangiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with unregulated vascularization including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. Likewise, cellular antiproliferative agents are desirable to slow or inhibit tumor growth.
Phosphatidylinositol (here abbreviated as "PI") is one of a number of phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. Cell signaling through 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, for example, malignant transformation, growth factor signaling, inflammation and immunity (Rameh et al (1999) J. Biol Chem, 274: 8347- 8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor tyrosine kinase receptors that phosphorylate phosphatidylinositol ( PI) and its derivatives phosphorylated in the 3'-hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2: 358-60).
Phosphoinositides 3-kinases (PI3Ks) are a family of enzymes that regulate various biological functions in each cell type through the generation of second messenger phosphatidylinositide molecules. As the activity of these second messengers phosphatidylinositide is determined by their phosphorylation status, the kinases and phosphatases that act to modify these lipids are essential for the correct execution of intracellular signaling events. Phosphoinositide 3-kinases (PI3K) phosphorylate lipids in 3-hydroxyl residue of an inositol ring (Whitman et al (1988) Nature, 332: 664) to generate phosphorylated phospholipids (PlP3s) that act as second messengers that recruit kinases with domain domains lipid binding (including plecstrin homology (PH) regions), such as Akt and phosphoinositide 1 dependent kinase (PDK.1). The binding of Akt to the PIP3s membrane causes the translocation of Akt to the plasma membrane, bringing Akt in contact with PDK.1, which is responsible for the activation of Akt. Tumor suppressor phosphatase, PTEN, dephosphorylates PJP3 and therefore acts as a negative regulator of Akt activation. Akt PI3-kinases and PDK.1 are important in the regulation of many cellular processes, including regulation of the cell cycle, proliferation, survival, apoptosis, and motility and are important components of the molecular mechanisms of diseases such as cancer, diabetes, immune inflammation (Vivanco et al and (2002) Nature Rev. Cancer 2: 489; Phillips et al (1998) Cancer 83:41).
The PI3K family consists of four different classes: classes I, II and III are lipid kinases, while members of class IV are Ser / Thr protein kinases.
Members of the PI3Ks class I family are dimers of a regulatory and a catalytic subunit. The class I family consists of four isoforms, determined by the catalytic subunits α, β, y, and δ (see Engelman JA, Nat Genet Rev 2006; 7: 606-19; Carnero A, Curr Cancer Drug Targets 2008; 8: 187 -98; Vanhaesebroeck B,
I Biends Biochem Sci 2005; 30: 194-204). Class I can be subdivided into two subclasses: Ia, formed by a combination of pllOα, β and δ and a regulatory subunit (p85, p55 or p50) and lb, formed by pllOyeplOl regulatory subunits.The p85 regulatory subunit contains Src homology of 2 domains, which bind to phosphotyrosines and bring the catalytic subunit attached to pl 10 in the complexes located on the membrane around the receptor. The activation of PI3K. it is induced by growth factors and insulin marking the catalytic subunit for the membrane where it is in close proximity to its substrates, mainly PIP2. Alternatively, GTP-linked Ras can bind and activate p10O subunits in a p85-independent manner. Class 1 phosphoinositide 3-kinases (PDKs) are kinases that phosphorylate phosphatidyl-inositides (PI) lipids at the D3 position of the inositol ring producing second lipid messengers (PIPS). PI3K activity products, mainly PI (3,4,5) -P3 (PIP3), are present in very low levels in quiescent cells, but are rapidly produced during cellular stimulation and are involved in the regulation of various biological responses, including mitogenesis, apoptosis, vesicular traffic and cytoskeleton rearrangement. The result of increased levels of PEP2 is the activation of 3-phosphoinositide-dependent protein kinase 1 and its substrate AK.T, which triggers most of the pathway's biological activities. Phosphatase and tensin homologue on chromosome 10 (PTEN) is a lipid phosphatase that constitutes the main negative regulator of the PDP3 to PI (4,5), P2 (PIP2) dephosphorylation route. Class fl exhibits the ability to phosphorylate PI and PI-4 phosphate in vitro. Class III, composed of Vps34 single member, phosphorylates PI in position 3, generating PI 3-phosphate. Vps34 has been implicated in Golgi protein traffic, autophagy, and target activation of rapamycin in mammals (mTOR) by amino acids (see Backer JM. Biochem J 2008; 410: 1-17). These classes are generally resistant to PI3K class 1 inhibitors. Class IV, however, is important because it constitutes the main cross-activity proteins for class I inhibitors. This class includes enzymes involved in signal transduction and response to DNA damage , such as mTOR, DNA-dependent protein kinase (DNA-PK) or ATM. This fourth class of enzymes related to PI3K. contains a PI3K-like catalytic nucleus, which may represent cross-inhibition by 'selective' class I compounds. However, small differences, especially in the hinge region, and the resolution of PI3K-related structures can lead to fine adjustment of different selective parallels for PI3K members. (see Expert Opin. Investig. Drugs (2009) 18 (9): 1265-1277).
Currently, there is considerable evidence indicating that Class Ia PI3K enzymes contribute to tumorigenesis in a wide variety of human cancers, directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10a subunit is amplified in some tumors such as ovary (Shayesteh et al, Nature Genetics. 1999, 21: 99-102) and cervix (Ma et al, Oncogene, 2000, 19: 2739-2744 ). More recently, activation mutations within the pi 10a catalytic site have been associated with several other tumors, such as those of the colorectal region and of the breast and lung (Samuels et al, Science, 2004, 304, 554). P85a tumor-related mutations have also been identified in cancers, such as those of the ovary and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to the direct effects, Class Ia PI3K activation is believed to contribute to tumorigenic events that occur upstream in signaling pathways, for example, through activation of dependent ligand or ligand independent of tyrosine kinase receptors, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204). Examples of said upstream signaling pathways include overexpression of the Erb2 tyrosine kinase receptor in a variety of tumors that lead to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and overexpression from the Ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In addition, Class Ia PBKs can indirectly contribute to tumorigenesis caused by various signaling events downstream. For example, loss of PTEN tumor suppressor phosphatase effect that catalyzes the conversion of PI (3,4,5) P3 back to PI (4,5) P2 is associated with a wide variety of tumors through deregulation of mediated production by PI3K.de PI (3,4,5) P3 (Simpson and Parsons, Exp. Cell Res. 2001, 264, 29-41). In addition, the increased effects of other PI3K-mediated signaling events are believed to contribute to a variety of cancers, for example, through Akt activation (Nicholson and Anderson, Cellular Signalling, 2002, H, 381-395) .
In addition, to a role in mediating proliferative signaling and survival in tumor cells, it also presents good evidence that enzymes of class Ia PI3K will also contribute to tumorigenesis through their function in tumor-associated stromal cells. For example, PI3K signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors, such as VEGF (Abid et al., Arterioscler. Thromb. Vase. Biol., 2004, 24, 294-300). As Class I PI3K enzymes. are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, JJ., 1-19), PI3K inhibitors. they should provide therapeutic benefit by inhibiting tumor cell invasion and cell metastasis.
In addition, class I PI3K enzymes. play an important role in the regulation of immune cells with PI3K activity. contributing to pro-tumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867). These findings suggest that pharmacological inhibitors of class 1 PI3K enzymes should have therapeutic value for the treatment of various forms of cancer disease that comprise solid tumors, such as carcinomas and sarcomas and lymphoid leukemias and malignancies. In particular, Class I PI3K enzyme inhibitors should have therapeutic value for the treatment of, for example, breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchialveolar cancer ) and prostate, and cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix, and, vulva and leukemias (including ALL and CML), multiple myeloma and lymphomas.
A recent review by Romina Marone et. al., Biochimica et Biophysica Acta 1784 (2008) 159-185, describes the activation of the PI3K signaling cascade containing a positive effect on cell survival, growth and proliferation. The upward regulation constitutive of P13K signaling. it can have a deleterious effect on cells that lead to uncontrolled proliferation, increased migration and growth independent of adhesion. These events favor not only the formation of malignant tumors, but also the development of autoimmune inflammatory disease indicating the role of PI3K in several diseases, including chronic inflammation and allergies, cardiovascular diseases, cancer and metabolic diseases.
Several components of the PI3-kinase / Akt / PTEN pathway are implicated in oncogenesis. In addition to growth factor tyrosine kinase receptors, integrin-dependent cell adhesion and G protein-coupled receptors activate PI3-kinase both directly and indirectly, through adapter molecules. Functional loss of PTEN (the tumor suppressor gene most commonly mutated in cancer after p53), oncogenic mutations in PI3 kinase (Samuels et al (2004) Science 304: 554), amplification of P13-kinase and Akt overexpression have been established in many malignancies In addition, signaling via the persistent PI3-kinase / Akt pathway by stimulating the insulin-like growth factor receptor is a mechanism of resistance to epidermal growth factor receptor inhibitors, such as AG 1478 and trastuzumab. Oncogenic mutations of pllOalfa have been found in a significant frequency in colon, breast, brain, liver, ovary, gastric, lung, head and neck tumors and solid tumors. PTEN abnormalities are found in glioblastoma, melanoma, prostate, endometrial, ovarian, breast, lung, head and neck, hepatocellular, and thyroid cancers.
Levels of phosphatidylinositol-3 4,5-triphosphate (PIP3), the primary product of PI3 kinase activation, increase after treatment of cells with a variety of agonists. The activation of PI3-kinase, therefore, is believed to be involved in a variety of cell responses including cell growth, differentiation, and apoptosis (Parker et al (1995) Current Biology, 5: 577-99; Yao et al ( 1995) Science, 267: 2003-05). Although the targets downstream of phosphorylated lipids generated after PI3 kinase activation have not been well characterized, the evidence suggests that proteins containing the pleestrin homology domain and the FYVE-finger domain are activated when binding to the various phosphatidylinositol lipids (Sternmark et al (1999) J Cell Sei, 112: 4175-83; Lemmon et al (1997) Trends Cell Biol, 7: 237-42). In vitro, some isoforms of protein kinase C (PK.C) are directly activated by PIP3, and the protein kinase related to PK.C, PK.B has been shown to be activated by PI3 kinase (Burgering et al (1995) Nature, 376: 599-602).
PI3 kinase also appears to be involved in leukocyte activation. An activity of P13 kinase associated with p85 has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T cells in response to the antigen (Pages et al (1994) Nature, 369: 327-29 ; Rudd, (1996) Immunity 4: 527-34). Activation of T cells through CD28 reduces the threshold for antigen activation and increases the amplitude and duration of the proliferative response. These effects are linked to an increase in the transcription of a number of genes, including interlucucin-2 (IL2), an important T-cell growth factor (Fraser et al (1991) Science, 251: 313-16). The mutation of CD28 so that it can no longer interact with PI3 kinase leads to a failure to start IL2 production, suggesting a critical role for PI3 kinase in T cell activation.
Inhibition of class I PI3 kinase induces apoptosis, blocks tumor induced by angiogenesis in vivo, and increases the radiosensitivity of certain tumors. At least two compounds, LY294002 and wortmanine, have been widely used as inhibitors of PI3 kinase. These compounds, however, are non-specific inhibitors of PI3K, since they do not distinguish between the four members of Class I PI3 kinases. For example, the IC50 values of wortmannin (US Patent 6,703,414) against each of the various Class 1 PI3 kinases are in the range of 1-10 nanomolar (nM). LY294002 (2- (4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one) is a specific well-known inhibitor of class I PI3 kinases and has anticancer properties (Chiosis et al (2001) Bioorganic & Mcd. Chem. Lett. 11: 909-913; VIahos et al (1994) J. Biol. Chem. 269 (7): 5241-5248; Walker et al (2000) Mol. Cell 6: 909-919; Fruman et al ( 1998) Ann Rev Biochem, 67: 481-507).
The patent literature that belongs to the various research groups around the world includes several said patents and / or patent applications, namely, US 6,608,056; US 6,608,053; US 6,838,457; US 6,770,641; US 6,653,320; US 6,403,588; WO 2004017950; US 2004092561; WO 2004007491; WO 2004006916; WO 2003037886; US 2003149074; WO 2003035618; WO 2003034997; US 2003158212; EP 1417976; US 2004053946; JP 2001247477; JP 08175990; JP 08176070). WO 97/15658. US 7,173,029; US 7,037,915; US 6,703,414; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004'007491; W02004 / 006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; including PLLO alpha binding activity US 2008/0207611; US 2008/0039459; US 2008/0076768; WO 2008/073785; WO 2008/070740; US20090270430A1; US2006270673 Al W02009129211A1; US2009 0263398A1; US20090263397A1; W02009129259A2 US7605160; US7605155; US7608622; US20090270621; US20090270445: US20090247567A1; US7592342; US2009 0239847A1; US7595320; US20090247538A1 US20090239936A1; US7595330; US20090239859A1; W02009117482A1 W02009117097Al; US20090247565Al; W02009 120094A2; US20090258852A1 US7601724; WO2009126635A1; US7601718; US7598245; US20090239859A1 US20090247554; US20090238828; W020091 14874A2; W020091 14870 A2 US20090234132A1; W02009112565A1; US20090233950A1; US20090233926A1 US7589101; W02009111547A1; W0200911 1531A1; W02009109867 A2 and W02009105712A1.
Reviews and studies on PI3K pathways. and related protein kinase were given by Pixu Liu et. al. (Nature Reviews Drug Discovery, 2009, 8, 627-644); Nathan T. et. al. (Mol Cancer Ther., 2009; 8 (1) Jan., 2009); Romina Marone et, al. (Biochimica et Biophysica
Acta 1784 (2008) 159-185) and B. Markman et. al. (Annals of oncology Advance access published in August 2009). All of these patents and / or patent applications and literature disclosures are hereby incorporated by reference in their entirety for all purposes.
There remains an unmet need and directed towards small molecule kinase modulators to regulate and / or modulate the transduction of kinases, particularly PI3K and protein kinase for the treatment of diseases and disorders associated with kinase-mediated events.
Another reference is made here to international patent application No. PCT / IB2010 / 002804, filed on November 3, 2010, and US patent application 12 / 938,609 filed on November 3, 2010 which generally reveals 2.3 disubstituted-4H -cromen-4-one and are incorporated herein by reference in their entirety for all purposes. SUMMARY OF THE INVENTION
The present invention is directed to compounds, which are useful as PI3K protein kinase modulators. and cm as PI3K inhibitors. In one embodiment, the compound of the present invention has the formula:
where each occurrence of R is independently selected from hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or unsubstituted - COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxRy, -NRxCONRxRy, - N (RX) SORX, -N ( Rx) SO2Ry, - (= NN (Rx) Ry),. NRxC (O) ORy, -NRxRy, -NRxC (O) Ry-, NRxC (S) Ry -NRxC (S) NRxRy, -SONRxRy-, -SO2NRxRy-, -ORX, -ORxC (O) NRxRy, - ORXC ( O) ORX-, -OC (O) RX, -OC (O) NRxRy, - RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, - RxC (O) NRxRy, -RxC (O) Ry, -RxOC (O) Ry, -SRX, -SORX, -SO2RX, -0N02, where Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted alkenyl or unsubstituted, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl substituted, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry can be joined to form a 3-14 membered satur ring or unsaturated, substituted or unsubstituted, which can optionally include heteroatoms which can be the same or different and are selected from O, NRZ or S, or (ii) any two of Rx and Ry together to form an oxo (= 0) , uncle (= S) or imino (= NR1) (where R1 is hydrogen or substituted or unsubstituted alkyl). R1 and R * can be the same or different and are independently selected from hydrogen, halogen, C | .6 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted cycloalkenyl or unsubstituted, substituted or unsubstituted cycloalkylalkyl and substituted or unsubstituted heterocyclyl, or both R1 and R2 directly attached to an atom, can be joined to form a substituted saturated or unsaturated oxo group (= O) or a 3-10 membered or unsaturated ring or unsubstituted (including the carbon atom to which R1 and R2 are attached), which can optionally include one or more heteroatoms which can be the same or different and are selected from O, NRa and S; Cy1 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; L | is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -. each occurrence of Rae Rb can be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (Ci.6) alkyl, -NRLRd (where RL and Rd are independently hydrogen, halogen, hydroxy , cyano, (C | -6) substituted or unsubstituted alkyl, or (C1) alkoxy) and -ORC (where Rc is substituted or unsubstituted (C | .ô) alkyl) or when Ra and Rb are directly linked to an atom, they can be joined to form an oxo group (= O) or to form a 3-10 membered saturated or unsaturated, substituted or unsubstituted ring (including the common atom to which Ra and Rb are directly attached), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (C1-6) alkyl) or S; Y is selected from O, S, and NRa; eq is 0, 1 or 2 or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. Yet another embodiment is a compound containing the formula (IA) (IA) in which each occurrence of R is independently selected from halogen, CN, C | ^ substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, C2-6 substituted alkenyl or unsubstituted, C2.6 substituted or unsubstituted alkynyl, C3.8 substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclic group; R and R can be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C1 .6 alkyl, or both R1 and R2 directly attached to an atom, can be joined to form an oxo group (= 0) or a saturated or unsaturated, substituted or unsubstituted 3-10 membered ring (including the carbon atom to which R1 and R2 are attached), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRa and S; Cy1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; L | is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -. each occurrence of Rae Rb can be the same or different and are independently selected from substituted or unsubstituted hydrogen, halogen, hydroxy, cyano, (Ci.6) alkyl, -NR ^ R11 (where RL and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (C1-6) alkyl or (C1-6) alkoxy) and -ORC (where Rc is (C1-6) substituted or unsubstituted alkyl) or when Ra and Rb are directly linked to an atom, these can be joined to form an oxo group (= 0) or form a 3-10 membered saturated or unsaturated, substituted or unsubstituted ring (including the common atom to which Rd and Rb are directly attached), which can optionally include one or more heteroatoms which can be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (C1-6) alkyl) or S; Y is selected from O, S, and NRa; eq is 0, 1 or 2 or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
Yet another embodiment is a compound containing the formula (I) or (IA)
wherein R is selected from halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3.8 cycloalkyl, and substituted or unsubstituted heterocyclic group or ORa.
Yet another embodiment is a compound containing the formula (I) or (IA) in which R is selected from fluorine, methyl, morpholine or -OCH3.
Another preferred is a compound containing the formula (I) or (IA) in which Cy1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
Illustrative examples of optionally substituted Cy1 groups include those shown below:

Another preferred is a compound containing the formula (I) or (IA), wherein Cy1 is substituted or unsubstituted phenyl or pyrazole. Another preferred is a compound containing the formula (I) or (IA) in which Cy1 is substituted phenyl. Another preferred is a compound containing the formula (I) or (IA), wherein Cy1 is 2-methyl phenyl, 2-fluorine phenyl, 3-fluorine phenyl, 4-fluorine phenyl or pyrazol-4-yl. Yet another embodiment is a compound containing the formula (1) or (IA)
, wherein R and R2 independently represent hydrogen or C i-6 substituted or unsubstituted alkyl (for example, methyl). 15 Yet another embodiment is a compound containing the formula (I) or (IA), where L | is selected from -S (= O) q- or -NRa. Yet another embodiment is a compound containing the formula (I) or (IA), where q is 0.
Yet another embodiment is a compound containing the formula (I) or (IA), in which Ra is hydrogen.
Yet another embodiment is a compound containing the formula (I) or (IA), in which Li is absent.
Yet another modality is a compound containing the formula (I) or (IA), in which Lj-Cy2 is selected from
where X is CR3; and each occurrence of R3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl ring, or unsubstituted heterocyclyl ring, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl substituted or unsubstituted guanidine, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRyRz, - NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), - NRxC (O) ORy, -NRxRy, - NRxC (O) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz, -SONRxRy -, -SO2NRxRy-, -ORX, - ORxC (O) NRyRz, -ORxC (O) ORy-, -OC (O) RX, -OC (O) NRxRy, - RxNRyC (O) Rz, -RxORy , - RxC (O) ORy, -RxC (O) NRyRz, -RXC (O) RX, -RxOC (O) Ry, -SRX, -SORX, -SO2RX, or -ONO2, where Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl , substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of Rx, Ry and Rz can be joined to form a 3-10 membered saturated or unsaturated, substituted or unsubstituted ring, which can optionally include heteroatoms which can be the same or different and are selected from O, NR 1 or S (where R1 is hydrogen or substituted or unsubstituted alkyl).
Yet another modality is a compound containing the formula (I) and (IA), in which L | - Cy2 is selected from
where X and R3 are the same as defined above; and each occurrence of R and R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted aryl or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or heterocyclyl alkyl ring unsubstituted, substituted or unsubstituted guanidine, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, - NRyRz, -NRxCONRyRz, -N (Rx ) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), - NRxC (O) ORy, - NRxRy, -NRxC (O) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz , -SONRxRy-, -SO2NRxRy-, -ORX, - ORxC (O) NRyRz, -ORxC (O) ORy-, -OC (O) RX, -OC (O) NRxRy, -RxNR yC (O) Rz, -RxORy, - RxC (O) ORy, -RxC (O) NRyRz, -RXC (O) RX, -RxOC (O) Ry, -SRX, -SORX, -SO2RX, and -ONO2, or both R 'and R "' together with the nitrogen atom can be joined to form a saturated or unsaturated, substituted or unsubstituted 3-10 membered ring, which can optionally include heteroatoms which can be the same or different and are selected from O, NR1 (where R1 is hydrogen or substituted or unsubstituted alkyl) or S; Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl , substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted amino ring, or substituted or unsubstituted amino or any two of Rx, R} and Rz can be joined to form a saturated or unsaturated, substituted or unsubstituted 3-10 membered ring, which can optionally include heteroatoms which can be the same or different and are selected from O, NR1 or S (where R1 is hydrogen or 10 substituted or unsubstituted alkyl); eq is 0, 1 or 2. Yet another modality is a compound containing the formula (I) and (IA), in which Lp Cy2 is selected from
where X and R are the same as defined above. For example, LpCy2 is represented as the formula a, bc, de, or f above can be



Yet another modality is a compound containing the formula (I) and (IA) in which Li-Cy2 is selected from




Yet another modality is a compound containing the formula (I) or (iA) in which L | - Cy2 is selected from
Yet another embodiment is a compound containing the formula (IA-I), (IA-II), (IA-III), (IA-IV) or (IA-V).
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. where R is selected from hydrogen, halogen, -ORa, CN, CM substituted or unsubstituted alkyl, C2.6 substituted or unsubstituted alkenyl, C2-6 substituted or unsubstituted alkynyl, C3.8 substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclic group; R1 and R2 can be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl CM or both R1 and R2 directly attached to an atom, can be joined to form an oxo group (= 0) or can be joined to form a saturated or unsaturated 3-10 membered substituted or unsubstituted ring (including the common atom to which R1 and R2 are directly attached), which can optionally include one or more heteroatoms which can be the same or different and are selected from O, NRa and S; Cy1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; each occurrence of X is independently selected from CR3 or N; each occurrence of R3 is independently selected from hydrogen, hydroxy. halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, or unsubstituted heterocyclyl ring, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted guanidine, -COORX, -C (O ) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRyRz, - NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx ) Ry), - NRxC (O) ORy, -NRxRy, - NRxC (O) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, - ORxC (O ) NRyRz, -ORxC (O) ORy-, -OC (O) RX, -OC (O) NRxRy, - RxNRyC (O) Rz, -RxORy, - RxC (O) ORy, -RxC (O) NRyRz, - RXC (O) RX, -RxOC (O) Ry, -SRX, -SORX, -SO2RX, or -ONO 2, wherein Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, arylalkyl substituted or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or substituted heterocyclyl alkyl, or substituted or substituted amino unsubstituted, or any two of Rx, Ry and Rz can be joined to form a 3-10 membered saturated or unsaturated, substituted or unsubstituted ring, which can optionally include heteroatoms which can be the same or different and are selected from O , NRr (where R1 is hydrogen or substituted or unsubstituted alkyl) or S; eq is 0, 1 or 2.
Yet another embodiment is a compound containing the formula (IA-la), (IA-IIa). (IA-IIIa), (IA-Ib) or (IA-IIb).
where X, R3, R and R are the same as defined above.
Yet another embodiment is a compound containing the formula (IA-1), (IA-1I), (IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa) , (IA-IIIa), (IA-Ib) or (IA-IIb) where R is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, ORa or morpholine.
Yet another embodiment is a compound containing the formula (IA-1), (IA-II), (IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa) , (IA-IIIa), (IA-Ib) or (IA-IIb) where R is selected from hydrogen, halogen, ORa or morpholine.
Yet another embodiment is a compound containing the formula (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa) , (IA-IIIa), (IA-Ib) or (IA-IIb) where Cy1 is selected from

Yet another embodiment is a compound containing the formula (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa) , (IA-IIIa), (IA-Ib) or (IA-IIb) where R1 and R2 independently represent hydrogen or substituted or unsubstituted alkyl
Yet another embodiment is a compound containing the formula (IA-II), (IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) in which R3 is selected from iodine, cyano, substituted alkynyl or unsubstituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
Yet another embodiment is a compound containing the formula (IA-II), (IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) in which R3 is selected from substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
Yet another embodiment is a compound containing the formula (IA-II), (IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) in which R3 is selected from
where 5 each occurrence of X is independently CR4 or N; X1 is O, S, or NR4; and each occurrence of R4 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl 10 substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, or unsubstituted heterocyclyl ring, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl substituted, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted guanidine, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRyRz, - NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy, - NRxC (O) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, ORxC (O) NRyRz, -ORxC (O) ORy-, -OC (O) RX, -OC (O) NRxRy, -R xNRyC (O) Rz, -RxORy, - RxC (O) ORy, -RxC (O) NRyRz, -RXC (O) RX, -RxOC (O) Ry, -SRX, -SORX, -SO2RX, or -ONO2. where Rx, R> and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted arylalkyl or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted amino ring substituted, or any two of Rx, Ry and Rz can be joined to form a 3-10 membered saturated or unsaturated, substituted or unsubstituted ring, which can optionally include heteroatoms which can be the same or different and are selected from O, NR (where R is hydrogen or substituted or unsubstituted alkyl) or S; For example, RJ can be any of the following:


Yet another embodiment is a compound containing the formula (IA-III) or (IA-IIIa) 5 in which RJ is selected from substituted or unsubstituted iodine, cyano and alkynyl.
Yet another embodiment is a compound containing the formula (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa) , (IA-IIIa), (IA-Ib) or (IA-IIb) where X is CR3 and each occurrence of R3 is independently hydrogen, halogen, hydroxyl or NH2.
Yet another modality is a compound of formula (IA-VI)
or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R, R and X are as defined above with respect to any of the formulas (I), (IA) or (IA-II); each occurrence of R5 is hydrogen, C1-6 alkyl or halogen; and p is 0, 1,2, 3, 4 or 5. 5 Yet another modality is a compound containing the formula (IA-II) or (IA-VI) in ■> that R is selected from

Yet another embodiment is a compound of formula (IA-VII)
or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, RJ and X are as defined above with respect to any of formulas (I). (IA) or (IA-III); each occurrence of R5 is hydrogen, C | .6 alkyl or halogen; and p is 0, 1,2, 3, 4 or 5. Yet another modality is a compound containing the formula (IA-VII) in which RJ is halogen or cyan. Yet another embodiment is a compound of the formula (IA-VIII) (IA-VIII)
or a pharmaceutically acceptable salt thereof, wherein R, R1, R ~ and X are as defined above with respect to any of the formulas are as defined above with respect to any of the formulas (I), (IA) or (IA -IV); each occurrence of R5 is hydrogen, C alkyl or halogen; and p is 0, 1, 2, 3, 4 or 5.
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) in which R is halogen (as fluorine) or C1-6 alkyl (as methyl).
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) where p is 0.
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) where p is 1 and R 'is 3-fluorine, 2-fluorine, 4-fluorine or 2-methyl .
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) in which R1 is methyl and R2 is hydrogen.
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) in which R1 is ethyl and R2 is hydrogen.
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) in which R1 and R2 are hydrogens.
Yet another embodiment is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) where X is C-H, C-F, C-Cl, C-NH2 or C-OH.
Another preferred is a compound containing the formula (IA-VI), (IA-VII) or (IA-VIII) where X is C-H.
Yet another embodiment is a compound containing the formula (IA-VI) in which each of R 'and R ”is selected from hydrogen or C1-6 alkyl (as methyl).
Yet another modality is a compound containing the formula (IA-VI) in which - NR'R ”together represent

Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof. The present invention should not be construed as limited to these. 1. 2- (6-Amino-9H-purin-9-yl) methyl) -3- (3-fluorophenyl) -5-methoxy-4H-chromen-4-one 2. 2 - ((4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -3- (3-fluorophenyl) -5-mctoxy-4H-chromen-4-one 3 2 - (((4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5-fluoro-3- (3-fluorophenyl ) -4H-chromen-4-one 4. 2 - (((4-amino-3- (3-fluoro-5-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) - 5-fluoro-3- (3-fluorfenyl) -4H-chromen-4-one 5. 2 - ((4-amino-3- (3-fluoro-5-hydroxyphenyl) -1H-pyrazolo [3.4-d | pyrimidin -l- yl) methyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 6. 2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 7. (+) - 2- (l - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-noro-3- (3-fluorophenyl) - 4H-chromen-4-one 8. (-) - 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4- d] pyrimidin-l- il) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 9. 2- (1 - (4-amino- 3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H -cromen-4-one 9a. (+) - 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 9b. (-) - 2- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -fluoro-3- (3-nuorfenil) -4H-chromcn-4-one 10. 2- (1 - (4-amino-3- (1 H-pyrazol-4-yl) -1 H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 11. 2- (l- (6-amino-9H-purin-9- il) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 12. 2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H -pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one 13. 2- (l- (4-amino-3 - (3-fluor-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrininin-1-yl) ethyl) -5-fluorine-3-phenyl-4H-chromen-4-one 14. 2- ( 1- (4-amino-3- (benzofuran-2-yl) -H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H- chromen-4-one 15. 2- (1 - (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorenyl) -4H-chromen-4-one 16. 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 16a. (+) - 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorenyl) -4H-chromen-4-one 16b . (-) - 2- (l - (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4 -one 17. 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-ilyl -3- (3-fluorophenyl) -4H-chromen-4-one 18. 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (1H-pyrazol-4-yl) -4H-chromen-4-one 19. 2- (1 - (4-amino-3- (3-fluorine -4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H- chromen-4-one 20. 2- (1 - (4-amino-3- (3-isopropyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-l-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 21. 2- (1- (4-amino-3- (3-fluorine-4- (piperidin-4-yloxy ) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 22. 2- (l- ( 4-amino-3- (3-fluorine-4- (2-hydroxyethylamino) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl ) -4H-chromen-4-one 23. 2- (1- (4-amino-3- (3-fluoro-4- (isopropylamino) phenyl) -1H-pyrazolo [3,4- dJpirimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -411-chromn-4-one 24. 2- (1 - (4-amino-3- (4- (dimethylamino) -3 -fluorfenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorphenyl) -4H-chromen-4-one 25. 2- (l- (4-amino-3- (3-fluor-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H- chromen-4-one 26. 2- (l- (4-amino-3- (2-methyl-1H-benzo [d] imidazol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-l -yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 27. 2- (l- (4-amino-3- (3-fluoro-4- (4-methylpipcrazin -l-yl) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-crornen-4-one 28. 2- (1 - (4- (dimethylamino) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4I I-chromcn-4-one 29. 2- (1- (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one 30. 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one 31. 2 - (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1 -yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one 32. 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromon-4-one 33. 2- (1 - (4-amino-3- methyl-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 34. 2- (1 - (4 -amino-3-ethyl-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 35. 2- (1- (4-amino-3-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 36. 2- (1 - (4-amino-3- (benzo [b] thiophen-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-ioriior- 3- (3-Ωuorfenyl) -4H-chromen-4-one 37. 2- (1 - (4-amino-3-morpholino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-lluorfenil) -4H-chromen-4-one 38. 2- (1 - (4-amino-3- (dimethylamino) -1 H-pyrazolo [3,4-d] pyrimidin -1 -yl) ethyl) -5- ioriior-3- (3-Ωuorfenyl) -4H-chromen-4-one 39. 2- (1 - (4-amino-3- (pipcridin-1-yl) -11 1-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 40. 2 - (1- (4-amino-3- (6-isopropoxypyridin-3-yl) -1 H-pyrazolo [3.4-d | pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 41. 2- (1 - (4-amino-3- (methylthio) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one 42. 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin -l-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromon-4-one 4-methylbenzenesulfonate 43. 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-oruor-3- (3-Ωuorfenyl) -4H-chromen-4-one 4- methylbenzenesulfonate 44. 2- (l- (4-amino-3- (4- (l-benzhydrylazetidin-3-yloxy) -3-Ωuorfenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ctil ) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 45. 2- (1- (4-amino-3- (3-fluorine-4- (trifluomethoxy) phenyl) -l H -pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-yluror-3- (3-fluorophenyl) -4H-chromen-4-one 46. 2- (l- (4-amino-3 - (3-fluoro-4- (oxetan-3-yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-lloro-3- (3-fluorophenyl) -4H -cromen-4-one 47. 2- (l- (4-amino-3- (pyrrolidin-l -yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5- Ωuor-3- (3-Ωuorfenyl) -4H-crornen-4-one 4 8. N- (4- (4-amino-1 - (1 - (5-Ωilor-3- (3-Ωuorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 1H-pyrazolo [3,4-d] pyrimidin- 3-yl) phenyl) isobutyramide 49. 2- (1- (4-amino-3- (4-isobutylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5- ioriior- 3- (3-Ωuorienyl) -4H-chromen-4-one 50. 2- (1 - (4-amino-3- (4-isopropoxy-3-inethylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-ioriior-3- (3-Ωuorfenyl) -4H-chromen-4-one 51. 2- (1 - (4-amino-3- (4- (5,6- dihydro-4H-1,3-oxazin-2-yl) phenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-ioriior-3- (3-Ωuorfenil) -4H -cromen-4-one 5 2. 4- (4-amino-1 - (1 - (5-Ωiior-3- (3-Ωuorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H - pyrazolo [3,4-d] pyrimidin-3-yl) -N-methylbenzenesulfonamide 53. 4- (4-amino-1- (1- (5-Ωiior-3- (3-Ωuorfenyl) -4-oxo- 4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluoro-N-isopropylbenzamide 54. 2- (1 - (4-amino-3- ( 4- (5- (methylamino) -1,3> 4-thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor r-3- (3-fluorophenyl) -4H-chromen-4-one 5 5. N- (4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4- oxo-4H-croinen-2-yl) ethyl) - 1H-pyrazolo [3.4-d] pyrimidin-3-yl) benzyl) methanesulfonamide 56. 4- (4-amino-l- (l- (5-fluor-3 - (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -N-isopropylbenzenesulfonamide 5 7. 4- (4- amino-1 - (1 - (5-Ω6or-3- (3-Ωuorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl ) -N-cyclopropylbenzenesulfonamide 58. 2- (1- (4-amino-3- (2-isopropoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5- Ωilor-3- (3-Ωuorfenil) -4H-chromen-4-one 5 9. (R) / (S) -2- (1 - (4-amino-3- (3-fluor-4-morphophenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-crornen-4-one 60. 4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) benzenesulfonamide 61 methyl 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 1H-pyrazolo [3,4- d] pyrimidin-3-yl) thiophene-2-carboxylate 62. 2- (l- (4 -amino-3- (5-methylthiophen-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) - 5-fluor-3- (3-fluorophenyl) -4H-chromen 4-one 63. 2- (l- (4-amino-3- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 64. methyl 4- (4-amino-l- (l- (5-ioriior-3- (3-Ωuorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 1H-pyrazolo [3,4-d] pyrimidin-3-yl) -3-Ωuorbenzoate 65. 2- (l- (9H-purin-6- iIamino) propyl) -5-oror-3-phenyl-4H-chromen-4-one 66. 2- (1- (4-amino-3- (3-hydroxyprop-1-ynyl) -H-pyrazole [3, 4-d] pyrimidin-1-yl) ethyl) -5-ioriior-3- (3-Ωuorfenyl) -4H-chromen-4-one 6 7. (S) / (R) -2- (1 - (4 -amino-3- (3-Ω6or-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-djpirimidin-1 -yl) ethyl) -5-Ωilor-3- (3-Ωuorfenyl) -4H-cromen-4 -one 4-methylbenzenesulfonate 68. (+) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-Ωuor-3- (3-Ωuorfenyl) -4H-chromen-4- 69. 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluor-3- (3-fluorenyl) -4H-chromen-4-one 7 0. (R) / (S) -2- (1 - (4-amino-3- (3-fluoro-4-morpholinophenyl) -1 H-pyrazolo [3,4-dJpirimidin-1-yl) ethyl) -5-fluoro-3- (3-nuorfenyl) -4H-chromen-4-one 71. 2- (1- (4-amino-3- (4-methoxy-3,5-dimethylphenyl) -H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 72. 2- (1 - (4-amino-3- (4- (methoxymethyl) phenyl) -1 H-pyrazole [ 3,4-dJpirimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one or 73. 2- (l- (4-amino-3- (imidazo [ 1,2-a] pyridin-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4- ona 7 4. tert-but i 1 (5- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 1H-pyrazolo [3,4-d] pyrimidin-3-yl) furan-2-yl) methylcarbamate 75. 2- (1 - (4-amino-3- (2,4-dimethylthiazol-5-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 76. 2- (l- (4-amino- 3- (5- (moríòlinomethyl) thiophen-2-yl) -1H-pyrazolo [3,4-djpirimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4- ona 77. 2- (1 - (4-amino-3- (4- (5-amino-1,3,4-thiadiazol-2-yl) phenyl) -1 H-pyrazolo [3,4- d] pyrimidin -1 -yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 7 8. (-) - 2- (1 - (9H-purin-6-ylami no) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 79. 2- (1 - (4-amino-3- (1,3-dimethyl-1 H-indazole- 6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 80. 2- (l - (4-amino-3- (2,3-dimethyl-2H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- ( 3-fluorophenyl) -4H-chromon-4-one 81. N- (4- (4-amino-l- (l- (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen 2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluorphenyl) isobutyramide 82. N- (4- (4-amino-l- (l- (5-fluorine -3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluorophenyl) acetamide 83. 2- (1 - (4- (dimethylamino) -3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3 -fluorfenyl) -4H-crornen-4-one 84. 5-fluoro-2- (l- (3- (3-fluoro-4-isopropoxyphenyl) -4- (methylamino) -1H-pyrazolo [3,4- d ] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-cromcin-4-one 8 5. 5-fluorine-2- (1 - (3- (3-fluorine-4-isopropoxyphenyl) - 4-morpholino-1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4- ona 86. N- (2-fluorine-4- (1 - (1 - (5-fluorine-3- (4-fluorophenyl) -4-oxo-4H-chromen-2-yl) elyl) -4-morpholino- 1H-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) isobutyramide 8 7. N- (2-fluor-4- (1 - (1 - (5-fluor-3- (3-fluorophenyl) - 4-oxo-4H-chromen-2-yl) ethyl) -4-morpholino-1H-pyrazolo [3,4-dJpirimidin-3-yl) phenyl) isobutyramide 8 8. (S) / (R) -2- ( 1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one sulfate 8 9. (S) / (R) - 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazole [3,4 - d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 90. (S) / (R) - 2- (l- (4-amino -3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4 -one camphorsulfonate 91. 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (1H-pyrazol-4-yl) -4H-chromen-4-one 92. 2- (l- (4-amino-3- (3-fluor-4-morpholinophenyl) -1H-pyrazole [ 3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one 93. 2- (l- (4-amino-3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 4-fluorophenyl) -4H-chromen-4-one 94. and 95. (S) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazole [3,4 - d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one and (R) -2- (l- (4-amino-3- (3 - fluorine-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one. 96 and 97. (S) -2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one and (R) - 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -lH -pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one 98 2- (l- (4- (dimethylamino) - 3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-crornen-4-one 99 5-fluoro-2- (l- (3- (3-fluoro-4-morpholinophenyl) -4- (methylamino) -lll-pyrazolo [3,4- d] pyrimidin-l-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one 100 and 101. (S) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -H-pyrazole [3,4 - d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one and (R) - 2- (l- (4-amino-3- (3-fluor-4 - isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one. 102 and 103. (S) - 2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one and (R) - 2- (l- (4-amino- 3- (4- (difluomyethoxy) -3-fluorophenyl) -1 H-pyrazolo [ 3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one 104 (+) - 5-fluor-2- (1 - (3- (3- fluorine-4-isopropoxyphenyl) -4- (methylamino) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one and 105 ( -) - 5-fluoro-2- (l - (3- (3-fluoro-4-isopropoxyphenyl) -4- (methylamino) -1H-pyrazolo [3,4-d] pyrirnidin-l-yl) ethyl) - 3- (3-fluorophenyl) -4H-chromen-4-one. 106 2- (1 - (6-amino-2-fluoro-9H-purin-9-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H- chromen-4-one 107 2- (1 - (6-amino-2-fluorine-9H-purin-9-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H- chromen-4-one 108 5-fluorine-3- (4- fluorphenyl) -2- (1- (6-morpholino-9H-purin-9-yl) ethyl) -4H-chromen-4-one 109 5-fluorine-3- (4-fluorophenyl) -2- (1 - ( 6- (4-methylpiperazin-1-yl) -9H-purin-9-yl) ethyl) - 4H-chromen-4-one 110 2- (l- (6- (dimethylamino) -9H-purin-9-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H- chromon-4-one 111 2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine -3- (3-fluorphenyl) -4H- chromen-4-one 112 5-fluorine-3- (3-fluorophenyl) -2- (l- (3- (3-methyl-1H-indazol-6-yl) -4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -4H-chromen-4-one 113 2- (l- (4-amino-3- (3-chloro-4 -morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 114 (+) - 2- ( 1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor-3- (3-fluorophenyl) - 4H-chromen-4-one 115 (-) - 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3 , 4- d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 116 (S) / (R) - 5-fluor-2- (l - (3- (3-fluoro-4-isopropoxyphenyl) -4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4 -one 117 2- (1 - (4-amino-3- (3-chloro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine-3 - (3-fluorophenyl) -4H-chromen-4-one 118 2- (1 - (4-amino-3- (2-methylbenzo [d] oxazol-6-yl) -1 H-pyrazolo [3.4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 119 5-fluorine-3- (3-fluorophenyl) -2- (l- (6-morpholino -9H-purin-9-yl) ethyl) -4H-chromen-4-one 120 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -5-morpholino-4H-chromen-4-one 121 2- (l- (4-amino-3- (3-fluorine-4- isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-morpholino-3-phenyl-4H-chromen-4-one 122 6- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) isoindolin-1-one 123 5- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H -cromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) isoindolin-1-one 124 2- (l- (3- (4-acetyl-3-fluorphenyl) - 4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 125 5-fluorine-3- ( 3-fluorophenyl) -2- (1 - (6- (4-methylpiperazin-1-yl) -9H-purin-9-yl) ethyl) - 4H-chromen-4-one 126 and 127. (S) - 2 - (l- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor-3- (3-fluorophenyl ) -4H-chromen-4-one and (R) - 2- (l- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-l- il) ethyl) -5-fluorine-3- (3-fluorophenyl) - 4H-chromen-4-one 128 N- (3- (4-amino-l- (l- (5-fluorine-3- (3- fluorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 111-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) methanesulfamide 129 and 130. (S) - 2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3- Ωuorfenyl) -4H-chromen-4-one and (R) - 2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 131 2- (1 - (9H-purin-6-ylamino) ethyl ) -5-fluorine-3- (2-fluorophenyl) -4H-chromen-4-one 132 2- (1 - (4-amino-3- (4-ethoxy-3- (trifluormethyl) phenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4 -one 133 2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) propyl) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one 134 and 135. (S) -5-fluorine-3- (3-fluorophenyl) -2- (l- (2-methoxy-9H-purin-6- ylamino) ethyl) - 4H-chromen-4-one and (R) -5-fluoro-3- (3-fluorophenyl) -2- (l- (2-methoxy-9H-purin-6-ylamino) ethyl) - 4H-chromen-4-one. 136 (S) / (R) - 5-fluorine-2- (1- (2-fluorine-9H-purin-6-ylamino) ethyl) -3- (3-fluorine-phenyl) -4H- 137 (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-methyl-3 -phenyl-4H-chromen-4-one 138 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3-o-tolyl-4H-chromen-4-one and pharmaceutically acceptable salts of same








where the variables are the same as defined above. Yet another embodiment of the present invention is a process for preparing the compound of formula
comprising the steps as described in scheme 1 below. Yet another embodiment of the present invention is a compound of the formula in which the variables are the same as defined above.
Yet another embodiment of the present invention is a process for preparing the compound of formula
comprising the steps as described and described in Scheme IA below.
Yet another embodiment of the present invention is a process for preparing the compound of formula (1)
comprising the steps of converting a compound of formula (10) as described and described in scheme 2, 3 or 4 below.
Yet another embodiment of the present invention is a process for preparing the compound of formula (I)
comprising the steps of converting the compound of formula (12) as described and described in scheme 2, 3 or 4 below.
Yet another embodiment of the present invention is a process for preparing the compound of formula (10), (14) or (15) comprising the steps of converting the compound of formula (12) as described and described in scheme IA below.
Yet another embodiment of the present invention is a method for inhibiting P13K in patient by administering to the patient an effective amount of at least one compound of the present invention (for example, a compound of formula (I), (IA), (IA-I) , (IA-11), (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA -IIa), (IA-IIIa), (IA-Ib) or (IA-IIb) as defined above).
Yet another embodiment of the present invention is a method of treating a proliferative disease via modulation of a protein kinase (such as PI3K) by administering to a patient in need of said treatment an effective amount of at least one compound of the present invention. In one embodiment, the compound of the present invention inhibits a protein kinase (such as P13K).
Yet another embodiment of the present invention is a method of treating a proliferative disease by modulating a protein kinase (such as P13K.) By administering to a patient in need of said treatment an effective amount of at least one compound of the present invention, in combination ( simultaneously or sequentially) as at least one other anticancer agent. In one embodiment, the compound of formula I), (IA), (IA-I), (IA-II), (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb) inhibits a protein kinase (such as PI3K).
More particularly, the compounds of formula I), (IA), (IA-I), (IA-II). (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa), (IA- IIIa), (IA-Ib) or (IA-IIb) and pharmaceutically acceptable esters or salts thereof can be administered for the treatment, prevention and / or alleviation of PI3K. and protein kinase-related diseases or disorders, including but not limited to cancer and other proliferative diseases or disorders.
The compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to, the following: • carcinoma, including bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; • hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; • hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promuelocytic leukemia; • tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; • tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and • other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctantoma, follicular thyroid cancer and Kaposi's sarcoma.
Due to the role of protein kinases in regulating cell proliferation in general, the protein kinase inhibitors of the present invention could act as reversible cytostatic agents that can be useful in the treatment of any disease that is characterized by abnormal cell proliferation, for example, benign hyperplasia prostate gland, familial adenomatous polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infections.
The compounds of the present invention as apoptosis modulators are useful in the treatment of cancer (including, but not limited to, the types mentioned above), viral infections (including among other herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of development of AIDS in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus, critematous, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes melitus), neurodegenerative disorders (including among others Alzheimer's disease , AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction, infarction and reperfusion injury, arrhythmia, atherosclerosis, diseases alcohol-related or toxin-induced liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.
The compounds of the present invention can modulate the level of cellular RNA and DNA synthesis. These agents are therefore useful in the treatment of viral infections (including among others H1V, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
The compounds of the present invention are useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by blocking the onset of the mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or by inhibiting tumor recurrence. The compounds are also useful in inhibiting tumor angiogenesis and metastasis. One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need of it by administering an effective amount of one or more compounds of the present invention.
Another embodiment of the present invention is a method of treating a disease related to the immune system (for example, an autoimmune disease), a disease or disorder involving inflammation (for example, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomeruloncphritis , neuroinflammatory diseases, multiple sclerosis, uveitis and immune system disorders), cancer or proliferative disease, liver disease or disorder, kidney disease or disorder. The method includes administering an effective amount of one or more compounds of the present invention.
Examples of immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogenic (organ, bone marrow) transplant. , stem cells and other cells and tissues) graft rejection, graft-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (eg, Hashimoto's thyroiditis and autoimmune) , myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, recurrent chronic hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.
In one embodiment, the compounds described are used as immunosuppressants to prevent graft transplant rejection, allogeneic or xenogenic transplant rejection (from organ, bone marrow, stem cells, other cells and tissues), and graft-host disease. In other modalities, graft transplant rejections result from tissue or organ transplantation. In other modalities, graft-host disease results from bone marrow or stem cell transplantation. One modality is a method of preventing or reducing the risk of graft transplant rejection allogeneic or xenogenic transplant rejection (of organ, bone marrow, stem cells, other cells and tissues), or host graft disease by administering a effective amount of one or more compounds of the present invention.
The compounds of the present invention are further useful in combination (administered together or sequentially) with anticancer treatments such as radiation therapy or with cytostatic or cytotoxic anticancer agents, such as, among others, DNA interacting agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase 1 inhibitors such as CPT-11 or topotecan; interacting agents with tubulin, such as paclitaxel, docetaxel or epothilones (for example, ixabepilone), naturally occurring or synthetic; hormonal agents such as tamoxifen; limidylate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; SRC inhibitors; c-Kit inhibitors; Herl / 2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2) and other protein kinase modulators as such.
The compounds of the present invention are further useful in combination (administered together or sequentially) with one or more anti-inflammatory steroidal drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or Immune Selective Anti-inflammatory Derivatives (ImSAIDs).
The invention further provides a pharmaceutical composition comprising one or more compounds of the present invention (such as a compound containing the formula (I), (IA), (IA-I), (IA-II), (IA-III) (IA- IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb)) together with a pharmaceutically acceptable canner. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anti-cancer agents.
In one embodiment, the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of formula (I), (IA), (IA-I), (IA-II), (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or (IA -IIb).
Yet another embodiment is a method of treating leukemia in a patient in need of it by administering a therapeutically effective amount of a compound of the present invention. For example, the compounds of the present invention are effective for treating chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), and non-Hodgkin's lymphoma indolent (I-NHL).
Yet another embodiment is a method of treating allergic rhinitis in a patient in need of it by administering a therapeutically effective amount of a compound of the present invention. DETAILED DESCRIPTION OF THE INVENTION
As used here, the following definitions apply unless otherwise indicated. Yet many of the groups defined here can be optionally substituted. The list of substituents in the definition is exemplary and should not be interpreted as a limit on the substituents defined elsewhere in the specification.
The term "alkyl", unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, containing from one to eight carbon atoms, and which it is joined to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "(C1-6) alkyl" refers to an alkyl group as defined above containing up to 6 carbon atoms.
The term "alkenyl", unless otherwise specified, refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain containing about 2 to about 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. The term "(C2-O) alkenyl" refers to an alkenyl group as defined above containing up to 6 carbon atoms.
The term "alkynyl", unless otherwise specified, refers to a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond, and containing in the range of 2 to 12 carbon atoms (with radicals containing at range of 2 to 10 carbon atoms currently being preferred) eg, ethynyl, propynyl, and butynyl. The term "(C2-6) alkynyl" refers to an alkynyl group as defined above containing up to 6 carbon atoms.
The term "alkoxy", unless otherwise specified, denotes an alkyl, cycloalkyl, or cycloalkylalkyl group as defined above attached through an oxygen bond to the rest of the molecule. The term "substituted alkoxy" refers to an alkoxy group where the alkyl constituent is substituted (i.e., -O- (substituted alkyl) where the term "substituted alkyl" is the same as defined above for "alkyl". For example, "alkoxy" refers to an -O-alkyl group, including from 1 to 8 carbon atoms of a linear, branched, cyclic configuration and combinations thereof connected by a parent structure through oxygen. Examples include methoxy, ethoxy , propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.
The term "cycloalkyl", unless otherwise defined, denotes a mono or multi-cyclic non-aromatic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of cycloalkyl muticyclic groups include perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups, and spirobicyclic groups, for example, (4.4) non-2-yl. The term "(Cj.8) cycloalkyl" refers to a cycloalkyl group as defined above containing up to 8 carbon atoms.
The term "cycloalkylalkyl", unless otherwise indicated, refers to a radical containing a cyclic ring in the range of about 3 to 8 carbon atoms directly attached to an alkyl group which are then attached to the main structure of any carbon in the alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "cycloalkenyl", unless otherwise specified, refers to radicals containing cyclic ring in the range of about 3 to 8 carbon atoms as at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group directly attached to an alkyl group which are then attached to the main structure of any carbon in the alkyl group which results in the creation of a stable structure.
The term "aryl", unless otherwise specified, refers to aromatic radicals containing 6 to 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.
The term "arylalkyl", unless otherwise specified, refers to an aryl group as defined above directly attached to an alkyl group as defined above, for example, -CH2C6H5 and -C2H5C6H5.
The term "heterocyclic ring", unless otherwise specified, refers to a 3- to 15-membered non-aromatic ring consisting of carbon atoms and at least one hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of this invention, the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro systems, and the atoms of nitrogen, phosphorus, carbon, oxygen or sulfur in the heterocyclic ring radical can be optionally oxidized in various oxidation states. In addition, the nitrogen atom can be optionally quaternized. The heterocyclic ring radical can be attached to the main structure on any heteroatom or carbon atom which results in the creation of a stable structure.
The term "heterocyclyl", unless otherwise specified, refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical can be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable structure.
The term "heterocyclylalkyl", unless otherwise specified, refers to a heterocyclic ring radical as defined above directly attached to an alkyl group. The heterocyclylalkyl radical may be attached to the carbon atom main structure in the alkyl group which results in the creation of a stable structure. Examples of said heterocycloalkyl radicals include, but are not limited to, dioxolanil, thienyl [1,3] dithianyl, decahidroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, mofolinyl, octahidroindolil, octahidroisoindolil, 2-oxopyrilin, 2-oxopyrilin, 2-oxopyrazil, 2 piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl. tetrahydrofuril, tritianyl, tetrahydropyranyl, thiomofolinyl, thiamofolinyl, 1-oxo-thiomofolinyl, and 1,1-dioxide-thiomofolinyl.
The term "heteroaryl", unless otherwise specified, refers to an optionally substituted 5- to 14-membered aromatic ring containing one or more heteroatoms selected from N, O, and S as ring atoms. The heteroaryl can be a mono-, bi- or tricyclic ring system. Examples of said group "heterocyclic ring" or "heteroaryl" include, among others, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl , benzodioxolil, benzodioxanil, benzofuranyl, carbazolyl, cinnolinyl, dioxolanil, indolizinil, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, piperidinyl, pylinyl, pylinyl, piperidine , 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl. triazolyl, indanyl, isoxazolyl, isoxazolidinyl, mofolinil, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahidroindolil, octahidroisoindolil, decahidroisoquinolil, benzimidazolyl, thiadiazolyl, bcnzopiranil, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, tiamofolinil, tiamofolinil sulfoxide , thiamofolinyl sulfone, dioxafosfolanil, oxadiazolil, cromanil, and isochromanil. The heteroaryl ring radical can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "substituted heteroaryl" further includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.
The term "heteroarylalkyl", unless otherwise specified, refers to a heteroaryl ring radical as defined above directly attached to an alkyl group. The heteroarylalkyl radical can be attached to the backbone of any alkyl group carbon atom which results in the creation of a stable structure.
The term "cyclic ring" refers to a cyclic ring containing 3 to 10 carbon atoms.
The term "substituted" unless otherwise specified, refers to substitution with any or any combination of the following substituents which may be the same or different and are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= 0), thio (= S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted cycloalkyl or unsubstituted, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine ring , -COORX, -C (O) RX, -C (S) RX, - C (O) NRxRy, -C ( O) ONRxRy, -NRyRz, -NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= N- N (Rx) Ry), - NRxC (O) ORy, -NRxRy, -NRxC (O ) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz, - SONRxRy-, -SO2NRxRy-, -ORX, -ORxC (O) NRyRz, -ORxC (O) ORy-, -OC (O) RX, - OC (O) NRxRy, - RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RXC (O) RX, - RxOC (O) Ry, -SRX, -SORX , -SO2RX, and -ONO2, where Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl substituted or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted heterocyclic ring or unsubstituted, or substituted heterocyclylalkyl ring, or any r two of Rx, Ry and Rz can be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which can optionally include heteroatoms which can be the same or different and are selected from O, NRX (for For example, Rx may be hydrogen or C1 -6 alkyl) or S. The substitution or combinations of substituents envisaged by this invention are preferably those that result in the formation of a stable or chemically viable compound. The term stable as used here refers to compounds or the structure that is not substantially altered when subjected to the conditions to permit their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition. Substituents in the above-mentioned “substituted” groups cannot be replaced again. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent or "substituted aryl" cannot be "substituted alkenyl".
The term "halo", "halide", or alternatively, "halogen" means fluorine, chlorine, bromine or iodine. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more of the halo groups or combinations thereof. For example, the terms "fluoralkyl" and "fluoralkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.
The term "protection group" or "PG" refers to a substituent that is used to block or protect a particular feature. Other functional groups in the compound may remain reactive. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects amino functionality in the compound. Amino protecting groups include, but are not limited to, acetyl, trifluoracetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects hydroxy functionality. Suitable hydroxyl protecting groups include, among others, acetyl and silyl. A "carboxy protecting group" refers to a substituent of the carboxy group that blocks or protects carboxy functionality. Suitable carboxy protecting groups include, but are not limited to - CH2CH2SO2PI1, cyanoethyl, 2- (trimethylsilyl) ethyl , 2- (trimethylsilyl) ethoxymethyl, -2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphine) -ethyl, and nitroethyl. For a general description of protection groups and their uses, see TW Greene, Protective Gr oups in Organic Synthesis, John Wiley & Sons, New York, 1991.
Certain compounds described here contain one or more asymmetric centers and can thus generate enantiomers, diastereoisomers and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R) - or (S) -. The chemical entities present, pharmaceutical compositions and methods are intended to include all possible isomers, including racemic mixtures, optionally pure forms and intermediate mixtures. For example, non-limiting examples of intermediate mixtures of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 2:78. Optically active (R) - and (S) - isomers can be prepared using chiral syntones or chiral reagents, or resolved using conventional techniques. When the compounds described here contain olefinic double bonds or other centers of geometric asymmetry unless otherwise specified, the compounds are intended to include both geometric E and Z isomers.
The term "tautomers" refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. “Tautomers” are structurally distinct isomers that are interconverted by tautomerization. "Tautomerization" is a form of isomerization and includes proton exchange tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton exchange tautomerization" involves the migration of a proton accompanied by changes in the order of binding, usually the exchange of a single bond with an adjacent double bond. Where tautomerization is possible (for example, in solution), a chemical balance of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers.
An "leaving group or atom" is any group that will, under the reaction conditions, cleave from the starting material, thereby promoting the reaction at a specified site. Suitable examples of said groups unless otherwise specified are halogen atoms and mesyloxy, p-nitrobenzensulfonyloxy and tosyloxy groups.
The term "pro-drug" refers to a compound, which is an inactive precursor to a compound, converted to its active form in the body by normal metabolic processes. The pro-drug design is generally described in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., Pp. 11-16 (1996). A full discussion is provided in Higuchi, et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987 ). To illustrate, prodrugs can be converted to a pharmacologically active form of, for example, an ester or an amide bond, thereby introducing or exposing a functional group to the resulting product. Prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further improves the compound's pharmacological properties, for example, increased circulatory half-life. Alternatively, pro-drugs can be designed to undergo covalent modification in a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or generated more potently than the parent compound. High molecular weight conjugates can still be excreted in bile, subjected to enzymatic cleavage and released back into the circulation, thereby effectively increasing the biological half-life of the compound originally administered.
The term "ester" refers to a compound, which is formed by reacting an acid and an alcohol with water elimination. An ester can be represented by the general formula RCOOR '.
These prodrugs and esters are intended to be covered within the scope of this invention.
In addition, the present invention further includes compounds which differ only in the presence of one or more isotopically enriched atoms for example substitution of hydrogen with deuterium or tritium, or substitution of a carbon for carbon enriched in 13C- or 14C-.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute said compounds. For example, compounds can be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (l25I) or carbon-14 (l4C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
Pharmaceutically acceptable salts that form part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of inorganic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine. alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of the invention with alkyl halides, alkyl sulfates such as Mel and (McjjSO.}; unnatural amino acids such as D-isomers or substituted amino acids; guanidine; and substituted guanidine in which the substituents are selected from nitro, amino , alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts.Salts may include acid addition salts where appropriate which are sulfates, nitrates, phosphates, perchlorate, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
When ranges are used here for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombination of ranges and specific modalities are intended to be included here. The term “about” when referring to a numeric range number means that the number or numeric range referenced to is an approximation within the experimental variability (or within the experimental statistical error), and thus the number or numerical range may range from, for example, between 1% and 15% of the declared number or numerical range. The term "comprising" (and related terms such as "comprises" or "comprise" or "containing" or "including") includes those modalities, for example, a modality of any composition of matter, composition, method or process or the like, which “Consists of or” consists essentially of the characteristics described.
The following abbreviations and we will have the meanings indicated: P13-K = Phosphoinositide 3-kinase; PI = phosphatidylinositol; PDK = Phosphoinositide-Dependent Kinase: DNA-PK. = Deoxyrubonucleic acid dependent protein kinase; PTEN = Phosphatase and Tensin homologues deleted on chromosome Ten; PIK.K. = Phosphoinositide kinase type kinase; AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus; Honey = methyl iodide; POCI3 = phosphorus oxychloride; KCNS = potassium isothiocionate; TLC = thin layer chromatography; MeOH = methanol; c CHCh = chloroform.
The abbreviations used here have their conventional meanings meaning within the chemical and biological techniques.
The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term further includes cell growth by which cell morphology has been altered (for example, increased in size) consistent with a proliferative signal.
The term "co-administration," "administered in combination with," and its grammatical equivalents, as used here, includes administration of two or more agents to an animal so that both and / or its metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application including, among others, treatment of disease, as defined below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and condition of the disease to be treated, for example, the subject's weight and age, the severity of the disease condition, the mode of administration and the like, which can readily be determined by a person skilled in the art. The term further implies a dose that will induce a particular response in target cells, for example reduced platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compounds chosen, the dose regimen to be followed, whether it is administered in combination with other compounds, time of administration, the tissue to which it is administered, and the released physical system into which it is conducted.
As used here, "treatment," "treat," or "soften" are used interchangeably. These terms refer to an approach to obtain beneficial or desired results including but not limited to therapeutic benefit and / or prophylactic benefit. Therapeutic benefit means the eradication or alleviation of the underlying disease being treated. In addition, a therapeutic benefit is achieved by eradicating or alleviating one or more of the physiological symptoms associated with the underlying disease that an improvement is observed in the patient, despite the fact that the patient may still be afflicted with the underlying disease. For prophylactic benefit, the composition can be administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of an illness, although a diagnosis of this illness may not have been made.
A "therapeutic effect," as the term is used here, includes a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, reducing, stopping, reversing the progression of a disease or condition, or any combination thereof.
The term "subject" or "patient" refers to an animal, such as a mammal, for example, a human. The methods described here can be useful in both human and veterinary therapeutic applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human. “Radiotherapy” means exposing a patient, using routine methods and compositions known to the specialist, to radiation emitters such as alpha particle emission radionuclides (eg, actinium and thorium radionuclides), low linear energy transfer radiation (LET) emitters ) (ie beta emitters), conversion electron emitters (for example strontium-89 and samarium-153-EDTMP, or high energy radiation, including but not limited to X-rays, gamma rays and neutrons. “Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted in and within a cell to elicit an intracellular response. A modulator of the signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator can increase (agonist) or suppress (antagonist) the activity of a signaling molecule.
The term “selective inhibition” or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to reduce target signaling activity compared to off-target signaling activity, through direct or indirect interaction with the target.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion medium, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants, one or more appropriate diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, release control matrices, dyes / flavorings, carriers, excipients, buffers, stabilizers, solubilizers and combinations thereof. Except to the extent that any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Complementary active ingredients can also be incorporated into the compositions.
In some embodiments, one or more object compounds specifically bind to PI3 kinase or a protein kinase selected from the group consisting of mTor, DNA-dependent protein kinase (Pubmed protein accession number (PPAN) AAA79184), Ablose tyrosine kinase (CAA52387 ), Bcr-Abl, hemopoietic cell kinase (PPAN CAI 19695), Src (PPAN CAA24495), vascular endothelial growth factor receptor 2 (PPAN ABB 82619), epidermal growth factor dc receptor (PPAN AG43241), EPH B4 receptor (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141), TIE-2 protein tyrosine kinase receptor (PPAN Q02858), fms 3-related tyrosine kinase (PPAN NP 004110), growth factor alpha receptor derived from platelet (PPAN NP 990080), RET (PPAN CAA73131), and any other related protein kinases, as well as any functional mutants thereof.
In some embodiments, the 1C50 of an object compound for pi 10a, pi 10β, pi 10y, or pi 10δ is less than about 1 µM, less than about 100 nM, less than about 50 nM, less than than about 10 nM, less than 1 nM or even less than about 0.5 nM. In some embodiments, the IC50 of an object compound for ml or less is less than about 1 µM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5nM. In some other embodiments, one or more of the object compounds have double bond specificity and are capable of inhibiting a PI3 kinase (eg, a class I PI3 kinase) as well as a protein kinase (eg, mTor) with an IC50 value less than about 1 µM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5 nM.
In some embodiments, the compounds of the present invention have one or more functional characteristics disclosed herein. For example, one or more compound objects specifically bind to a PI3 kinase. In some embodiments, the IC50 of an object compound for pi 10a, pi 10β, pi 10y, or pi 105 is less than about 1 µM, less than about 100 nM, less than about 50 nM, less than than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM.
In some embodiments, one or more of the object compounds may selectively inhibit one or more members of type I or class I phosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM , 100 pM, 10 pM or 1 pM, or less as measured in an in vitro kinase assay.
In some embodiments, one or more of the subject compounds may selectively inhibit one or two members of type 1 or class I phosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase-α, PI3-kinase β, PI3-kinase y, and P13-kinase δ. In some respects, some of the object compounds selectively inhibit PI3-kinase δ compared to other types 1 PI3-kinases. In other respects, some of the object compounds selectively inhibit PI3-kinase δ and PI3-kinase y as compared to the rest of type I PI3-kinases. In still other aspects, some of the object compounds selectively inhibit PI3-kinase and a PI3-kinase β compared to the rest of type 1 PI3-kinases. In still other aspects, some of the object compounds selectively inhibit PI3-kinaseδ and a PI3-kinase compared to the rest of type I PI3-kinases. In still other aspects, some of the object compounds selectively inhibit PI3-kinase δ and P13-kinase β compared to the rest of type I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase α compared to the rest of type I PI3- kinases, or selectively inhibit PI3-kinase α and PI3-kinase y purchased from the rest of type 1 PI3-kinases, or selectively inhibit PI3-kinase y PI3-kinase β compared to the rest of type I PI3-kinases.
In yet another aspect, an inhibitor that selectively inhibits one or more type I PI3-kinase members, or an inhibitor that selectively inhibits one or more type I PI3-kinase-mediated signaling pathways, alternatively can be understood to refer to a compound that has a 50% inhibitory concentration (IC50) with respect to a certain type I PI3-kinase, that is, at least 10 times, at least 20 times, at least 50 times, at least 100 times, at least 1000 times , or less, than the IC50 of inhibitors with respect to the rest of other type I PI3-kinases.
As used herein, the term "selective PI3-kinase δ inhibitor" generally refers to a compound that inhibits the activity of PI3-kinase δ isozyme more effectively than other isozymes of the P13K family. A selective PI3 kinase inhibitor compound δ is therefore more selective for PI3 kinase δ than conventional P13K inhibitors like wortmannin and LY294002, which are “non-selective PI3K inhibitors.”
Inhibition of PI3-kinase δ can be of therapeutic benefit in the treatment of various conditions, for example, conditions characterized by an inflammatory response including among other autoimmune diseases, allergic diseases, and arthritic diseases. Importantly, inhibition of δ PI3-kinase function does not appear to affect biological functions such as viability and fertility. "Inflammatory response" as used here is characterized by redness, heat, swelling and pain (ie inflammation) and typically involves injury or destruction of tissue. An inflammatory response is usually a localized protective response induced by tissue damage or destruction, which serves to destroy, dilute or wall off (sequester) both the harmful agent and the damaged tissue. Inflammatory responses are notably associated with leukocyte influx and / or leukocyte chemotaxis (eg, neutrophil). Inflammatory responses can result from infection with pathogenic organisms and viruses, non-infectious means such as trauma or reperfusion after myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune diseases. Inflammatory responses amenable to treatment with the methods and compounds according to the invention include conditions associated with specific defense system reactions as well as conditions associated with non-specific defense system reactions.
Therapeutic methods of the invention include methods of alleviating conditions associated with inflammatory cell activation. “Inflammatory cell activation” refers to the induction by a stimulus (including but not limited to cytokines, antigens or auto-antibodies) of a proliferative cell response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids , or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatibility antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (polymorphonuclear leukocytes including neutrophils, basophils, and eosinophils) mast cells, dendritic cells, Langerhans cells, and endothelial cells). It will be appreciated by experts in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation or exacerbation of an inflammatory condition. "Autoimmune disease" as used here refers to any group of disorders in which tissue damage is associated with cell-mediated or humoral responses to the body's own constituents. “Transplant rejection” as used here refers to any immune response directed against grafted tissue (including organs or cells (eg, bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia). “Allergic disease” as used here refers to any symptom, tissue damage or loss of tissue function resulting from an allergy. "Arthritic disease" as used here refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies. "Dermatitis" as used here refers to any of a large family of skin disorders that are characterized by inflammation of the skin attributable to a variety of etiologies.
As previously described, the term "selective P13-kinase δ inhibitor" generally refers to a compound that inhibits PI3-kinase δ isozyme activity more effectively than other isozymes of the PI3K family. The relative efficacies of the compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a pre-defined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, that is, 50% inhibitory concentration or "IC50". IC50 determinations can be performed using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The values obtained experimentally of the enzymatic activity, then, are plotted according to the concentrations of inhibitor used. The concentration of the inhibitor that shows 50% activity of the enzyme (compared to the activity in the absence of any inhibitor) is taken as the value 1C50. Similarly, other inhibitory concentrations can be defined through appropriate activity determinations. For example, in some configurations, it may be desirable to establish a 90% inhibitory concentration, i.e., IC90, etc.
Thus, a selective inhibitor of PI3-kinase δ alternatively can be understood as referring to a compound that has an inhibitory concentration of 50% (IC50) with respect to PI3-kinase δ, that is, it is at least 10 times, in another aspect at least. at least 20 times, and in another respect at least 30 times, less than the IC50 value with respect to any or all other members of the class I PI3K family. In an alternative embodiment of the invention, the term selective PI3-kinase inhibitor δ can be understood as being a compound that has an IC50 with respect to PI3-kinase δ which is at least 50 times, in another aspect at least 100 times, in an additional aspect at least 200 times, and in yet another aspect at least 500 times, less than IC50 with respect to any or all other members of the PI3K class I family. A selective inhibitor of PI3 kinase δ is typically administered in an amount so that it selectively inhibits δ PI3-kinase activity, as described above.
The methods of the invention can be applied to populations of cells in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human or in a subject's body. In this context, the methods of the invention can be used therapeutically or prophylactically, in an individual. "Ex vivo" or "In vitro" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, among other fluid or tissue samples obtained from individuals. Said samples can be obtained by methods known in the art. Examples of biological fluid samples include blood, cerebrospinal fluid, urine and saliva. Exemplary tissue samples include tumors and biopsies of the same. In this context, the invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention can be used ex vivo or in vitro to determine the ideal dosing schedule and / or administration of a selective δ P13 kinase inhibitor for a certain cell type, indication, individual, and other parameters. The information acquired from said use can be used for experimental or diagnostic purposes or in the clinic to adjust protocols for in vivo treatment. Other ex vivo uses for which the invention may be appropriate are described below or will be apparent to those skilled in the art. Pharmaceutical compositions
The invention provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition can include one or more additional active ingredients as described here. A pharmaceutical composition can be administered for any of the disorders described here.
In some embodiments, the invention provides pharmaceutical compositions for treating diseases or conditions related to an undesirable, overactive, harmful or harmful response in a mammal. Said undesirable immune response may be associated with or result in, asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxis, autoimmune diseases, rheumatoid arthritis, graft-host disease, and lupus erythematosus. The pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lung lobes, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or other nerves and muscles for breathing.
In some embodiments, the invention provides pharmaceutical compositions for the treatment of disorders such as hyperproliferative disorder including, but not limited to, cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral and oropharyngeal cavity , bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, kidney, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, related to AIDS (for example Lymphoma and Kaposi's sarcoma) or virus-induced cancer. In some embodiments, the pharmaceutical composition is for the treatment of non-cancerous hyperproliferative disorders such as benign skin hyperplasia (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hypertrophy (BPH)).
The invention further relates to a composition for treating a disease related to vasculogenesis or angiogenesis in a mammal that can manifest itself as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and sclerodrma, diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's and ovarian sarcoma, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention further provides compositions for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomcruloncphritis and diabetes-induced kidney disease) or pain in a mammal.
The invention further provides a composition for preventing blastocyte implantation in a mammal.
The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient, or a pharmaceutically acceptable salt, ester, or prodrug thereof. Where desired, pharmaceutical compositions contain a compound of the present invention as the active ingredient or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, as diluents and inert solid fillers, diluents, including sterile aqueous solution and various organic solvents, permeability enhancers, solubilizers and adjuvants.
The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are still typically administered in the form of pharmaceutical compositions. Where desired, the object compounds and other agents can be mixed in the preparation or both components can be formulated in separate preparations for use in combination separately or at the same time.
Methods include administering an inhibitor alone, or in combination as described here, and in each case optionally including one or more appropriate diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, dyes / flavorings, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.
Preparations of various pharmaceutical compositions are known in the art. See, for example, Anderson, Philip O .; Knoben, James E .; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990;
Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated by reference in their entirety.
The pharmaceutical compounds or compositions of the present invention can be administered by any route that allows the release of the compounds to the site of action such as oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), administration topical (eg, transdermal application), rectal administration, via local delivery via catheter or stent or through inhalation. The compounds can also be administered intra-adiposally or intrathecally.
The compositions can be administered in solid, semi-solid form. liquid or gaseous, or they can be dry powder, as a lyophilized form. The pharmaceutical compositions can be packaged in convenient forms for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatines, papers, tablets, capsules, suppositories, pellets, pills, lozenges, and lozenges. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations are also contemplated, as are transdermal formulations. Routes of Administration
In the methods according to the invention, the inhibitory compounds can be administered in several ways. For example, pharmaceutical compositions can be for injection, or for oral, nasal, transdermal or other forms of administration, including, for example, intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, intraocular, retrobulbar, intrapulmonary (eg, drugs aerolyzed) or subcutaneous injection (including administration in deposits for long-term release, for example, embedded under the splenic capsule, brain or cornea); by sublingual, anal, or vaginal administration, or by surgical implantation, for example, embedded under the splenic capsule, brain, or in the chest. Treatment can consist of a single dose or a plurality of doses over a period of time. In general, the methods of the invention involve administering effective amounts of a modulator of the invention together with one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers, as described above.
The subject pharmaceutical composition can, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for administration topical as an ointment or cream for rectal administration as a suppository. The pharmaceutical composition can be a unit dosage form for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, and adjuvants.
In one aspect, the invention provides methods for oral administration of a pharmaceutical composition of the invention. Solid oral dosage forms are generally described in Remington's Pharmaceutical Sciences, supra at Chapter 89. Solid dosage forms include tablets, capsules, pills, lozenges or lozenges, and cachets or pellets. In addition, liposomal or proteinoid encapsulation can be used to formulate the compositions (such as, for example, proteinoid microspheres reported in US Patent 4,925,673). Liposomal encapsulation can include liposomes that are derivatized with various polymers (for example, US patent 5,013,556). The formulation can include a compound of the invention and inert ingredients that protect against degradation in the stomach and that allow the release of biologically active material in the intestine.
The toxicity and therapeutic efficacy of compounds selective for PI3-kinase δ can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for the determination of LD50 (the target dose for 50% of the population) and ED50 ( the therapeutically effective dose in 50% of the population). In addition, this information can be determined in cell cultures or experimental animals additionally treated with other therapies including but not limited to radiation, chemotherapeutic agents, photodynamic therapies, radiofrequency ablation, anti-angiogenic agents, and combinations thereof.
The amount of compound administered will be dependent on the mammal to be treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effects, for example, by dividing said larger doses into several small doses for administration throughout the day.
In some embodiments, a compound of the invention is administered in a single dose. Typically, said administration will be by injection, for example, intravenous injection, to introduce the agent quickly. However, other routes can be used as appropriate. A single dose of a compound of the invention can still be used for the treatment of an acute condition.
In practicing the methods of the invention, pharmaceutical compositions are generally supplied in doses ranging from 1 pg of compound / kg body weight to 1000 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg kg to 50 mg kg, and 1 to 20 mg / kg, administered in daily doses or equivalent doses at greater or lesser intervals, for example, on alternate days, twice a week, weekly, or two or three times a day. The inhibitory compositions can be administered by an initial bolus followed by a continuous infusion to maintain circulating therapeutic levels of drug product. Those skilled in the art will readily optimize effective dosages and administration regimens as determined by good medical practice and the clinical condition of the individual to be treated. The frequency of dosing will depend on the pharmacokinetic parameters of the agents and the route of administration. The ideal pharmaceutical formulation will be determined by a person skilled in the art depending on the route of administration and the desired dosage [see, for example, Remington's Pharmaceutical Sciences, pp. 1435-1712, the disclosure of which is hereby incorporated by reference]. Said formulations can influence the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered agents. Depending on the route of administration, an appropriate dose can be calculated according to body weight, body surface area or organ size. Another refinement of the calculations necessary to determine the appropriate dosage for the treatment that involves each of the aforementioned formulations is routinely prepared by those skilled in the art without undue experimentation, especially in light of the dosage and assay information disclosed here, as well as the observed pharmacokinetic data in human clinical studies. Appropriate dosages can be designed using assays established for determining blood level dosages in conjunction with an appropriate physician considering several factors that modify the action of drugs, for example, the specific activity of the drug, the severity of indication, and the responsiveness of the individual, the age, condition, body weight, sex and diet of the individual, the time of administration and other clinical factors. As studies are conducted, further information will emerge regarding the appropriate dosage levels and treatment duration for various diseases and conditions capable of being treated with the drugs. methods of the invention.
In some embodiments, a compound of the invention is administered in multiple doses. The dosage can be about once. twice, three times, four times, five times, six times, or more than six times a day. The dosage can be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, a compound of the invention and another agent are administered together about once a day to about 6 times a day. In another embodiment, administration of a compound of the invention and an agent continues for less than about 7 days. In yet another modality, administration continues for more than about 6, 10, 14, 28 days, two months, six months or a year. In some cases, continuous dosing is obtained and maintained as needed.
Administration of the agents of the invention can continue as needed. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14. or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on a continuous basis, for example, for the treatment of chronic effects.
An effective amount of a compound of the invention can be administered in single or multiple doses by any of the accepted modes of administration of agents containing similar utilities including rectal, buccal, intranasal and transdermal routes, by intraarterial, intravenous, intraperitoneal, parenteral, intramuscular injection. , subcutaneous, oral, topical, or as an inhaler.
The compounds of the invention can be administered in dosages. It is known in the art that due to the variability between subjects in the pharmacokinetics of the compound, individualization of the dosage regimen is necessary for optimal therapy. Dosage for
a compound of the invention can be found by routine experimentation in light of the current disclosure.
When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half-life than the unit dose forms of the compound of the invention and the compound of the invention can be adjusted accordingly.
The inhibitors of the invention can be covalently or non-covalently associated with a carrier molecule including, among others, a linear polymer (for example, polyethylene glycol, polylysine, dextran, etc.), a branched chain polymer (see US Patent 4,289,872 and 5,229 .490; PCT publication WO 93/21259), a lipid, a cholesterol group (such as a steroid), or a carbohydrate or oligosaccharide. Specific examples of carriers for use in the pharmaceutical compositions of the invention include carbohydrate-based polymers such as trehalose, mannitol, xylitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran, cellulose, and cellulose derivatives. Still, the use of liposomes, microcapsules or microspheres, inclusion complexes or other types of carriers is contemplated.
Other carriers include one or more water-soluble polymer bonds such as polyoxyethylene glycol, or polypropylene glycol as described in US patents 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. Still other useful carrier polymers known in the art include monomethoxy-polyethylene glycol, poly- (N-vinyl pyrrolidone) -polyethylene glycol, homopolymer propylene glycol, a co-polymer polypropylene oxyethylene oxide, polyoxyethylated polyols (e.g. glycerol) and polyvinyl alcohol, as well as mixtures of these polymers.
Derivatization with bifunctional agents is useful for cross-linking a compound of the invention to a support or carrier matrix. A carrier is polyethylene glycol (PEG). The PEG group can be of any convenient molecular weight and can be straight or branched. The average molecular weight of PEG can vary from about 2 kDa to about 100 kDa, in another aspect from about 5 kDa to about 50 kDa, and in another aspect from about 5 kDa to about 10 kDa. PEG groups will generally be linked to the compounds of the invention via acylation. Reductive alkylation, Michael addition, thiol alkylation or other chemoselective conjugation / bonding methods via a reactive group in the PEG fraction (e.g., an aldehyde, amino, ester, thiol, cyhaloacetyl, maleimido or hydrazino) to a reactive group in the target inhibitory compound (for example, an aldehyde, amino, ester, thiol, α-haloacetyl, maleimido or hydrazino group). Cross-linking agents can include, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters like 3,3'-dithiobis (succinimidyl propionate), and bifunctional maleimides like bis-N-maleimido-1,8- octane. Derivating agents such as methyl-3 - [(p-azidophenyl) dithiolpropioimidata generate photoactivable intermediates that are capable of forming cross-links in the presence of light. Alternatively, reactive water-insoluble matrices such as carbohydrates activated by cyanogen bromide and the reactive substrates described in US patent 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440 can be used for inhibitor immobilization. Treatment method
The invention further provides methods of using the compounds or pharmaceutical compositions of the present invention to treat diseases and conditions, including but not limited to diseases associated with malfunction of one or more types of PI3 kinase. A detailed description of conditions and disorders mediated by pi 105 kinase activity is defined in WO 2001/81346 and US 2005/043239, both of which are incorporated herein by reference in their entirety for all purposes.
The treatment method provided here comprises administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
Disorders, diseases or conditions treatable with a compound provided here include, but are not limited to, • inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, hives, drug allergies, insect bite allergies, food allergies (including celiac disease and the like), anaphylaxis, serum sickness, drug reactions, insect venom allergies, hypersensitivity pneumonitis, angioedema, erythema multiforme, Stcvens-Johnson syndrome, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis , and mastocytosis; inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, enteritis, and necrotizing enterocolitis; vasculitis, and Behcet's syndrome; psoriasis and inflammatory dermatoses, including dermatitis, eczema, allergic contact dermatitis, viral skin pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, fungal, and other parasitic pathologies, and cutaneous lupus erythematosus; asthma and allergic respiratory diseases, including allergic asthma, exercise-induced asthma, allergic rhinitis, otitis media, lung hypersensitivity diseases, chronic obstructive pulmonary disease and other respiratory problems; autoimmune diseases and inflammatory conditions, including but not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (PHC), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn's disease, Diabetes mellitus (type 1), Goodpasture, Graves' disease, Guillain-Barre syndrome (GBS), Reynaud's syndrome, Hashimoto's disease, lupus erythematosus, systemic lupus erythematosus (SLE), multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (WHO), optic neuritis, Ord thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, psoriatic arthritis, gouty arthritis, spondylitis, reactive arthritis, chronic or acute glomerulonephritis, lupus nephritis, Reiter's syndrome, Takayasu's arteritis (also known as Takayasu “Giant cell arteritis”), autoimmune hemolytic anemia moma, Wegener's granulomatosis, universal alopecia, Chagas disease, chronic fatigue syndrome, dysa utonomy, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, connective tissue disease, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, vitiligo, and vulvodynia. Other disorders include disorders of bone resorption and thrombosis; disorders of tissue or organ transplant rejection including but not limited to graft rejection (including homologous graft rejection and host graft disease (GVHD)), for example, skin graft rejection, solid organ transplant rejection, rejection of Bone marrow transplant; fever; cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; cancers of the breast, skin, prostate, cervix, uterus, ovary, tests, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (eg esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; fibrosis, connective tissue disease, and sarcoidosis; congenital and reproductive conditions, including erectile dysfunction; gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; neurological disorders, including Alzheimer's disease; sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick syndrome; pain, myalgia due to infection; kidney disorders; eye disorders, including glaucoma; infectious diseases, including HIV; sepsis; septic shock; endotoxic shock; gram negative sepsis; gram positive sepsis; toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; pulmonary or respiratory conditions including but not limited to asthma, chronic bronchitis, allergic rhinitis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), chronic inflammatory lung diseases (eg, chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis , pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis, hereditary emphysema, and pulmonary oxygen toxicity; • ischemic reperfusion injury, for example, of the myocardium, brain, or extremities; • fibrosis including, among others, cystic fibrosis; keloid formation or scar tissue formation; • inflammatory conditions of the central or peripheral nervous system including, among others, meningitis (eg, acute purulent meningitis), encephalitis, and brain or spine injury due to minor trauma; • Sjorgren's syndrome; diseases involving leukocyte diapedesis; alcoholic hepatitis; bacterial pneumonia; community-acquired pneumonia (CAP); Pneumocystis carinii pneumonia (PCP); diseases of antigen-antibody complexes; hypovolemic shock; delayed and acute hypersensitivity; disease states due to leukocyte dyscrasia and metastasis; thermal injury; syndromes associated with granulocyte transfusion; cytokine-induced toxicity; leakage; pancreatitis; myocardial infarction, respiratory syncytial virus (RSV) infection; and spinal injury.
In certain embodiments, cancer or cancers treatable with the methods provided here include, but are not limited to, • leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblasts, promyelocyte, myelomonocytic, monocytic, erythroleukemia leukemia and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML); • chronic leukemias, including, but not limited to, chronic myelocytic leukemia (granulocytic), chronic lymphocytic leukemia, and hairy cell leukemia; • polycythemia vera; • lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; • multiple myelomas, including, but not limited to, latent multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; • Waldenstrom's macroglobulinemia; • monoclonal gammopathy of undetermined significance; • benign monoclonal gammopathy; • heavy chain disease; • bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, malignant giant cell tumor, bone fibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangioarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; • brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, non-glial tumor, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; • breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; • adrenal cancer, including, but not limited to, pheochromocytoma and adrenocortical carcinoma; • thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; • pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; • pituitary cancer, including, but not limited to, Gushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipidus; • eye cancer, including, but not limited to, eye melanoma such as iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; • vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; • vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; • cervical cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma; • uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; • ovarian cancer, including, but not limited to, epithelial ovarian carcinoma, borderline tumor, germ cell tumor, and stromal tumor; Oesophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and small cell (small cell) carcinoma; • stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerative, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; • colon cancer; • rectal cancer; • liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; • gallbladder cancer, including, but not limited to, adenocarcinoma; • cholangiocarcinomas, including, but not limited to, papillary. nodular, and diffuse; • lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; • testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastico, classic (typical), spermatocytic, non-seminoma, embryonic carcinoma, teratoma carcinoma, and choriocarcinoma (yolk sac tumor); • prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; • penile cancer; • oral cancer, including, but not limited to, squamous cell carcinoma; • basal cancer; • salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; • pharyngeal cancer, including, but not limited to, squamous and warty cell cancer; • skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, malignant lentigo melanoma, and lentiginous acral melanoma; • kidney cancer, including, but not limited to, kidney cell cancer, adenocarcinoma, • hypernefroma, fibrosarcoma, and transient cell cancer (renal pelvis and / or ureter); • Wilms' tuner; • bladder cancer, including, but not limited to, transient cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancers, including, but not limited to, myiosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioma endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, carcinoma, sweat gland, carcinoma, carcinoma, carcinoma, sweat gland, carcinoma, carcinoma.
See Fishman et al., 1985, Medicine, 2d Ed., JB Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and RecoveRy, Viking Penguin, Penguin Books USA, Inc., United States of America.
It will be appreciated that the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated can be a mammal, preferably human or other animals. For veterinary purposes, individuals include among other farm animals including cows, sheep, pigs, horses, and goats; companion animals like dogs and cats; exotic and / or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
In some embodiments, the method of treating inflammatory or autoimmune diseases comprises administering to a subject (for example a mammal) a therapeutically amount of one or more compounds of the present invention that selectively inhibit PI3K-δ and or P13K-y compared to all others types I PI3 kinases. Said selective inhibition of PI3K-δ and / or P13K.-y can be advantageous to treat any of the diseases or conditions described here. For example, selective inhibition of PI3K- δ can inhibit inflammatory responses associated with inflammatory diseases, autoimmune disease, or diseases related to undesirable immune responses including but not limited to asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, or graft-host. Selective inhibition of POK-δ can also provide a reduction in the undesirable inflammatory immune response without a concomitant reduction in the ability to reduce a bacterial, viral, and / or fungal infection. Selective inhibition of both P13K-δ and PI3K-y may be advantageous for inhibiting the inflammatory response in the subject to a greater degree than could be provided for inhibitors that selectively inhibit PI3K. -δ or PI3K-y alone. In one aspect, one or more of the object methods are effective in reducing production of specific antibody to antigen in vivo by about 2 times, 3 times, 4 times, 5 times, 7.5 times, 10 times, 25 times, 50 times, 100 times, 250 times, 500 times, 750 times, or about 1000 times or more. In another aspect, one or more of the object methods are effective in reducing the production of antigen-specific IgG3 and / or IgGM in vivo by about 2 times, 3 times, 4 times, 5 times, 7.5 times, 10 times, 25 times, 50 times, 100 times, 250 times, 500 times, 750 times, or about 1000 times or more.
In one aspect, one or more of the object methods are effective in alleviating symptoms associated with rheumatoid arthritis including, among others, a reduction in joint swelling, a reduction in serum anti-collagen levels, and / or a reduction in joint pathology such as bone resorption, cartilage damage, pannus, and / or inflammation. In another aspect, the object methods are effective in reducing ankle inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90%. In another aspect, the object methods are effective in reducing knee inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. Yet another aspect, the object methods are effective in reducing serum levels of anti-collagen type II by at least about 10%, 12%, 15%, 20%, 24%, 25%, 30%, 35%, 50 %, 60%, 75%, 80%, 86%, 87%, or about 90% or more. In another aspect, the object methods are effective in reducing ankle histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%. 40%. 50%. 60%. 75%. 80%. 90% or more. In yet another aspect, object methods are effective in reducing knee histopathology scores by approximately 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75% , 80%, 90% or more.
In other embodiments, the present invention provides methods of using the compounds or pharmaceutical compositions to treat respiratory diseases including among other diseases that affect the lung lobes, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscles for breath. For example, methods are provided to treat obstructive lung disease. Chronic obstructive pulmonary disease (COPD) is an umbrella term for a group of diseases of the respiratory tract that are characterized by airflow obstruction or limitation. Conditions included in this umbrella term are: chronic bronchitis, emphysema, and bronchiectasis.
In another embodiment, the compounds described here are used for the treatment of asthma. In addition, the compounds or pharmaceutical compositions as described herein can be used for the treatment of endotoxemia and sepsis. In one embodiment, the pharmaceutical compounds or compositions as described here are used for the treatment of rheumatoid arthritis (RA). In yet another embodiment, the compounds or pharmaceutical compositions as described herein are used for the treatment of contact or atopic dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact dermatitis and the like. Irritating dermatitis can occur when too much substance is used on the skin when the skin is sensitive to a certain substance. Atopic dermatitis, sometimes called eczema, is a type of dermatitis, a disease of atopic skin.
The invention further relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative the same. In some modalities, this method refers to the treatment of cancer such as acute myeloid leukemia, cancer of the thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral and oropharyngeal cavity, bladder, gastric, stomach, pancreatic , bladder, breast, cervical, head, neck, kidney, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's sarcoma) or induced cancer by viruses. In some modalities, this method refers to the treatment of a non-cancerous hyperproliferative disorder such as benign skin hyperplasia (for example, psoriasis), restenosis, or prostate (for example, benign prostatic hypertrophy (BPH)).
The invention further relates to a method for treating diseases related to vasculogenesis or angiogenesis in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some modalities, this method is to treat a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's and ovarian sarcoma, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Patients who can be treated with compounds of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of this invention include, for example, patients who have been diagnosed containing psoriasis ; restenosis; atherosclerosis; BPH; breast cancer as a ductal carcinoma in duet tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as epithelial cervical adenocarcinoma including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer as an epithelial carcinoma in pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer as a transient cell carcinoma of the bladder, urothelial carcinomas (transient cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinoma, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenic leukemia (AML), chronic myelogenous leukemia (CML) (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinoma, adenocarcinomas, and undifferentiated large cell carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular melanoma (eye); primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, immunoblastic B-cell lymphoma and small non-cleaved cell lymphoma; Kaposi's sarcoma; virus-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus type 1 (HTLV-1) and adult T cell leukemia / lymphoma; and human papillomavirus (HPV) and cervical cancer; cancers of the central nervous system (CNS) as a primary brain tumor, which includes gliomas (astrocytoma, anaplastico astrocytoma, or glioblastoma multiforme), oligodendroglioma, Ependimoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumors (MPNST) including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and mixed malignant Müllerian tumor; oral and oropharyngeal cavity cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer like lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and non-seminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as thymomas, thymic carcinomas, Hodgkin's disease, non-Hodgkin's carcinoid lymphoma, carcinoid tumors; rectal cancer; and colon cancer.
The invention further relates to a method of treating diabetes in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof .
In addition, the compounds described here can be used to treat acne.
In addition, the compounds described here can be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term that describes a stiffening of large and medium arteries. Atherosclerosis is a stiffening of an artery specifically due to an atheromatous plaque.
Also the compounds described here can be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune kidney disease characterized by inflammation of the glomeruli. It may be asymptomatic or present with hematuria and / or proteinuria. There are many recognized types, divided into acute, subacute or chronic glomerulonephritis. The causes are infections (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.
In addition, the compounds described here can be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), addiso's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn's disease, diabetes mellitus (type 1), goodpasture syndrome, severe disease, guillain-barre syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (WHO), optic neuritis, thyroiditis ord, osteoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, reiter's syndrome, takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, universal alopecia, chagas disease 1, chronic fatigue syndrome, dysautonomia, endometriosis , suppurative hidradenitis, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis, b lefaritis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacrioadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, cpicondilitis, epididymitis, fascitis, fibrositis, hepatitis, gastritis, gastritis, gasitis, gasitis ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orcitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctone, prostatitis, piel rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
The invention further relates to a method of treating cardiovascular disease in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative the same. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and obstructive carotid disease.
In another aspect, the present invention provides methods of disrupting leukocyte function or disrupting osteoclast function. The method includes contacting the leukocyte or osteoclast with a function that interrupts the amount of a compound of the invention.
In another aspect of the present invention, methods are provided for treating ophthalmic disease by administering one or more of the object compounds or pharmaceutical compositions to a subject's eye.
The invention further provides methods of modulating kinase activity by contacting the kinase with an amount of a compound of the invention sufficient to modulate kinase activity. Modular can be inhibiting or activating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting the kinase with an amount of a compound of the invention sufficient to inhibit kinase activity. In some embodiments, the invention provides methods of inhibiting the kinase activity in a solution by contacting said solution with an amount of a compound of the invention sufficient to inhibit the kinase activity in said solution. In some embodiments, the invention provides methods of inhibiting kinase activity in a cell by contacting said cell with an amount of a compound of the invention sufficient to inhibit the kinase activity in said cell. In some embodiments, the invention provides methods of inhibiting kinase activity in a tissue by contacting said tissue with an amount of a compound of the invention sufficient to inhibit kinase activity in said tissue. In some embodiments, the invention provides methods of inhibiting kinase activity in an organism by contacting said organism with an amount of a compound of the invention sufficient to inhibit kinase activity in said organism. In some embodiments, the invention provides methods of inhibiting kinase activity in an animal by contacting said animal with an amount of a compound of the invention sufficient to inhibit kinase activity in said animal. In some embodiments, the invention provides methods of inhibiting kinase activity in a mammal by contacting said mammal with an amount of a compound of the invention sufficient to inhibit kinase activity in said mammal. In some embodiments, a provides methods of inhibiting kinase activity in a human by contacting said human with an amount of a compound of the invention sufficient to inhibit kinase activity in said human. In some embodiments, the% kinase activity after contacting the kinase with a compound of the invention is less than 1.5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% kinase activity in the absence of said contact stage.
In some embodiments, the kinase is a lipid kinase or a protein kinase. In some embodiments, the kinase is selected from the group consisting of PI3 kinase including different isoforms such as PI3 kinase α, PI3 kinase β, PI3 kinase y, PI3 kinase δ; DNA-PK; mTor; Abl, VEGFR, Ephrin B4 receptor (EphB4); tyrosine kinase receptor TEK (HE2); tyrosine kinase related to FMS 3 (FLT-3); platelet-derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; epidermal growth factor receptor (EGFR); KIT; insulin receptor (IR) and IGFR.
The invention further provides methods of modulating PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to modulate PI3 kinase activity. Modular can be inhibiting or activating PI3 kinase activity. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to inhibit PI3 kinase activity. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity. Said inhibition can occur in solution, in a cell that expresses one or more PI3 kinases, in a tissue that comprises a cell that expresses one or more PI3 kinases, or in an organism that expresses one or more PI3 kinases. In some embodiments, the invention provides methods of inhibiting P13 kinase activity in an animal (including mammals such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit PI3 kinase activity in said animal ..
The ability of the compounds of the invention to treat arthritis can be demonstrated in a model of collagen-induced arthritis [Kakimoto, et al., Cell. Immunol., 142: 326-337 (1992)], in a mouse collagen-induced model of arthritis [Knoerzer, et al., Toxicol. Pathol., 25: 13-19- (1997)], in a rat adjuvant arthritis model [Halloran, et al., Rheum arthritis., 39: 810-819 (1996)], in a model of arthritis induced in looks like streptococcal cell in rat [Schimmer, et al., J. Immunol., 160: 1466-1477 (1998)], or in a SCID mouse model of human rheumatoid arthritis [Oppenheimer-Marks, et al., J. Clin . Invest., 101: 1261-1272 (1998)].
The ability of the compounds of the invention to treat Lyme arthritis can be demonstrated according to the method of Gross, et al., Science, 218: 703-706, (1998).
The ability of the compounds of the invention to treat asthma can be demonstrated in a model of allergic asthma in mice according to the method of Wegner, et al., Science, 247: 456-459 (1990), or in a model of asthma allergic in mice according to the method of Bloemen, et al, Am. J. Respir. Crit. Care Med., 153: 521-529 (1996).
The ability of the compounds of the invention to treat inflammatory lung injury can be demonstrated in a model of oxygen-induced lung injury in mice according to the method of Wegner, et al., Lung, 170: 267-279 (1992), in a model of lung injury induced by immune complexes in murines according to the method of Mulligan, et al., J. Immunol., 154: 1350-1363 (1995), or in a model of lung injury induced by acid in murines according to the method of Nagase, et al., Am. J. Respir. Crit. Care Med., 154: 504-510 (1996).
The ability of the compounds of the invention to treat inflammatory bowel disease can be demonstrated in a model of chemical-induced colitis according to the method of Bennett, et al., J. Pharmacol. Exp. Then, 280: 988-1000 (1997).
The ability of the compounds of the invention to treat autoimmune diabetes can be demonstrated in a NOD mouse model according to the method of Hasagawa, et al., Int. Immunol., 6: 831-838 (1994), or in a model of streptozotocin-induced diabetes according to the method of Hcrrold, et al., Cell Immunol., 157: 489-500 (1994).
The ability of the compounds of the invention to treat inflammatory liver damage can be demonstrated in a model of liver injury in mice according to the method of Tanaka, et al., J. Immunol., 151: 5088-5095 (1993).
The ability of the compounds of the invention to treat inflammatory glomerular injury can be demonstrated in a model of nephrotoxic serum nephritis according to the method of Kawasaki, et al., J. Immunol., 150: 1074-1083 (1993).
The ability of the compounds of the invention to treat radiation-induced enteritis can be demonstrated in a model of abdominal rat irradiation according to the method of Panes, et al., Gastroenterology, 108: 1761-1769 (1995).
The ability of selective PI3K delta inhibitors to treat radiation pneumonitis can be demonstrated in a murine lung irradiation model according to the method of Hallahan, et al., Proc. Natl. Acad. Sci (USA), 94: 6432-6437 (1997).
The ability of the compounds of the invention to treat reperfusion injury can be demonstrated in the isolated heart according to the method of Tamiya, et al., Immunopharmacology, 29: 53-63 (1995), or in the anesthetized dog model according to model by Hartman, et al., Cardiovasc. Res., 30: 47-54 (1995).
The ability of the compounds of the invention to treat pulmonary reperfusion injury can be demonstrated in a model of lung allograft reperfusion injury according to the method of DeMeester, et al., Transplantation, 62: 1477-1485 (1996), or in a rabbit lung model according to the method of Horgan, et al., Am. J. Physiol., 261.H1578-H1584 (1991).
The ability of the compounds of the invention to treat stroke can be demonstrated in a stroke model of rabbit cerebral embolism according to the method of Bowes, et al., Exp. Neurol., 119: 215-219 (1993), in a reperfusion model of middle cerebral artery ischemia in rats according to the method of Chopp, et al., Derrame, 25: 869-875 (1994), or in a model of reversible spine ischemia in rabbits according to the method of Clark, et al., Neurosurg., 75: 623-627 (1991).
The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated in an experimental rat model of vasospasm according to the method of Oshiro, et al., Stroke, 28: 2031-2038 (1997).
The ability of the compounds of the invention to treat peripheral arterial occlusion can be demonstrated in a skeletal muscle reperfusion / ischemia model according to the method of Gute, et al., Mol. Cell Biochem., 179: 169-187 (1998) .
The ability of the compounds of the invention to treat graft rejection can be demonstrated in a murine cardiac allograft rejection model according to the method of Isobe, et al., Science, 255: 1125-1127 (1992), in a model of renal capsule of the thyroid gland according to the method of Talento, et al., Transplantation, 55: 418- 422 (1993), in a model of renal allograft of the cynomolgus monkey according to the method of Cosimi, et al., J. Immunol., 144: 4604-4612 (1990), in a rat nerve allograft model according to the method of Nakao, et al., Muscle Nerve, 18: 93-102 (1995), in a model of murine skin allograft according to the method of Gorczynski and Wojcik, J. Immunol., 152: 2011-2019 (1994), in a murine corneal allograft model according to the method of He, et al. , Opthalmol. Vis. Sci., 35: 3218-3225 (1994), or in a xcnogenic pancreatic islet cell transplant model according to the method of Zeng, et al., Transplantation, 58: 681-689 (1994).
The ability of the compounds of the invention to treat graft-host disease (GVHD) can be demonstrated in a mouse lethal GVHD model according to the method of Harning, et al., Transplantation, 52: 842-845 (1991).
The ability of the compounds of the invention to treat cancers can be demonstrated in a human lymphoma metastasis model (in mice) according to the method of Aoudjit, et al., J. Immunol., 161: 2333-2338 (1998). Combination Treatment
The present invention further provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or overlapping sets of target enzymes are used in combination with a compound of the present invention, or a pharmaceutically acceptable salt. , ester, prodrug, solvate, hydrate or derivative thereof. In one aspect, said therapy includes, among others, the combination of the subject compound with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or therapeutic therapeutic effect.
In one aspect, the pharmaceutical compounds or compositions of the present invention may have a synergistic or additive effect when administered in combination with agents that inhibit IgE production or activity. Said combination can reduce the unwanted effect of high level of IgE associated with the use of one or more P13K5 inhibitors, if said effect occurs. This can be particularly useful in the treatment of autoimmune and inflammatory disorders (A1ID) such as rheumatoid arthritis. In addition, the administration of PI3K.5 or PI3Kδ / y inhibitors of the present invention in combination with mTOR inhibitors may also show synergy through improved inhibition of the PI3K pathway.
In a separate but related aspect, the present invention provides a combination treatment of a disease associated with PI3K.8 comprising administering a PI3K inhibitor. δ and an agent that inhibits the production or activity of IgE. Other exemplary PI3K.5 inhibitors are applicable to this combination and are described, for example, in US Patent 6,800,620. Said combination treatment is particularly useful for treating autoimmune and inflammatory diseases (AIID) including but not limited to rheumatoid arthritis.
Agents that inhibit the production of IgE are known in the art and include among others one or more of TEI-9874, 2- (4- (6-cyclohexyloxy-2-naphtho! Oxy) phenylacetamide) benzoic acid, rapamycin, rapamycin analogs ( (ie, rapalogues), TORCl / mTORCl inhibitors, mTORC2 / TORC2 inhibitors, and any other compound that inhibits TORCl / mTORCl and mTORC2 / TORC2. Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as Omalizumab TNX-901.
For the treatment of autoimmune diseases, the object compounds or pharmaceutical compositions can be used in combination with commonly described drugs including but not limited to Enbrel®, Remicade01, Humira®, Avonex®, and Rebif®. For the treatment of respiratory diseases, the object compounds or pharmaceutical compositions can be administered in combination with commonly prescribed drugs including among others Xolair®, Advair®, Singulair, and Spiriva®.
The compounds of the invention can be formulated or administered in conjunction with other agents that act to alleviate the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and other diseases described herein. These agents include non-steroidal anti-inflammatory drugs (NSAIDs), for example acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids are used to reduce inflammation and suppress immune system activity. The most commonly prescribed drug of this type is Prednisone. Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) can still be very useful in some individuals with lupus. They are the most frequently prescribed for skin and joint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide (Citoxan) suppress inflammation and tend to suppress the immune system. Other agents, for example, methotrexate and cyclosporine are used to control symptoms of lupus. Anticoagulants are used to prevent bleeding from rapidly clotting. They range from very low dose aspirin that prevents platelets from joining, to heparin / coumadin.
In another aspect, this invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative. of it, in combination with an amount of an anticancer agent (for example, a chemotherapeutic agent). Many chemotherapeutics are currently known in the art and can be used in combination with the compounds of the invention.
In some modalities, chemotherapy is selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and small non-peptide molecules such as Gleevec (Imatinib Mesylate), Velcade (bortezomib), Iressa (gefitinib), Spricel (Dasatinib), and Adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN ™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenomelamine, triethylenepophosphoramide, triethylcnotiophosphoramide and trimethylolomelamine; nitrogen mustards such as corambucila, clomafazine, colofosfamide, estramustina, ifosfamide, mecloretamina, mecloretamina hydrochloride oxide, melphalan, novembichina, fenesterina, prednimustina, trophosphamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, photemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, caliceamicin, carabicin, carminomycin, carzinophylline, Casodex ™, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diaz-5-oxo-oxubin, noruborin-5-oxo-lorubin, and , idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, pK) tfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, tiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane; anti-adrenals such as aminoglutetimide, mitotane, trilostane; folic acid improver such as frolinic acid; aceglatone; glycoside aldophosphamide; aminolevulinic acid; amsacrine; bestrabucil; bisantrenp; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarabicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK..R ™ -; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2.2 ', 2 ”- trichlorotriethylamine; urethane; vindesina; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; tiotcpa; taxanes, for example paclitaxel (TAXOL ™, Bristol-Myers Squibb Oncology, Princeton, NJ.) and docetaxel (TAXOTERE ™, Rhone-Poulenc Rorer, Antony, France); retinoic; csperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit the hormone action in tumors as anti-estrogens including, for example, tamoxifen (Nolvadex ™), raloxifene, aromatase inhibitor 4 (5) -imidazois, 4-hydroxy tamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide , bicalutamide (Casodex), leuprolide, and goserelin (Zoladex); chlorambucil; gemeitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); mitos; cinin C; mitoxantrone; vincristine; vinorelbine; navelbine; new chair; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase RFS 2000 inhibitors; difluormethylomitina (DMFO), 17a-Ethinylestradiol, Dietilstilbestrol, Testosterone, Prednisona, Fluoximesterona, Megestrolacetato, Methylprednisolona, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Inhibitor of, Methylprotein, Aminoglutinone, Aminoglutinone Her, VEGF inhibitors, including anti-VEGF antibodies like Avastin, and small molecules like ZD6474 and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055. Anti-HeR antibodies (such as Herceptin from Genentech) can still be used. Suitable EGFR inhibitors include gefitinib, erlotinib, and cetuximab. Pan Her inhibitors include canertinib, EK.B-569, and GW-572016. Other suitable anticancer agents include, but are not limited to, Src inhibitors, MEK.-1 kinase inhibitors, MAPK inhibitors. kinase, P13 kinase inhibitors, and PDGF inhibitors, such as imatinib. Also included are anti-angiogenic agents and antivascular agents that, by interrupting the blood flow of solid tumors, generate quiescent cancer cells depriving them of nutrition. Castration will still generate non-proliferative androgen-dependent carcinomas, it can still be used. Also included are IGF1R inhibitors, receptor and non-receptor tyrosine kinase inhibitors, and integrin signaling inhibitors. Additional anticancer agents include microtubule stabilizing agents 7-0-methylthiomethylpaclitaxel (disclosed in US patent 5,646,176), 4-deacetyl-4-methylcarbonatepaclitaxel, 3'-tert-butyl-3 '-N-tert-butyloxycarbonyl-4-deacetyl -3'-defenyl-3'- N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in US 09 / 712,352 filed November 14, 2000), C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, deoxypotilone A, deoxypotilone B, [1S- [1R *, 3R * (E), 7R *, 1OS *, 1 lR *, 12R *, 16S *]] - 7-l-dihydroxy-8 , 8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17 oxabicyclo [14.1.0] heptadccane-5,9-dione (disclosed in WO 99/02514), [1S- [1R *, 3R * (E), 7R *, 10S *, 1 1 R *, 12R *, 16S *]] - 3- [2- [2- ( aminomethyl) -4-thiazolyl] -1-methyl ethyl] -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo [14.1.0] -heptadecane-5, -9- dione (as disclosed in US Patent No. 6,262,094) and derivatives thereof; and agents that interrupt the microtubule. Still suitable are CDK inhibitors, an antiproliferative cell cycle inhibitor, epidophyllotoxin; an antineolpastic enzyme; biological response modifiers; growth inhibitors; anti-hormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.
Additional cytotoxic agents include, hexamethyl melamine. idatrexate. L- asparaginase, camptothecin, topotecan, pyridobenzoindole derivatives, interferons, and interleukins. Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anticancer drugs such as Herceptin8, Avastin®, Erbitux®, Rituxan® , Taxol®, Arimidex®, Taxotere®, and Velcade®.
This invention further relates to a method for using the compounds or pharmaceutical composition in combination with radiotherapy to inhibit abnormal cell growth or to treat the hyperproliferative disorder in the mammal. Techniques for administering radiotherapy are known in the art and these techniques can be used in the combination therapy described here. The administration of the compound of the invention in this combination therapy can be determined as described here.
Radiotherapy can be administered through a variety of methods, or a combination of methods, including but not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used here, refers to radiotherapy released by a radioactive material confined spatially into the body or close to a tumor or other site of diseased proliferative tissue. The term is intended, without limitation, to include exposure to radioactive isotopes (for example, At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P- 32, and radioactive isotopes (Lu). Sources of radiation suitable for use as a cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, lr-192 as a solid source, 1-125 as a solid patient, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can further be a fluid made of any solution of radionuclides), for example, a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a mixture of an appropriate fluid containing small particles of radionuclides solids, such as Au-198, Y-90. In addition, radionuclides can be embedded in a gel or radioactive microspheres.
Without wishing to be bound by any theory, the compounds of the present invention can generate abnormal cells more sensitive to radiation treatment for the purpose of killing and / or inhibiting the growth of said cells. Thus, this invention also relates to a method for sensitizing abnormal cells in a mammal for radiation treatment which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derived from it, the amount of which is effective in sensitizing abnormal cells for radiation treatment. The amount of the compound, salt, or solvate in this method can be determined according to the means for verifying the effective amount of said compounds described herein.
The pharmaceutical compounds or compositions of the present invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
Anti-angiogenesis agents, such as MMP-2 inhibitors (matrix-metalloprothienase 2), MMP-9 inhibitors (matrix-metalloprothienase 9), and COX-H inhibitors (cyclooxygenase 11), can be used in conjunction with a compound from the present invention and pharmaceutical compositions as described herein. Examples of useful COX-II inhibitors include CELEBREX ™ (alecoxib), valdecoxib, and rofecoxib. Useful examples of metalloproteinase matrix inhibitors are described in WO 96/33172 (published on October 24, 1996), WO 96/27583 (published on March 7, 1996), European patent application No. 97304971.1 (filed on 8 July 1997), European patent application 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98 / 34918 (published on August 13, 1998), WO 98/34915 (published on August 13, 1998), WO 98/33768 (published on August 6, 1998), WO 98/30566 (published on July 16 , 1998), European patent publication 606,046 (published on July 13, 1994), European patent publication 931,788 (published on July 28, 1999), WO 90/05719 (published on May 31, 1990), WO 99 / 52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published on June 17, 1999), PCT International application PCT / IB98 / 01113 (deposited cm 21 July, 199 8), European patent application 99302232.1 (filed March 25, 1999), British patent application 9912961.1 (filed June 3, 1999), Provisional application US 60 / 148,464 (filed August 12, 1999), Patent US 5,863. 949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein into their wholes as a reference. Preferred MMP-2 and MMP-9 inhibitors are those that have no activity or have little activity in inhibiting MMP-I. Most preferred are those that selectively inhibit MMP-2 and / or AMP-9 over matrix metalloproteinases (ie MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7 , MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
The invention further relates to a method and a pharmaceutical composition of treating cardiovascular disease in a mammal comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of the same, or an isotopically labeled derivative thereof, and an amount of one or more therapeutic agents used to treat cardiovascular diseases.
Examples for use in cardiovascular disease applications are antithrombotic agents, for example, prostacyclin and na salicylates, thrombolytic agents, for example, streptokinase, urokinase, tissue plasminogen activator (TPA) and aniseylated streptokinase-plasminogen activator complex (APSAC), anti-platelet agents, for example, acetylsalicylic acid (ASA) and clopidrogel, vasodilating agents, for example, nitrates, calcium channel blocking drugs, antiproliferative agents, for example, colchicine and alkylating agents, intercalating agents, modulating factors growth factors such as interleukins, beta-transforming growth factor and platelet-derived growth factor counterparts, monoclonal antibodies directed against growth factors, anti-inflammatory agents, both steroidal and non-steroidal, and other agents that can modulate tone, function , arteriosclerosis, and the healing response to damage to the vessel or organ after int prevention. Antibiotics can also be included in a combination or coatings comprised by the invention. In addition, a coating can be used to effect the therapeutic release focally within the vessel wall. By incorporating the active agent into an expandable polymer, the active agent will be released on swelling the polymer.
Other exemplary therapeutic agents useful for combination therapy include, among other agents as described above, radiation therapy, hormone antagonists, hormones and their release factors, thyroid and antithyroid drugs, estrogens and progestians, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents that affect calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, agonists and antagonists of muscarinic receptor; anticholinasterase agents; agents that act at the neuromuscular junction and / or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine receptor agonists and antagonists (5-HT, serotonin).
Therapeutic agents may also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of products from the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins , thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit prostaglandin and thromboxane synthesis, selective inducible cyclooxygenase inhibitors, selective inducible cyclooxygenase-2 inducible inhibitors, autacoids, paracrine hormones , gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers , and membrane stabilizers and leukotriene inhibitors.
Additional therapeutic agents contemplated here include diuretics, vasopressin, agents that affect renal water conservation, renin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, p-adrenergic receptor antagonists , agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.
Other therapeutic agents contemplated include drugs used to control gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease. Therapeutic agents used for protozoal infections, drugs used to treat malaria, Amebiasis, Giardiases, Trichomoniase, Trypanosomiasis, and / or Leishmaniasis, and / or drugs used for chemotherapy of hclmintiasis. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and others, P-Lactamic antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in tuberculosis chemotherapy, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including non-retroviral agents and antiretroviral agents.
Examples of therapeutic antibodies that can be combined with an object compound include, among other anti-tyrosine kinase receptor antibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumabc, and gemtuzumab.
In addition, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods here. In addition, therapeutic agents in the blood and blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulants, thrombolytics, and antiplatelet agents.
Other therapeutic agents that can be combined with an object compound can be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or Physician's Desk Reference, both of which are incorporated herein by reference in their totalities.
The compounds described here can be used in combination with the agents disclosed herein or other appropriate agents, depending on the condition to be treated. Thus, in some embodiments, the compounds of the invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described here can be administered with the second agent simultaneously or separately. This combination administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be administered simultaneously, wherein both agents are present in separate formulations. In another alternative, a compound of the present invention can be administered immediately followed by and any of the agents described above, or vice versa. In the separate administration protocol, a compound of the present invention and any of the agents described above can be administered within a few minutes of separation, or a few hours of separation, or a few days of separation.
Methods according to the invention may include administering a selective inhibitor of PI3 kinase δ with one or more other agents that increase the activity of the inhibitor or complement its activity or use in treatment. Said additional factors and / or agents can produce an increased or synergistic effect when administered with a selective inhibitor of PI3-kinase δ, or minimize side effects.
In one embodiment, methods of the invention may include administering formulations that comprise a selective PI3-kinase δ inhibitor of the invention with a particular cytokine, lymphokine, other hematopoietic, thrombolytic or antithrombotic factors, or anti-inflammatory agent before, during, or after administration of the selective PI3 kinase inhibitor δ. A specialist can easily determine whether a particular cytokine is lymphokine. hematopoietic factor. thrombolytic agent of antithrombolytic factor. and / or anti-inflammatory agent improves or complements the activity or use of selective PI3-kinase δ inhibitors in the treatment.
More specifically, and without limitation, the methods of the invention may comprise administering a selective PI3-kinase δ inhibitor with one or more TNF, IL-1, IL-2, IL-3, IL4, IL-5, IL-6 , IL-7, IL-8, II-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IEN , G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, and erythropoietin. The compositions according to the invention can also include other known angiopoietins such as Ang-2, Ang4, and Ang-Y, growth factors such as bone morphogenic protein 1, bone morphogenic protein 2, bone morphogenic protein 3, bone morphogenic protein bone 4, bone morphogenic protein 5, bone morphogenic protein 6, bone morphogenic protein 7, bone morphogenic protein 8, bone morphogenic protein 9, bone morphogenic protein 10, bone morphogenic protein 11, bone morphogenic protein 12 bone morphogenic protein 13, bone morphogenic protein 14, bone morphogenic protein 15, bone morphogenic protein IA receptor, bone morphogenic protein receptor IB, brain-derived neurotrophic factor, ciliary neurotrophic factor, ciliary neurotrophic factor a. cytokine-induced neutrophil chemotactic factor, cytokine 2-induced neutrophil chemotactic factor, cytokine 2-induced neutrophil chemotactic factor, beta endothelial growth factor, endothelin 1, epidermal-attractive, epidermal growth factor, epithelial factor fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth 9, fibroblast growth factor 10, acid fibroblast growth factor, basic fibroblast growth factor, neurotrophic factor receptor derived from glial cell lineage 1, neurotrophic factor receptor derived from glial cell lineage a2. growth-related protein, growth-related protein a, growth-related protein .beta., gamma-related protein, heparin-binding epidermal growth factor, hepatocyte growth factor, receptor hepatocyte growth factor, growth factor type insulin I, insulin type growth factor receptor, insulin type growth factor II, protein binding type insulin growth factor, keratinocyte growth factor, leukemia inhibiting factor, leukemia inhibitory factor alpha, growth factor nerve, receptor nerve growth factor, neurotrophin-3, neurotrophin-4, placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor, platelet-derived growth factor, growth factor platelet-derived A chain, platelet-derived growth factor AA, pl-derived growth factor aqueta AB, platelet-derived growth factor B, platelet-derived growth factor BB, platelet-derived growth factor a, beta-platelet-derived growth factor, pre-B cell stimulatory growth factor, stem cell, stem cell growth factor receptor, transforming growth factor alpha, transforming growth factor beta, transforming growth factor beta 1, transforming growth factor beta 1.2, transforming growth factor beta 2, transforming growth factor beta 3, transforming growth factor beta 5, latent transforming growth factor beta 1, transforming growth factor beta binding to protein I, transforming growth factor beta binding to protein II, factor of transformation transformation beta binding to protein III, tumor necrosis factor receptor type I, tumor necrosis factor receptor type 11, urokinase-type plasminogen activator receptor, and chimeric proteins and biologically or immunologically active fragments thereof.
The following general methodology described here provides a way and processes for producing and using the compound of the present invention and is illustrative rather than limiting. Other modifications to the methodology provided and additionally new methods can still be derived to obtain and serve the purpose of the invention. Thus, it should be understood that there may be other modalities that are within the spirit and scope of the invention as defined by the specification therein.
Representative compounds of the present invention include those specified above in Table 1 and pharmaceutically acceptable salts thereof. The present invention should not be construed as limited to these. General method of preparing the compounds of the invention
The compounds of the present invention can be prepared by the following processes. Unless otherwise indicated, variables (for example, R, R1. R2, Li, Cy1 and Cy2) when used in the formulas below should be understood as presenets to those 5 groups described above in relation to formula (1). These methods can similarly be applied to other compounds of formula as provided herein with or without modification. Scheme 1: This scheme provides a synthetic route for the preparation of a compound of formula (10) in which all variables are as described here above. (The compound of formula (10) can then be converted to the desired compounds of the invention as provided in schemes 2 and 3 below.
The compound of formula (1) where PG is a protecting group as an alkyl group can be reacted with compound of formula (A) in which R3 and R4 can be alkyl groups or in the presence of an appropriate base such as n-butyl lithium or lithium diisopropylamide 15 to generate the compound of formula (2). Compound of formula (2) can be reacted with a Grignard metal reagent such as methylmagnesium iodide to generate the compound of formula (3), which can be oxidized using an oxidizing agent such as pyridinium dichromate to generate the compound of formula (4 ). Layout 1
The compound of formula (1) can further be reacted with a compound of formula (B) in which R3 and R4 can be alkyl or alkoxy groups in the presence of an appropriate base such as n-butyl lithium or lithium diisopropylamide to generate the compound of formula ( 4). 5 Compound of formula (4) can be deprotected to generate the compound of formula (5) using an appropriate reagent such as boron tribromide or aluminum chloride. Compound of formula (5) can be acylated with a compound of formula (C) at presence of an appropriate base such as pyridine to generate the compound of formula (6). The compound of formula (6) can undergo Baker-venkataraman rearrangement in treatment with an appropriate base 10 such as trialkylamine, lithium dialkylamide or lithium disilylamide, for example lithium hexamethyl disilazide, to generate the formula compound (7 ). Compound of formula (7) can be reacted with an acid such as hydrochloric acid to generate the compound of formula (8). A compound of formula (8) can be halogenated to generate the compound of formula (9) where X is halogen when reacted with a halogenating agent such as bromine 15 or N-bromosuccinimide. Compound of formula (9) can be converted to generate the compound of formula (10) by reacting with a boronic acid of formula Cy'-B (OH) 7 where Cy1 is aryl or heteroaryl in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) and a base such as sodium carbonate. Scheme IA: This scheme provides a synthetic route for the preparation of the compound of formula (10), (12), (14) and (15) in which all variables are as described here above, the compound of formula (10), (12), (14) and (15) can then be converted to the desired compounds of the invention as provided in scheme 2, 3 or 4 below. This scheme provides a synthetic route for the preparation of a compound of formula (1) in which all the variables are as described here above Scheme IA
Compound of formula (la) where PG is a protecting group as an alkyl group can be reacted with hydroxylamine hydrochloride to generate the compound of formula (2a). Compound of formula (2a) can be reacted with N, N'-carbonyldiimidazole to generate the compound of formula (3a). Compound of formula (3a) can be reacted with compound of formula (4a) to generate the compound of formula (5a). Compound of formula (5a) can be deprotected to the compound of formula (6a) using an appropriate reagent such as boron tribromide or aluminum chloride. Compound of formula (6a) can be cyclized with benzyl lactic acid to the compound of formula (12a). Compound of formula (12a) can be deprotected to the compound of formula (12) using an appropriate reagent such as boron tribromide or aluminum chloride. Compound of formula (12) can be reacted with phosphorus halides to generate the compound of formula (10). Compound of formula (10) can be reacted with sodium azide to generate the compound of formula (14). Compound of formula (14) can be converted to generate the compound of formula (15) by reacting with triphenylphosphmo. Illustration of scheme lA: Step 1
Step 2
Scheme 2: 5 This scheme provides a synthetic route for the preparation of the compound of formula (IA-II) of the compound of formula (10) in which all variables are as described here above.

Compound of formula (10) can be reacted with compound of formula (11) in the presence of a base such as a metal carbonate, for example, potassium carbonate to generate the compound of formula (IA-I). Alternatively, the compound of formula (10) can be converted to a compound of formula (12) by reacting with an appropriate reagent such as dimethyl sulfoxide. Compound of formula (12) can be subjected to Mitsunobu reaction with compound of formula (11) in the presence of a dialkyl azodicarboxylate and a phosphine triaryl such as triphenyl phosphine to generate a compound of formula (IA-I).
Scheme 3: This scheme provides a synthetic route for the preparation of the compound of formula (IA-II) of the compound of formula (10) in which all variables are as described here above
Compound of formula (10) can be reacted with compound of formula (11a) in the presence of a base such as a metal carbonate, for example, potassium carbonate to generate the compound of formula (IA-II). Alternatively, the compound of formula (10) can be converted to a compound of formula (12) by reacting with an appropriate reagent such as dimethyl sulfoxide. Compound of formula (12) can be subjected to Mitsunobu reaction with compound of formula (Ha) in the presence of a dialkyl azodicarboxylate and a phosphine triaryl such as triphenyl phosphine to generate compound of formula (IA-II). SCHEME 3

Scheme 4; This scheme provides a synthetic route for the preparation of the compound of formula (IA-IV) of the compound of formula (10) in which all variables are as described here above

The compound of formula (10) can be reacted with a metal azide such as sodium azide to generate the compound of formula (14) which can be reduced to the compound of formula (15) using methods known to those skilled in the art. A compound of formula (15) can be reacted with a compound of formula (11b) or (11c) in the presence of an appropriate base such as N-ethyldiisopropylamine to generate the compound of formula (IA-IV) and (IA-III), respectively.
Similar methodologies with certain modifications as known to those skilled in the art can be used to synthesize the compound of formula (I) and (IA) in which all variables, it should be understood, present those groups described above in relation to formula (I) and (IA) using appropriate intermediates and reagents. Experimental
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing said compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. These molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereoisomers. Simple enantiomers / diastereoisomers can be obtained by methods known to those skilled in the art. List of Intermediates





Intermediate 1: 2-fluoro-6-methoxybenzaldehyde: n-BuLi (1.6M in hexane. 74.3 ml, 0.118 mol) was added dropwise to a solution of diisopropylamine (13.23 g, 0.130 mol) in THF ( 50 ml) at 0 ° C, maintained for 15 min. and cooled to -78 ° C. 3-Fluoranisol (15 g, 0.118 mol) in THF (5th ml) was added, stirred at -78 ° C for 1h, and N, N-5 dimethylformamide (6.75 ml) was added and stirred for an additional hour. The reaction mixture was quenched with 2N HCl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to generate the title compound as a waxy red solid (17.45 g, 95%) which was used without purification in the next step. Intermediate 2: 1- (2-fluor-6-methoxyphenyl) ethanol: To an ice-cooled solution of methylmagnesium iodide 10 prepared from magnesium (8.8 g, 0.366 mol) and methylode (52.06 g, 0.366 mol) in diethyl ether (150 ml), intermediate 1 (18.85 g, 0.122 mol) in diethyl ether (50 ml) was added and warmed to room temperature. After 12h, the reaction mixture was cooled to 0 ° C, quenched with diluted aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure 15 to generate the title compound as a red liquid (18.9 g, 99%) which was used without purification in the next step. Intermediate 3: 1- (2-fluor-6-methoxyphenyl) ethanone: Pyridinium dichromate (44 g, 0.116 mol) was added to a solution of intermediate 2 (13.1 g, 0.077 mol) in DMF (130 ml) and stirred at room temperature for 12h. Water (300 ml) was added to the reaction mixture and diluted with ethyl acetate and filtered through celite. The organic layer was washed with brine solution and dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a brown liquid (9.2 g, 70%). 'H- NMR (δ ppm, CDCh, 400 MHz): 7.73 (dd, J = 15.1, 8.4 Hz, 1H), 6.73 (m, 2H), 3.85 (s, 3H ), 2.53 (s, 3H). Intermediate 4: 1- (2-fluor-6-hydroxyphenyl) ethanone: To an ice-cooled solution of intermediate 3 (9.0 g, 53.5 mmol) in dichloromethane (70 ml), aluminum chloride (14.3 g, 0.107 mol) was added and heated to room temperature. After 12h, the reaction mixture was quenched with 2N aqueous HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a brown liquid (5.48 g, 66%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 12.72 (s, 1H), 7.40 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6, 62 (dd, J = 11.3, 8.3 Hz, 1H), 2.69 (d, J = 7.2 Hz, 3H). Intermediate 5: 2-acetyl-3-fluorophenyl acetate: Pyridine (7.8 ml) and acetyl chloride (3.60 g, 45.93 mmol) were added to an ice-cooled solution of intermediate 4 (5.9 g , 38.27 mmol) in dichloromethane (50 ml) and heated to 45 ° C. After 3h, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvents evaporated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (6.2 g, 82%). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7.45 (m, 1H), 7 05 (t, J = 8.9 Hz, 1H), 6.93 (d, J = 8.1 Hz , 1H), 2.56 (d, J = 3.3 Hz, 3H), 2.27 fs, 3H). Intermediate 6: 5-hydroxy-2-methyl-4H-chromen-4-one: To an ice-cooled solution of intermediate 5 (3.0 g, 15.29 mmol) in dimethyl sulfoxide (15 ml), sodium hydride ( 0.367 mg, 15.29 mmol) was added and heated to 100 ° C. After 12h, the reaction mixture was quenched with 10% aqueous HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (1.3 g, 48%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 12.54 (s, 1H), 7.50 (t, J = 8.3 Hz, 1 H>, 6.86 (d, J = 8, 4 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.10 (s, / H), 2.38 (s, 3H). Intermediate 7: 5-methoxy-2- methyl-4H-chromen-4-one: To a solution of intermediate 6 (1.12 g, 15.29 mmol) in DMF (10 ml), potassium carbonate (1.31 g, 9.53 mmol) and iodide methyl compounds were added and heated to 50-60 ° C. After 12 hours, water was added to the mixture and extracted with ethyl acetate.The organic layer was washed with water, dried over sodium sulfate and concentrated to generate the title compound as a yellow solid (0.85 g, 70%). * H-NMR (δ ppm, CDCI3, 400 MHz): 7.52 (t, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.07 (s, 1H), 3.96 (s, 3H), 2.29 (s, 3H) Intermediate 8: 3-bromo-5-methoxy-2-methyl-4H-chromen-4-one: N-Bromosuccinimide (0.795 g, 4.46 mmol) was added to a solution of intermediate 7 (0.85 g, 4.46 mmol) in DMF (10 ml) in RT, after 12 hours, water was added to the mixture and extracted with acetate ethyl. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a yellow solid (0.985 g, 82%). 'H-NMR (δ ppm, CDC13, 400 MHz): 7.56 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.2 Hz. 1H), 6.82 ( d, J = 8.1 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 3H). Intermediate 9: 3- (3-fluorophenyl) -5-methoxy-2-methyl-4H-chromen-4-one: To a solution of Intermediate 8 (0.985 g, 3.66 mmol) and 3-Fluorphenylboronic acid (0.819 g , 5.85 mmol) in dioxane (10 ml), potassium carbonate (1.51 g, 10.98 mmol) and water (2 ml) were added and degassed for 30 min. Tetrakis (triphenylphosphino) palladium (0) (0.253 g, 0.219 mmol) was added under nitrogen at RT and the reaction mixture refluxed for 12h. The solvent was completely evaporated and water was added to the residue and extracted with ethyl acetate, organic layer dried over sodium sulfate and concentrated. The obtained residue was purified by column chromatography w to generate the title compound as a yellow solid (0.875 g, 81%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.55 (t, J = 8.4 Hz, 1H), 7.38 (dd, J = 13.9, 7.8 Hz, 1H), 7.06-6.99 (m, 4H), 6.79 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H), 2.25 (s, 3H). Intermediate 10: 2- (bromomethyl) -3- (3-fluorophenyl) -5-methoxy-4H-chromen-4-one: To a solution of Intermediate 9 (0.875 g, 3.07 mmol in carbon tetrachloride (10 ml ) N-bromosuccinimide (0.547 g, 3.07 mmol) was added and heated to 80 ° C, azobisisobutyronitrile (20 mg) added and stirred at the same temperature for 12h The reaction mixture was cooled to RT, diluted with dichloromethane and washed The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an almost white solid (0.440g, 39 % yield) which was used without purification in the next step Intermediate 11: 4-bromo-2-fluoro-1-isopropoxybenzene: To a solution of 4-bromo-2-fluorophenol (10g, 52.35 mmol) in THF ( 100ml), isopropyl alcohol (4.8ml, 62.62mmol) and triphenylphosphine (20.6g, 78.52mmol) were added and heated to 45 ° C followed by diisopropylazodicarboxylate (15.4 ml, 78 52 mmol). The mixture was refluxed for 1h, concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a colorless liquid (13.1 g, 99%) which was used without purification in the step Following. Intermediate 12: 2- (3-fluor-4-isopropoxyphenyl) -4,4,5,5-tetramethyl-1,2,2-dioxaborolane: Potassium acetate (10.52 g, 107.2 mmol) and bis ( pinacolate) diboro (15g, 58.96 mmol) were added to a solution of intermediate 11 (10.52 g, 107.2 mmol) in dioxane (125 ml), and the solution was degassed for 30 min. [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (4.4 g, 5.36 mmol) was added under a nitrogen atmosphere and heated to 80 ° C. After 12h the reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow oil (13.9g, 99%) which was used without purification in the next step. Intermediate 13: 3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine; To a solution of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (11.0 g, 42.14 mmol) in DMF 110 ml), ethanol (55 ml) and water (55 ml ), intermediate 12 (23.4 g, 84.28 mmol) and sodium carbonate (13.3 g, 126.42 mmol) were added and degassed for 30 min. Tetrakis (triphenylphosphmo) palladium (0) (2.4 g, 2.10 mmol) was added under a nitrogen atmosphere and heated to 80 ° C. After 12h, the reaction mixture was filtered through celite, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried in vacuo to give the title compound as a light brown solid (3.2 g, 26% yield) which is used as such for the next step. Intermediate 14: 5-fluorine-2-methyl-4H-chromen-4-one: To a solution of Intermediate 5 (5.0 g, 25.48 mmol) in THF (70 ml) cooled to -78 ° C, lithium bis (trimethylsilylamide) (1M in THF, 25.45 ml, 25.48 mmol) was added kept at the same temperature for 2h. The mixture was heated to RT and stirred for 4 h. The reaction was quenched by the addition of aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvents removed. The crude product was dissolved in dioxane (8 ml) and sulfuric acid (8 ml) was added and heated to reflux for 4 hours. Aqueous sodium bicarbonate solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.91 g, 20%). 'H-NMR (δ ppm, CDClj, 400 MHz): 7.58 (m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 9.7 Hz, 1H), 6.11 (s, 1H), 2.34 (s, 3H). Intermediate 15: 3-bromo-5-fluoro-2-methyl-4H-chromen-4-one: To a solution of intermediate 14 (0.910 g, 5.10 mmol) in DMF (8 ml), N-bromosuccinimide (0.908 g, 5.10 mmol) was added in RT. After 12h, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvent was removed to generate the title compound as an off-white solid (0.410 g, 31%). 'H-NMR (δ ppm, CDC13, 400 MHz): 7.62 (m, 1H), 7.25 (d, J = 8.28 Hz, 1H), 7.09 (t, J = 9.6 Hz, 1H), 2.63 (s, 3H). Intermediate 16: 5-fluorine-3- (3-fluorophenyl) -2-methyl-4H-chromen-4-one: To a solution of intermediate 15 (0.150 g, 0.583 mmol) and 3-fluorophenylboronic acid (0.129 g, 0.933 mmol) in dioxane (2 ml), potassium carbonate (0.241 g, 1.75 mmol) and water (0.5 ml) were added and degassed for 30 min. Tetrakis (triphenylphosphmo) palladium (0) (0.040 g, 0.035 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow solid (0.100 g, 63%). 'H- NMR (δ ppm, CDCI3, 400 MHz): 7.61 (m, 1H), 7.42 (dd, J = 14.2, 8.0 Hz, 1H), 7.09-6.99 (m, 4H), 2.29 (s, 3H). Intermediate 17: 2- (bromomethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of Intermediate 16 (0.245 g, 0.900 mmol in carbon tetrachloride (5 ml) N -bromosuccinimide (0.160 g, 0.900 mmol) was added and heated to 80 ° C, azobisisobutyronitrile (10 mg) added and stirred at the same temperature for 12h The reaction mixture was cooled to RT, diluted with dichloromethane and washed with water. organic layer was dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a red semi-solid (0.326 g) which was used without purification in the next step Intermediate 18: 2-acetyl-3-fluorophenyl propionate: Pyridine (7 , 2 ml) and propionyl chloride (3.85 g, 41.65 mmol) were added to an ice-cooled solution of intermediate 4 (5.35 g, 37.70 mmol) in dichloromethane (40 ml) and heated to 45 ° C. After 3h, water was added to the mixture and extracted in ethyl acetate.The organic layer was washed with water, dried over sodium sulfate and solved eveporados. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (6.4 g, 81%). H-NMR (δ ppm, CDCl3, 400 MHz): 7.44 (dt. J = 8.2.6.4. 1H). 7 05 (t. J = 8.9 Hz. 1H). 6.92 (d ../ = 8.2 Hz. 1H). 2.59 (q. J = 7.5 Hz, 2H), 2.55 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H). Intermediate 19: 2-ethyl-5-fluoro-4H-chromen-4-one: To a solution of Intermediate 18 (5.1 g, 24.28 mmol) in DMSO (20 ml) cooled to 0 ° C, hydride sodium (0.582g, 24.28 mmol) was added kept at the same temperature for 1h. The mixture was heated to RT and stirred for 12h. The reaction was quenched by the addition of 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvents removed. The crude product was dissolved in dioxane (20 ml) and sulfuric acid (6 ml) was added and heated to reflux for 12h. Aqueous sodium bicarbonate solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (2.49 g, 51%). H-NMR (δ ppm, CDCl3, 400 MHz): 7.58 (dt, J = 13.9.5.6 Hz. 1H). 7.54 (d ../ = 5.6 Hz. 1H). 7.04 (t ../ = 8.4 Hz, 1H), 6.14 (s, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.5 Hz , 3H). Intermediate 20: 3-bromo-2-ethyl-5-fluoro-4H-chromen-4-one: To a solution of intermediate 19 (2.49 g, 12.95 mmol) in DMF (15 ml), N-bromosuccinimide (2.30 g, 12.95 mmol) was added at RT. After 12h, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvent was removed to generate the title compound as a reddish brown solid (2.60 g, 74%). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7. 62 (dt, J = 13.8.5.5 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 7.09 (dt, J = 9.5.1.1 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H ). Intermediate 21: 2-ethyl-5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 20 (2.60 g, 9.59 mmol) and 3-fluorophenylboronic acid ( 2.13 g, 15.34 mmol) in dioxane (15 ml), potassium carbonate (3.97 g, 28.77 mmol) and water (2 ml) were added and degassed for 30 min. Tetrakis (triphenylphosphino) palladium (0) (0.664 g. 0.575 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (1.20 g, 44%). * H- NMR (δ ppm, CDCI3, 400 MHz): 7. 61 (dt, J = 13.8.5.5 Hz, 1H), 7.41 (dd, J = 14.0.7.8 Hz , 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.10-6.98 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1 , 27 (t, J = 7.5 Hz, 3H). Intermediate 22: 2- (1-bromoethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of Intermediate 21 (0.500 g, 1.86 mmol in carbon tetrachloride ( 5 ml) N-bromosuccinimide (0.331 g, 0.900 mmol) was added and heated to 80 ° C, azobisisobutyronitrile (5 mg) added and stirred at the same temperature for 12h The reaction mixture was cooled to RT, diluted with dichloromethane and washed The organic layer was dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as an off-white solid (0.460 g, 68%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7 , 68 (dt, J = 8,4,5,4 Hz, 1H), 7,46 (dd, J = 14,1,8,0 Hz, 1H), 7,37 (d, J = 8,5 Hz, 1H), 7.15-7.05 (m, 4H), 4.91 (q, J = 6.9 Hz, 1H), 1.98 (d, J = 6.9 Hz, 3H). Intermediate 23: 5-fluorine-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: To a solution of Intermediate 22 (0.950 g, 2.60 mmol) in DMSO (9 , 5 ml), n-butanol (0.47 ml) was added and heated to 120 ° C for 3h., The reaction mixture was cooled to R T, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow solid (0.700 g, 89%). 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 7.84 (dt, J = 14.2.5.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H ), 7.49 (m, 1H), 7.27 (m, 2H), 7.15 (m, 2H), 5.62 (d, J = 4.8 Hz, 1H), 4.44 (m , 1H), 1.37 (d, J = 6.5 Hz, 3H). Intermediate 23a and 23b: (+) - 5-fluorine-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H- chromen-4-one and (-) - 5-fluorine-3- (3- fluorfenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: The two enantiomerically pure isomers were separated by preparative SEC conditions from intermediate 23 (0.300 g) in a CHIRALPAK column. AD-H (250 x 4.6 mm; 5pm) using methanol: CO2 (20: 80) as the mobile phase at a flow rate of 3.0 ml / min. Intermediate 23a: Off-white solid (0.140 g). ee 100%. Rt: 2.41 min. [a] 2 ^ 4.17 (c = 1, MeOH). Mass: 302.9 (M +). Intermediate 23b: Off-white solid (0.143 g). ee 100%. Rt: 3.06 min. [a] 25o - 4.17 (c = 1, MeOH). Mass: 302.9 (M +). Intermediate 24: 2-acetyl-5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: DMSO (0.657 ml, 9.26 mmol) was added to the dichloromethane (8 ml) cooled to -78 ° C, followed by oxalyl chloride (0.40 ml, 4.63 mmol). After 10 min. intermediate 23 (0.700 g, 2.31 mmol) in dichloromethane (4 ml) was added under a drip and stirred for 20 min. Triethylamine (1.3 ml) was added and stirred for 1h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to give the title compound as a yellow solid (0.450 g, 65%). 'H-NMR (δ ppm, CDC13, 400 MHz): 7.71 (dt, J = 11.2.2.9 Hz, 1H), 7.40 (m, 2H), 7.14-7.00 (m, 4H), 2.32 (s, 3H). Intermediate 25: (R) / (S) -5-fluorine-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: To intermediate 24 (0.280 g, 0.93 mmol ), S-Alpine borane (0.5M in THF, 10 ml) was added and heated to 70 ° C for 24h. The reaction mixture was quenched with aq. 2N HC1, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.200 g, 71%). Cnantiomeric excess: 73%, enriched in the late eluting isomer (retention time: 8.72 min. As determined by HPLC on a chiralpak AD-H column. Intermediate 26: (R) / (S) -5-fluorine-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: Intermediate 24 (0.280 g, 0.93 mmol), R-Alpine borane (0.5M in THF, 2.8 ml ) was added and heated to 60 ° C for 24h The reaction mixture quenched with 2N aq. HCl, and extracted with ethyl acetate The organic layer was dried over sodium sulfate and concentrated under reduced pressure The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the compound as a pale yellow solid (0.110 g, 37%). Enantiomeric excess: 94.6%, enriched in the fast eluting isomer (retention time: 7.16 ) as determined by HPLC on a chiralpak AD-H column. Intermediate 27: 2- (1- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 - fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.800 g, 2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) was added and stirred at RT for 30 min. To this mixture, intermediate 22 (0.500 g, 1.44 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as an off-white solid (0.300 g, 38%). 'H-NMR (δ ppm, DMSO-d63, 400 MHz): 8.02 (s, 1H), 7.94 (s, 1H), 7.84 (dt, J = 8.4.5.7 Hz , 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, J = 8.8.2.3 Hz, 1H), 6 , 87 (s, 2H), 5.88 (q, J = 7.0 Hz, 1H), 1.82 (d, J = 7.0 Hz, 3H). Intermediate 28: 3-bromo-2- (1-bromoethyl) -5-fluorine-4H-chromen-4-one: The title compound was obtained as a brown solid (3.60 g, 94%) using a procedure that is similar to one described for intermediate 22 from intermediate 20 (3.0 g, 11.06 mmol), carbon tetrachloride (30 ml) N-bromosuccinimide (1.96 g, 11.06 mmol) and azobisisobutyronitrile (30 mg) which is used as such in the next step. Intermediate 29: 2- (1- (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3-bromo-5- fluorine-4H-chromen-4-one: The title compound was obtained as a brown solid (0.800 g, 36%) using a procedure similar to that described for intermediate 27 from intermediate 13 (1.11 g, 4.28 mmol ), cesium carbonate (1.39 g, 4.28 mmol), DMF (5 ml) and intermediate 28. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.37 (s, 1H), 7 62 (dt, J = 8,4,5,4 Hz, 1H), 7,45 (dd, J = 11,5,2,1 Hz, 1H), 7,39 (m, 1H), 7, 22 (d, J = 8.6 Hz, 1H), 7.14-7.04 (m, 2H), 6.60 (q, J = 7.1 Hz, 1H), 5.67 (s, 2H ), 4.65 (q, J = 6.0 Hz, 1H), 2.08 (d, J = 7.1 Hz, 3H), 1.41 (d, J = 6.1 Hz, 6H). Intermediate 30: 2-ethyl-5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.680 g, 54%) using a procedure similar to that described for intermediate 21 from intermediate 20 (1.20 g, 4.42 mmol), 4-fluorophenylboronic acid (0.991 g, 7.08 mmol), dioxane (9 ml), potassium carbonate (1.83 g, 13 , 27 mmol), water (1.2 ml) and tetrakis (triphenylphosphmo) palladium (0) (0.306 g, 0.265 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.60 (dt, J = 8.3, 5.5 Hz, 1H), 7.27 (m, 3H), 7.13 (t, J = 8.7 Hz, 2H), 7.04 (t, J = 9, 1 Hz, 1H), 2.55 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7 , 6 Hz, 3H). Intermediate 31: 2- (l-bromoethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.740 g, 85%) using a procedure similar to that described for intermediate 22 from intermediate 30 (0.680 g, 2.37 mmol), carbon tetrachloride (10 ml) N-bromosuccinimide (0.423 g, 2.37 mmol) and azobisisobutyronitrile (30 mg). * H-NMR (δ ppm, CDCI3, 400 MHz): 7. 67 (dt, J = 8.4, 5.5 Hz, 1H), 7.37 (m, 3H), 7. 18 (t, J = 8.7 Hz, 2H), 7.09 (t, J = 8.5 Hz, 1H), 4.92 (q, J = 6.9 Hz, 1H), 1.97 (d. J = 6 , 9 Hz, 3H). Intermediate 32: 2-ethyl-5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as an off-white solid (0.680 g, 54%) using a procedure that is similar to that described for intermediate 21 from intermediate 20 (1.20 g, 4.42 mmol), 4-fluorophenylboronic acid (0.864 g, 7.08 mmol), dioxane (9 ml), potassium carbonate (1.83 g, 13.27 mmol ), water (1.2 ml) and tetrakis (triphenylphosphino) palladium (0) (0.306 g, 0.265 mmol). H-NMR (δ ppm, CDCl3, 400 MHz): 7. 61 (dt, J = 8.4, 5.5 Hz, 1H), 7.45 (m, 3H), 7.28 (m, 3H ), 7.05 (dt, J = 8.5.1.3 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.5 Hz , 3H). Intermediate 33: 2- (1-bromoethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as a brown solid (0.590 g, 76%) using a procedure similar to that described for intermediate 22 from intermediate 32 (0.600 g, 2.23 mmol), carbon tetrachloride (9 ml) N-bromosuccinimide (0.398 g, 2.37 mmol) and azobisisobutyronitrile (30 mg). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7. 66 (dt, J = 8.4, 5.5 Hz, 1H), 7.48 (m, 3H), 7. 37 (m, 3H ), 7.08 (t, J = 9.8 Hz, 1H), 4.95 (q, J = 6.8 Hz, 1H), 1.97 (d, J = 6.9 Hz, 3H). Intermediate 34: 2- (1- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (4-fluorophenyl) -4H- chromen-4-one: To a solution of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.800 g, 2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) was added and stirred at RT for 30 min. To this intermediate mixture 22 (0.500 g, 1.44 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as an off-white solid (0.300 g, 38%). * H-NMR (δ ppm, DMSO-d63, 400 MHz): 8.02 (s, 1H), 7.94 (s, 1H), 7.84 (dt, J = 8.4.5.7 Hz , 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, J = 8.8.2.3 Hz, 1H), 6 , 87 (s, 2H), 5.88 (q, J = 7.0 Hz, 1H), 1.82 (d, J = 7.0 Hz, 3H). Intermediate 35: 2- (1- (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) isoindoline-1,3-dione: To a solution of phthalimide (0.420 g, 2.88 mmol) in DMF (4 ml), potassium carbonate (0.43 g, 2.88 mmol) was added and stirred at RT for 30 min. To this intermediate mixture 22 (0.400 g, 2.88 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.350 g, 32%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.77 (m, 4H), 7.63 (dt, J = 8.4.5.4 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.28 (m, 1H), 7.08 (m, 1H), 6.97 (m, 2H), 6.86 (d, J = 7.4 Hz, 1H ), 5.79 (q, J = 7.2 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H). Intermediate 36: 2- (1-aminoethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 35 (0.350 g, 0.847 mmol) in methanol (3.5 ml), hydrated hydrazine (0.070 g, 1.27 mmol) was added and refluxed for 3 h. The reaction mass is cooled, filtered and washed with chloroform. The filtrate was concentrated to generate the title compound as a brown solid (0.200 g, 78%). H-NMR (δ ppm, DMSO-d63, 400 MHz): 7.29 (dt. J = 8.0.6.4 Hz. 1H). 7.19 (q. J = 8.2 Hz. 1H). 7.02 (m. 3H). 6.69 (d ../ = 8.2 Hz, 1H), 6.59 (t, J = 8.8 Hz, 1H), 4.12 (q, J = 6.6 Hz, 1H), 1.32 (d , J = 6.7 Hz, 3H). Intermediate 37: 4-bromo-1- (difluormethoxy) -2-fluorbenzene: To a solution of 4-bromo-2-fluorophenol (1.00 g, 5.23 mmol) in DMF (17 ml) and water (2, 3 ml), sodium chlorodifluoracetate (1.60 g, 1047 mmol) and potassium carbonate (0.866 g, 6.282 mmol) were added. The flask was purged with nitrogen for 15 min. and heated to 100 ° C. After 2.5 h, cooled to room temperature, concentrated HCl (2.5 ml) and water (2.5 ml) were added and stirred for 1 h. The reaction mixture was cooled to 0 ° C, quenched with aq. IN sodium hydroxide solution, extracted with ethyl acetate and dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a colorless liquid (0.545 g, 43%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.36 (dd, J = 9.7.2.3 Hz, 1H), 7.28 (td, J = 8.7, 1.5 Hz , 1H), 7.15 (t, <7 = 8.3 Hz, 1H), 6.71 (t, J = 73.0 Hz, 1H). Intermediate 38: 2- (4- (difluormethoxy) -3-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane: The title compound was obtained as a yellow liquid (0.475 g, 76% ) using a procedure similar to that described for intermediate 12 from intermediate 35 (0.520 g, 2.15 mmol), potassium acetate (0.423 g, 4.31 mmol), bis (pinacolate) diboro (0.602 g, 2.37 mmol) dioxane (10 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.088 g, 0.107 mmol). 'H-NMR (δ ppm, CDCl3, 400 MHz): 7. 59 (m, 2H), 7.23 (t, J = 7.9 Hz, 1H), 6.75 (t, J = 73.5 Hz, 1H), 1.35 (s, 12H). Intermediate 39: 3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a light brown solid (0.321 g, 28%) using a procedure similar to that described for intermediate 13 from intermediate 38 (1.70 g, 5.74 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.0 g , 3.83 mmol), DMF (5 ml), ethanol (2.5 ml), water (2.5 ml) sodium carbonate (1.21 g, 11.49 mmol) and tetrakis (triphenylphosphine) palladium (0 ) (0.221 g, 0.191 mmol) 'H-NMR (δ ppm, DMSO-dβ, 400 MHz): 13.66 (s, 1H), 8.21 (s, lH), 7.62 dd, J = 10 , 6.5.4 Hz, 1H), 7.51 (m, 2H), 7.48 (t, J = 73.2 Hz, 1H), 6.92 (s, 2H). Intermediate 40: 4- (4-bromo-2-fluorfenoxy) tetrahydro-2H-pyran: To a solution of 4-bromo-2-fluorphenol (3.89 g, 20.39 mmol) in THF (50 ml), 4 -hydroxytetrahydropyran (2.50 g, 24.47 mmol) and triphenylphosphine (8. 02 g, 30.58 mmol) were added and heated to reflux for 2h. The reaction mixture was cooled to 0 ° C, diisopropylazodicarboxylate (6.02 ml, 30.58 mmol) was added and heated to reflux for 12h. The reaction mixture was concentrated and the crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a colorless liquid (0.3.6 g, 83%). 'H-NMR (δ ppm, CDC13, 400 MHz): 7.26 (dd, J = 10.4.2.1 Hz, 1H), 7.18 (m, 1H), 6.90 (t, J = 8.7 Hz, 1H), 4.45 (m, 1H), 4.01 (m, 2H), 3.57 (m, 2H), 2.02-1.76 (m, 4H). Intermediate 41: 2- (3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -4,4,5,5-tetramethyl-1,2,2-dioxaborolane: The title compound was obtained as an off-white solid (2.50 g, 59%) using a procedure similar to that described for intermediate 12 from intermediate 40 (3.50 g, 16.49 mmol), potassium acetate (3.25 g, 32, 99 mmol), bis (pinacolate) diboro (4.60 g, 18.14 mmol) dioxane (40 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (1.34 g, 1.64 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): 7. 50 (m, 2H), 6.97 (t, J = 7.9 Hz, 1H), 4.54 (m, 1H), 4.00 (m, 2H), 3.57 (m, 2H), 2.02-1.76 (m, 4H), 1.31 (s, 12H). Intermediate 42: 1- (4-bromo-2-fluorophenyl) -2-methylpropan-1-ol: To an ice-cooled solution of isopropylmagnesium bromide prepared from magnesium (8. 8 g, 0. 147 mol) and 2-bromopropane (18.1 g, 0.147 mol) in diethyl ether (80 ml), 4-bromo-2-fluorbenzaldehyde (10.0 g, 0.049 mol) in diethyl ether (20 ml) was added and heated to room temperature. After 12h, the reaction mixture was cooled to 0 ° C, quenched with diluted aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a brown liquid (12.0 g, 99%) which was used without purification in the next step. Intermediate 43: 1- (4-bromo-2-fluorphenyl) -2-methylpropan-1-one: The title compound was obtained as a light brown liquid (0.5.8 g, 59%) using a procedure similar to that described for intermediate 3 from intermediate 42 (10.0 g, 40.46 mmol), pyridinium dichromate (22.8 g, 60.70 mmol) and DMF (50 ml) which was used without purification in the next step. Intermediate 44: 6-bromo-3-isopropyl-1H-indazole: To a solution of intermediate 42 (5.80 g, 23.66 mmol) in ethylene glycol (39 ml), hydrated hydrazine (2.3 g, 47, 32 mmol) was added and heated to 160 ° C for 12h. The reaction mixture was cooled and quenched with ethyl acetate and extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as a pale brown solid (3.0 g, 54%). ). 'H-NMR (δ ppm, CDCl3, 400 MHz): 9.80 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.61 (s, 1H), 7, 24 (dd, J = 8.5, 1.5 Hz, 1H), 3.43 (quintet, J = 7.0 Hz, 1H), 1.45 (d, J = 6.9 Hz, 6H). Intermediate 45: tert-butyl 6-bromo-3-isopropyl-1 H-indazol-1-carboxylate: To a solution of intermediate 44 (2.0 g, 8.36 mmol) in acetonitrile (20 ml), 4-dimethylaminopyridine (0.102 g, 0.836 mmol), Boc-anhydride (1.82 g, 8.36 mmol) were added at 20-25 ° C followed by triethylamine (0. 846 g, 8.36 mmol). After 12h, the reaction mixture was concentrated and quenched with water, extracted with ethyl acetate, dried with ethyl acetate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a colorless liquid (1.70 g, 61%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.29 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.5 , 1.5 Hz, 1H), 3.41 (quintet, J = 7.0 Hz, 1H), 1.71 (s, 9H), 1.46 (d, J = 7.0 Hz, 6H). Intermediate 46: tert-butyl 3-isopropyl-6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-indazol-1-carboxylate The title compound was obtained as a off-white solid (1.50 g, 79%) using a procedure similar to that described for intermediate 12 from intermediate 45 (1.70 g, 5.01 mmol), potassium acetate (0.980 g, 10.02 mmol) , bis (pinacolato) diboro (1.40 g, 5.51 mmol) dioxane (17 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.200 g, 0.250 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.59 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.68 (d, J ~ 8.1 Hz, 1H), 3.45 (quintet, J = 7.0 Hz, 1H), 1.73 (s, 9H), 1.48 (d, J = 7.0 Hz, 6H), 1.36 ( s, 12H). Intermediate 47: tert-butyl 4- (4-bromo-2-fluorfenoxy) piperidine-1-carboxylate: To a solution of 4-bromo-2-fluorophenol (1.66 g, 8.69 mmol) in THF (20 ml ), 4-hydroxy-1-Bocpiperidine (2.10 g, 10.43 mmol) and triphenylphosphine (3.42 g, 13.04 mmol) were added and heated to 45 ° C. After 30 min. diisopropylazodicarboxylate (2.56 ml, 13.04 mmol) was added and stirred for 12h. The reaction mixture was concentrated and the crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a colorless liquid (1.20 g, 38%). 'H-NMR (δ ppm. CDCh. 400 MHz): 7.25 (dd, J = 8.7.2.7 Hz, 1H), 7.18 (m, 1H), 6.89 (t, J = 8.7 Hz, 1H), 4 , 42 (septet, J = 3.6 Hz, 1H), 3.73 (m, 2H), 3.34 (m, 2H), 1.92-1.72 (m, 4H) „1.46 ( s, 9H). Intermediate 48: tert-butyl 4- (2-fluorine-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenoxy) piperidine-l-carboxylate: The title compound was obtained as a pale yellow solid (1.90 g, 99%) using a procedure similar to that described for intermediate 12 from intermediate 47 (1.10 g, 2.92 mmol), potassium acetate (0.573 g, 5, 84 mmol), bis (pinacolate) diboro (0.816 g, 3.21 mmol) dioxane (12 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.230 g, 0.292 mmol). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7.51 (m, 2H), 6.98 (t, J = 7.9 Hz, 1H), 4.53 (septet, J = 3.5 Hz, 1H), 3.72 (m, 2H), 3.36 (m, 2H), 1.92-1.74 (m, 4H), 1.45 (s, 9H), 1.31 (s , 12H). Intermediate 49: 2- (2-fluor-4-nitrophenylamino) ethanol: To a solution of 3,4-difluor — nitrobenzene (3.50 g, 22.0 mmol) in acetonitrile (35 ml), ethanolamine (1.98 ml, 33.0 mmol) was added and heated to reflux for 4h. The reaction mass was concentrated and the residue was triturated with petroleum ether and filtered and dried in vacuo to generate the title compound as a yellow solid (3.2 g, 73%) which was used without purification in the next step. Intermediate 50: 2- (4-amino-2-fluorophenylamino) ethanol: To a solution of intermediate 49 (3.2 g, 15.98 mmol) in methanol, palladium on activated carbon (0.800 g, 5% Pd / C) it was added and hydrogenated in an autoclave at 4kg / cm2 for 4h at room temperature. The reaction mass was filtered through celite, washed with methanol and concentrated in vacuo to generate the title compound as a brown liquid (3.00 g, 99%) which was used without purification in the next step. Intermediate 51: 2- (4-bromo-2-fluorophenylamino) ethanol: To intermediate 50 (3.00 g, 17.62 mmol), 48% hydrobromic acid (36 ml) was added and cooled to 0 ° C, nitrite from sodium (3.64 g, 52.88 mmol) in water (42 ml) was added under a drip and stirred at room temperature for 15 min. The reaction mixture was cooled again to 0 ° C and copper (I) bromide (3.79 g, 26.44 mmol) was added and heated to 140 ° C for 4 h. The reaction mass was cooled to room temperature and basified with saturated sodium bicarbonate solution, filtered through celite, washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a brown liquid (1.40 g, 34%). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7.14 (m, 2H), 6.61 (t, J = 8.7 Hz, 1H), 4.21 (br s, 1H), 3 , 86 (t, J = 5.1 Hz, 2H), 3.32 (t, J = 5.0 Hz, 2H) ,. 1.72 (s, 1H). Intermediate 52: 2- (2-11-fluor-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenylamino) ethanol: The title compound was obtained as a brown liquid (1 , 40 g, 58%) using a procedure similar to that described for intermediate 12 from intermediate 50 (1.40 g, 2.92 mmol), potassium acetate (1.17 g, 11.95 mmol), bis ( pinacolate) diboro (1.67 g, 6.57 mmol) dioxane (35 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium. CHzCh (0.240 g, 0.292 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): 7.46 (m, 1H), 7.39 (m, 1H), 6.71 (t, J = 8.2 Hz, 1H), 4, 07 (t, J = 5.2 Hz, 1H), 3.86 (t, J = 5.2 Hz, 2H), 3.38 (t, J = 5.3 Hz, 2H), 1.97 ( s, 1H), 1.31 (s, 12H). Intermediate 53: 2-fluor-N-isopropyl-4-nitroaniline: To a solution of 3,4-difluor-nitrobenzene (4.00 g, 25.14 mmol) in ethyl acetate (40 ml) and triethylamine (3, 86 ml) cooled to 0 ° C, isopropylamine (2.30 ml, 27.65 mmol) was added slowly and stirred at room temperature for 24 hours. The reaction mass was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (1.80 g, 36%). 1 H-NMR (Ô ppm, DMSO-do, 400 MHz): 7.94 dd, J = 9.1.1.5 Hz, 1H), 7.89 (dd, J = 12.2,2.5 Hz, 1H), 6.84 (t, J = 8.9 Hz, 1H), 6.78 (d, J = 10.7 Hz, 1H), 3.83 (m, 1H), 1.20 ( d, J = 6.4 Hz, 6H). Intermediate 54: 2-fluorine-N1-isopropylbenzene-1,4-diamine: The title compound was obtained as a brown liquid (1.30 g, 90%) using a procedure similar to that described for intermediate 50 from intermediate 53 ( 1.70 g, 8.62 mmol), ethyl acetate (20 ml) and palladium on activated carbon (0.170 g, 5% Pd / C) which was used without purification in the next step. Intermediate 55: 4-bromo-2-fluorine-N-isopropylaniline: The title compound was obtained as a brown liquid (2.00 g, crude) using a procedure that is similar to that described for intermediate 51 from intermediate 54 ( 1.30 g, 7.73 mmol), 48% hydrobromic acid (16 ml), sodium nitrite (1.60 g, 23.21 mmol), water (19 ml) and copper (I) bromide (1, 66 g, 22.21 mmol) which was used without purification in the next step. Intermediate 56: 2-fluorine-N-isopropyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) aniline: The title compound was obtained as a brown liquid (1, 40 g, 58%) using a procedure similar to that described for intermediate 12 from intermediate 55 (2.00 g, 8.65 mmol), potassium acetate (2.50 g, 25.97 mmol), bis (pinacolate ) diboro (2.60 g, 10.38 mmol) dioxane (20 ml) and [1,1 r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2Cl2 (0.212 g, 0.259 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.45 (dd,' 7 = 8.1, 1.2 Hz, 1H), 7.37 (dd, J = 12.3.1.2 Hz, 1H), 6.67 (t, J = 8.1 Hz, 1H), 3.95 (m, 1H), 3.68 (m, 1H), 1.26 (s, 12H), 1, 24 (d, J = 6.3 Hz, 6H). Intermediate 57: 2-fluorine-N, N-dimethyl-4-nitroaniline: The title compound was obtained as a yellow liquid (2.70 g, 58%) using a procedure similar to that described for intermediate 3,4-difluor 53 -nitrobenzene (4.00 g, 25.14 mmol) in ethyl acetate (40 ml) and triethylamine (7.36 ml) and dimethylamine hydrochloride (2.25 g, 27.65 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.93 (dd, J = 9.1.2.6 Hz, 1H), 7.89 (dd, J = 14.1, 2.6 Hz , 1H), 6.73 (t, J = 9.1 Hz, 1H), 3.09 (s, 6H). Intermediate 58: 2-fluorine-N1, N1-dimethylbenzene-1,4-diamine: The title compound was obtained as a brown liquid (2.10 g, 93%) using a procedure similar to that described for intermediate 50 from the intermediate 57 (2.70 g, 14.67 mmol), ethyl acetate (20 ml) and palladium on activated carbon (0.270 g, 5% Pd / C) which was used without purification in the next step. Intermediate 59: 4-bromo-2-fluoro-N, N-dimethylaniline: The title compound was obtained as a yellow liquid (2.20 g. 74%) using a procedure similar to that described for intermediate 51 from intermediate 58 (2.10 g, 13.63 mmol), 48% hydrobromic acid (26 ml), sodium nitrite (2.30 g, 40.90 mmol), water (30 ml) and copper (I) bromide (2.93 g, 20.45 mmol). 1 H-NMR (δ ppm, CDCl3, 400 MHz): 7.17 (m, 2H), 6.76 (t, J = 8.6 Hz, 1H), 2.86 (s, 6H). Intermediate 60: 2-fluorine-N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline: The title compound was obtained as a yellow liquid ( 0.950 g, 37%) using a procedure similar to that described for intermediate 12 from intermediate 59 (2.10 g, 9.67 mmol), potassium acetate (2.84 g, 29.03 mmol), bis (pinacolate ) diboro (2.94 g, 11.61 mmol), dioxane (22 ml) and [1,1 l'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.237 g, 0.290 mmol). 'H-NMR (Ô ppm, CDCI3, 400 MHz): 7.48 (dd, J = 8.0.1.4 Hz, 1H), 7.43 (dd, J = 13.7.1.4 Hz , 1H), 6.84 (t, J = 8.5 Hz, 1H), 2.90 (s, 6H), 1.32 (s, 12H). Intermediate 61: 2 4- (2-fluorine-4- (4. 4. 5,5-tetramethyl-1,3. 2-dioxaborolan-2-yl) phenyl) morpholine: The title compound was obtained as an off-white solid (2.00 g, 91%) using a procedure similar to that described for intermediate 12 of 4- (4-bromo-2- fluorphenyl) morpholine (1.90 g, 7.30 mmol; for preparation, see Bioorganic Med. Chem. Lett, 2006, 16, 176-180), potassium acetate (1.43 g, 14.60 mmol), bis (pinacolate) diboro (2.00 g, 8.03 mmol), dioxane (48 ml) and [ 1,1 l'-Bis (diphenylphosphmo) ferrocene] dichloro palladium QiyCFhCh (0.290 g, 0.365 mmol). 1 H-NMR. (δ ppm, CDCh, 400 MHz): 7.51 (dd, J = 7.9.1.3 Hz, 1H), 7.45 (dd, J = 13.5.1.3 Hz, 1H), 6.92 (t, J = 8.3 Hz, 1H), 3.87 (t,. 7 = 4.7 Hz, 4H), 3.14 (t, J = 4.7 Hz, 1H), 1.32 (s, 12H). Intermediate 62: 1- (4-bromo-2-fluorophenyl) -4-methylpiperazine: The title compound was obtained as a brown liquid (1.20 g, 31%) using a procedure similar to that described for intermediate 51 of 3-11 fluorine. -4- (4-methylpiperazin-1-yl) aniline (3.00 g, 14.31 mmol; for preparation, see Synth. Commun. 2010, 40, 789-798), 48% hydrobromic acid (35 ml), sodium nitrite (2.96 g, 42.95 mmol), water (40 ml) and copper (l) bromide (3.00 g , 21.47 mmol) which was used as such in the next step. Intermediate 63: 1- (2-fluor-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine: The title compound was obtained as a liquid brown (0.450 g, 24%) using a procedure similar to that described for intermediate 12 from intermediate 62 (1.20 g, 4.38 mmol), potassium acetate (0.86 g, 8.77 mmol), bis (pinacolate) diboro (1.22 g, 4.82 mmol), dioxane (30 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium. CH3Ch (0.179 g, 0.219 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): 7.50 (dd, J = 8.0.1.8 Hz, 1H), 7.44 (dd, J = 13.4.1.3 Hz , 1H), 6.91 (t, J = 8.3 Hz, 1H), 3.23 (t, J = 4.7 Hz, 4H), 2.77 (t, J = 4.5 Hz, 4H ), 2.42 (s, 3H), 1.32 (s, 12H). Intermediate 64: 2- (1-methoxypropylidene) malononitrile: Malononitrile (2.24 g, 33.90 mmol), trimethylortopropionate (5.0 g, 37.26 mmol) was added and heated to reflux for 3h. The reaction mixture was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as a brown solid (4.3 g, 93%) which was used in the next step. Intermediate 65: 5-amino-3-ethyl-1 H-pyrazol-4-carbonitrile: To a solution of intermediate 64 (4.30 g, 31.58 mmol) in ethanol (15 ml), hydrated hydrazine (2.37 g, 47.37 mmol) was added and refluxed for 12h. The reaction mass was concentrated under reduced pressure and the ice residue was added and the precipitate formed was filtered and dried in vacuo to generate the title compound as off-white solid (2.0 g, 47%). * H- NMR (δ ppm, DMSO-dc, 400 MHz): 11.61 (s, 1H), 5.85 (s, 2H), 2.52 (q, J = 7.9 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). Intermediate 66: 3-ethyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine: To intermediate 65 (1.00 g, 7.34 mmol), formamide (8.2 ml) was added and heated at 130 ° C for 12h. The reaction mass was quenched with water and the solid formed was filtered, dried in vacuo to generate the title compound as off-white solid (0.600 g, 50%). 'H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.90 (s, 1H), 8.07 (s, 1H), 7.09 (s, 2H), 2.95 (q, J = 7.4 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). Intermediate 67: 3- (benzo [b] thiophene-2-yl) -1 H-pyrazolo [3. 4-d] pyrimidin-4-amine: The title compound was obtained as a light brown solid (0.600 g, 30%) using a procedure similar to that described for benzothiophene-2borinic acid intermediate 13 (2.00 g, 11.23 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.95 g, 7.49 mmol), 1,2-dimethoxyethane (20 ml), water (10 ml) carbonate sodium (2.30 g, 22.47 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (1.20 g, 1.49 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) per hour that is used in the next step. Intermediate 68: 2- (morpholino (propylthio) methylene) malononitrile: To a 2- (bis (propylthio) methylene) malononitrile solution (1.00 g, 4.41 mmol; for preparation, see J. Med. Chem, 2003, 46, 1229-1241) in ethanol (10 ml), morpholine (0.384 g, 4.41 mmol) was added and refluxed for 4 h. The reaction mass was extinguished with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as a brown liquid (0. 810 g, 77%) which is used in the next step. Intermediate 69: 5-amino-3-morpholino-1H-pyrazol-4-carbonitrile: To a solution of intermediate 68 (0.800 g, 3.37 mmol) in ethanol (8 ml), hydrated hydrazine (0.32 ml, 6 , 75 mmol) was added stirred at room temperature for 4h. . The reaction mass was concentrated and quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as brown solid (0.450 g, 69%) 'H-NMR (δ ppm, DMSO-d6 , 400 MHz): 11.05 (s, 1H), 6.18 (s, 2H), 3.66 (t, J = 4.7 Hz, 4H), 3.11 (t, J = 4.7 Hz, 4H). Intermediate 70: 3-morpholino-1H-pyrazolo [3,4-dJpirimidin-4-amine: To intermediate 69 (0.450 g, 2.32 mmol), formamide (4 ml) was added and heated at 130 ° C for 12h. The reaction mass was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with methanol: ethyl acetate to generate the title compound as an almost white solid (0.200 g, 39%). 'H-NMR (δ ppm, DMSO-do, 400 MHz): 12.56 (s, 1H), 8.08 (s, 1H), 6.86 (s, 2H), 3.79 (t, J = 4.5 Hz, 4H), 3.07 (t, J = 4.6 Hz, 4H). Intermediate 71: 2 - ((dimethylamino) (propylthio) methylene) malononitrile: The title compound was obtained as a manom liquid (0.830 g, 96%) using a procedure similar to that described for intermediate 68 of 2- (bis (propylthio) methylene) ) malononitrile (1.00 g, 4.41 mmol) in ethanol (10 ml), dimethylamine hydrochloride (0.360 g, 4.41 mmol) and triethylamine (0.446 g, 4.41 mmol) which was used as such in the next step . Intermediate 72: 5-amino-3- (dimethylamino) -1H-pyrazol-4-carbonitrile: The title compound was obtained as a brown solid (0.510 g, 71%) using a procedure similar to that described for intermediate 69 from the intermediate 71 (0.930 g, 4.76 mmol), ethanol (10 ml) and hydrated hydrazine (0.46 ml, 9.52 mmol) which was used as such in the next step. Intermediate 73: N3, N3-dimethyl-1H-pyrazolo [3,4-d] pyrimidine-3,4-diamine: The title compound was obtained as a brown solid (0.280 g, 47%) using a procedure similar to that described for intermediate 70 from intermediate 72 (0.510 g, 3.37 mmol) and formamide (5 ml). 'H-NMR (δ ppm, DMSO-do, 400 MHz): 12.37 (s, 1H), 8.04 (s, 1H), 6.88 (s, 2H), 2.76 (s, 6H ). Intermediate 74: 2- (piperidin-1-yl (propylthio) methylene) malononitrile: The title compound was obtained as a brown liquid (0.840 g, 60%) using a procedure similar to that described for intermediate 68 of 2- (bis (propylthio) ) methylene) malononitrile (1.00 g, 4.41 mmol) in ethanol (10 ml), piperidine (0.376 g, 4.41 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): 3.79 (t, J = 5.0 Hz, 4H), 3.01 (t, J = 7.2 Hz, 2H), 1.74 ( m, 6H), 1.72 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H). Intermediate 75: 5-amino-3- (piperidin-1-yl) -1H-pyrazol-4-carbonitrile: The title compound was obtained as a brown liquid (0.500 g, 73%) using a procedure similar to that described for intermediate 69 from intermediate 74 (0.840 g, 3.56 mmol), ethanol (10 ml) and hydrated hydrazine (0.40 ml, 8.27 mmol). 'H-NMR (δ ppm, DMSO-dé, 400 MHz): 10.92 (s, 1H), 6.09 (s, 1H), 3.12 (m, 4H), 1.53 (m, 6H ). Intermediate 76: 3- (piperidin-1-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a brown solid (0.600 g, 95%) using a procedure similar to described for intermediate 70 from intermediate 75 (0.550 g, 2.87 mmol) and formamide (5 ml). 'H-NMR (δ ppm, DMSO-do, 400 MHz): 12.44 (s, 1H), 8.07 (s, 1H), 6.69 (s, 2H), 3.05 (t, J = 5.1 Hz, 4H), 1.69 (m, 4H), 1.54 (m, 2H). Intermediate 77: 2- (propylthio (pyrrolidin-1-yl) methylene) malononitrile: The title compound was obtained as a brown liquid (0.950 g, 97%) using a procedure similar to that described for intermediate 68 of 2- (bis (propylthio ) methylene) malononitrile (1.00 g, 4.41 mmol) in ethanol (10 ml), pyrrolidine (0.314 g, 4.41 mmol) which was used as such in the next step. Intermediate 78: 5-amino-3- (pyrrolidin-1-yl) -1H-pyrazol-4-carbonitrile: The title compound was obtained as a brown liquid (0.640 g, 84%) using a procedure similar to that described for intermediate 69 from intermediate 77 (0.950 g, 4.29 mmol), ethanol (10 ml) and hydrated hydrazine (0.42 ml, 8.58 mmol) which was used as such in the next step. Intermediate 79: 3- (pyrrolidin-1-yl) -1 H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a brown solid (0.350 g, 29%) using a similar procedure to that described for intermediate 70 from intermediate 78 (0.640 g, 3.61 mmol) and formamide (6 ml). 'H-NMR (δ ppm, DMSO-do, 400 MHz): 12.28 (s, 1H), 8.02 (s, 1H), 6.79 (s, 2H), 3.32 (t, J = 6.6 Hz, 4H), 1.89 (m, 4H). Intermediate 80: 1-benzhydryl-3- (4-bromo-2-fluorfenoxy) azetidine: The title compound was obtained as a colorless liquid (0.631 g, 30%) using a procedure similar to that described for intermediate 4 of 4-bromo- 2-fluorpheneI (1.00 g, 5.23 mmol) in THF (12 ml), 1-benzhydrylazctidin-3-ol (1.25 g, 5.23 mmol) and phosphine tris (4-methoxyphenyl) (2, 70 g, 7.85 mmol) and diisopropylazodicarboxylate (1.60 ml, 7.85 mmol). ). 'H-NMR (δ ppm, CDCh, 400 MHz): 7.42 (m, 4H), 7.29-7.17 (m, 7H), 7.11 (m, III), 6.59 (t , J ~ 8.8 Hz, 1H), 4.80 (quintet,. / = 5.8 Hz, 1H), 4.43 (s, IH), 3.72 (dd, J = 6.1.2.0 Hz, 2H), 3.17 (dd, J = 5.7 , 1.9 Hz, 2H). Intermediate 81: 1-benzhydryl-3- (2-fluorine-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenoxy) azetidine: The title compound was obtained as a off-white solid (0.850 g, 76%) using a procedure similar to that described for intermediate 12 from intermediate 80 (1.00 g, 2.42 mmol), potassium acetate (0.713 g, 7.27 mmol), bis (pinacolate) diboro (0.738 g, 2.90 mmol) dioxane (10 ml) and [1,1'-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.059 g, 0.072 mmol). 1 H-NMR (δ ppm, CDCb, 400 MHz): 7.49 (dd, J = 11.0.1.3 Hz, IH), 7.42 (m, 4H), 7.29 (m, 5H ), 7.21 (m, 2H), 6.68 (t, J = 8.1 Hz, 1H), 4.86 (quintet, J = 5.9 Hz, 1H), 4.44 (s, 1H ), 3.74 (dd, J = 6.1.1.9 Hz, 2H), 3.19 (dd, J = 5.8.1.9 Hz, 2H), 1.31 (s, 12H) . Intermediate 82: 3- (4-bromo-2-fluorphenoxy) oxetane: The title compound was obtained as a brown solid (0.900 g, 54%) using a procedure similar to that described for intermediate 47 of 4-bromo-2-fluorphenol ( 1.28 g, 6.74 mmol) in THF (6 ml), 3-hydroxyoxethane (0.500 g, 6.74 mmol) and triphenylphosphine (2.65 g, 10.12 mmol) and diisopropylazodicarboxylate (1.99 ml, 10.12 mmol). ). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.28 (dd, J = 12.9.2.4 Hz, 1H), 7.17 (m, 1H), 6.52 (t, J = 8.7 Hz, 1H), 5.20 (m, 1H), 4.96 (dd, J = 8.0.7.0 Hz, 2H), 4.82 (dd, J = 6.3, 5.3 Hz, 2H). Intermediate 83: 2- (3-fluorine-4- (oxetan-3-yloxy) phenyl) -4,4,5,5-tetramethyl-1,2,2-dioxaborolane: The title compound was obtained as a brown liquid ( 0.800 g, 80%) using a procedure similar to that described for intermediate 12 from intermediate 82 (0.900 g, 3.64 mmol), potassium acetate (1.00 g, 10.92 mmol), bis (pinacolate) diboro (1.10 g, 4.37 mmol) dioxane (10 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium QiyCHjClz (0.090 g, 0.109 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.53 (dd, J = 11.8.1.4 Hz, 1H),): 7.47 (d, J = 8.1 Hz, 1H ), 6.58 (t, J = 8.0 Hz, 1H), 5.27 (m, 1H), 4.98 (dd, J = 7.7.6.9 Hz, 2H), 4.83 (dd, J = 7.9.5.3 Hz, 2H), 1.32 (s, 12H). Intermediate 84: 3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a pale yellow solid (0.143 g, 52%) using a procedure similar to that described for intermediate 4-isopropoxy-3-methylphenylboronic acid (0.241 g, 1.24 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.250 g, 0.957 mmol), DMF (1.5 ml), ethanol (0.6 ml), water (0.6 ml), sodium carbonate (0.304 g, 2.87 mmol) and tetrakis (triphenylphosphmo) palladium (0) (0.055 g, 0.047 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) for 3h. Mass: 284.1 (M ++ 1). Intermediate 85: 2-isopropoxy-5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) pyrimidine: The title compound was obtained as a brown liquid (0.400 g, 65%) using a procedure similar to that described for intermediate 12 of 5-bromo-2-isopropoxypyrimidine (0.500 g, 2.30 mmol for preparation, see Organic. Lett. 2010, 12, 4478-4481. ), potassium acetate (0.688 g, 6.91 mmol), bis (pinacolate) diboro (0.702 g, 2.76 mmol) dioxane (5 ml) and [l, r-Bis (diphenylphosphmo) ferrocene] dichloride palladium (II ). CH2 Cl2 (0.056 g, 0.069 mmol). 'H-NMR (δ ppm, CDC13, 400 MHz): 8.77 (s, 2H), 5.35 (m, 1H), 1.39 (d, J = 6.1 Hz, 6H), 1, 33 (s, 12H). Intermediate 86: 3- (3-fluor-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a pale yellow solid (0.095 g, 20%) using a procedure similar to that described for intermediate 13 from intermediate 61 (0.393 g, 1.505 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.700 g, 2.25 mmol), DMF (2.5 ml), ethanol (1.5 ml), water (1.0 ml), sodium carbonate (0.478 g, 4.51 mmol) and tetrakis (triphenylphosphmo) palladium (0) (0.087 g, 0.075 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) for 2h. Mass: 315.0 (M ++ 1). Intermediate 87: 2-acetyl-3-fluorophenyl butyrate: Pyridine (7.2 ml) and propionyl chloride (3.85 g, 41.65 mmol) were added to a cooled solution of intermediate 4 (5.00 g, 32 , 43 mmol) in dichloromethane (750 ml), butyric acid (2.85 g, 32.43 mmol), dicyclohexylcarbodiimide (6.67 g, 32.43 mmol) and 4-dimethylaminopyridine (0.79 g, 6.48 mmol) were added and stirred at room temperature for 12 h. The reaction mixture was filtered, washed with dichloromethane and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (2.80 g, 39%) which was used as such in the next step. Intermediate 88: 5-fluorine-2-propyl-4H-chromen-4-one: To a solution of 87 (2.8 g, 12.55 mmol) in DMSO (15 ml) cooled to 0 ° C, sodium hydride (0.301 g, 12.55 mmol) was added kept at the same temperature for 1 h. The mixture was heated to RT and stirred for 12h. The reaction was quenched by the addition of 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvents removed. The crude product was dissolved in dioxane (6 ml) and sulfuric acid (8 ml) was added and heated to 100 ° C for 12h. Aqueous sodium bicarbonate solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a yellow liquid (1.6 g, 62%) which was used as such in the next step. Intermediate 89: 3-bromo-5-fluoro-2-propyl-4H-chromen-4-one: To a solution of intermediate 88 (1.50 g, 7.27 mmol) in DMF (9 ml), N-bromosuccinimide (1.29 g, 7.27 mmol) was added at RT. After 12h, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and the solvent was removed to generate the title compound as an off-white solid (1.60 g, 77%) which was used as such in the next step. Intermediate 90: 5-fluorine-3-phenyl-2-propyl-4H-chromen-4-one: The title compound was obtained as an off-white solid (1.10 g, 69%) using a procedure similar to that described for intermediate 21 from intermediate 89 (1.60 g, 5.61 mmol), phenylboronic acid (1.09 g, 8.97 mmol), dioxane (18 ml), potassium carbonate (2.32 g, 16.83 mmol), water (5 ml) and tetrakis (triphenylphosphmo) palladium (0) (0.388 g, 0.336 mmol). Mass: 283.4 (M + +1). Intermediate 91: 2- (1-bromopropyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as an off-white solid (1.3 g, 925%) using a similar procedure to that described for intermediate 22 from intermediate 90 (1.10 g, 3.89 mmol), carbon tetrachloride (22 ml) N-bromosuccinimide (0.69 g, 3.89 mmol) and azobisisobutyronitrile (42 mg). Mass: 362.8 (M + +1). Intermediate 92: 2- (1- (5-fluor-4-oxo-3-phenyl-4H-chromen-2-yl) propyl) isoindoline-1,3-dione: To a solution of potassium phthalimide (0.97 g, 5.23 mmol) in DMF (10 ml), intermediate 91 (2.0 g, 3.49 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (1.0 g, 67%). Mass: 428.1 (M + +1). Intermediate 93: 2- (1-aminopropyl) -5-fluoro-3-phenyl-4H-chromen-4-one: To a solution of intermediate 92 (0.50 g, 1.16 mmol) in methanol (5 ml) , hydrated hydrazine (0.087 g, 1.75 mmol) was added and refluxed for 3 h. The reaction mass is cooled, filtered and washed with chloroform and concentrated. The crude product was purified by column chromatography with dichloromethane: methanol to give the title compound as an off-white solid (0.34 g, 98%). Mass: 297.1 (M +). Intermediate 94: N- (4-bromo-2-fluorophenyl) isobutyramide: To a solution of 4-bromo-2-fluoraniline (2.0g, 10.51 mmol) in dichloromethane (20 ml) cooled to 0 ° C, triethylamine (2.90 ml, 21.02) was added followed by isobutyryl chloride (1.20 ml, 12.61 mol). After stirring at room temperature for 8h, the reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated to generate the title compound as an almost white solid (2.60g, 96%). 'H-NMR (δ ppm, CDCh, 400 MHz): 8.29 (t, J = 8.4 Hz, 1H), 7.31 (br s, 1H), 7.27 (m, 2H), 2 , 59 (quintet, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H). Intermediate 95: N- (2-fluorine-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) isobutyramide: The title compound was obtained as an off-white solid ( 0.900 g, 77%) using a procedure similar to that described for intermediate 12 from intermediate 94 (1.00 g, 3.84 mmol), potassium acetate (0.750 g, 7.68 mmol), bis (pinacolate) diboro (1.07 g, 4.22 mmol) dioxane (15 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.62 g, 0.768 mmol) which was used as such in the next step. Intermediate 96: N- (4-bromo-2-fluorophenyl) acetamide: To a solution of 4-bromo-2-fluoraniline (2.0g, 10.51 mmol) in dichloromethane (20 ml) cooled to 0 ° C, triethylamine (2.90 ml, 21.02) was added followed by acetyl chloride (0.90 ml, 12.61 mol). After stirring at room temperature for 8h, the reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated to generate the title compound as an off-white solid (2.60g, 99%) which was used as this in the next step. Intermediate 97: N- (2-fluorine-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) acetamide: The title compound was obtained as an off-white solid ( 0.800 g, 67%) using a procedure similar to that described for intermediate 12 from intermediate 96 (1.00 g, 4.30 mmol), potassium acetate (0.840 g, 8.61 mmol), bis (pinacolate) diboro (1.20 g, 4.74 mmol) dioxane (15 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.70 g, 0.861 mmol) which was used as such in the next step. Intermediate 98: 3-iodo-N, N-dimethyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine: To a solution of N, N-dimethyl-1H-pyrazolo [3,4-d] pyrimidin -4-amine (0.500 g, 3.06 mmol for preparation, see J. Amer. Chem. Soc. 1956, 784-790. ) in DMF (4 ml), N-lodosuccinimide (1.00 g, 4.59 mmol) was added and stirred at 80 ° C for 22h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as a brown solid (0.460 g, 46%) which was used as such in the next step. Intermediate 99: 3- (3-fluoro-4-isopropoxyphenyl) -N, N-dimethyl-1 H-pyrazolo [3,4- d] pyrimidin-4-amine: The title compound was obtained as a light brown solid (0.220 g, 50%) using a procedure similar to that described for intermediate 13 from intermediate 12 (0.581 g, 2.07 mmol), intermediate 98 (0.400 g, 1.38 mmol), DMF (3 ml), ethanol (1 , 5 ml), water (1.5 ml) sodium carbonate (0.440 g, 4.15 mmol) and tetrakis (triphenylphosphino) palladium (0) (0.080 g, 0.069 mmol). Mass: 316.3 (M * + 1). intermediate 100: 3-iodo-N-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine: To a solution of N-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.10 g, 7.37 mmol, for preparation, see J. Amer. Chem. Soc. 1956, 784-790) in DMF (8 ml), N-Iodosuccinimide (2.48 g, 11.06 mmol) was added and stirred at 80 ° C for 12h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as a brown solid (0.970 g, 48%). Mass: 275.9 (M ++ 1). Intermediate 101: 5-fluorine-3- (3-fluorophenyl) -2- (1 - (3-iodo-4- (methylamino) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -4H-chromen-4-one: The title compound was obtained as a light brown solid (0.230 g, 32%) using a procedure similar to that described for intermediate 34 from intermediate 22 (0.650 g, 1.78 mmol), intermediate 100 (0.350 g, 1.27 mmol), DMF (3 ml) and potassium carbonate (0.175 g, 1.27 mmol). Mass: 560.1 (M ++ 1). Intermediate 102: 4- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) morpholine: To a solution of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (2.00 g, 12 , 97 mmol) in dioxane (20 ml), morpholine 5.65 g, 64.86 mmol) was added and refluxed for 2h. The reaction mixture was quenched with water, filtered and dried in vacuo to generate the title compound as a brown solid (2.40 g, 90%). 'H-NMR (δ ppm, CDClj, 400 MHz): 12.49 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 3.95 (t, J = 4 , 6 Hz, 4H), 3.83 (t, J = 5.2 Hz, 4H). Intermediate 103: 4- (3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-yl) morpholine: To a solution of intermediate 102 (1.50 g, 7.31 mmol) in DMF (12 ml ), N-lodosuccinimide (2.46 g, 10.97 mmol) was added and stirred at 80 ° C for 22h. The reaction mixture was quenched with water, filtered, washed with petroleum ether and dried in vacuo to generate the title compound as a brown solid (1.90 g, 79%). 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 14.06 (s, 1H), 8.34 (s, 1H), 3.78 (t, J = 5.0 Hz, 4H), 3.73 (t, J = 5.0 Hz, 4H). Intermediate 104: 4- (3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) morpholine: The title compound was obtained as a light brown solid (0.180 g, 33%) using a procedure similar to that described for intermediate 13 from intermediate 12 (0.634 g, 2.26 mmol), intermediate 103 (0.500 g, 1.51 mmol), DMF (4 ml), ethanol (2.0 ml), water (2.0 ml) sodium carbonate (0.480 g, 4.53 mmol) and tetrakis (triphenylphosphino) palladium (0) (0.087 g, 0.075 mmol). Mass: 357.38 (M ++ 1). Intermediate 105: 5-fluorine-3- (4-fluorophenyl) -2- (1- (3-iodo-4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -4H- chromen-4-one: The title compound was obtained as a light brown solid (0.350 g, 53%) using a procedure similar to that described for intermediate 34 from intermediate 31 (0.734 g, 2.11 mmol), intermediate 103 ( 0.350 g, 1.05 mmol), DMF (4 ml) and cesium carbonate (0.343 g, 1.05 mmol). Mass: 616.2 (M ++ 1). Intermediate 106: 5-fluorine-3- (3-fluorophenyl) -2- (1- (3-iodo-4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -4H- chromen-4-one: The title compound was obtained as an off-white solid (0.400 g, 54%) using a procedure similar to that described for intermediate 34 from intermediate 22 (0.629 g, 1.81 mmol), intermediate 103 ( 0.400 g, 1.20 mmol), DMF (4 ml) and potassium carbonate (0.167 g, 1.20 mmol). Mass: 616.2 (M ++ 1). Intermediate 107: 2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3-bromo- 5-fluorine-4H-chromen-4-one: The title compound was obtained as a brown solid (0.650 g, 68%) using a procedure similar to that described for intermediate 27 from intermediate 39 (0.500 g, 1.69 mmol ), potassium carbonate (0.46 g, 3.38 mmol), DMF (10 ml) and intermediate 28 (0.82 g, 2.37 mmol) which was used as such for the next step. Intermediate 108: 2- (1 - (4-amino-3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4 -one: The title compound was obtained as a pale brown solid (2.00 g, 64%) using a procedure similar to that described for intermediate 34 from intermediate 33 (2.10 g, 6. 01 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (3.13 g, 12.02 mmol), DMF (8.4 ml) and cesium carbonate (3.91 g, 12.02 mmol) which was used as such in the next step. Intermediate 109: 5-fluorine-3- (4-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (3.50 g, 78%) using a procedure similar to that described for intermediate 23 from intermediate 31 (5.50 g, 15.01 mmol), DMSO (55 ml) and n-butanol (2.75 ml). Mass: 303.1 (M ++ 1). Intermediate 110: 5-fluorine-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one: The title compound was obtained as a pale brown solid (2.60 g, 60%) using a similar procedure to that described for intermediate 23 from intermediate 33 (5.30 g, 15.26 mmol), DMSO (40 ml) and n-butanol (2.20 ml). Mass: 284.8 (M +). Intermediate 111: 2-acetyl-5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale yellow solid (2.20 g, 64%) using a similar procedure to that described for intermediate 24 from intermediate 109 (3.50 g, 11.54 mmol), DMSO (3.27 ml, 46.16 mmol), dichloromethane (50 ml), oxalyl chloride (1.99 ml, 23.08 mmol) and triethylamine (7 ml) which was used as such in the next step. Intermediate 112: 2-acetyl-5-fluoro-3-phenyl-4H-chromen-4-one: The title compound was obtained as a pale yellow solid (1.80 g, 63%) using a procedure similar to that described for intermediate 24 from intermediate 110 (2.50 g, 8.76 mmol), DMSO (2.48 ml, 35.05 mmol), dichloromethane (42 ml), oxalyl chloride (1.51 ml, 17.52 mmol ) and triethylamine (5.5 ml) which was used as such in the next step. Intermediate 113: (R) / (S) -5-fluorine-3- (4-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: To a solution of intermediate 111 (0.568 g, 1 , 89 mmol) in DMF (4 ml) under nitrogen purging, formic acid: triethylamine 5: 2 azeotrope (1 ml) was added followed by [(S, S) tethTsDpcnRuCl] (3 mg). The reaction mixture was heated at 80 ° C for 1.5 hours in a continuous nitrogen purge. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0420 g, 74%). Enantiomeric excess: 74%, enriched in the late eluting isomer (retention time: 9.24 min. as determined by HPLC on an AD-H chiralpak column. Intermediate 114: (R) / (S) -5-fluorine-3- (4-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: To a solution of intermediate 111 (0.568 g, 1 , 89 mmol) in DMF (4 ml) under nitrogen purging, formic acid: triethylamine 5: 2 azeotrope (1 ml) was added followed by [(R, R) tethTsDpenRuCl] (3 mg). The reaction mixture was heated at 80 ° C for 1.5h in continuous nitrogen purging. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0430 g, 75%). Enantiomeric excess: 74%, enriched in the isomer eluting fast (retention time: 7.75 min. as determined by HPLC on an AD-H chiralpak column. Intermediate 115: (R) / (S) - 5-fluorine-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one: To a solution of intermediate 112 (0.568 g, 1.89 mmol) in DMF (4 ml) under nitrogen purging, formic acid: triethylamine 5: 2 azeotrope (1 ml) was added followed by [(S, S) tethTsDpenRuCl] (3 mg). The reaction mixture was heated at 80 ° C for 1.5 hours in a continuous nitrogen purge. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.380 g, 66%). Enanliomeric excess: 64%, enriched in the late eluting isomer (retention time: 8.85 min. as determined by HPLC on an AD-H chiralpak column. Intermediate 116: (R) / (S) - 5-fluorine-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one: To a solution of intermediate 112 (0.568 g, 1.89 mmol) in DMF (4 ml) under nitrogen purging, formic acid: triethylamine 5: 2 azeotrope (1 ml) was added followed by [(R, R) tethTsDpenRuCl] (3 mg). The reaction mixture was heated at 80 ° C for 1.5h in continuous nitrogen purging. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.410 g, 72%). Enantiomeric excess: 64%, enriched in the isomer eluting fast (retention time: 7.43 min. as determined by 11PLC on an AD-H chiralpak column. Intermediate 117: 3- (3-fluor-4-morpholinophenyl) -N, N-dimethyl-1H-pyrazolo [3,4- d] pyrimidin-4-amine: The title compound was obtained as a pale brown solid (0.340 g , 36%) using a procedure similar to that described for intermediate 13 from intermediate 61 (1.27 g, 4.15 mmol), intermediate 98 (0.800 g, 2.76 mmol), DMF (6 ml), ethanol ( 3 ml), water (3 ml), sodium carbonate (0.880 g, 8.30 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.160 g, 0.138 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) for 2h. Mass: 343.1 (M ++ 1). Intermediate 118: 3- (3-fluor-4-morpholinophenyl) -N-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as an off-white solid (0.350 g, 29 %) using a procedure similar to that described for intermediate 13 from intermediate 61 (1.67 g, 5.45 mmol), intermediate 100 (1.00 g, 3.63 mmol), DMF (7 ml), ethanol ( 3.5 ml), water (3.5 ml), sodium carbonate (1.15 g, 10.89 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.209 g, 0.181 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) for 2h. Mass: 329.2 (M ++ 1). Intermediate 119: 3- (3-fluor-4-isopropoxyphenyl) -N-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a brown solid (0.205 g, 19% ) using a procedure similar to that described for intermediate 13 from intermediate 12 (1.52 g, 5.45 mmol), intermediate 100 (1.00 g, 3.63 mmol), DMF (7 ml), ethanol (3 , 5 ml), water (3.5 ml), sodium carbonate (1.15 g, 10.89 mmol) and tetrakis (triphenylphosphino) palladium (0) (0.209 g, 0.181 mmol) in a microwave oven ( microwave power = 100W. temperature = 100 ° C) for 2h. Mass: 301.9 (M +). Intermediate 120: 4- (2-chloro-4-nitrophenyl) morpholine: The title compound was obtained as a yellow liquid (6.70 g, 53%) using a procedure similar to that described for intermediate 53 of 3,4-dichloro- nitrobenzene (10.00 g, 52.08 mmol) in ethyl acetate (83 ml) and triethylamine (7.99 ml) and morpholine (4.99 g, 57.29 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.25 (d, J = 2.6 Hz, 1H), 8.12 (dd, J = 8.5.2.6 Hz, 1H) , 7.05 (d, «7 = 8.9 Hz, 1H), 3.90 (t, J = 4.5 Hz, 1H), 3.22 (t,« 7 = 4.6 Hz, 1H) . Intermediate 121: 3-chloro-4-morpholinoaniline: To a solution of intermediate 120 (6.00 g, 24.72 mmol) in ethanol (60 ml) and water (30 ml), iron (6.89 g, 123, 60 mmol) and ammonium chloride (2.64 g, 49.44 mmol) were added and refluxed for 3 h. The reaction mixture was filtered through celite, washed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to generate the title compound obtained as a brown solid (5.50 g) which was used without purification in the next step. Intermediate 122: 4- (4-bromo-2-chlorophenyl) morpholine: The title compound was obtained as a brown liquid (5.20 g, 72%) using a procedure similar to that described for intermediate 51 from intermediate 121 (5 , 50 g, 25.85 mmol), 48% hydrobromic acid (64 ml), sodium nitrite (5.35 g, 77.57 mmol), water (73 ml) and copper (I) bromide (5.56 g, 38.78 mmol) which was used without purification in the next step. Intermediate 123: 4- (2-chloro-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) morpholine: The title compound was obtained as a colorless liquid (2 .00 g, 89%) using a procedure similar to that described for intermediate 12 from intermediate 122 (2.00 g, 7.23 mmol), potassium acetate (1.41 g, 14.46 mmol), bis ( pinacolate) diboro (2.01 g, 7.95 mmol), dioxane (15 ml) and [1,1-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.290 g, 0.360 mmol). 1 H-NMR (δ ppm, CDCh, 400 MHz): 7.80 (d, J = 1.4 Hz, 1H), 7.66 (dd, J = 8.0.1.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.89 (t, J = 4.4 Hz, 4H), 3.12 (t, J = 4.5 Hz, 4H), 1, 33 (s, 12H). Intermediate 124: 4-bromo-2-chloro-1-isopropoxybenzene: The title compound was obtained as a colorless liquid (5.60 g, 93%) using a procedure similar to that described for intermediate 47 of 4-bromo-2-chlorophenol (5.00 g, 24.10 mmol) in THF (50 ml), isopropanol (1.85 ml, 24.10 mmol), triphenylphosphmo (9.48 g, 36.51 mmol) and diisopropylazodicarboxylate (7.10 ml , 36.51 mmol) which was used as such in the next step. Intermediate 125: 2- (3-chloro-4-isopropoxyphenyl) -4,4,5,5-tetramethyl-1,2,2-dioxaborolane: The title compound was obtained as a yellow liquid (6.50 g, 99% ) using a procedure similar to that described for intermediate 12 from intermediate 124 (6.00 g, 24.04 mmol), potassium acetate (4.71 g, 48.04 mmol), bis (pinacolate) diboro (6, 71 g, 26.44 mmol) dioxane (95 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Ch (0.980 g, 12.02 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): δ 7.79 (d, J = 1.4 Hz, 1H), 7.63 (dd, J = 8.2.1.4 Hz, 1H) , 6.92 (d, J = 8.2 Hz, 1H), 4.64 (quintet, J = 6.1 Hz, 1H), 1.38 (d, J = 6.1 Hz, 6H), 1 , 25 (s, 12H). Intermediate 126: 6-bromo-2-methylbenzo [d] oxazole: À 2-amino-5-bromophenol (1.00 g, 5.32 mmol), acetic acid ((0.006 ml) and triethylortoacetate (1.75 ml, 9 , 58 mmol) were added and refluxed for 30 min. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate the title compound as an orange solid ((0.756 g, 65%). 'H-NMR (δ ppm, CDCh, 400 MHz): δ 7.64 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8. 4 Hz, 1H), 7.43 (dd, J = 8.4.1.7 Hz, 1H), 2.67 (s, 3H). Intermediate 127: 2-methyl-6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) benzo [d] oxazole: The title compound was obtained as an orange solid (0.965 g , 88%) using a procedure similar to that described for intermediate 12 from intermediate 126 (0.900 g, 4.24 mmol), potassium acetate (0.833 g, 8.48 mmol), bis (pinacolate) diboro (1.18 g, 4.66 mmol) dioxane (10 ml) and [1,1'-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2Ch (0.173 g, 0.212 mmol). 'H-NMR (δ ppm, CDCh, 400 MHz): δ 7.90 (s, 1H), 7.76 (dd, J = 7.8, 0.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 2.64 (s, 3H), 1.36 (s, 12H). Intermediate 128: 6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) isoindolin-1-one: The title compound was obtained as an off-white solid (0.850 g, 39% ) using a procedure similar to that described for intermediate 12 of 6-bromoisoindolin-l-one (1.00 g, 4.71 mmol for preparation, see J. Pharm. Science & Technol. 2010.2, 380-390. ), potassium acetate (1.60 g, 16.50 mmol), bis (pinacolate) diboro (1.30 g, 5.18 mmol) dioxane (18 ml) and [1,1 l'-Bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. CH2 Cl2 (0.190 g, 0.235 mmol). 'H-NMR (δ ppm, CDC13,400 MHz): δ 8.36 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7, 6 Hz, 1H), 6.55 (s, 1H), 4.46 (s, 2H), 1.35 (s, 12H). Intermediate 129: 5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) isoindolin-1-one: The title compound was obtained as an off-white solid (0.410 g, 84% ) using a procedure similar to that described for intermediate 12 of 5-bromoisoindolin-l-one (0.400 g, 1.88 mmol), potassium acetate (0.645 g, 6.58 mmol), bis (pinacolate) diboro (0.520 g, 2.07 mmol) dioxane (7 ml) and [1,1, r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.076 g, 0.094 mmol). 1H-NMR (δ ppm, CDC13. 400 MHz): δ 7.93 (m, 2H), 7.87 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 1H), 4.45 (s, 2H) , 1.36 (s, 12H). Intermediate 130: 1- (2-fluorine-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) ethanone: The title compound was obtained as a colorless liquid (1 , 50 g, 82%) using a procedure similar to that described for intermediate 12 of 1- (4-bromo-2-fluorophenyl) ethanone (1.50 g, 6.91 mmol), potassium acetate (1.35 g, 13.82 mmol), bis (pinacolate) diboro (1.92 g, 7.60 mmol) dioxane (30 ml) and [1,1'-Bis (diphenylphosphmo) ferrocene-dichloro palladium (II). CH2 Cl2 (0.282 g, 0.345 mmol). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.84 (t, J = 7.5 Hz, 1H), 7.62 (dd, J = 7.6.0.6 Hz, 1H), 7.55 (d, J = 11.0 Hz, 1H), 2.62 (d, J = 4.8 Hz, 3H), 1.35 (s, 12H). Intermediate 131: 3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine: The title compound was obtained as a pale brown solid (0.250 g, 20%) using a procedure similar to that described for intermediate 13 from intermediate 123 (1.87 g, 5.74 mmol), 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.00 g, 3 , 83 mmol), DMF (6.4 ml), ethanol (2.1 ml), water (1.4 ml), sodium carbonate (1.21 g, 11.49 mmol) and tetrakis (triphenylphosphmo) palladium ( 0) (0.220 g, 0.190 mmol) in a microwave oven (microwave power = 100W, temperature = 100 ° C) per hour. 1 H-NMR (δ ppm, DMSO-Dé, 400 MHz): 13.57 (s, 1H), 8.20 (s, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 8.2.1.9 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.79 (s, 2H), 3.77 (t , J = 4.3 Hz, 4H), 3.05 (t, J = 4.3 Hz, 4H). Intermediate 132: N- (3- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl) methanesulfonamide: The title compound was obtained as an off-white solid (1.00 g , 84%) using a procedure similar to that described for intermediate 12 of N- (3-bromophenyl) methanesulfonamide (1.00 g, 3.99 mmol), potassium acetate (0.78 g, 7.98 mmol), bis (pinacolate) diboro (1.11 g, 4.39 mmol) dioxane (10 ml) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (Il). CH2 Cl2 (0.162 g, 0.199 mmol). 'H-NMR (δ ppm, DMSO-DÔ, 400 MHz): 9.66 (s, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.41 (dd, J = 5 , 2.0.9 Hz, 1H), 7.35 (m, 2H), 2.94 (s, 3H), 1.28 (s, 12H). Intermediate 133: 2-ethyl-5-fluorine-3- (2-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.500 g, 47%) using a procedure similar to that described for intermediate 21 from intermediate 20 (1.00 g, 3.68 mmol), 2-fluorine phenylboronic acid (0.820 g, 5.90 mmol), dioxane (6 ml), potassium carbonate (1.50 g, 11 , 04 mmol), water (1.0 ml) and tetrakis (triphenylphosphino) palladium (0) (0.255 g, 0.220 mmol). Mass: 287.3 (M ++ 1). Intermediate 134: 2- (1-bromoethyl) -5-fluorine-3- (2-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.510 g, 78%) using a procedure similar to that described for intermediate 22 from intermediate 133 (0.500 g, 1.74 mmol), carbon tetrachloride (13 ml) N-bromosuccinimide (0.309 g, 1.74 mmol) and azobisisobutyronitrile (30 mg) that was used as for the next step. Intermediate 135: 5-fluorine-3- (2-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.210 g, 50%) using a similar procedure to that described for intermediate 23 starting from intermediate 134 (0.500 g, 1.36 mmol), DMSO (5 ml) and n-butanol (1 ml). Mass: 302.8 (M +). Intermediate 136: 5-fluorine-3- (3-fluorophenyl) -2-propyl-4H-chromen-4-one: The title compound was obtained as a pale yellow solid (2.60 g, 69%) using a similar procedure to that described for intermediate 21 from intermediate 89 (2.80 g, 9.89 mmol), phenylboronic 3-fluoracid (2.20 g, 15.82 mmol), dioxane (18 ml), potassium carbonate (4, 10 g, 29.67 mmol), water (2. 6 ml) and tetrakis (triphenylphosphino) palladium (0) (0.685 g, 0.593 mmol) which was used as such in the next step. Intermediate 137: 2- (1-bromopropyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (2.95 g, 89%) using a procedure similar to that described for intermediate 22 starting from intermediate 136 (2.60 g, 9.21 mmol), carbon tetrachloride (25 ml) N-bromosuccinimide (1.64 g, 9.21 mmol) and azobisisobutyronitrile (0.247 g) that was used as such in the next step. Intermediate 138: 2-fluorine-9-trityl-9H-purin-6-amine: To a solution of 2-fluorine-9H-purin-6-amine (0.50 g, 3.26 mmol) in DMF (3 ml ), pyridine (0.5 ml) followed by trityl chloride (1.00 g, 3.91 mmol). After stirring at room temperature for 12, the reaction mass was quenched with water, the precipitate formed was filtered, washed with water and dried in vacuo to generate the title compound as an almost white solid (1.20 g, 93%) which was used as such in the next step. Intermediate 139: N, N-Diboc-2-fluorine-9-trityl-9H-purin-6-amine: To a solution of intermediate 138 (1.10 g, 2.78 mmol) in THF (11 ml) cooled to 0 ° C, boc-anhydride (1.40 ml, 6.12 mmol) and 4-dimethylaminopyridine (0.034 g, 0.278 mmol) were added and stirred at room temperature for 15h. The reaction mass was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to generate the title compound as an almost white solid (1.60 g, 97%) which was used as such in the next step . Intermediate 140: tert-butyl 2-methoxy-9-trityl-9H-purin-6-ylcarbamate: To a solution of intermediate 139 (1.50 g, 2.51 mmol) in methanol (6 ml), potassium carbonate ( 0.34 g, 2.51 mmol) was added and heated to 90 ° C for 2h. The reaction mass was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate the title compound as an almost white solid (0.255 gg, 20%). 'H-NMR (δ ppm, DMSO-DÔ, 400 MHz): 10.00 (s, 1H), 7.89 (s, 1H), 7.89 (m, 9H), 7.19 (m, 6H ), 3.33 (s, 3H), 1.44 (s, 9H). Intermediate 141: (S) / (R) -l- (5-fluor-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl methanesulfonate: To a cooled solution of intermediate 23a (0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol), methanesulfonyl chloride (0.400 ml, 5.27 mmol) was added stirred at room temperature for 2h. The reaction mass was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated to generate the title compound as a brown solid (1.00 g, 100%) which was used as such in the next step Intermediate 142: (S ) / (R) -2- (1-azidoethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 141 (0.900 g, 2.36 mmol) in DMF (18 ml), sodium azide (0.306 g, 4.72 mmol) was added heated to 60 ° C. After 2h, the reaction mass was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate the title compound as a brown liquid (0.650 g, 84%) which was used as such in the next step. Intermediate 143: (S) / (R) - 2 2- (1-aminoethyl) -5-fluorine-3- (3-fluorophenyl) -4H-croinen 4-one: To a solution of intermediate 142 (0.600 g, 1.82 mmol) in THF (2.4 ml) and water (1.2 ml), triphenylphosphine (0.455 g, 1.73 mmol) was added stirred at room temperature for 14h. The reaction mass was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was column chromatographed with methanol: dichloromethane to generate the title compound as a brown liquid (0.300 g, 55%) which was used as such in the next step. Intermediate 144: 2-methoxy-6-methylbenzaldehyde oxime: À 2-methoxy-6-methylbenzaldehyde (11.0 g, 73.25 mmol) in triethylamine (132 ml), hydroxylamine hydrochloride (6.10 g, 69.49 mmol ) was added and heated to 80 ° C. After 3 hours, the reaction mass was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to generate the title compound as an almost white solid (7.50 g, 62%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.54 (s, 1H), 8.31 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 6, 84 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H), 2.46 (s, 3H). Intermediate 145: 2-methoxy-6-methylbenzonitrile: To intermediate 144 (7.50 g, 45.41 mmol) in dichloromethane (55 ml), N, N'-dicarbonyl diimidazole (8.09 g, 49.95 mmol) was added and stirred at room temperature for 15h. The reaction mass was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated to generate the title compound as a brown solid (5.0 g, 75%). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7.41 (t, J = 8.1 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.78 ( d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.50 (s, 3H). Intermediate 146: 1- (2-methoxy-6-methylphenyl) -2-phenylethanone: To intermediate 145 (5.0 g, 34.03 mmol) in THF (50 ml), benzene chloride Imagnésio (34 ml, 2M in THF, 68.02 mmol) was added at 0 ° C for 30 min. and heated to reflux for 15 h. The reaction mixture was cooled to room temperature, 2N HCl (200 ml) was added and refluxed again for 4h. The reaction mixture was cooled and extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was chromatographed on a column with ethyl acetate: petroleum ether to generate the title compound as a brown liquid (3.7 g, 45%). 1 H-NMR (δ ppm, CDCI3, 400 MHz): 7.30-7.18 (m, 6H), 6.76 (m, 2H), 4.07 (s, 2H), 3.83 (s , 3H), 2.02 (s, 3H). Intermediate 147: 1- (2-hydroxy-6-methylphenyl) -2-phenylethanone: Intermediate 146 (2.0 g, 8.31 mmol) in dichloromethane (20 ml) at -78 ° C, boron tribromide (2 , 84 ml, 1M in dichloromethane, 16.64 mmol) was added slowly and maintained for 4 h. The reaction mass was quenched at -78 ° C using 2N HCI (50 ml), extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate to generate the title compound as an almost white solid (1.20 g, 64%). 'H-NMR (δ ppm, CDCI3, 400 MHz): 11.18 (s, 1H), 7.37-7.27 (m, 4H), 7.19 (m, 2H), 6.84 (d , J = 8.3 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.27 (s, 2H), 2.62 (s, 3H). Intermediate 148: 2- (1- (benzyloxy) ethyl) -5-methyl-3-phenyl-4H-chromen-4-one: To intermediate 147 (0.400 g, 1.76 mmol) in dichloromethane (4 ml), acid R (+) - benzyloxypropionic (0.382 g, 2.12 mmol) and HATU (2.01 g, 5.30 mmol) were added followed by triethylamine (2.6 ml, 19.08 mmol). After 20h at room temperature, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate to generate the title compound as an almost white solid (0.080 g, 12%). 'H-NMR (δ ppm, CDCh, 400 MHz): 7.55 (t, J = 8.1 Hz, HI), 7.43-7.13 (m, 1211), 4.47 (m, 2H ), 4.30 (d, J = 11.8 Hz, 1H), 2.84 (s, 3H), 21.54 (d, J = 6.5 Hz, 3H). Intermediate 149: 2- (1-hydroxyethyl) -5-methyl-3-phenyl-4H-chromen-4-one: To intermediate 148 (0.140 g, 0.377 mmol) in dichloromethane (2.0 ml) at -78 ° C , boron tribromide (0.12 ml, 1M in dichloromethane, 0.755 mmol) was added slowly and maintained for 4 hours. The reaction mass was quenched at -78 ° C using 2N HCI (50 ml), extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was column chromatographed with ethyl acetate: petroleum ether to generate to generate the title compound as a pale yellow liquid (0.100 g, 95%) which was used as such in the next step. Intermediate 150: 3-bromo-5-fluoro-2- (1-hydroxyethyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (1.90 g, 61%) using a similar procedure to that described for intermediate 23 from intermediate 28 (3.90 g, 11.14 mmol), DMSO (40 ml) and n-butanol (3.0 ml) which was used as such in the next step. Intermediate 151: 2-acetyl-3-bromo-5-fluoro-4H-chromen-4-one: The title compound was obtained as a pale yellow solid (0.80 g, 80%) using a procedure similar to that described for intermediate 24 from intermediate 150 (1.00 g, 3.48 mmol), DMSO (0.98 ml, 13.92 mmol), dichloromethane (104 ml), oxalyl chloride (0.59 ml, 6.96 mmol ) and triethylamine (2 ml). 'H-NMR (δ ppm, CDCI3, 400 MHz): 7.73 (dt, J = 8.4.5.4 Hz, 1H), 7.36 (td, J = 8.6.0.9 Hz , 1H), 7.18 (m, 1H), 2.70 (s, 3H). Intermediate 152: 2-acetyl-5-fluoro-3-o-tolyl-4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.165 g, 32%) using a procedure similar to that described for intermediate 21 from intermediate 151 (0.500 g, 1.75 mmol), 2-methyl phenylboronic acid (0.382 g, 2.80 mmol), dioxane (11 ml), potassium acetate (0.573 g, 3.33 mmol) and tetrakis (triphenylphosphmo) palladium (0) (0.162 g, 0.140 mmol) which was used as such in the next step. Intermediate 153: (R) / (S) - 5-fluorine-2- (1-hydroxyethyl) -3-o-tolyl-4H-chromen-4-one: To a solution of intermediate 152 (0.155 g, 0.523 mmol) in DMF (2 ml) under nitrogen purging, formic acid: triethylamine 5: 2 azeotrope (0.5 ml) was added followed by [(S, S) tethTsDpenRuCl] (1 mg). The reaction mixture was heated at 80 ° C for 1.5h in continuous nitrogen purging. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as an off-white solid (0.090 g, 66%) which was used as such in the next step. EXAMPLES Example 1 2- (6-Amino-9H-purin-9-yl) methyl) -3- (3-fluorophenyl) -5-methoxy-4H-chromen-4-one 2- (6-Amino-9H-purin -9-yl) methyl) -3- (3-fluorophenyl) -5-methoxy-4H-chromen-4-one: To a solution of adenine (0.030 g, 0.222 mmol) in DMF (2 ml), potassium carbonate (0.061 g, 0.444 mmol) was added and stirred at RT for 10 min. To this intermediate mixture 10 (0.120 g, 0.333 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as an off-white solid (0.028 g, 30%). 'H-NMR (δ ppm, DMSO-C, 400 MHz): 8.09 (s, 1H), 8.07 (s, 1H), 7.64 (t, J = 8'4 Hz, 1H), 7.46 (dd, J = 15.0, 6.7 Hz, 1H), 7.22-7.20 (m, 5H), 6.98 (d, J = 8.3 Hz, 1H), 6 , 91 (d, J = 8.5 Hz, 1H), 5.26 (s, 2H), 3.81 (s, 3H). 2 - (((4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) πietyl) -3- (3-fluorophenyl) -5-niethoxy -4H-cromcn-4-one 2 - (((4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) - 3- ( 3-fluorophenyl) -5-inetoxy-4H-chromen-4-one: To a solution of Intermediate 13 (0.060 g, 0.220 mmol) in DMF (2 ml), potassium carbonate (0.060 g, 0.440 mmol) was added and stirred at RT for 10 min. To this intermediate mixture 9 (0.120 g, 0.330 mmoles) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the compound as a pale yellow solid (0.35g, 28%). MP: 145-148 ° C. 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 8.37 (s, 1H), 7.51 (t, J = 8.3 Hz, 1H), 7.42-7.29 (m , 3H), 7.18-7.09 (m, 3H), 7.00 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6 , 78 (d, J = 8.3 Hz, 1H), 5.53 (s, 2H), 5.47 (s, 2H), 4.66 (quintet, J = 6.0 Hz, 1H), 3 , 95 (s, 3H>, 1.41 (d, J = 5.9 Hz, 6H). Example 3 2 - (((4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-dJpirimidin-1-yl) methyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 2 - (((4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) methyl) - 5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of Intermediate 13 (0.100 g, 0.367 mmol) in DMF (2 ml), potassium carbonate (0.101 g, 0.734 mmol) was added and stirred at RT for 10 min. To this intermediate mixture 17 (0.173 g, 0.550 mmoles) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as a pale brown solid (0.011 g, 5%). MP: 156-159 ° C. 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 8.20 (s, 1H), 8.79 (dd, J = 13.9.8.2 Hz, 1H), 7.63-7 , 53 (m, 4H), 7.40-7.22 (m, 5H), 7.15 (m, 2H), 5.47 (s, 2H), 4.71 (quintet, J = 5.9 Hz, 1H), 1.32 (d, J = 5.9 Hz, 6H). Example 4 2 - ((4-amino-3- (3-fluoro-5-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) - 5-fluoro-3- (3- fluorfenyl) -4H-chromen-4-one 2 - (((4-amino-3- (3-fluoro-5-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5 - fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of 3- (3-fluorine-5-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.150 g, 0.578 mmol) in DMF (2 ml), potassium carbonate (0.159 g, 1.15 mmol) was added and stirred at RT for 10 min. To this intermediate mixture 17 (0.564 g, 1.78 mmoles) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as a pale brown solid (0.200 g, 65%) which is used as such for the next step. Example 5 2 - ((4-amino-3- (3-fluoro-5-hydroxyphenyl) -1H-pyrazolo [3,4-d | pyriniidin-1-yl) methyl) - 5-fluoro-3- (3- fluorfenyl) -4H-chromen-4-one 2 - (((4-amino-3- (3-fluoro-5-hydroxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5 - fluorine-3- (3-fluorophenyl) -4H-chromon-4-one: To a solution example 4 (0.200 g, 0.377 mmol) in dichloromethane (2 ml) at 0 ° C, boron tribromide (1M in dichloromethane, 2ml) was added and heated to RT and stirred for 12h. The reaction mixture was quenched by the addition of aqueous HCI solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to generate the title compound as a pale brown solid (0.030 g, 15%). MP: 136-138 ° C. 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 10.17 (s, 1H), 8.22 (s, 1H), 7.78 (dt, J = 14.2.8.3 Hz , 1H), 7.63 (dd, J = 12.0.7.3 Hz, 1H), 7.56 (m, 1H), 7.38-7.23 (m, 3H), 7.14- 7.07 (m, 3H), 6.85 (s, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.65 (d, J = 10.8 Hz, 1H), 5.50 (s, 2H). Example 6 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of 13 (0.120 g, 0.440 mmol) in DMF (2 ml), potassium carbonate (0.121 g, 0.881 mmol) was added and stirred at RT for 10 min. To this intermediate mixture 22 (0.217 g, 0.661 mmoles) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as an off-white solid (0.120 g, 48%). MP: 228-230 ° C. * H- NMR (δ ppm, CDCh, 400 MHz): 8.23 (s, 1H), 7.62 (dt, J = 8.4.5.9 Hz, 1H), 7.44 (d, J = 11.5.1.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (m, 2H), 7.14 (t, J = 8.4 Hz , 1H), 7.06 (m, 3H), 6.92 (d, J = 9.5 Hz, 1H), 6.07 (q. J = 7.1 Hz, 1H), 5.52 (s, 2H), 4.65 (quintet, J = 6.1 Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H) , 1.42 (d, J = 6.1 Hz, 6H). Examples 7 and 8 (+) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one and (-) - 2- (1- (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1H-pyrazole [3 , 4-d] pyriniidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one The two enantiomerically pure isomers were separated by preparative SEC conditions of example 6 (0.300 g ) in a CHIRALPAK AS-H column (250 x 4.6 mm; 5pm) using methanol: CO2 (30: 70) as the mobile phase at a flow rate of 3.0 ml / min. Example 7: Off-white solid (0.145 g). and. and. 98.16%. Rt: 2.06 min. [CC] 25D 177.47 (c = 1, CHCl3). MP: 217-220 ° C. Mass: 571.2 (M +). Example 8: Off-white solid (0.136 g). and. and. 100%. Rt: 2.73 min. [a] 2'o -173.56 (c = 1, CHCl3). MP: 218-221 ° C. Mass: 571.8 (M +). Example 9 2- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 27 (0.100 g, 0.183 mmol) in 1,2-dimethoxyethane (2 ml), and water (1 ml), 3-methyl-6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-indazole (0.099 g, 0.275 mmol) and sodium carbonate (0.058 g, 0.549 mmol) were added and the system is degassed for 30 min. Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (0.030 g, 0.036 mmol) was added under a nitrogen atmosphere and degassed for 30 min and kept in microwave irradiation (microwave power = 100W, temperature = 100 ° C) for 1h. . The reaction mixture was filtered through celite, washed with ethyl acetate, dried over sodium sulfate and concentrated. The residue was dissolved in dichloromethane (2 ml) and triflutoacetic acid (2 ml) was added and stirred for 1h. The reaction mixture neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to generate the title compound as a brown solid (0.033 g, 33% yield). MP: 156-159 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.21 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.73 (s, lH), 7, 60 (dt, J = 8.4.5.5 Hz, 1H), 7.45 (dd, J = 8.2.1.1 Hz, 1H), 7.29 (m, 2H), 7.06 -6.98 (m, 4H), 6.10 (q, J = 7.2 Hz, 1H), 5.89 (m, 1H), 2.64 (s, 3H), 1.96 (d, J = 7.2 Hz, 3H). Examples 9a and 9b (+) - 2- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one and (-) - 2- (1- (4-amino-3- (3-methyl-1H-indazole-6- il) -lH-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one The two enantiomerically pure isomers were separated by conditions SEC preparations of example 9 (0.300 g) on a CHIRALPAK AD-H column (250 x 4.6 mm; 5pm) using methanol: CO2 (30: 70) as the mobile phase at a flow rate of 3.0 ml / min. Example 9a: Brown solid (0.097 g). and. and. 98.12%. Rt: 4.54 min. [a] 25 ° 161.30 (c = 1, CHCl3). MP: 190-192 ° C. Mass: 549.8 (M +). Example 9b: Brown solid (0.098 g). and. and. 96.1%. Rt: 5.92 min. [CX] 25D -209.90 (c = 1, CHC13). MP: 193-195 ° C. Mass: 549.2 (M +). Example 10 2- (l- (4-amino-3- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro- 3- ( 3-fluorphenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (1 H-pyrazol-4-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - il) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.016 g, 18%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml), 1-Boc-pyrazol-4-boronic acid (0.058 g, 0.275 mmol), sodium carbonate (0.058 g, 0.549 mmol) and bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.030 g, 0.036 mmol) MP: 165-168 ° C. 'H-NMR (δ ppm, CDCl3, 400 MHz): 8.24 (s, 1H), 7.94 (s, 2H), 7.59 (m, 1H), 7.28 (m, 2H), 7.04 -6.87 (m, 4H), 6.04 (q, J = 7.0 Hz, 1H), 5.49 (s, 2H), 1.99 (d, J = 7.1 Hz , 3H). Example 11 2- (l- (6-amino-9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (6- amino-9H-purin-9-i!) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale green solid (0.047 g, 26%) using a procedure that is similar to that described for example 6 of adenine (0.116 g, 0.864 mmol), DMF (5 ml), potassium carbonate (0.140 g, 1.08 mmol) and intermediate 22 (0.150 g, 0.432 mmol) MP: 222-224 ° C. 'H-NMR (δ ppm, DMSO-D6) 400 MHz): 8.44 (s, 1H), 8.03 (s, 1H), 7.82 (dt, J = 8.4.5.7 Hz , 1H), 7.51 (m, 2H), 7.27-7.16 (m, 6H), 5.64 (q, J = 7.0 Hz, 1H), 1.88 (d, J = 7.2 Hz, 3H). Example 12 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 4-fluorophenyl) -4H-chromn-4-one 22- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.085 g, 38%) using a procedure that is similar to that described for the example 6 from intermediate 13 (0.150 g, 0.522 mmol), DMF (2 ml), potassium carbonate (0.152 g, 1.10 mmol) and intermediate 31 (0.272 g, 0.0.744 mmol) MP: 218-221 ° Ç. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.24 (s, 1H), 7.61 (dt, J = 8.5.5.5 Hz, 1H), 7.44 (dd, J = 11.5.2.0 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.23 (m, 3H), 7.15 (t, J = 8.4 Hz , 1H), 7.08 (m, 3H), 6.06 (q, J = 7.1 Hz, 1H), 5.79 (s, 2H), 4.67 (quintet, J = 6.1 Hz , 1H), 1.99 (d,. 7 = 7.1 Hz, 3H), 1.42 (d,. 7 = 7.1 Hz, 6H). Example 13 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) - 5 -fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.060 g, 25%) using a procedure that is similar to that described for example 6 from intermediate 13 (0.150 g, 0.522 mmol), DMF (2 ml), potassium carbonate (0.152 g, 1.10 mmol) and intermediate 33 (0.291 g, 0.838 mmol) MP: 226-229 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.22 (s, 1H), 7.60 (dt, J = 8.5.5.5 Hz, 1H), 7.44 (dd, J = 11.5.2.0 Hz, 1H), 7.36 (m, 4H), 7.23 (m, 3H), 7.14 (t, J = 8.4 Hz, 1H), 7.04 (t, J = 9.7 Hz, 1H), 6.06 (q, J = 7.2 Hz, 1H). 5.52 (s, 2H), 4.64 (quintet, J = 6. 1 Hz. 1H). 1. 98 (d. . 7 = 7. 1 Hz, 3H), 1.42 (d, J = 6.0 Hz, 6H). Example 14 2- (l- (4-amino-3- (benzofuran-2-yl) -1H-pyrazolo | 3,4-d | pyrimidin-1-yl) ethyl) -5-fluorine-3- (3- fluorfenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (benzofuran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as off-white solid (0.026 g, 26%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml), benzofuran-2-boronic acid (0.045 g, 0.275 mmol), sodium carbonate (0.058 g, 0.549 mmol) and bis (diphenylphosphmo) ferrocene-dichloro palladium (II). CH2 Cl2 (0.062 g, 0.073 mmol) MP: 238-241 ° C. 1 H-NMR (δ ppm, CDCh, 400 MHz): 8.27 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.62-7.57 (m, 2H ), 7.41 (s, 1H), 7.39 (m, 3H), 7.28 (m, 1H), 7.07-6.99 (m, 4H), 6.07 (q, J = 8.1 Hz, 1H), 2.05 (d, J = 8.3 Hz, 3H). Example 15 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (9H-purin-6- ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 36 (0.20 g, 0.663 mmol), tert-butanol (1.5 ml) N, N-diisopropylethylamine (0.23 ml, 1.32 mmol) and 6-chloropurine (0.102 g, 0.663 mmol) were added and heated to reflux for 48h. The reaction mixture was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with methanol: ethyl acetate to generate the title compound as a brown solid (0.080 g, 30% yield). MP: 195-198 ° C. 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 12.96 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.21-6.94 (m, 5H), 6.71 (m, 2H), 5.64 (m, 1H), 1.52 (br s, 3H). Example 16 2- (1- (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) - 4H-chromen-4-one 22- (l - (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: O title compound was obtained as a brown solid (0.030 g, 25%) using a procedure that is similar to that described for example 6 of 1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.077 g, 0.576 mmol), DMF (1 ml), potassium carbonate (0.099 g, 0.720 mmol) and intermediate 22 (0.100 g, 0.288 mmol). MP: 267-269 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.25 (s, 1H), 7.92 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H ), 7.32 (m, 2H), 7.06 (m, 3H), 6.92 (d, J = 9.7 Hz, 1H), 6.02 (q, J = 7.1 Hz, 1H ), 5.41 (s, 2H), 1.96 (d, J = 7.1 Hz, 3H). Examples 16a and 16b (+) - 22- (1- (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H -cromen-4-one and (-) - 2- (1- (4-amino-1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl ) -4H-chromen-4-one The two enantiomerically pure isomers were separated by preparative SEC conditions of example 16 (0.300 g) in a CHIRALPAK AD-II column (250 x 4.6 mm; 5pm) using methanol: CO2 (30 : 70) as the mobile phase at a flow rate of 3.0 ml / min. Example 16a: Off-white solid (0.145 g). and. and. 98.07%. Rt: 2.49 min. [OC] 25D 90.52 (c = 1, CHC13). MP: 197-200 ° C. Mass: 419.8 (M +). Example 16b: Off-white solid (0.150 g). and. and. 98.8%. Rt: 3.56 min. [OC] 25D - 73.03 (c = 1, CHC13). MP: 198-201 ° C. Mass: 419.8 (M +). Example 17 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazole | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d ] pyrimidin-1 - yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.042 g, 27%) using a procedure that is similar to that described for example 6 from intermediate 39 (0.081 g, 0.273 mmol), DMF (2 ml), potassium carbonate (0.075 g, 0.546 mmol) and intermediate 22 (0.100 g, 0.0.273 mmol) MP : 230-233 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.26 (s, 1H), 7.62 (dt, J = 8.4.5.4 Hz, 1H), 7.56 (dd, J = 10.3.1.3 Hz, 1H), 7.47 (m, 2H), 7.32 (d, J = 6.5 Hz, 1H), 7.27 (m, 1H), 7.06 (m, 3H), 6.91 (d, J = 9.1 Hz, 1H), 6.81 (t, J = 72.9 Hz, 1H), 6.63 (s, 2H), 6.07 (q, J = 7.2 Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H). Example 18 2- (l- (4-anino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d | pyrimidin-l-yl) ethyl) -5-fluorine-3- ( 1H-pyrazol-4-yl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) ethyl) - 5-fluoro-3- (1H-pyrazol-4-yl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.020 g, 20%) using a procedure that is similar to that described for example 9 from intermediate 29 (0.100 g, 0.188 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml), l-Boc-pyrazol-4-boronic acid (0.098 g , 0.282 mmol), sodium carbonate (0.059 g, 0.565 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (H). CH2 Cl2 (0.030 g, 0.037 mmol) MP: 181-184 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.34 (s, 1H), 7.93 (s, 2H), 7.57 (dt, J = 8.4.5.5 Hz, 1H ), 7.47 (dd, J = 11.5.2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.24 (m, 1H), 7.15 (t, J = 8.4 Hz, 1H), 7.04 (dd, J = 10.2.8.9 Hz, 1H), 6.36 (q, J = 7.1 Hz, 1H), 5 , 51 (s, 2H), 4.65 (q, J = 6.0 Hz, 1H), 2.03 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6, 0 Hz, 6H). Example 19 2- (l- (4-amino-3- (3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1- (4-amino-3- (3-fluorine-4- (tetrahydro-2H-pyran-4 -yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as brown solid (0.022 g, 22%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml) , intermediate 41 (0.070 g, 0.276 mmol), sodium carbonate (0.038 g, 0.366 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.030 g, 0.036 mmol). MP: 234-237 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.24 (s, 1H), 7.62 (dt, J = 8.4.5.5 Hz, 1H), 7.46 (dd, J = 11.4.1.9 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.32 (m, 2H), 7.17 (t, J = 8.3 Hz , 1H), 7.06-6.96 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 6.08 (q, J = 7.0 Hz, 1H), 5 , 44 (s, 2H), 4.58 (quintet, J = 3.9 Hz, 1H), 4.05 (m, 2H), 3.62 (m, 2H), 2.09 (m, 2H) , 1.99 (d, J = 7.1 Hz, 3H), 1.91 (m, 2H). Example 20 2- (l- (4-amino-3- (3-isopropyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-d | pyrimidin-l-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (3-isopropyl-1 H-indazol-6-yl) -1 H-pyrazole [3, 4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.026 g, 13%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxytan (2 ml), water (1 ml), intermediate 46 (0.140 g, 0.276 mmol), carbonate sodium (0.038 g, 0.366 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.030 g, 0.036 mmol). MP: 249-252 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.25 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7, 61 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (dd, J = 8.2.1.2 Hz, 1H), 7.30 (m, 2H), 7.06 -6.95 (m, 3H), 6.92 (d, J = 8.0 Hz, 1H), 6.10 (q, J = 7.1 Hz, 1H), 5.47 (s, 2H) , 3.48 (q, J = 7.1 Hz, 1H), 2.02 (d, J = 7.1 Hz, 3H), 1.50 (d, J = 7.1 Hz, 6H). Example 21 2- (l- (4-amino-3- (3-fluoro-4- (pipcridin-4-yloxy) phenyl) -1H-pyrazolo (3,4-d | pyrimidin-l-yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluorine-4- (pipcridin-4-yloxy) phenyl) -lH- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.030 g, 13 %) using a procedure that is similar to that described for example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml), intermediate 48 (0.150 g, 0.276 mmol), sodium carbonate (0.038 g, 0.366 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.030 g, 0.036 mmol). MP: 280-283 ° C. 'H-NMR (δ ppm, DMSO-D6, 400 MHz): 8.06 (s, 1H), 7.83 (dt, J = 8.4.5.7 Hz, 1H), 7.49 (d , J = 8.5 Hz, 1H), 7.41 (dd, J = 12.6.1.5 Hz, 1H), 7.34 (m, 4H), 7.07 (dt, J = 8, 9.2.6 Hz, 1H), 6.92 (m, 2H), 5.96 (q, J = 7.0 Hz, 1H), 4.50 (m, 1H), 3.40 (m, 1H), 2.99 (m, 2H), 2.62 (m, 2H), 1.97 (m, 2H), 1.87 (d, J = 7.0 Hz, 3H), 1.54 ( m, 2H). Example 22 2- (l- (4-amino-3- (3-fluoro-4- (2-hydroxyethylamino) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-l-yl) ethyl) -5- fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluorine-4- (2-hydroxyethylamino) phenyl) -lH-pyrazole [3, 4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.018 g, 9%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 52 (0.167 g, 0.411 mmol) , sodium carbonate (0.058 g, 0.549 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.045 g, 0.054 mmol). MP: 154-157 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.20 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.34-7.28 (m, 4H), 7.06-6.96 (m, 3H), 6.91 (d, J = 9.0 Hz, 1H), 6.87 (t, J = 8.3 Hz, 1H) , 6.06 (q, J = 7.1 Hz, 1H), 5.62 (s, 2H), 4.5l (s, 1H), 3.92 (t, J = 5.1 Hz, 2H) , 3.42 (t, J = 5.2 Hz, 2H), 2.09 (s, 1H), 1.98 (d, J = 7.1 Hz, 3H). Example 23 2- (l- (4-amino-3- (3-fluoro-4- (isopropylamino) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor- 3- (3-fluorophene!) - 4H-chromen-4-one 2- (1- (4-amino-3- (3-fluoro-4- (isopropylamino) phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.065 g, 25%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml), water (1 ml), intermediate 56 (0.192 g, 0.686 mmol), sodium carbonate ( 0.097 g, 0.915 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.074 g, 0.091 mmol). MP: 224-226 ° C. * H- NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (s, 1H), 7.83 (dt, J = 8.4.5.6 Hz, 1H), 7.49 (d , J = 8.6 Hz, 1H), 7.28-7.21 (m, 4H), 7.06 (dt, J = 8.4.1.8 Hz, 1H), 6.91-6, 82 (m, 3H), 5.95 (q, J = 6.7 Hz, 1H), 5.37 (d, J = 6.6 Hz, 1H), 3.72 (m, 1H), 1, 86 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 6.2 Hz, 6H). Example 24 2- (l- (4-amino-3- (4- (dimethylamino) -3-fluorophenyl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-fluorine-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (1- (4-amino-3- (4- (dimethylamino) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin -l- yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.070 g, 28%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml), water (1 ml), intermediate 60 (0.182 g, 0.686 mmol), sodium carbonate (0.097 g, 0.915 mmol) and bis (diphenylphosphino) phacosocene] dichloro palladium (II). CH2 Cl2 (0.074 g, 0.091 mmol). MP: 252-254 ° C. 'H-NMR NMR (δ ppm, DMSO-d6, 400 MHz): 8.06 (s, 1H), 7.83 (dt, J = 8.5.5.7 Hz, 1H), 7.49 ( d, J = 8.7 Hz, 1H), 7.32-7.24 (m, 4H), 7.09 (m, 2H), 6.88 (m, 2H), 5.95 (q, J = 7.0 Hz, 1H), 2.85 (s, 6H), 1.87 (d, J = 7.0 Hz, 3H). Example 25 2- (1- (4-amino-3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo | 3,4-d | pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (3-fluoro-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl ) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.055 g, 33%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 61 (0.127 g, 0.411 mmol), sodium carbonate (0.058 g, 0.549 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.045 g, 0.054 mmol). MP: 270-272 ° C. 'H-NMR NMR (δ ppm, CDC13, 400 MHz): 8.24 (s, 1H), 7.59 (dt, J = 8.4.5.4 Hz, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 7.09-6.86 (m, 5H), 6.06 (q, J = 7.1 Hz, 1H), 5.43 (s, 2H), 3.91 (t, J = 4.6 Hz, 4H), 3.48 (t, J = 4.7 Hz, 4H), 1.99 (d, J = 7.1 Hz, 3H). Example 26 2- (l- (4-amino-3- (2-methyl-1H-benzo [d] imidazol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (2-methyl-1H-benzo [d] imidazol-5-yl) - 1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.032 g, 13%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml), water (1 ml), tert-butyl 2 -methyl-6- (4. 4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate (0.246 g, 0.686 mmol), sodium carbonate (0.097 g, 0.915 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.074 g, 0.091 mmol). MP: 236-238 ° C. 'H-NMR NMR (δ ppm, CDCl3, 400 MHz): 8.25 (s, 1H), 7.81 (br s, 1H), 7.66 (m, 1H), 7.62 (dt, J = 8.4.5.4 Hz, 1H), 7.52 (dd, J = 8.2.1.6 Hz, 1H), 7.30 (m, 2H), 7.06-6.95 ( m, 3H), 6.92 (d, J = 9.3 Hz, 1H), 6.10 (q, J = 6.9 Hz, 1H), 5.71 (s, 2H), 2.67 ( s, 3H), 2.01 (d, J = 7.2 Hz, 3H). Example 27 2- (1- (4-amino-3- (3-fluor-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl ) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluorine-4- (4-methylpiperazin-l-yl) phenyl ) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.080 g, 20%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.300 g, 0.549 mmol), 1,2-dimethoxytan (5 ml), water (2.5 ml), intermediate 63 (0.260 g, 0.604 mmol), sodium carbonate (0.116 g, 1.09 mmol) and tetrakistriphenylphosphine palladium (O) (0.032 g, 0.027 mmol). MP: 246-249 ° C. 'H-NMR NMR (δ ppm, CDC13, 400 MHz): 8.23 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.38 (m, 2H), 7.29 (m, 2H), 7.08-6.96 (m, 4H), 6.91 (d, J = 9.2 Hz, IH), 6.07 (q, J = 7 , 2 Hz, 1H), 5.51 (s, 2H), 3.22 (t, J = 4.6 Hz, 4H), 2.67 (t, J = 4.6 Hz, 4H), 2, 37 (s, 3H), 1.98 (d, J = 7.2 Hz, 3H). Example 28 2- (l- (4- (dimethylamino) -1H-pyrazolo [3,4-dJpirimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorphenyl) -4H-chromen-4-one 2- (l- (4- (dimethylamino) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one : The title compound was obtained as a pale brown solid (0.040 g, 18%) using a procedure that is similar to that described for example 6 of N, N-dimethyl-1H-pyrazolo [3,4-d] pyrimidin-4- amine (0.080 g, 0.49 mmol for preparation, see J. Amer. Chem. Soc. 1956, 784-790), DMF (10 ml), cesium carbonate (0.319 g, 0.546 mmol) and intermediate 22 (0.179 g, 0.0490 mmol) MP: 200-202 ° C. 'H-NMR NMR (δ ppm, CDCl3, 400 MHz): 8.20 (s, 1H), 7.95 (s, 1H), 7.60 (dt, J = 8.4.5.5 Hz, 1H), 7.31 (m, 2H), 7.05 (m, 3H), 6.86 (d, J = 9.2 Hz, 1H), 6.02 (q, J = 7.1 Hz, 1H), 3.36 (s, 6H), 1.93 (d, J = 7.1 Hz, 3H). Example 29 2- (l- (4-amino-1H-pyrazolo [3,4-d | pyrimidin-l-yl) ethyl) -5-fluor-3-phenyl-4H- 2- (l- (4-amino -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as a pale green solid (0.030 g, 25 %) using a procedure that is similar to that described for example 6 from 1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.061 g, 0.455 mmol), DMF (1 ml), cesium carbonate (0.148 g , 0.455 mmol) and intermediate 33 (0.100 g, 0.0303 mmol). MP: 223-226 ° C. 'H-NMR NMR (δ ppm, CDCh, 400 MHz): 8.23 (s, 1H), 7.92 (s, 1H), 7.57 (dt, J = 8.4.5.4 Hz, 1H), 7.34 (m, 3H), 7.23 (s, 1H), 7.19 (m, 2H), 7.04 (dt, J = 8.2.0.9 Hz, 1H), 6.01 (q, J = 7.1 Hz, 1H), 5.40 (s, 2H), 1.95 (d, J = 7.1 Hz, 3H). Example 30 2- (1- (4-amino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (4-fluorophenyl) - 4H-chromen-4-one 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H- chromen-4-one: The title compound was obtained as a pale green solid (0.040 g, 34%) using a procedure that is similar to that described for example 6 from 1H-pyrazolo [3,4-d] pyrimidin-4-amine (0.058 g, 0.432 mmol ), DMF (1 ml), cesium carbonate (0.140 g, 0.432 mmol) and intermediate 31 (0.100 g, 0.0.288 mmol). MP: 242-245 ° C. * H- NMR NMR (δ ppm, CDC13, 400 MHz): 8.26 (s, 1H), 7.92 (s, 1H), 7.60 (dt, J = 8.4.5.4 Hz, 1H), 7.25 (m, 3H), 7.07-7.00 (m, 3H), 6.01 (q, J = 7.2 Hz, 1H), 5.45 (s, 2H), 1.96 (d, J = 7.1 Hz, 3H). Example 31 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3 - (4-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.053 g, 33%) using a procedure that is similar to described for example 6 from intermediate 39 (0.081 g, 0.273 mmol), DMF (2 ml), potassium carbonate (0.075 g, 0.546 mmol) and intermediate 31 (0.100 g, 0.0.273 mmol) MP: 233- 235 ° C. 'H-NMR (δ ppm, CDClj, 400 MHz): 8.28 (s, 1H), 7.61-7.55 (m, 2H), 7.47 (m, 2H), 7.25 (m , 3H), 7.08 (m, 3H), 6.82 (t, J = 72.9 Hz, 1H), 6.01 (q, J = 7.1 Hz, 1H), 5.42 (s , 2H), 1.99 (d, J = 7.2 Hz, 3H). Example 32 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo | 3,4-d | pyrimidin-1-yl) ethyl) -5-fluorine-3 -phenyl-4H-chromen-4-one 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl ) ethyl) -5-fluorine-3-phenyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.021 g, 33%) using a procedure that is similar to that described for example 6 from intermediate 39 (0.090 g, 0.303 mmol), DMF (2 ml), potassium carbonate (0.084 g, 0.607 mmol) and intermediate 33 (0.100 g, 0.0303 mmol) MP: 247-250 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.22 (s, 1H), 7.69-7.20 (m, 10H), 7.05 (dd, J = 9.5.8, 5 Hz, 1H), 6.81 (t, J = 72.9 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 5.43 (s, 2H), 1.99 (d, J = 7.1 Hz, 3H). Example 33 2- (l- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen -4-one 2- (1 - (4-amino-3-methyl-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) - 4H-chromen-4-one: The title compound was obtained as off-white solid (0.025 g, 21%) using a procedure that is similar to that described for example 6 from 3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine (0.043 g, 0.288 mmol for preparation, see J. Org. Chem. 1956, 21, 1240-1256), DMF (2 ml), potassium carbonate (0.079 g, 0.576 mmol) and intermediate 22 (0.100 g, 0.0.288 mmol). MP: 240-242 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.16 (s, 1H), 7.59 (dt, J = 8.4.3.4 Hz, 1H), 7.29 (m, 2H), 7.06 - 6.84 (m, 4H), 5.94 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 2.59 (s, 3H), 1.92 (d, J = 7.1 Hz, 3H). Example 34 2- (l- (4-amino-3-ethyl-1H-pyrazolo | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen -4-one 2- (l- (4-amino-3-ethyl-1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor-3- (3-fluorophenyl) - 4H -cromen-4-one: The title compound was obtained as off-white solid (0.038 g, 30%) using a procedure that is similar to that described for example 6 from intermediate 66 (0.048 g, 0.288 mmol), DMF ( 2 ml), potassium carbonate (0.079 g, 0.576 mmol) and intermediate 22 (0.100 g, 0.0.288 mmol) MP: 196-198 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.18 (s, 1H), 7.60 (dt, J = 8.4.3.0 Hz, 1H), 7.29 (m, 2H ), 7.05 - 6.78 (m, 4H), 5.94 (q, J = 7.2 Hz, 1H), 5.31 (s, 2H), 2.95 (q, J = 6, 6 Hz, 2H), 1.93 (d, J = 7.2 Hz, 3H), 1.40 (d, J = 76 Hz, 3H). Example 35 2- (l- (4-amino-3-isopropyl-1H-pyrazolo (3,4-d] pyrimidin-l-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen -4-one 2- (l- (4-amino-3-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor-3- (3-fluorine phenyl) - 4H-chromen-4-one: The title compound was obtained as an off-white solid (0.035 g, 18%) using a procedure that is similar to that described for example 6 of 3-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine (0.079 g, 0.432 mmol for preparation, see J. Amer. Chem. Soc, 2002,124, 12118), DMF (3 ml), potassium carbonate (0,119 g, 0.864 mmol) and intermediate 22 (0.150 g, 0.0.432 mmol) MP: 212-214 ° C. 1 H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.19 (s, 1H), 7.59 (dt, J = 8.5.5.4 Hz, 1H), 7.32 (m, 2H), 7.03-6.92 (m, 4H), 5.93 (q, J = 7.5 Hz, 1H), 5.34 (s, 2H), 3.20 (m, 1H), 1.93 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H). Example 36 2- (l- (4-amino-3- (benzo | b] thiophene-2-yl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (benzo [bJthiophene-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -il) ethyl) -5-fluorine-3- (3-tluorfenyl) -4H-cromcin-4-one: The title compound was obtained as a brown solid (0.070 g, 15%) using a procedure that is similar to that described for example 6 from intermediate 67 (0.294 g, 1.10 mmol), DMF (3 ml), cesium carbonate (0.358 g, 1.10 mmol) and intermediate 22 (0.300 g, 0.0.864 mmol). MP: 248-250 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.28 (s, 1H), 7.91 (m, 2H), 7.62 (s, 1H), 7.60 (dt, J = 8 , 0.3.0 Hz, 1H), 7.44 (m, 2H), 7.29 (m, 2H), 7.06 (m, 4H), 6.08 (q, J = 7.1 Hz , 1H), 5.73 (s, 2H), 2.02 (d, J = 7.1 Hz, 3H). Example 37 2- (l- (4-amino-3-morpholino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen -4-one 2- (1 - (4-amino-3-morpholino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) - 4H-chromen-4-one: The title compound was obtained as a yellow solid (0.040 g, 18%) using a procedure that is similar to that described for example 6 from intermediate 70 (0.114 g, 0.518 mmol), DMF ( 2 ml), potassium carbonate (0.119 g, 0.864 mmol) and intermediate 22 (0.150 g, 0.0.432 mmol). MP: 171-173 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.15 (s, 1H), 7.62 (dt, J = 8.4.5.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.06-6.99 (m, 3H), 6.90 (d, J = 9.4 Hz, 1H), 5.89 (d, J = 7.2 Hz, 1H) , 5.29 (s, 2H), 3.88 (t, J = 4.6 Hz, 4H), 3.32 (t, J = 4.6 Hz, 4H), 1.91 (d, J = 7.2 Hz, 3H). 2- (1- (4-amino-3- (dimethylamino) -LH-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen -4-one 2- (l- (4-amino-3- (dimethylamino) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.032 g, 14%) using a procedure that is similar to that described for example 6 from intermediate 73 (0.092 g, 0.518 mmol), DMF (2 ml), cesium carbonate (0.119 g, 0.432 mmol) and intermediate 22 (0.150 g, 0.0.432 mmol). MP: 169-171 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.14 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.29 (m, 2H ), 7.05 (m, 3H), 6.89 (d, J = 8.9 Hz, 1H), 5.87 (q, J = 7.0 Hz, 1H), 5.46 (s, 2H ), 2.86 (s, 6H), 1.01 (d, J = 7.1 Hz, 3H). Example 39 2- (l- (4-amino-3- (piperidin-1-yl) -1H-pyrazolo [3,4-djpyrimidin-1-yl) ethyl) -5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (piperidin-l-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.014 g, 10%) using a procedure that is similar to that described for example 6 from intermediate 76 ( 0.063 g, 0.288 mmol), DMF (1 ml), cesium hydroxide (0.048 g, 0.288 mmol) and intermediate 22 (0.100 g, 0.0.288 mmol). MP: 160-162 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.14 (s, 1H), 7.55 (dt, J = 8.4.5.5 Hz, 1H), 7.29 (m, 2H ), 7.05 (m, 3H), 6.89 (d, J = 8.9 Hz, 1H), 5.85 (q, J = 7.1 Hz, 1H), 5.41 (s, 2H ), 3.48 (t, J = 7.1 Hz, 4H), 1.90 (d, J = 7.1 Hz, 3H), 1.73-1.61 (m, 6H). Example 40 2- (1- (4-amino-3- (6-isopropoxypyridin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- ( 3-fluorphenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (6-isopropoxypyridin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.028 g, 28%) using a procedure that is similar to that described for the example 9 from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water (1 ml), 2-isopropoxy-5- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) pyridine (0.072 g, 0.274 mmol), sodium carbonate (0.038 g, 0.366 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Ch (0.029 g, 0.036 mmol). MP: 196-199 ° C. 'H-NMR NMR (δ ppm, CDCh, 400 MHz): 8.45 (d, J = 2.3 Hz, 1H), 8.25 (s, 1H), 7.87 (dd, J = 8, 6.2.5 Hz, 1H), 7.62 (dt, J = 8.4.5.5 Hz, 1H), 7.32 (m, 2H), 7.06 (m, 3H), 6, 92 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.06 (q, J = 7.1 Hz, 1H), 5.40 ( quintet, J = 6.3 Hz, 1H), 5.37 (s, 2H), 1.99 (d, J = 7.1 Hz, 3H), 1.40 (d, J = 6.2 Hz, 6H). Example 41 2- (l- (4-amino-3- (methylthio) -1H-pyrazolo | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H -chromen-4-one 2- (1 - (4-amino-3- (methylthio) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3 - fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.030 g, 22%) using a procedure that is similar to that described for example 6 of 3- (methylthio) -1H-pyrazole [ 3,4-d] pyrimidin-4-amine (0.078 g, 0.432 mmol for preparation, see J. Het. Chem, 1990, 27, 775-783), DMF (2 ml), cesium carbonate (0.140 g, 0.432 mmol) and intermediate 22 (0.100 g, 0.228 mmol). MP: 102-105 ° C. 'H-NMR (δ ppm, CDCl3, 400 MHz): 8.19 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.34 (m, 2H ), 7.06 (m, 3H), 6.95 (d, J = 9.5 Hz, 1H), 5.95 (q, J = 7.1 Hz, 1H), 5.82 (s, 2H ), 2.63 (s, 6H), 1.95 (d, J = 7.1 Hz, 3H). Example 42 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l -yl) ethyl) - 5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate: For example 6 (0.100 g, 0.174 mmol) in isopropanol (4 ml), p-toluenesulfonic acid (0.037 g, 0.192 mmol) was added and refluxed for 1h. The reaction mixture was concentrated, co-distilled with petroleum ether and dried. To the residue, water (3 ml) was added and stirred for 30 min. The solid was filtered, washed with petroleum ether and dried in vacuo to generate the title compound as off-white solid (0.102 g, 78%). MP: 153-156 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 8.15 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.64 (dt, J = 8.4 , 5.4 Hz, 1H), 7.42 (dd, J = 11.2.2.0 Hz, 1H), 7.34 (m, 3H), 7.22 (d, J = 8.0 Hz , 2H), 7.15 (t, J = 8.4 Hz, 1H), 7.08-6.99 (m, 3H), 6.87 (m, 1H), 6.07 (q, J = 7.1 Hz, 1H), 4.67 (quintet, J = 6.1 Hz, 1H), 2.37 (s, 3H), 2.01 (d, J = 7.2 Hz, 3H), 1 , 43 (d. <7 = 6.1 Hz, 6H). Example 43 2- (l- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo | 3,4-d | pyrimidin-I-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate 2- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazole [3 , 4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate: The title compound was obtained as an almost white solid (0.120 g, 84%) using a procedure that is similar to that described for example 43 of example 9 (0.10 g, 0.200 mmol), isopropanol (4 ml) and p-toluenesulfonic acid (0.042 g, 0.220 mmol). MP: 172-175 ° C. δ 'H-NMR (δ ppm, CDCh, 400 MHz): 10.15 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7 , 76 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.61 (dt, J = 8.2.3.0 Hz, 1H), 7.38 (m, 3H), 7.27 (m, 1H), 7.11 - 6.88 (m, 7H), 6.08 (q, J = 6.9 Hz, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 2.04 (d, J = 7.2 Hz, 3H). Example 44 2- (l- (4-amino-3- (4- (l-benzhydrylazetidin-3-yloxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (4- (1-benzhydrylazetidin-3-yloxy) -3-fluorophenyl) - 1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid ( 0.035 g, 13%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 81 (0.252 g, 0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.060 g, 0.073 mmol). MP: 211-214 ° C. δ * H-NMR (δ ppm, CDC13, 400 MHz): 8.23 (s, 1H), 7.59 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (m, 5H), 7.29-7.18 (m, 9H), 7.05 (m, 3H), 6.90 (m, 1H), 6.86 (t, J = 8.4 Hz, 1H), 6.04 (q, J = 7.2 Hz, 1H), 5.35 (s, 2H), 4.91 (quintet, J = 4.7 Hz, 1H), 4.47 (s, 1H), 3.78 (m, 2H), 3.23 (m, 2H), 1.97 (d, J = 7.2 Hz, 3H). Example 45 2- (l- (4-amino-3- (3-fluoro-4- (trifluormethoxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluoro-4- (trifluormethoxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.043 g, 19%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), 3-fluoro-4- (trifluormethoxy) phenylboronic acid ( 0.122 g, 0.550 mmol for preparation, see J. Med. Chem. 2010, 53, 8421-8439), sodium carbonate (0.116 g, 1.10 mmol) and [1., r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II) .CH2Cl2 (0.060 g, 0.073 mmol). MP: 247-249 ° C. Mass: 598.0 (M +) Example 46 2- (1- (4-amylium-3- (3-fluoro-4- (oxetan-3-yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin -l- yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-fluorine-4- (oxetan-3 -yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.040 g, 18%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1, 5 ml), intermediate 83 (0.162 g, 0.550 mmol), sodium carbonate (0.116 g. 1.10 mmol) and [1., r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2Cl2 (0.060 g, 0.073 mmol) . MP: 235-237 ° C. Mass: 586.2.0 (M ++ 1). Example 47 2- (l- (4-amino-3- (pyrrolidin-1-yl) -1H-pyrazoyl [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro- 3- (3- fluorfenyl) -4U-chromen-4-one 2- (l- (4-amino-3- (pyrrolidin-l-yl) -1H-pyrazolo [3,4-djpirimidin-l-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a yellow solid (0.040 g, 10%) using a procedure that is similar to that described for example 6 from intermediate 79 ( 0.211 g, 1.03 mmol), DMF (4 ml), cesium carbonate (0.281 g, 0.864 mmol) and intermediate 22 (0.300 g, 0.0.864 mmol). MP: 203-205 ° C. Mass: 489.1 (M ++ 1). Example 48 N- (4- (4-amino-l- (l- (5-fluor-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazole | 3 , 4-d | pyrimidin-3-yl) phenyl) isobutyramide N- (4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen 2-yl) ethyl) -111- pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) isobutyramide: The title compound was obtained as a pale brown solid (0.047 g, 22%) using a procedure that is similar to described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.0 ml), 4-isobutyramido phenylboronic acid (0.114 g, 0.550 mmol), carbonate sodium (0.116 g, 1.10 mmol) and [1,1-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.060 g, 0.073 mmol). MP: 154-157 ° C. Mass: 581.1 (M ++ 1). Example 49 2- (1- (4-amino-3- (4-isobutylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro- 3- (3-fluorphenyl! ) -4H-chromen-4-one 2- (l- (4-amino-3- (4-isobutylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.061 g, 30%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.0 ml), 4-isobutyl phenylboronic acid (0.098 g, 0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and [1, r-Bis (diphenylphosphine) ferrocene] dichloro palladium (II). CH2C12 (0.060 g, 0.073 mmol). MP: 221-223 ° C. Mass: 552.3 (M ++ 1). Example 50 2- (l- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.038 g, 31%) using a procedure that is similar to that described for the example 6 from intermediate 84 (0.060 g, 0.211 mmol), DMF (2 ml), sodium carbonate (0.059 g, 0.423 mmol) and intermediate 22 (0.116 g, 0.317 mmol). MP: 185-188 ° C. Mass: 568.0 (M ++ 1). Example 51 2- (1- (4-amino-3- (4- (5,6-dihydro-4H-1,3-oxazin-2-yl) phenyl) -1H-pyrazolo [3,4- d] pyrimidin -l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (4- (5,6-dihydro-4H -1,3-oxazin-2-yl) phenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorphenyl) -4H-chromen 4-one: The title compound was obtained as a brown solid (0.035 g, 17%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane ( 3 ml), water (1.0 ml), 4- (5,6-dihydro-4H-1,3,3-oxazin-2-yl) phenylboronic acid (0.113 g, 0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium QO.CFhCh (0.060 g, 0.073 mmol). MP: 228- 230 ° C. Mass: 579.1 (M ++ 1). Example 52 4- (4-amino-l- (l- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4- d] pyrimidin-3-yl) -N-methylbenzenesulfonamide 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl ) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -N-methylbenzenesulfonamide: The title compound was obtained as a brown solid (0.060 g, 28%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.5 ml), water (1.5 ml), 4- (N-methylsulfamoyl) phenylboronic acid (0.118 g, 0.550 mmol), sodium carbonate (0.077 g, 0.732 mmol) and [1.1 * - Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2d2 (0.060 g, 0.073 mmol). MP: 175-178 ° C. Mass: 589.1 (M ++ 1). Example 53 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -H-pyrazole [3, 4-d] pyrimidin-3-yl) -2-fluoro-N-isopropylbenzamide 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-crornen -2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluor-N-isopropylbenzamide: The title compound was obtained as a brown solid (0.063 g, 29%) using a procedure that is similar to that described for example 9 from intermediate 27 (0,200 g, 0,366 mmol), 1,2-dimethoxyethane (3.5 ml), water (1.5 ml), 3-fluoro-4- acid (isopropylcarbamoyl) phenylboronic (0.123 g, 0.550 mmol), sodium carbonate (0.077 g, 0.732 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (H). CH2C12 (0.060 g, 0.073 mmol). MP: 254-257 ° C. Mass: 599.1 (M ++ 1). Example 54 2- (l- (4-amino-3- (4- (5- (methylamino) -l, 3,4-thiadiazol-2-yl) phenyl) -1H-pyrazolo | 3,4- d | pyrimidin -l-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (4- (5- (methylamino) -l , 3,4-thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4 -one: The title compound was obtained as an off-white solid (0.068 g, 41%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane ( 3.0 ml), water (1.5 ml), 4- (5- (methylamino) -1.3-thiadiazol-2-yl) phenylboronic acid (0.097 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.045 g, 0.055 mmol). MP: 199-201 ° C. Mass: 609.0 (M +). Example 55 N- (4- (4-amino-1-- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromcn-2-yl) ethyl) -lH-pyrazole | 3 , 4-d] pyrimidin-3-yl) benzyl) methanesulfonamide N- (4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen 2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) benzyl) methanesulfonamide: The title compound was obtained as a brown solid (0.055 g, 33%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4- (methylSulfonamidomethyl) phenylboronic acid (0.094 g, 0.411 mmol ), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium QiyCHzCh (0.045 g, 0.055 mmol). MP: 252-255 ° C. Mass: 603.0 (M ++ 1). Example 56 4- (4-amino-l- (l- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4- d | pyrimidin-3-yl) -N-isopropylbenzenesulfonamide 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl ) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -N-isopropylbenzenesulfonamide: The title compound was obtained as an almost white solid (0.075 g, 44%) using a procedure that is similar to that described for the example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4- (N-isopropylsulfamoyl) phenylboronic acid (0.100 g, 0.411 mmol) , sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladiumUO.CFhCh (0.045 g, 0.055 mmol). MP: 211-214 ° C. Mass: 616.9 (M +). Example 57 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4- d] pyrimidin-3-yl) -N-cyclopropylbenzenesulfonamide 4- (4-amino-l- (l- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl ) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -N-cyclopropylbenzenesulfonamide: The title compound was obtained as a brown solid (0.043 g, 26%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4- (N-cyclopropylsulfamoyl) phenylboronic acid (0.099 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (0.045 g, 0.055 mmol). MP: 225- 228 ° C. Mass: 614.8 (M +). Example 58 2- (l- (4-amino-3- (2-isopropoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (2-isopropoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.025 g, 12%) using a procedure that is similar to that described for the example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 85 (0.146 g, 0.550 mmol), sodium carbonate (0.116 g , 1.10 mmol) and [1,1 r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.060 g, 0.073 mmol). MP: 230-232 ° C. Mass: 556.0 (M + +1). (R) / (S) -2- (1- (4-amino-3- (3-fluor-4-morpholinophenyl) -1H-pyrazolo | 3,4- d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one (R) / (S) -2- (l- (4-amino-3- (3-fluor-4-morpholinophenyl) -lH- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromcin-4-one: The title compound was obtained as an almost white solid (0.015 g, 10%) using a procedure that is similar to that described for example 7 from intermediate 86 (0.080 g, 0.254 mmol), intermediate 23b (0.077 g, 0.254 mmol), tris (4-methoxyphenyl) phosphine (0.134 g, 0.381 mmol), THF (2 ml) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol). MP: 242-245 ° C. Enantiomeric excess: 96.21%. Mass: 599.1 (M '+1). Example 60 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo | 3,4- d | pyrimidin-3-yl) benzenesulfonamide 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -lH - pyrazolo [3,4-d] pyrimidin-3-yl) benzenesulfonamide: The title compound was obtained as a brown solid (0.060 g, 38%) using a procedure that is similar to that described for example 9 from intermediate 27 ( 0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4-sulfamoyl phenylboronic acid (0.083 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1, r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.045 g, 0.055 mmol). MP: 232-235 ° C. Mass: 575.3 (M + +1). Example 61 methyl 4- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4 -d] pyrimidin-3-yl) thiophene-2-carboxylate methyl 4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2- il) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) thiophene-2-carboxylate: The title compound was obtained as a brown solid (0.070 g, 46%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 5- (methoxycarbonyl) thiophene-3-ylboronic acid (0.076 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2Cl2 (0.045 g, 0.055 mmol). MP: 227-230 ° C. Mass: 560.2 (M + +1). Example 62 2- (l- (4-amino-3- (5-methylthiophene-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (5-methylthiophene-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.045 g, 32%) using a procedure that is similar to that described for the example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 5-methylthiophene-2-ylboronic acid (0.092 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (0.045 g, 0.055 mmol). MP: 223-226 ° C. Mass: 516.1 (M + +1). Example 63 2- (l- (4-amino-3- (1H-pyrrolo | 2,3-b | pyridin-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (1 H-pyrrolo [2,3-b] pyridin-5-i 1 ) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.030 g, 20%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml ), 1H-pyrrole [2,3-b] pyridin-5-ylboronic acid (0.100 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphino) ferrocene] palladium (II) dichloro. CH2 Cl2 (0.045 g, 0.055 mmol). MP: 303-306 ° C. Mass: 536.4 (M + +1). Example 64 methyl 4- (4-amino-l- (l- (5-fluor-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4 -d] pyrimidin-3-yl) -3-fluorbenzoate methyl 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl ) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -3-fluorbenzoate: The title compound was obtained as a brown solid (0.017 g, 8%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.0 ml), 2-fluoro-4- (methoxycarbonyl) phenylboronic acid (0.109 g, 0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and [1, r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.060 g, 0.073 mmol). MP: 258-260 ° C. Mass: 572.4 (M + +1). Example 65 2- (1- (9H-purin-6-ylamino) propyl) -5-fluor-3-phenyl-4H-chromen-4-one 2- (1- (9H-purin-6-ylamino) propyl) -5-fluorine-3-phenyl-4H-chromen-4-one: To a solution of intermediate 93 (0.190 g, 0.639 mmol), tert-butanol (2 ml) N, N-diisopropylethylamine (0.23 ml, 1 , 32 mmol) and 6-chloropurine (0.079 g, 0.511 mmol) were added and heated to reflux for 48h. The reaction mixture was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with methanol: ethyl acetate to generate the title compound as a brown solid (0.030 g, 140% yield). MP: 210-212 ° C. 'H-NMR (δ ppm, DMSO-DÔ, 400 MHz): δ 12.83 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.20-7, 14 (m, 6H), 6.69 (d, J = 8.1 Hz, 1H), 6.59 (t, J = 8.7 Hz, 1H), 5.57 (m, 1H), 2, 98 (m, 1H), 1.89 (m, 2H), 0.78 (t, J = 7.1 Hz, 3H). Example 66 2- (l- (4-amino-3- (3-hydroxyprop-1-ynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-hydroxyprop-l-ynyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: To a solution of intermediate 27 (0.200 g, 0.364 mmol) in THF (4 ml) propargyl alcohol (0.025 ml, 0.437 mmol ) was added and degassed with nitrogen for 10 min. copper (I) lodide (7 mg, 0.036 mmol), tetrakistriphenylphosphine palladium (0) (0.042 g, 0.036 mmol) and diisopropylamine (0.23 ml, 1.82 mmol) were added and again degassed for 10 min. and heated to reflux. After 4h, the reaction mixture was filtered through celite, washed with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to generate the title compound as a brown solid (0.050 g, 29% yield). MP: 220-222 ° C. Mass: 474.3 (M + +1). Example 67 (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 4-methyl benzenesulfonate (S) / (R) -2- (l- (4-amino-3- (3-fluorine-4 -isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate: For example 7 ( 0.100 g, 0.174 mmol) in isopropanol (4 ml), p-toluenesulfonic acid (0.037 g, 0.192 mmol) was added and refluxed for 1h. The reaction mixture was concentrated, co-distilled with petroleum ether and dried. To the residue, water (3 ml) was added and stirred for 30 min. The solid was filtered, washed with petroleum ether and dried in vacuo to generate the title compound as off-white solid (0.110 g, 82%). MP: 152-155 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.15 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.64 (dt, J = 8.4 , 5.4 Hz, 1H), 7.42 (dd, J = 11.3.2.0 Hz, 1H), 7.34 (m, 3H), 7.22 (d, J = 8.0 Hz , 2H), 7.16 (t, J = 8.6 Hz, HI), 7.08-6.97 (m, 3H), 6.88 (m, 1H), 6.08 (q, J = 7.1 Hz, 1H), 4.687 (quintet, J = 6.0 Hz, 1H), 2.37 (s, 3H), 2.02 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 6.1 Hz, 6H). Example 68 (+) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one (+) - 2- (1 - (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.090 g, 43%) using a procedure that is similar to that described for example 7 of tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol), intermediate 23b (0.150 g, 0.494 mmol), triphenylphosphmo (0.194 g, 0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol), followed by cleavage of intermediate with trifluoroacetic acid (1.8 ml) and dichloromethane (5 ml). MP: 194-197 ° C. Enantiomeric excess: 99.62%. [a] 2:> D 142.00 (c = 1, CHCl 3). Mass: 420.1 (M + +1). Example 69 2- (l- (9H-purin-6-ylamino) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (9U-purin-6- ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.081 g, 39%) using a procedure that is similar to that described for Example 7 of tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol), intermediate 23 (0.150 g, 0.494 mmol), triphenylphosphmo (0.194 g, 0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol), followed by cleavage of intermediate with trifluoroacetic acid (1.3 ml) and dichloromethane (8 ml). MP: 247-249 ° C. Mass: 420.1 (M + +1). Example 70 (R) / (S) -2- (1- (4-amino-3- (3-fluoro-4-morpholinophenyl) -1H-pyrazole] [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one (R) / (S) -2- (l- (4-amino-3- (3-fluor-4-morpholinophenyl ) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.022 g, 11%) using a procedure that is similar to that described for example 7 from intermediate 86 (0.100 g, 0.329 mmol), intermediate 23a (0.100 g, 0.329 mmol), tris (4-methoxyphenyl) phosphine ( 0.174 g, 0.494 mmol), THF (2 ml) and diisopropylazodicarboxylate (0.1 ml, 0.494 mmol). MP: 243-246 ° C. Enantiomeric excess: 85.4%. Mass: 599.4 (M + +1). Example 71 2- (l- (4-amino-3- (4-methoxy-3,5-dimethylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (4-methoxy-3,5-dimethylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin -1 -yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.070 g, 46%) using a procedure that is similar to described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4-methoxy-3,5-dimethyl acid phenylboronic acid (0.074 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r * Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.045 g, 0.055 mmol). MP: 232-235 ° C. Mass: 554.0 (M + +1). Example 72 2- (l- (4-amino-3- (4- (methoxyl) phenyl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-f! Uor-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (4- (methoxyl) phenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl ) et i 1) -5 - fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.062 g, 42%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4- (methoxyl) phenylboronic acid (0.068g, 0.411 mmol), carbonate sodium (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (H). CH2Cl2 (0.045 g, 0.055 mmol). MP: 204-207 ° C. Mass: 540.3 (M + +1). Example 73 2- (l- (4-amino-3- (imidazo [1,2-a] pyridin-6-yl) -1H-pyrazolo | 3,4-d] pyrimidin-l-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1- (4-amino-3- (imidazo [1,2-a] pyridin-6-yl) -lH-pyrazolo [ 3,4-d] pyrimidin-1-yl) ethyl) - 5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.052 g, 36%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), imidazo acid [l, 2-a] pyridin-6-ylboronic (0.066 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II) .CH2Cl2 (0.045 g, 0.055 mmol). MP: 317-320 ° C. Mass: 536.3 (M + +1). Example 74 tert-butyl (5- (4-amino-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) - 1H-pyrazolo [ 3,4-d] pyrimidin-3-yl) furan-2-yl) methylcarbamate tert-butyl (5- (4-amino-1 - (1 - (5-fluor-3- (3-fluorophenyl) -4- oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3.4-d] pyrimidin-3-yl) furan-2-yl) methylcarbamate: The title compound was obtained as a brown solid (0.100 g, 63% ) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 5- ( (tert-butoxycarbonylamino) methyl) furan-2-ylboronic (0.099 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II) .CH2C12 (0.045 g, 0.055 mmol). MP: 163-166 ° C. Mass: 615.7 (M ++ 1). Example 75 2- (l- (4-amino-3- (2,4-dimethylthiazol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) - 5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (2,4-dimethylthiazol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.050 g, 39%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 2,4-dimethyl-5- (4.4, 5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) thiazole (0.098 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphino) ferrocene ] palladium (II) dichloro. CH2Cl2 (0.045 g, 0.055 mmol). MP: 252-255 ° C. Mass: 531.3 (M ++ 1). Example 76 2- (l- (4-amino-3- (5- (morpholinomethyl) thiophene-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine- 3- (3-fluorophenyl) -4H-chromen-4-one 2- (1- (4-amino-3- (5- (morpholinomethyl) thiophene-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.047 g, 29%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 4 - ((5- (4.4, 5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) thiophene-2-yl) methyl) morpholine (0.127 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1 , 1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.045 g, 0.055 mmol). MP: 193-196 ° C. Mass: 601.6 (M ++ 1). Example 77 2- (l- (4-amino-3- (4- (5-amino-1,3,4-thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1 -yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (4- (5-amino-l, 3,4 -thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: O title compound was obtained as a brown solid (0.071 g, 44%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml) , water (1.5 ml), 4- (5-amino-1, 3,4-thiadiazol-2-yl) phenylboronic acid (0.091 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladiumOO.CHzCh (0.045 g, 0.055 mmol). MP: 202 - 205 ° C. Mass: 595.6 (M + +1). Example 78 (-) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one (-) - 2- (1 - (9H-purin-6-ylamino) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.075 g, 36%) using a procedure that is similar to that described for example 7 of tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol), intermediate 23a (0.150 g, 0.494 mmol), triphenylphosphmo (0.194 g, 0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol), followed by dividing the intermediate with trifluoroacetic acid (0.50 ml) and dichloromethane (6 ml). MP: 205-208 ° C. Enantiomeric excess: 100%. [a] 2:, D -180.47 (c = 1, CHCl3). Mass: 420.5 (M + +1). Example 79 2- (1- (4-amino-3- (1,3-dimethyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l - (4-amino-3- (1,3-dimethyl-1 H-indazol-6-yl) -1 H- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.039 g, 26 %) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 1.3 -dimethyl-6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-indazole (0.112 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1,1'-Bis (diphenylphosphino) fcrocene] dichloro palladium (II). CH2 Cl2 (0.045 g, 0.055 mmol). MP: 220-224 ° C. Mass: 564.0 (M ++ 1). Example 80 2- (l- (4-amino-3- (2,3-dimethyl-2H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (2,3-dimethyl-2H-indazol-6-yl) -1 H-pyrazole [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.060 g, 40% ) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), 2,3- dimethyl-6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -2H-indazole (0.112 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol ) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (0.045 g, 0.055 mmol). MP: 232- 235 ° C. Mass: 563.8 (M +). Example 81 N- (4- (4-amino-l- (l- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3 , 4-d] pyrimidin-3-yl) -2-fluorophenyl) isobutyramide N- (4- (4-amino-l- (l- (5-fluor-3- (3-fluorophenyl) -4-oxo-4H -cromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluorophenyl) isobutyramide: The title compound was obtained as a brown solid (0.061 g, 37%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 95 (0.125 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.045 g, 0.055 mmol). MP: 249-252 ° C. Mass: 598.8 (M +). Example 82 N- (4- (4-amino-l- (l- (5-fluor-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3 , 4-d] pyrimidin-3-yl) -2-fluorophenyl) acetamide N- (4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H -cromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluorophenyl) acetamide: The title compound was obtained as a brown solid (0.030 g, 19%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 97 (0.114 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and [1, r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Cl2 (0.045 g, 0.055 mmol). MP: 220-223 ° C. Mass: 571,198.8 (M ++ 1). Example 83 2- (l- (4- (dimethylamino) -3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-luor-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4- (dimethylamino) -3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as pale yellow solid (0.050 g, 13%) using a procedure that is similar to that described for example 7 from intermediate 99 (0.200 g, 0.630 mmol), intermediate 23 (0.229 g, 0.756 mmol), tris-4-methoxytriphenylphosphine (0.288 g, 0.819 mmol), THF (3 ml) and diisopropylazodicarboxylate ( 0.18 ml, 0.945 mmol). MP: 122-124 ° C. Mass: 600.2 (M + Example 84 5-fluorine-2- (1- (3- (3-fluoro-4-isopropoxyphenyl) -4- (methylamino) -HH-pyrazolo | 3,4- d] pyriniidin-l -yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one 5-fluorine-2- (l- (3- (3-fluor-4-isopropoxyphenyl) -4- (methylamino) -lH -pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a mangan solid (0.038 g, 25%) using a procedure that is similar to that described for example 9 from intermediate 101 (0.150 g, 0.267 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 12 (0.110 g, 0.401 mmol), sodium carbonate (0.057 g, 0.535 mmol) and [1,1, r-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2C12 (0.044 g, 0.053 mmol). MP: 193-196 ° C. : 586.3 (M ++ 1) Example 85 5-fluoro-2- (1- (3- (3-fluoro-4-isopropoxyphenyl) -4-morpholino-1H-pyrazole [3,4-d] pyrimidine -l-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one 5-fluor-2- (l- (3- (3-fluor-4-isopropoxyphenyl) -4-morpholino-1H -pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: O with the title was obtained as an almost white solid (0.120 g, 46%) using a procedure that is similar to that described for example 7 from intermediate 104 (0.150 g, 0.402 mmol), intermediate 23 (0.146 g, 0.483 mmol), tris-4-methoxytriphenylphosphine (0.184 g, 0.523 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.604 mmol). MP: 116-119 ° C. Mass: 641.8 (M4 + 1). Example 86 N- (2-fluorine-4- (l- (l- (5-fluorine-3- (4-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -4-morpholino-1H -pyrazolo | 3,4-d] pyrimidin-3-yl) phenyl) isobutyramide N- (2-fluorine-4- (l- (l- (5-fluor-3- (4-fluorophenyl) -4-oxo- 4H-chromen-2-yl) ethyl) -4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) isobutyramide: The title compound was obtained as a brown solid (0.030 g, 18%) using a procedure that is similar to that described for example 9 from intermediate 105 (0.150 g, 0.243 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 95 (0.111 g , 0.365 mmol), sodium carbonate (0.051 g, 0.487 mmol) and [1,1'-Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.040 g, 0.048 mmol). MP: 165-167 ° C. Mass: 669.2 (M + +1). Example 87 N- (2-fluorine-4- (l- (l- (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -4-morpholino-1H -pyrazolo [3,4-d | pyrimidin-3-yl) phenyl) isobutyramide N- (2-fluorine-4- (1 - (1 - (5-fluor-3- (3-fluorophenyl) -4-oxo- 4H-chromen-2-yl) ethyl) -4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) isobutyramide: The title compound was obtained as a brown solid (0.050 g, 31%) using a procedure that is similar to that described for example 9 from intermediate 106 (0.150 g, 0.243 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 95 (0.111 g , 0.365 mmol), sodium carbonate (0.051 g, 0.487 mmol) and [1, r-Bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2Cl2 (0.040 g, 0.048 mmol). MP: 168-170 ° C. Mass: 669.2 (M + +1). Example 88 (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d | pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one sulfate (S) / (R) -2- (l- (4-amino-3- (3-fluorine-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one sulfate: The title compound was obtained as an almost white solid (0.120 g, 68%) using a procedure that is similar to that described for example 67 of example 6a (0.150 g, 0.262 mmol), isopropanol (6 ml), sulfuric acid (0.028 g, 0.288 mmol). MP: 205-207 ° C. * H-NMR (δ ppm, CDC13, 400 MHz): δ 8.12 (s, 1H), 7.64 (dt, J = 8.4.5.4 Hz, 1H), 7.41 (dd, J = 11.2,2.0 Hz, 1H), 7.29 (m, 3H), 7.15 (t, J = 8.3 Hz, 1H), 7.08 (m, 2H), 6, 97 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 7.1 Hz, 1H), 6.07 (q, J = 6.9 Hz, 1H), 4.68 ( quintet, J = 6.1 Hz, 1H), 2.01 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H). Example 89 (S) / (R) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one benzenesulfonate (S) / (R) -2- (l- (4-amino-3- (3-fluorine-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one benzenesulfonate: The title compound was obtained as an almost white solid (0.120 g, 62%) using a procedure that is similar to that described for example 67 of example 6a (0.150 g, 0.262 mmol), isopropanol (6 ml), benzenesulfonic acid (0.045 g, 0.288 mmol). MP: 172-174 ° C. 'H- NMR (δ ppm, CDCh, 400 MHz): δ 8.14 (s, 1H), 7.92 (dd, J = 6.8.1.7 Hz, 2H), 7.64 (dt, J = 8.4.5.4 Hz, 1H), 7.42-7.28 (m, 7H), 7.16 (t, J = 8.3 Hz, 1H), 7.11 (m, 3H ), 6.87 (d. J = 7.1 Hz, 1H), 6.08 (q, J = 7.0 Hz, 1H), 4.68 (quintet, J = 6.1 Hz, 1H), 2.02 (d, J = 7.1 Hz, 3H), 1.43 (d, J = 6.0 Hz, 6H). (S) / (R) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one camphorsulfonate (S) / (R) -2- (l- (4-amino-3- (3-fluor-4-isopropoxyphenyl) -lH -pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one camphorsulfonate: The title compound was obtained as an almost white solid (0.120 g, 57%) using a procedure that is similar to that described for example 67 of example 6a (0.150 g, 0.262 mmol), isopropanol (6 ml), camphorsulfonic acid (0.066 g, 0.288 mmol). MP: 190-193 ° C. * H- NMR (δ ppm, CDCh, 400 MHz): δ 8.23 (s, 1H), 7.64 (dt, J = 8.4.5.4 Hz, 1H), 7.42 (dd, J = 11.2.2.1 Hz, 1H), 7.35 (m, 3H), 7.16 (t, J = 8.4 Hz, 1H), 7.08 (m, 3H), 6, 92 (d, J = 8.3 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 4.68 (quintet, J = 6.1 Hz, 1H),), 3, 36 (d, ./= 4.4 Hz, 1H), 2.95 (d, J = 4.6 Hz, 1H), 2.59 (m, 1H), 2.35 (m, 1H), 2 .09 (m, 2H), 2.02 (d, J = 7.2 Hz, 3H), 1.93-1.83 (m, 3H), 1.43 (d, J = 6.1 Hz, 6H), 1.07 (s, 3H), 0.84 (s, 3H). Example 91 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -5-fluorine-3 - (1H-pyrazol-4-yl) -4H-chromen-4-one 2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (1H-pyrazol-4-yl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.120 g, 30%) using a procedure that is similar to that described for example 9 from intermediate 107 (0.400 g, 0.708 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), l-boc- pyrazole-4-boronic (0.220 g, 1.06 mmol), sodium carbonate (0.220 g, 2.12 mmol) and [1,1 l'-Bis (diphenylphosphine) ferrocene] dichloro palladium (II) .CH2Ch (0.115 g , 0.141 mmol). MP: 135-138 ° C. Mass: 552.0 (M + +1). Example 92 2- (l- (4-amino-3- (3-fluor-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl -4H-chromen-4-one 2- (1 - (4-amino-3- (3-fluor-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) - 5-fluorine-3-phenyl-4H-chromen-4-one: The title compound was obtained as a brown solid (0.045 g, 27%) using a procedure that is similar to that described for example 9 from intermediate 108 (0.150 g, 0.285 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 61 (0.130 g, 0.427 mmol), sodium carbonate (0.060 g, 0.570 mmol) and [1, 1'- Bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2Ch (0.046 g, 0.057 mmol). MP: 256-258 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt, J = 8.4.5.5 Hz, 1H), 7.40-7, 32 (m, 2H), 7.23 (m, 6H), 7.09 (m, 2H), 6.09 (q, J = 7.1 Hz, 1H), 5.38 (s, 2H), 3.91 (t, J = 4.5 Hz, 4H), 3.18 (t, J = 4.7 Hz, 4H), 1.98 (d, J = 7.1 Hz, 3H). Example 93 2- (1- (4-amino-3- (3-fluor-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- ( 4-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (3-fluoro-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl ) ethyl) - 5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.040 g, 24%) using a procedure that is similar to that described for the example 9 from intermediate 34 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3.0 ml), water (1.5 ml), intermediate 61 (0.127 g, 0.412 mmol), sodium carbonate (0.058 g , 0.550 mmol) and [1, r-Bis (diphenylphosphino) ferrocene] dichloro palladiumOO.CHjCh (0.045 g, 0.055 mmol). MP: 240-242 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): δ 8.26 (s, 1H), 7.60 (dt, J = 8.3.5.5 Hz, 1H), 7.40 (m, 2H), 7.28 (m, 3H), 7.09-6.99 (m, 4H), 6.06 (q, J = 7.2 Hz, 1H), 5.45 (s, 2H), 3.91 (t, J = 4.5 Hz, 4H), 3.18 (t, J = 4.6 Hz, 4H), 1.99 (d, J = 7.1 Hz, 3H). Example 94 (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d | pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one (S) / (R) -2- (l- (4-amino-3- (3-fluorine-4-isopropoxyphenyl) - 1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.033 g, 10%) using a procedure that is similar to that described for example 7 from intermediate 13 (0.199 g, 0.692 mmol), intermediate 113 (0.175 g, 0.577 mmol), tris-4-methoxytriphenylphosphine (0.305 g, 0.865 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.17 ml, 0.865 mmol). MP: 192-194 ° C. 'H-NMR (Ô ppm, CDCI3, 400 MHz): δ 8.22 (s, 1H), 7.58 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (dd, J = 11.5,2.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.23 (m, 2H), 7.15 (t, J = 8.3 Hz, 1H), 7.07 (m, 3H), 6.04 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.65 (quintet, J = 6.2 Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H). Enantiomeric excess: 68.2% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 10.43min.). Example 95 (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluor-3- (4-fluorophenyl) -4H-chromen-4-one (S) / (R) -2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) - 1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid ( 0.071 g, 18%) using a procedure that is similar to that described for example 7 from intermediate 13 (0.277 g, 0.791 mmol), intermediate 114 (0.200 g, 0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.989 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP: 209-212 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.26 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (dd, J = 11.4.2.0 Hz, 1H), 7.37 (dd, J = 8.3.1.0 Hz, 1H), 7.23 (m, 2H), 7.15 (t, J = 8.4 Hz, 1H), 7.07 (m, 3H), 6.06 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.66 (quintet, J = 6.1 Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H), 1.42 (d, J - 6.0 Hz, 6H). Enantiomeric excess: 66% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 15.96 min.). Example 96 (S) / (R) - 2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4- d] pyriniidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one (S) / (R) -2- (l- (4-amino-3- (4- (difluormethoxy) -3 -fluorfenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as yellow pale (0.018 g, 5%) using a procedure that is similar to that described for example 7 from intermediate 39 (0.204 g, 0.692 mmol), intermediate 113 (0.175 g, 0.577 mmol), tris-4-methoxytriphenylphosphine (0.305 g, 0.865 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.17 ml, 0.865 mmol). MP: 246-248 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): δ 8.28 (s, 1H), 7.61 (m, 2H), 7.47 (m, 2H), 7.22 (m, 3H) , 7.08 (m, 3H), 6.82 (t, J = 73 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 5.43 (s, 2H), 1 .99 (d, J = 7.1 Hz, 3H). Enantiomeric excess: 38.4% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 10.34 min.). Example 97 (S) / (R) - 2- (1- (4-aniino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo | 3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one (S) / (R) -2- (l- (4-amino-3- (4- (difluormethoxy) -3 -fluorfenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (4-fluorenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.045 g, 12%) using a procedure that is similar to that described for example 7 from intermediate 39 (0.233 g, 0.791 mmol), intermediate 114 (0.200 g, 0.659 mmol), tris-4 -methoxytriphenylphosphine (0.348 g, 0.989 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP: 242-244 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.29 (s, 1H), 7.61 (m, 2H), 7.47 (m, 2H), 7.25 (m, 3H) , 7.08 (m, 3H), 6.82 (t, J = 73 Hz, 1H), 6.06 (q, J = 7.1 Hz, 1H), 5.39 (s, 2H), 1 .99 (d, J = 7.1 Hz, 3H). Enantiomeric excess: 46.8% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 18.36 min.). Example 98 2- (l- (4- (dimethylamino) -3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4- d] pyrimidin-l-yl) ethyl) -5-fluorine-3 - (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4- (dimethylamino) -3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.085 g, 31%) using a procedure that is similar to that described for example 6 from intermediate 117 (0.150 g, 0.438 mmol), DMF (2 ml), potassium carbonate (0.073 g, 0.525 mmol) and intermediate 22 (0.224 g, 0.613 mmol). MP: 208-210 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.23 (s, 1H), 7.62 (dt, J = 8.4.5.5 Hz, 1H), 7.34 -7.28 (m, 4H), 7.06-6.92 (m, 4H), 6.83 (d, J = 8.1 Hz, 1H), 6.10 (q, J = 7.1 Hz, 1H) , 3.91 (t, J = 4.5 Hz, 4H), 3.16 (t, J = 4.6 Hz, 4H), 2.92 (s, 6H), 1.96 (d, J = 7.1 Hz, 3H). Example 99 5-fluor-2- (1- (3- (3-fluor-4-morpholinophenyl) -4- (methylamino) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3 - (3-fluorophenyl) -4H-chromen-4-one 5-fluor-2- (1- (3- (3-fluor-4-morpholinophenyl) -4- (methylamino) -H-pyrazole [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.075 g, 27%) using a procedure that is similar to that described for example 6 from intermediate 118 (0.150 g. 0.456 mmol). DMF (2 ml), potassium carbonate (0.075 g, 0.540 mmol) and intermediate 22 (0.237 g, 0.630 mmol). MP: 238-240 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.30 (s, 1H), 7.62 (dt, J = 8.4.5.5 Hz, 1H), 7.36 -7.27 (m, 4H), 7.06-6.98 (m, 4H), 6.89 (d, J = 10.6 Hz, 1H), 6.04 (q, J = 7.2 Hz, 1H) , 5.32 (q, J = 4.8 Hz, 1H), 3.92 (t, J = 4.5 Hz, 4H), 3.19 (t, J = 4.6 Hz, 4H), 3 .09 (d, J = 4.9 Hz, 3H), 1.97 (d, J = 7.2 Hz, 3H). Example 100 (S) / (R) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one (S) / (R) -2- (1 - (4-amino-3- (3-yl-4-isopropoxyphenyl) -1 H-pyrazole [3,4-d] pinmidin-1 - yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.050 g, 14%) using a procedure that is similar to that described for example 7 from intermediate 13 (0.212 g, 0.738 mmol), intermediate 115 (0.175 g, 0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF (3 ml ) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP: 205-208 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (dd, J = 11.5,2.0 Hz, 1H), 7.37-7.29 9m, 4H), 7.23 (m, 3H), 7.14 (t, J = 8.4 Hz, 1H) , 7.04 (t, J = 10.1 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.65 (quintet, J = 6.1 Hz, 1H), 1.98 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H). Enantiomeric excess: 81% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 10.12min.). Example 101 (S) / (R) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d | pyrimidin-1-yl) (ethyl) -5-fluor-3-phenyl-4H-chromen-4-one (S) / (R) -22- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazole [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.067 g, 19%) using a procedure that is similar to that described for example 7 from intermediate 13 (0.212 g, 0.738 mmol), intermediate 116 (0.175 g, 0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF (3 ml ) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP: 185-188 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt, J = 8.4.5.5 Hz, 1H), 7.44 (dd, J = 11.5,2.0 Hz, 1H), 7.37-7.29 (m, 4H), 7.23 (m, 3H), 7.14 (t, J = 8.3 Hz, 1H ), 7.04 (t, J = 9.9 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 5.43 (s, 2H), 4.64 (quintet, J = 6.0 Hz, 1H), 1.98 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 6.0 Hz, 6H). Enantiomeric excess: 73.5% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 13.20 min.). Example 102 (S) / (R) - 2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one (S) / (R) -2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorphenyl) - 1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.069 g, 20%) using a procedure that is similar to that described for example 7 from intermediate 39 (0.218 g, 0.738 mmol), intermediate 115 (0.175 g, 0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol) , THF (3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP: 247-250 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.26 (s, 1H), 7.60 (m, 2H), 7.47 (m, 2H), 7.35 (m, 3H) , 7.24 (m, 3H), 7.05 (t, J = 10.1 Hz, 1H), 6.81 (t, J = 73 Hz, 1H), 6.10 (q, J = 7, 1 Hz, 1H), 5.39 (s, 2H), 1.99 (d, J = 7.1 Hz, 3H). Enantiomeric excess: 64.7% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 9.78 min.). Example 103 (S) / (R) - 2- (1- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenyl-4H-chromen-4-one (S) / (R) -2- (l- (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) - 1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluor-3-phenyl-4H-chromen-4-one: The title compound was obtained as a yellow solid (0.033 g, 6% ) using a procedure that is similar to that described for example 7 from intermediate 39 (0.218 g, 0.738 mmol), intermediate 116 (0.175 g, 0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP: 217-220 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.26 (s, 1H), 7.60 (m, 2H), 7.47 (m, 2H), 7.35 (m, 3H) , 7.26 (m, 3H), 7.05 (t, J = 9.7 Hz, 1H), 6.81 (t, <7 = 73 Hz, 1H), 6.08 (q, J = 7.2 Hz, 1H), 5.38 (s, 2H), 1.99 (d, J = 7.2 Hz, 3H). Enantiomeric excess: 47.4% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 14.01 min.). Example 104 (+) - 5-fluoro-2- (1- (3- (3-fluoro-4-isopropoxyphenyl) -4- (methylamino) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one (+) - 5-fluorine-2- (l- (3- (3-fluor-4-isopropoxyphenyl) -4- (methylamino) - 1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.212 g, 54% ) using a procedure that is similar to that described for example 7 from intermediate 119 (0.218 g, 0.725 mmol), intermediate 23b (0.200 g, 0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.980 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP: 199-202 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): δ 8.30 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.39 (dd, J = 11.5,2.1 Hz, 1H), 7.31 (m, 3H), 7.15 (t, J = 8.4 Hz, 1H), 7.06 (m, 3H), 6, 90 (t, J = 9.9 Hz, 1H), 6.04 (q, J = 7.1 Hz, 1H), 5.31 (q, J = 4.9 Hz, 1H), 4.66 ( quintet, J = 6.1 Hz, 1H), 3.09 (d, J = 4.9 Hz, 3H), 1.97 (d, J = 7.1 Hz, 3H), 1.43 (d, J = 6.1 Hz, 6H). Enantiomeric excess: 96.5% as determined by HPLC on a chiralpak AD-H column. enriched in the fast eluting isomer (retention time = 8.91 min.), [a] 25o 181.67 (c = 1, CHCl3). Example 105 (-) - 5-fluoro-2- (1- (3- (3-fluoro-4-isopropoxyphenyl) -4- (methylamino) -1H-pyrazolo (3,4-d] pyrimidin-l-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one (-) - 5-fluorine-2- (l- (3- (3-fluor-4-isopropoxyphenyl) -4- (methylamino) - 1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.201 g, 52% ) using a procedure that is similar to that described for example 7 from intermediate 119 (0.218 g, 0.725 mmol), intermediate 23a (0.200 g, 0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.980 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol) MP: 216-218 ° C. 'H-NMR (δ ppm, CDCb, 400 MHz): δ 8.30 (s, 1H), 7, 61 (dt, J = 8.4.5.4 Hz, 1H), 7.39 (dd, J = 11.5.2.1 Hz, 1H), 7.31 (m, 2H), 7.27 (m, 1H), 7.15 (t, J = 8.4 Hz, 1H), 7.05 (m, 3H), 6.90 (t, J = 9.8 Hz, 1H), 6.06 (q , J = 7.1 Hz, 1H), 5.30 (q, J = 4.7 Hz, 1H), 4.99 (quintet, J = 6.2 Hz, 1H), 3.09 (d, J = 4.9 Hz, 3H), 1.97 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 6.0 Hz, 6H). Enantiomeric excess: 88.4% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 1.22 min.) [A] 25D 172.64 (c = LCHCI3) .. Example 106 2- (l- (6-amino-2-fluorine-9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 2- (l - (6-amino-2-fluorine-9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost solid white (0.180 g, 63%) using a procedure that is similar to that described for example 6 of 2-fluorine-9H-purin-6-amine (0.100 g, 0.653 mmol), DMF (2 ml), potassium carbonate ( 0.108 g, 0.783 mmol) and intermediate 22 (0.330 g, 0.914 mmol). MP: 255-258 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.42 (s, 1H), 7.83 (m, 3H), 7.53 (d, J = 8.6 Hz, 1H), 7, 49 (m, 1H), 7.28-7.13 (m, 4H), 5.52 (q, J = 7.1 Hz, 1H), 1.87 (d, J = 7.2 Hz, 3H ). Mass: 437.7 (M +). Example 107 2- (l- (6-amino-2-fluorine-9H-purin-9-yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4- 2- (l- (6-amino-2-fluor-9H-purin-9-yl) ethyl) -5-fluor-3- (4-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.120 g, 42%) using a procedure that is similar to that described for example 6 from 2-fluorine-9H-purin-6-amine (0.100 g, 0.653 mmol), DMF (2 ml), potassium carbonate (0.108 g, 0.783 mmol) and intermediate 31 (0.330 g, 0.914 mmol). MP: 272-275 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.41 (s, 1H), 7.83 (m, 3H), 7.52 (d, J = 8.6 Hz, 1H), 7, 35-7.22 (m, 5H), 5.49 (q, J = 7.2 Hz, 1H), 1.87 (d, J = 7.2 Hz, 3H). Example 108 5-fluorine-3- (4-fluorophenyl) -2- (1- (6-morpholino-9H-purin-9-yl) ethyl) -4H-chromen-4-one 5-fluorine-3- (4 -fluorfenyl) -2- (1- (6-morpholino-9H-purin-9-yl) ethyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.090 g, 47%) using a procedure that is similar to that described for example 6 of 4- (9H-purin-6-yl) morpholine (0.080 g, 0.389 mmol for the preparation, see Tetrahedron, 2007, 63, 5323- 5328), DMF (1 , 5 ml), potassium carbonate (0.064 g, 0.477 mmol) and intermediate 31 (0.185 g, 0.506 mmol). MP: 186-189 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.26 (s, 1H), 8.04 (s, 1H), 7.60 (dt, J = 8.4.5.4 Hz, 1H ), 7.37 (m, 2H), 7.26 (m, 3H), 7.04 (t, J = 9.4 Hz, 1H), 5.89 (q, J = 7.3 Hz, 1H ), 4.29 br s, 4H), 3.84 (t, J = 4.9 Hz, 4H), 1.90 (d, J = 7.3 Hz. 3H). Example 109 5-fluorine-3- (4-fluorophenyl) -2- (l- (6- (4-methylpiperazin-1-yl) -9H-purin-9-yl) ethyl) -4H- chromen-4-one 5-fluorine-3- (4-fluorophenyl) -2- (l- (6- (4-methylpiperazin-l-yl) -9H-purin-9-yl) ethyl) -4H- chromen-4-one: O title compound was obtained as an off-white solid (0.012 g, 8%) using a procedure that is similar to that described for example 6 of 6- (4-methylpiperazin-1-yl) -9H-purine (0.060 g, 0.274 mmol ), DMF (1.5 ml), potassium carbonate (0.046 g, 0.329 mmol) and intermediate 31 (0.130 g, 0.357 mmol). MP: 157-160 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.25 (s, 1H), 8.04 (s, 1H), 7.62 (dt, J = 8.4.5.4 Hz, 1H ), 7.37 (m, 2H), 7.25 (m, 3H), 7.07 (dt, J = 9., 0.7 Hz, 1H), 5.90 (q, J = 7.2 Hz, 1H), 4.31 br s, 4H), 2.54 (br s, 4H), 2.34 (s, 3H), 1.89 (d, J = 7.3 Hz, 3H). Example 110 2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen- 2- (l- (6- ( dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.045 g, 20%) using a procedure that is similar to that described for example 6 of N, N-dimethyl-9H-purin-6-amine (0.080 g, 0.490 mmol for preparation, see J.Het. Chem. 1983, 20, 295-199) , DMF (2 ml), potassium carbonate (0.081 g, 0.588 mmol) and intermediate 22 (0.250 g, 0.686 mmol). MP: 166-169 ° C. 'H-NMR (δ ppm, CDCI3, 400 MHz): 8.26 (s, 1H), 8.00 (s, 1H), 7.61 (dt, J = 8.5.5.5 Hz, 1H ), 7.48 (dd, J = 7.9.5.9 Hz, 1H), 7.22 (m, 4H), 7.07 (dt, J = 8.3.0.8 Hz, 1H) , 5.87 (q, J = 7.2 Hz, 1H), 3.52 (s, 6H), 1.90 (d, J = 7.3 Hz, 3H). Example 111 2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 5-fluorine-3- (3-fluorophenyl) -2- (1- (6- (methylamino) -9H-purin-9-yl) ethyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.020 g , 9%) using a procedure that is similar to that described for example 6 of N-methyl-9H-purin-6-amine (0.080 g, 0.534 mmol for preparation, see Bull.Soc. Jpn. 1986, 62, 3155- 3160.), DMF (2 ml), potassium carbonate (0.087 g, 0.641 mmol) and intermediate 22 (0.273 g, 0.748 mmol). MP: 207-209 ° C. Mass: 433.9 (M +). Example 112 5-fluorine-3- (3-fluorophenyl) -2- (l- (3- (3-methyl-1H-indazol-6-yl) -4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -4H-chromen-4-one 5-fluorine-3- (3-fluorophenyl) -2- (l- (3- (3-methyl-lH-indazol-6-yl) - 4-morpholino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.050 g, 25%) using a procedure that is similar to that described for example 9 from intermediate 106 (0.200 g, 0.325 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), tert-butyl 3-methyl-6- (4 , 4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-indazol-1-carboxylate (0.174 g, 0.477 mmol), sodium carbonate (0.103 g, 0.975 mmol) and bis ( diphenylphosphmo) ferrocene] dichloro palladium OI / CHzCh (0.053 g, 0.065 mmol) MP: 183-186 ° C. Mass: 619.8 (M ++ 1). Example 113 2- (l- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo | 3,4-d | pyrimidin-1-yl) ethyl) -5-fluor-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) - 5-fluor-3- (3-Ωuorfenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.018 g, 10%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 123 (0.134 g, 0.412 mmol), sodium carbonate (0.058 g, 0.550 mmol ) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.044 g, 0.055 mmol) MP: 250-253 ° C. * H-NMR (δ ppm, CDCh, 400 MHz): 8.25 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.59 (m, 2H), 7, 27 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.05-6.99 (m, 4H), 6.06 (q, J = 7.1 Hz, 1H ), 5.38 (s, 2H), 3.92 (t, J = 4.5 Hz, 4H), 3.14 (t, J = 4.6 Hz, 411), 1.99 (d, J = 7.2 Hz, 3H). Example 114 (+) 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one (+) - 2- (1 - (4-amino-3- (4-isopropoxy-3-methylphenyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.083 g, 30%) using a procedure which is similar to that described for example 7 from intermediate 84 (0.150 g, 0.529 mmol), intermediate 23b (0.145 g, 0.481 mmol), tris-4-methoxytriphenylphosphine (0.254 g, 0.721 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.14 ml, 0.721 mmol). MP: 217-220 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.22 (s, 1H), 7.61 (dt, J = 8.4.5.4 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.97 (m, 4H), 6.92 (d, J = 9.4 Hz, 1H), 6.07 (q, J = 7 , 1 Hz, 1H), 5.42 (s, 2H), 4.63 (quintet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 1.97 (d, J = 7 , 1 Hz, 3H), 1.39 (d, J = 6.0 Hz, 6H). Enantiomeric excess: 100% as determined by HPLC on an AD-H chiralpak column, enriched in the fast eluting isomer (retention time = 9.36 min.) [A] D 176.04 (c = 1.CHCH). Example 115 (-) 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one (-) - 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.066 g, 28%) using a procedure that is similar to that described for example 7 from intermediate 84 (0.128 g, 0.453 mmol), intermediate 23a (0.125 g, 0.412 mmol), tris-4-methoxytriphenylphosphine (0.217 g, 0.618 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.618 mmol). MP: 221-224 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): δ 8.22 (s, 1H), 7.61 (dt, J = 8.4.5.5 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.95 (m, 4H), 6.92 (d, J = 9.5 Hz, 1H), 6.05 (q, J = 7 , 1 Hz, 1H), 5.40 (s, 2H), 4.62 (quintet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 1.99 (d, J = 7 , 2 Hz, 3H), 1.39 (d, 6.0 Hz, 6H). Enantiomeric excess: 99.6% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 11.43 min.) [A] 25D -183.59 (c = 1, CHCI3 ) .. Example 116 (S) / (R) - 5-fluoro-2- (1- (3- (3-fluoro-4-isopropoxyphen) -4-morpholino-1H-pyrazolo | 3,4-d] pyrimidin -l-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one (S) / (R) - 5-fluorine-2- (1 - (3- (3-fluorine-4- isopropoxyphenyl) -4-morpholino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a pale brown solid (0.044 g, 12%) using a procedure that is similar to that described for example 7 from intermediate 104 (0.243 g, 0.652 mmol), intermediate 23a (0.180 g, 0.593 mmol), tris-4-methoxytriphenylphosphmo (0.272 g, 0.771 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.17 ml, 0.890 mmol). MP: 136-138 ° C. Mass: 642.0 (M +). Enantiomeric excess: 91.6% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 10.27 min.). Example 117 2- (l- (4-amino-3- (3-chloro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (1- (4-amino-3- (3-chloro-4-isopropoxyphenyl) -1H-pyrazolo [3.4-d] pyrimidin-1-yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.039 g, 24%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 125 (0.107 g, 0.412 mmol), sodium carbonate (0.088 g, 0.825 mmol) and bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2C12 (0.044 g, 0.055 mmol). MP: 207-210 ° C. 1 H-NMR (δ ppm, CDCI3, 400 MHz): 8.24 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.62 (dt, J = 8.3 , 5.3 Hz, 1H), 7.51 (dd, J = 8.4.2.2 Hz, 1H), 7.31 (m, 2H), 7.10 (d, J = 8.6 Hz , 1H), 7.06 (m, 3H), 6.92 (d, J = 9.6 Hz, 1H), 6.06 (q, J = 7.2 Hz, 1H), 5.38 (s , 2H), 4.66 (quintet, J = 6.1 Hz, 1H), 1.99 (d, J = 7.2 Hz, 3H). 1.44 (d, J = 6.0 Hz, 6H). Example 118 2- (l- (4-amino-3- (2-methylbenzo | d | oxazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (2-methylbenzo [d] oxazol-6-yl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.017 g, 11%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 127 (0.107 g, 0.412 mmol), carbonate sodium (0.088 g, 0.825 mmol) and bis (diphenylphosphino) fcrrocene] dichloro palladium (H). CH2 Cl2 (0.044 g, 0.055 mmol). MP: 215-217 ° C. 'H-NMR (δ ppm, CDCl3, 400 MHz): 8.26 (s, 1H), 7.81 (m, 2H), 7.63 (m, 2H), 7.30 (m, 2H), 7.06 (m, 3H), 6.94 (d, J = 9.3 Hz, 1H), 6.10 (q, J = 7.1 Hz, 1H), 5.48 (s, 2H), 2.70 (s, 3H), 2.01 (d, J = 7.1 Hz, 3H). Example 119 5-fluorine-3- (3-fluorophenyl) -2- (1- (6-morpholino-9H-purin-9-yl) ethyl) -4H-chromen-4-one 5-fluorine-3- (3 -fluorfenyl) -2- (1- (6-morpholino-9H-purin-9-yl) ethyl) -4H-chromcin-4-one: The title compound was obtained as a yellow solid (0.060 g, 31%) using a procedure that is similar to that described for example 6 of 4- (9H-purin-6-yl) morpholine (0.080 g, 0.389 mmol for preparation, see J. Med. Chem. 2010, 53, 8421- 8439), DMF (1.5 ml), potassium carbonate (0.064 g, 0.467 mmol) and intermediate 22 (0.185 g, 0.506 mmol). MP: 239-241 ° C. Mass: 490.1 (M + +1). Example 120 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d | pyrimidin-1-yl) ethyl) -3- (3-fluorophenyl) -5-morph! Ino-4H-chromen-4-one 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -il) et i1) - 3- (3-fluorophenyl) -5-morpholino-4H-chromen-4-one: To a solution of example 6 (0.100 g. 0.174 mmol) in dioxane (1 ml), morpholine (0.015 g, 0.174 mmol) was added and refluxed for 3h. The reaction mixture was quenched with water, the precipitated product was filtered, washed with water, petroleum ether and vacuum dried to generate the compound as a pale yellow solid (0.090 g, 80%). MP: 227-229 ° C.1 H-NMR (δ ppm, CDC13, 400 MHz): 8.23 (s, 1H), 7.54 (t, J = 8.3 Hz, 1H), 7.44 (dd, J = 11.5,2.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.29 (m, 1H), 7.14 (t, J = 8.4 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.98 (m, 2H), 6.85 (m, 2H), 5.98 (q, J = 7.2 Hz, 1H), 5.38 (s, 2H), 4.64 (quintet, J = 6.1 Hz, 1H), 3.90 (t, J = 4.2 Hz, 4H), 3 .07 (t, J = 4.2 Hz, 4H), 1.96 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 6.0 Hz, 6H). Mass: 638.8 (M +). 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-morpholino-3-phenyl-4H -chromen-4-one 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl 1) - 5 -morpholino-3-phenyl-4H-chromen-4-one: To a solution of example 13 (0.040 g, 0.072 mmol) in dioxane (1 ml), morpholine (0.007 g, 0.072 mmol) was added and refluxed for 3 h. The reaction mixture was quenched with water, the precipitated product was filtered, washed with water, petroleum ether and dried in vacuo to generate the compound as a pale yellow solid (0.030 g, 67%). MP: 211-214 ° C. Mass: 621.2 (M + +1). Example 122 6- (4-amino-1- (1- (5-fluoro-3- (3-f] uorfenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3, 4-d | pyrimidin-3-yl) isoindolin-l-one 6- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2- il) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) isoindolin-l-one: The title compound was obtained as a brown solid (0.045 g, 30%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 128 (0.106 g, 0.412 mmol), sodium carbonate (0.058 g, 0.550 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.044 g, 0.055 mmol). MP: 242-245 ° C. Mass: 551.0 (M + +1). Example 123 5- (4-ammo-1- (1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4- d] pyrimidin-3-yl) isoindolin-l-one 5- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) isoindolin-l-one: The title compound was obtained as a brown solid (0.052 g, 35%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 129 (0.106 g, 0.412 mmol), sodium carbonate (0.058 g, 0.550 mmol) and bis (diphenylphosphmo) ferrocene] dichloro palladium (II). CH2 Cl2 (0.044 g, 0.055 mmol). MP: 293-296 ° C. Mass: 550.7 (M +). Example 124 2- (l- (3- (4-acetyl-3-fluorophenyl) -4-amino-1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (1 - (3- (4-acetyl-3-fluorophenyl) -4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.045 g, 29%) using a procedure that is similar to that described for the example 9 from intermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 130 (0.106 g, 0.412 mmol), sodium carbonate (0.087 g, 0.825 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.044 g, 0.055 mmol). MP: 237- 239 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.29 (s, 1H), 8.08 (t, J = 7.7 Hz, 1H), 7.62 (m, 3H), 7, 32 (m, 2H), 7.07 (m, 3H), 6.92 (d, J = 9.1 Hz, 1H), 6.09 (q, J = 7.1 Hz, 1H), 5, 39 (s, 2H), 2.71 (d, J = 4.8 Hz, 3H), 2.01 (d, J = 7.1 Hz, 3H). Example 125 5-fluoro-3- (3-fluorfeni!) - 2- (l- (6- (4-methylpiperazin-l-yl) -9H-purin-9-yl) ethyl) -4H- chromen-4- 5-fluorine-3- (3-fluorophenyl) -2- (l- (6- (4-methylpiperazin-1-yl) -9H-purin-9-yl) ethyl) -4H- chromen-4-one: The title compound was obtained as an off-white solid (0.052 g, 9%) using a procedure that is similar to that described for example 6 of 6- (4-methylpiperazin-1-yl) -9H-purine (0.240 g, 1 , 09 mmol for preparation, see Tetrahedron, 2007, 63, 5323-5328.), DMF (4.8 ml), potassium carbonate (0.182 g, 1.31 mmol) and intermediate 22 (0.522 g, 1.429 mmol). MP: 199-201 ° C. Mass: 502.8 (M +). Example 126 (S) / (R) - 2- (1- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one (S) / (R) - 2- (l- (4-amino-3- (3-chloro-4-morpholinophenyl) - 1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.036 g, 12%) using a procedure that is similar to that described for example 7 from intermediate 131 (0.196 g, 0.592 mmol), intermediate 23b (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g, 0.741 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.13 ml, 0.741 mmol). MP: 256-258 ° C. 'H-NMR (δ ppm. CDCh, 400 MHz): δ 8.24 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.62 (dt, J = 8, 4.5.4 Hz, 1H), 7.55 (dd, J = 8.2.2.0 Hz, 1H), 7.31 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.06 (m, 3H), 6.91 (d, J = 9.7 Hz, 1H), 6.08 (q, J = 7.1 Hz, 1H), 5.43 ( s, 2H), 3.92 (t, J = 4.4 Hz, 4H), 3.14 (d, J = 4.5 Hz, 4H), 1.99 (d,. / = 7.2 Hz 3H). Enantiomeric excess: 98.8% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 15.07 min.). (S) / (R) - 2- (1- (4-amino-3- (3-chloro-4-morpholinophenyl) -1H-pyrazolo [3,4- d | pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one (S) / (R) - 2- (1- (4-amino-3- (3-chloro-4-morpholinophenyl) -lH- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as an almost white solid (0.085 g, 28%) using a procedure that is similar to that described for example 7 from intermediate 131 (0.196 g, 0.592 mmol), intermediate 23a (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g, 0.741 mmol) , THF (4 ml) and diisopropylazodicarboxylate (0.13 ml, 0.741 mmol). MP: 260-262 ° C. Mass: 616.9 (M ++ 1). Enantiomeric excess: 96% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 22.42 min.). Example 128 N- (3- (4-amino-l- (l- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1H-pyrazole | 3 , 4-d] pyrimidin-3-yl) phenyl) methanesulfonamide N- (3- (4-amino-1-- (1- (5-fluoro-3- (3-fluorphenyl) -4-oxo-4H-chromen 2-yl) ethyl) -1H-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) methanesulfonamide: The title compound was obtained as a brown solid (0.050 g, 23%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), intermediate 132 (0.163 g, 0.549 mmol), sodium carbonate (0.116 g, 1.10 mmol) and bis (diphenylphosphino) ferrocene] dichloro palladium (II). CH2 Cl2 (0.059 g, 0.073 mmol). MP: 259-261 ° C. 'H-NMR (δ ppm, CDC13, 400 MHz): 9.90 (s, 1H), 8.09 (s, 1H), 7.83 (dt, J = 6.6.1.0 Hz, 1H ), 7.51 (m, 3H), 7.36-7.24 (m, 4H), 7.07 (dt, J = 8.5.2.5 Hz, 1H), 6.93 (m, 2H), 5.99 (q, J = 7.1 Hz, 1H), 3.04 (s, 3H), 1.88 (d, J = 7.1 Hz, 3H). Example 129 (S) / (R) - 2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H- chromen-4 -one (S) / (R) -2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H- chromcn-4 -one: The title compound was obtained as an off-white solid (0.020 g. 9%) using a procedure that is similar to that described for example 7 of N, N-dimethyl-9H-purin-6-amine (0.088 g, 0.543 mmol), intermediate 23b (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphmo (0.261 g, 0.741 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.14 ml, 0.741 mmol). MP: 187-189 ° C. Mass: 448.0 (M ++ 1). Enantiomeric excess: 100% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes fast (retention time = 11.76 min.). Example 130 (S) / (R) - 2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4 -one (S) / (R) -2- (l- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H- chromen-4 -one: The title compound was obtained as an off-white solid (0.016 g, 7%) using a procedure that is similar to that described for example 7 of N, N-dimethyl-9H-purin-6-amine (0.088 g, 0.543 mmol), intermediate 23a (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g, 0.741 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.14 ml, 0.741 mmol). MP: 198-200 ° C. Mass: 447.7 (M +). Enantiomeric excess: 94.8% as determined by HPLC on a chiralpak AD-H column, enriched in the isomer that elutes slowly (retention time = 19.68 min.). Example 131 2- (l- (9H-purin-6-ylamino) ethyl) -5-fluoro-3- (2-fluorophenyl) -4H-chromen-4-one 2- (1 - (9H-purin-6- ylamino) ethyl) -5-fluorine-3- (2-fluorophenyl) -4H-chromin-4-one: The title compound was obtained as a pale yellow solid (0.095 g, 33%) using a procedure that is similar to that described for Example 7 of tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.396 g, 0.831 mmol), intermediate 135 (0.210 g, 0.692 mmol), triphenylphosphmo (0.272 g, 1.03 mmol), THF (6 ml) and diisopropylazodicarboxylate (0.20 ml, 1.038 mmol), followed by cleavage of intermediate with trifluoroacetic acid (0.6 ml) and dichloromethane (3 ml). MP: 203-205 ° C. Mass: 419.7 (M +). Example 132 2- (l- (4-amino-3- (4-ethoxy-3- (trifluoromethyl) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one 2- (l- (4-amino-3- (4-ethoxy-3- (trifluormethyl) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) ethyl) -5-yluor-3- (3-fluorophenyl) -4H-chromen-4-one: The title compound was obtained as a brown solid (0.026 g, 12%) using a procedure that is similar to that described for example 9 from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water (1.5 ml), 4-ethoxy-3- (trifluormethyl) phenylboronic acid (0.128 g, 0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and bis (diphenylphosyl) ferrocene] dichloro palladium (II). CH2Cl2 (0.059 g, 0.073 mmol). MP: 225-227 ° C. Mass: 608.1 (M + +1). Example 133 2- (l- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) propyl) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl ) propyl) -5-fluorine-3- (3-tluorfenyl) -4H-chromen-4-one: The title compound was obtained as an off-white solid (0.062 g, 36%) using a procedure that is similar to that described for example 6 from intermediate 13 (0.080 g, 0.293 mmol), DMF (2 ml), potassium carbonate (0.081 g, 0.587 mmol) and intermediate 137 (0.130 g, 0.440 mmol). MP: 241-243 ° C. 'H-NMR (δ ppm, CDCh, 400 MHz): 8.25 (s, 1H), 7.63 (dt, J = 8.4.5.4 Hz, 1H), 7.44 (dd, J = 11.5.2.0 Hz, 1H), 7.35 (m, 3H), 7.14 (t, J = 8.4 Hz, 1H), 7.06 (m, 3H), 6.92 (d, J = 7.5 Hz, 1H), 5.85 (dd, J = 9.0.6.6 Hz, 1H), 5.44 (s, 2H), 4.66 (quintet, J = 6.2 Hz, 1H), 2.64 (m, 1H), 2.46 (m, 1H), 1.42 (d, J = 6.0 Hz, 6H), 0.91 (t, J = 7.3 Hz, 3H). Example 134 (S) / (R) -5-fluorine-3- (3-fluorophenyl) -2- (1- (2-methoxy-9H-purin-6-iamino) ethyl) -4H- chromen-4-one (S) / (R) - 5-fluorine-3- (3-fluorophenyl) -2- (1- (2-methoxy-9H-purin-6-ylamino) ethyl) -4H- chromen-4-one: O title compound was obtained as a pale brown solid (0.055 g, 25%) using a procedure that is similar to that described for example 7 from intermediate 140 (0.245 g, 0.494 mmol), intermediate 23b (0.150 g, 0.494 mmol), triphenylphosphism (0.194 g, 0.741 mmol), THF (7 ml) and diisopropylazodicarboxylate (0.16 ml, 0.741 mmol), followed by cleavage of intermediate with trifluoroacetic acid (0.6 ml) and dichloromethane (8 ml). MP: 186-189 ° C. Mass: 449.8 (M +). Example 135 (S) / (R) -5-fluorine-3- (3-fluorophenyl) -2- (1- (2-methoxy-9H-purin-6-ylamino) ethyl) -4H- chromen-4-one (S) / (R) - 5-fluorine-3- (3-fluorophenyl) -2- (1 - (2-methoxy-9H-purin-6-ylamino) et i 1) -4H- chromen-4-one : The title compound was obtained as a pale brown solid (0.056 g, 34%) using a procedure that is similar to that described for example 7 from intermediate 140 (0.179 g, 0.362 mmol), intermediate 23a (0.110 g, 0.494 mmol ), triphenylphosphmo (0.142 g, 0.544 mmol), THF (7 ml) and diisopropylazodicarboxylate (0.11 ml, 0.544 mmol), followed by cleavage of intermediate with trifluoroacetic acid (0.6 ml) and dichloromethane (7 ml) .. MP: 219-222 ° C. Mass: 449.8 (M +). (S) / (R) - 5-fluorine-2- (1- (2-fluorine-9H-purin-6-amino) ethyl) -3- (3-fluorophenyl) -4H- chromen-4-one (S ) / (R) -5-fluorine-2- (1- (2-fluorine-9H-purin-6-ylamino) ethyl) -3- (3-fluorenyl) -4H-chromen 4-one: To a solution of intermediate 143 (0.22 g, 0.730 mmol), tert-butanol (1.5 ml) N, N-diisopropylethylamine (0.25 ml, 1.46 mmol) and 6-chloro-2-fluorine-9H-purine (0.102 g, 0.663 mmol) were added and heated to reflux for 248h. The reaction mixture was concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography with methanol: ethyl acetate to generate the title compound as a brown solid (0.042 g, 13% yield). MP: 183-186 ° C. Mass: 437.9 (M +). Enantiomeric excess: 33% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 7.21 min.). Example 137 (S) / (R) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4- d | pyrimidin-1-yl) ethyl) -5-methyl-3-phenyl-4H-chromen-4-one (S) / (R) -22- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazole [3,4-d] pyrimidin-1-yl) ethyl) -5-methyl-3-phenyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.030 g, 15%) using a procedure that is similar to that described for example 7 from intermediate 13 (0.122 g, 0.425 mmol), intermediate 149 (0.100 g, 0.354 mmol), triphenylphosphmo (0.140 g, 0.531 mmol), THF (1 ml) and diisopropylazodicarboxylate ( 0.10 ml, 0.531 mmol). MP: 208-210 ° C. Mass: 549.7 (M +). 'H-NMR (δ ppm, CDCh, 400 MHz): 8.20 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.43 (dd, J = 11.4 , 2.0 Hz, 1H), 7.34 (m, 5H), 7.20-7.10 (m, 4H), 6.09 (q, J = 7.1 Hz, 1H), 4.67 (quintet, J = 6.1 Hz, 1H), 2.80 (s, 3H), 1.99 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6.0 Hz , 6H). Enantiomeric excess: 99.34% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 8.77 min). Example 138 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluor-3-o-tolyl-4H-chromen-4-one 2- (1 - (9H-purin-6-ylamino) ethyl) -5-fluoro-3-o-tolyl-4H-chromen-4-one: The title compound was obtained as an almost white solid (0.025 g, 20%) using a procedure that is similar to that described for example 7 of tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.173 g, 0.362 mmol), intermediate 153 (0.090 g, 0.301 mmol), triphenylphosphmo (0.119 g, 0.451 mmol), THF (2.3 ml) and diisopropylazodicarboxylate (0.10 ml, 0.451 mmol), followed by cleavage of intermediate with trifluoroacetic acid (0.4 ml) and dichloromethane (2 ml). MP: 275-277 ° C. Mass: 416.0 (M +). BIOLOGICAL TEST
The pharmacological properties of the compounds of this invention can be confirmed by a series of pharmacological tests. The pharmacological tests that can be performed on the compounds according to the invention and / or their pharmaceutically acceptable salts are exemplified below.
Test 1: Fluorescent determination of PBKinase of the activity of the enzyme Kinase
Phosphoinositide 3 kinases (PI3K) belong to a class of lipid kinases that play a critical role in the regulation of several fundamental cellular processes. P13Ks are able to phosphorylate the 3-hydroxy position of phosphoinositol, thus generating the second messengers involved in downstream signaling events. The homogeneous time-resolved fluorescence assay (HTRF) allows the detection of 3,4,5-triphosphate (PIP3) formed as a result of phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K isoforms. such as α, β, y or δ.
The activity of the PI3K α, β, y or δ isoform was determined using a human PI3K HTRF (TM) Assay Kit (Millipore, Billerica, MA) with modifications. All incubations were performed at room temperature. Briefly, 0.5 pl of 40X inhibitor (in 100% DMSO) or 100% DMSO was added to each well of a 384-well black plate (Greiner Bio-One, Monroe, NC) containing 14.5 pl of reaction buffer 1X / PIP2 (10 mM MgC12, 5 mM DTT, 1.38 pM PIP2) mixed with or without enzyme and incubated for 10 min. After the initial incubation, 5 pl / well of 400 pM ATP was added and incubated for an additional 30 minutes. The reaction was stopped by adding 5 pl / well of interruption solution (Millipore, Billerica, MA). Five microliters of detection mixture (Millipore, Billerica, MA) was then added to each well and incubated for 6-18 h in the dark. The F1RTF ratio was measured on a microplate reader (BMG Labtech., Germany) at an excitation wavelength of 337 nm and emission lengths of 665 and 620 nm with an integration time of 400 pseg. Table 2






The data were analyzed using Graphpad Prism (Graphpad software; San Diego CA) to determine the IC50. Examples 1-59 were tested at 1 µM for Pi3kα & Pi3k β and at 0.3 µM for y and δ. Examples 60-137 were tested at 1 µM for Pi3kα & Pi3k β and at 0.1 µM for y and δ. Percent inhibition was calculated based on the values for the blank and enzyme controls. The results are as provided in Table 2 (where D = 0 to 25%; C => 25 to 50%; B => 50 to 75%; A => 75 to 100%; HH 1 = <50 nM; + +++ => 50 to <100 nM; +++ -> 100 to <300 nM; ++ => 300 to <500 nM; + => 500 nM)
Assay 2: In vitro cell proliferation assay in leukemic cell lines
Growth inhibition tests were performed using medium supplemented with 10% FBS. The cells were propagated at a concentration of 5000-20,000 cells / well in a 96-well plate. The test compound in a concentration range of 0.01 to 10,000 nM was added after 24 h. Growth was assessed using the reduction test with 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolic bromide (MTT) at 0 h (before adding the test compound) and 48 hours after adding the test compound. The absorbance was read on an Optima Fluostar (BMG Labtech, Germany) at a wavelength of 450 nm. The data were analyzed using the Graphpad Prism and the% inhibition due to the test compound compared to the control was calculated accordingly. Exemplary compounds of the present invention that are tested> 1 µM in THP-1; DLBCL; HL-60; MOLT-4; RPMI8226 and TOLEDO cell lines showed 20 to 80% inhibition.
Test 3: Inhibition of KT phosphorylation in leukemic cell lines:
Inhibition of AKT phosphorylation in leukemic cell lines: THP-1, HL-60, MOLT-4, RPM1-8226, or DLBCL cells were incubated with desired concentrations of compound for 48 h. The cells were lysed and pAKT was determined by Western Blotting. Bands were quantified using ImageJ and normalized for actin. Exemplary compounds of the present invention when tested at> 1 µM showed 50 to 90% inhibition.
Trial 4: Inhibition of P13KÔ signaling in basophils of Whole Human Blood
PI3Kδ signaling in basophils manifested by a change in anti-FcsRl-induced CD63 expression is a useful pharmacodynamic marker determined using the Flow2CAST® kit (Buhlmann Laboratories, Switzerle). In short, it involves the following steps:> Mix the anticoagulated blood sample by inverting the venipuncture tube several times. > Prepare fresh 3.5 ml pyrogen-free polypropylene or polystyrene tubes suitable for flow cytometry measurements. > Add 49 pl of patient's whole blood to each tube. > Add 1 pl of DMSO 10% (background) or compound (DMSO 10%) to the named tubes and mix gently. Incubate at room temperature for 15 min. > Pipette 50 pl of the stimulation buffer (background) or anti-FεcRI Ab into each tube. > Add 100 pl of Stimulation Buffer to each tube. > Mix gently. Add 20 µl of Dye Reagent (1: 1 mixture of FITC-CD63 and PE-CCR3) to each tube. > Mix gently, cover tubes and incubate for 15 minutes at 37 ° C in a water bath (using an incubator will take about 10 more minutes in the incubation time due to less efficient heat transfer). > Add 2 ml of the pre-heated Lysis Reagent (18-28 ° C) to each tube, mix gently. > Incubate for 5-10 minutes at 18-28 ° C. > Centrifuge the tubes for 5 minutes at 500 x g. > Decant the supernatant liquid using blotting paper. > Resuspend the cell pellet with 300-800 pl of Wash Buffer. > Vortex gently and obtain flow cytometer data on the same day.
The percentage of CD63 positive cells in the closed basophil population should be determined in different treatment groups and normalized to the control vehicle.
Assay 5: Inhibition of apoptosis in leukemic cell lines
Apoptosis in leukemic cells was determined using a Caspase 3 kit in situ (Millipore, US), as described below:
Propagating leukemic cells - at a density of 1 X 106 cells / well in a 6-well plate.
Add DMSO to the test compound at desired concentrations. > Incubate the plate for 24 hrs at 37 ° C in a 5% CO2 incubator> Collect cells in a 2 ml centrifuge tube. > Add 1.6 pL of freshly prepared 5 X FL1CA reagent and mix cells by gently vibrating the tubes. > Incubate the tubes for 1 hour at 37 ° C below 5% CO2. > Add 2 ml of wash buffer IX to each tube and mix.
Centrifuge cells at <400 x g for 5 minutes at room temperature. > Carefully remove and discard the supernatant and vortex the cell pellet to break up any cell-cell agglomerates. > Resuspend the cell pellet in 300 pl of wash buffer IX. > Place 100 pL of each cell suspension in each of the two wells of a black microtiter plate. Avoid formation of bubbles. > Read the absorbance of each microwell using an excitation wavelength of 490 nm and an emission wavelength of 520 nm. > The percentage of increase in caspase-3 activity manifested by an increase in fluorescence compared to the white control should be calculated.
Trial 6: Pulmonary neutrophilia induced by lipopolysaccharide in a male Sprague-Dawley rat model:
Excessive recruitment and subsequent neutrophil activation is possibly important for the development and course of various inflammatory diseases in the airways and lungs, such as severe asthma, chronic obstructive pulmonary disease, cystic fibrosis, and acute respiratory distress syndrome. The mechanisms by which the neutrophil contributes to these diseases may involve the release of proteolytic enzymes, such as neutrophil elastase, and free oxygen radicals. When released, these compounds can cause bronchoconstriction, bronchial hyper-reactivity, hyper-secretion, epithelial damage and tissue remodeling in the airways. After the quarantine period, fasting animals should be optimized and divided into several groups depending on their body weights. The test compound should be prepared as a suspension in a vehicle consisting of 0.5% methyl cellulose in which Tween 80 is a suspending agent. The compound or vehicle should be administered by oral gavage in a volume of 10 ml / kg. The animals must be anesthetized with ketamine and LPS solution was administered intratracheally one hour after administration of the compound in a dose of 1 mg / kg. 6 h after instillation of LPS, the animals are exsanguinated under anesthesia, and then the trachea must be cannulated and the lungs are washed with 5 ml aliquots of heparinized PBS (1 unit / ml) four times through the tracheal cannula (total volume 20 ml). BAL fluid should be stored at 2-8 ° C until evaluated for total cell and differential leukocyte count. Bronchialveolar fluid should be centrifuged (500 * g for 10 min) and the resulting cell pellet should be resuspended in 0.5 ml of heparinized saline. The total number of white blood cells must be determined in BAL fluid or blood using a blood cell counter and must be adjusted to 1 x 106 cells / ml. The differential count must be calculated manually. One hundred microliters of the cell suspension should be centrifuged using cytospin 3 to prepare a cell smear. The cell smear should be stained with a blood staining solution for differentiation and slices were microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear should be determined and expressed as a percentage. The number of eosinophils in each BALf or blood must be calculated.
Test 7: Model of inflammation of the air sac in a mouse mediated by lipopolissaearide:
Leukocyte recruitment and the formation of pro-inflammatory mediators, including different cytokines, are the hallmark of an inflammatory response. The air pocket model was originally developed as a facsimile synovium for the study of inflammatory processes that occur in RA. The model allows the differential quantification of leukocyte species that accumulate in the air pocket (tissue) wall as well as those that transmigrate in an air pocket (wash) cavity, and this allows the characterization of the chemokines and responsible adhesion molecules for diapedesis induced by a variety of inflammatory stimuli.
Male Wistar rats (175-200 g) are acclimatized for seven days before the start of the experiment. The animals are then randomly distributed into several groups based on their body weights. The animals are anesthetized with ether and subcutaneous air pockets are formed by injecting 20 ml of sterile air under the skin in the intra-scapular area (day 0) and maintained with a second injection of 10 ml of sterile filtered air on day 4. On day 6, oral treatment should be started 1 h before induction of inflammation by sc injection of LPS solution on day 6. A volume of 5 ml of LPS solution dissolved in sterile saline (100g / kg) should be injected into each pouch . Samples of bag fluid should be taken within 6 h after administration of LPS by washing the bag with 5 ml of sterile saline and removing 4 ml of fluid. The number of leukocytes present in the pouch fluid should be determined microscopically using a hematocytometer. The differential cell content should be determined by microscopic evaluation of fluid smears with Diff-Quik.
Assay 8: TNF-cc production induced by lipopolysaccharide:
Fasting female Wistar rats should be randomized into different groups depending on their body weights. The test compound should be prepared as a suspension in a vehicle that consists of 0.5% methylcellulose. The compound or vehicle should be administered by oral gavage in a volume of 10 ml / kg. LPS solution should be administered intraperitoneally one hour after administration of the compound in a dose of 0.3 mg / kg. Blood should be collected in serum separating tubes via cardiac puncture ninety minutes after LPS injection. The serum must be separated and stored at - 20 ° C and will be analyzed for TNFa by ELISA.
Trial 9: Pulmonary eosinophilia induced by ovoalbumin in male guinea pigs: Hyperresponsiveness and airway inflammation (AHR) are milestones and features that distinguish bronchial asthma. The provocation of mice pre-sensitized with the same allergen induces airway inflammation with preferential eosinophilic infiltration, and, as a consequence, AHR. Pulmonary eosinophilia and airway remodeling in conjunction with altered neural control of airway tone and airway epithelial desquamation may contribute to AHR in asthma. After the quarantine period, 0.3 mL of blood samples must be collected from the orbital vein by the retro-orbital plexus method of each individual animal and analyzed on a cell analyzer (ADVIA 2120, Siemens). Based on their total cell counts, guinea pigs should be randomized and divided into several groups. The pinna must be marked with an indelible marker pen for identification. On day 0, weights should be recorded and the animals are then sensitized with 50pg of Ovalbumin and 10 mg of alum solution (1 mL) intraperitoneally. On day 7 and day 14, the above sensitization protocol must be repeated. On day 18, the animals to be treated with test compound orally / intranasally. On day 19, & 20, animals should be treated with the test compound by oral / intranasal administration and exposed to 0.5% w / v Ovalbumin for 10 min using an ultrasonic nebulizer with a flow rate of 0.2 ml per min. On day 21, fasting animals should be treated with the test compound by oral / intranasal administration and 15 min after dosing, the animals should be nebulized with 1% w / v Ovalbumin solution for 10 min. Control group animals should be treated with 0.5% w / v methyl cellulose (vehicle). Simulated control groups should be sensitized with 10 mg of alum on days 0, 7 and 14 and exposed to the saline solution with the same nebulization rate cm d 19, d20 & d21. Twenty-four hours after the OVA challenge, blood and BAL fluid samples should be collected. The samples must be analyzed for total cell count using a blood analyzer (ADVIA 2120, Siemens) and differential leukocyte count must be performed manually.
Trial 10: Collagen-induced arthritis in Wistar rats:
Female Wistar rats must be acclimatized for seven days before the start of the experiment and are randomly distributed to the various groups based on their body weights. On day 0, the animals must be treated by intradermal injection of 500 pg of type II bovine collagen emulsified with complete Freund's adjuvant (IFA) containing MTB (4 mg / mL) released at the base of the tail. On day 7 after primary immunization, animals should be treated by booster injection of 300 pg CII in incomplete Freund's adjuvant by intradermal injection at the base of the tail. The onset of arthritis in ankle joints generally becomes visually apparent between days 12 and 14. Animals should be treated with the test compound or vehicle (orally administered) from the beginning of arthritis until the end of the experiment (day 28) as a therapeutic group. Arthritis scores should be taken for visual assessment for signs of joint inflammation regularly throughout the study period. Body weights and paw volumes, paw thickness should be taken on day 0, 3, 7, 10, 12, 14, 17 21, 24 and 28. At d28, at the end of the study, blood was drawn at necropsy and processed for serum or plasma and all joints must be taken and the front and rear legs must be fixed in 10% formalin for histopathology analysis after taking the small piece of tissue from each joint and stored at -80 ° C for cytokine analysis in fabric homogenate.
Physical classification criteria for hind and front legs: 0 = normal; 1 = 1 hind or front paw joint or minimal diffuse erythema and swelling; 2 = 2 affected front or rear leg joints or diffuse mild erythema and swelling; 3 = 3 front or rear paw joints or diffuse moderate erythema and swelling; 4 = diffuse marked erythema and swelling, or = 4 affected digital joints); 5 = severe diffuse erythema and severe swelling of the entire paw, unable to flex fingers).
Test 11: Cell infiltration induced by acute CSE in male Balb / c mice: The animals must be acclimatized for several days before the beginning of the experiment. The animals are then randomly distributed into several groups based on their body weights. On day 1, the mice are administered by test compound or vehicle by oral / intranasal route and after 1 hr of administration of the test compound are anesthetized with ether and cigarette smoke extract must be administered intranasally in a volume of 50 pl / mice c CSE exposure to animals was repeated daily after administration of the test compound for four days (dl to d4). On day 5, 24 hours after CSE exposure, the animals are exsanguinated in anesthesia, and the trachea must be cannulated and the lungs are washed with 0.5 ml aliquots of heparinized PBS (1 unit / ml) four times through the cannula. tracheal (total volume 2 ml). BAL should be stored at 2-8 ° C until evaluated for total cell and differential leukocyte count. Bronchialveolar fluid should be centrifuged (500xg for 10 min) and the resulting cell pellet should be resuspended in 0.5 ml of heparinized saline. The total number of white blood cells should be determined in BAL fluid and sample using a blood cell counter and adjusted to 1x106 cell / ml. The differential count must be calculated manually. Forty microliters of the cell suspension should be centrifuged using cytospin 3 to prepare a cell smear. The cell smear should be stained with a blood staining solution for differentiation and microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear must be determined and expressed as a percentage, and the number of neutrophils and macrophages in each BALf must be calculated.
Trial 12: Cell infiltration induced by sub-chronic CSE in male Balb / c mice: The animals must be acclimatized for seven days before the beginning of the experiment. The animals are then randomly distributed into several groups based on their body weights. On day 1, the animals are anesthetized with ether and extract of cigarette smoke extract must be administered intranasally in a volume of 50 pl / mouse and CSE exposure to animals repeated daily for eight days (dl to d8). On day 9, the mice are administered by the test compound or by oral / intranasal route and after 1 hr the administration of the test compound the animals must be anesthetized with ether and cigarette smoke extract must be administered intranasally in a volume of 50pl / mice and animals are exposed to CSE daily after administration of test compound for the next three days (d9 to dl 1). on day 12, twenty-four hours after the last exposure to CSE the animals are exsanguinated under anesthesia, and the trachea must be cannulated and the lungs must be washed with 0.5 ml aliquots of heparinized PBS (1 unit / ml) four times through the tracheal cannula (total volume 2 ml). BAL should be stored at 2-8 ° C until evaluated for total cell and differential leukocyte count. Bronchialveolar fluid was centrifuged (500 * g for 10 min) and the resulting cell pellet should be resuspended in 0.5 ml of heparinized saline. The total number of white blood cells should be determined in BAL fluid and blood using a blood cell counter and adjusted to 1 * 106 cells / ml. The differential count must be calculated manually. Forty microliters of the cell suspension should be centrifuged using cytospin 3 to prepare a cell smear. The cell smear should be stained with a blood staining solution for differentiation and microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear must be determined and expressed as a percentage, and the number of neutrophils and macrophages in each BALf must be calculated.
Trial 13: reversal of corticosteroid insensitivity in a model of lung inflammation induced by cigarette smoke extract (COPD):
Female Balb / c mice should be anesthetized for seven days prior to the start of the experiment. The animals are then randomly distributed into several groups based on their body weights. On day 1, animals must be anesthetized with ether and extract of cigarette smoke must be administered intranasally in a volume of 50 pl / mouse and animals must be exposed to CSE daily for the next five days (dl to c). On day 7, the mice should be administered 10 mg / kg dexamethasone by oral gavage and 60 mins later, the mice should be administered with CSE intranasally and should be repeated for the next four days (d7 to dl 1). From day 9 to day, animals must be administered the test compound or vehicle orally / intranasally and 30 mins after dexamethasone administration and 30 mins later the animals must be anesthetized with ether and cigarette smoke extract must be administered intranasally. in volume of 50pl / mouse and animals must be exposed to CSE daily after administration of the test compound for the next two days (ie, d9 to dl 1), at dl 2, twenty-four hours after exposure to CSE the animals are exsanguinated in anesthesia, and the trachea must be cannulated and the lungs must be washed with 0.5 ml in heparinized PBS aliquots (1 unit / ml) four times through the tracheal cannula (total volume 2 ml). BAL should be stored at 2-8 ° C until evaluated for total cell and differential leukocyte count. Bronchialveolar fluid should be centrifuged (500 * g for 10 min) and the resulting cell pellet should be resuspended in 0.5 ml of heparinized saline. The total number of white blood cells should be determined in BAL fluid and sample using a blood cell counter and adjusted to l> <106 cells / ml. The differential count must be calculated manually. Forty microliters of the cell suspension should be centrifuged using cytospin 3 to prepare a cell smear. The cell smear should be stained with a blood staining solution for differentiation and microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear must be determined and expressed as a percentage, and the number of neutrophils and macrophages in each BALf must be calculated.
Test 14: Cell infiltration induced by acute cigarette smoke in male Balb / c mice:
The animals must be acclimatized for seven days before the beginning of the experiment. The animals are then randomly distributed into several groups based on their body weights. On day 1, mice should be administered as a test compound or vehicle by oral / intranasal route and after 1 h of administration of the test compound the animals are placed in a full body exposure box. On day 1 and d2, mice are exposed to smoke from the mainstream of 6 cigarettes and 8 cigarettes on day 3, and 10 cigarettes on day 4. Exposure to smoke from each cigarette lasts 10 min (cigarettes are completely burned in first two minutes and followed by an air flow with an animal fan and the next 20 min of exposure with fresh ambient air). After each second cigarette, an additional 20 min break with exposure to fresh ambient air should be conducted. Control animals must be exposed to an ambient air chamber. From day 1 to d4 animals are administered test compound orally or intranasally. On day 5, 24 hours after exposure of the last cigarette (CS) animals are exsanguinated under anesthesia, and the trachea must be cannulated and the lungs are washed with 0.5 ml aliquots of heparinized PBS (1 unit / ml) four times through cannula (total volume 2 ml). Bronchialveolar (BAL) should be stored at 2-8 ° C until evaluated for total cell and differential leukocyte count. BAL fluid must be centrifuged (500xg for 10 min) and the resulting cell pellet is resuspended in 0.5 ml of heparinized saline. The total number of white blood cells should be determined in BAL fluid and sample using a blood cell counter and adjusted to 1x106 cell / ml. The differential count is calculated manually. Forty microliters of the cell suspension are centrifuged using cytospin 3 to prepare a cell smear. The cell smear is stained with a blood staining solution for differentiation and microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear is determined and will be expressed as a percentage, and the number of neutrophils and macrophages in each BALf must be calculated.
Trial 15: accumulation of eosinophil and nasal neutrophil induced by Ovalbumin in mice:
The animals must be acclimatized for seven days before the beginning of the experiment. The animals are then randomly distributed into several groups based on their body weights. Animals are then immunized with OVA (40 pg / kg ip) on day 1 and 5. To induce local inflammatory responses in the nose, mice are repeatedly challenged intrasally (10O / L / nostril) on days 12-19 with OVA (3 % OVA in saline). On day 19, non-fasted mice should be dosed intranasally (10pL / nostril) with vehicle or test compound 2 hours before the start of the final OVA challenge. Two hours later, each animal must be received for a final intranasal OVA ((3%) challenge). After an additional 8 hr, each animal must be anesthetized and nasal lavage must be performed by instillating 1 ml of PBS in the posterior nostrils through a tracheal cannula rostrally implanted in a position that is approximately 1 mm before the posterior nostrils. This procedure must be repeated to generate a yield of approximately 2 ml of washing fluid. The total cell number in nasal lavage fluid samples should be measured using a hematocytometer. Cytospin smears from nasal lavage fluid samples should be prepared by centrifugation at 1200 rpm for 2 min in RT and stained using a Diff-Quik staining system (Dade Behring) for differential cell counts. The cells must be counted using oil immersion microscopy.
Test 16: Cell accumulation induced by Poly-1: C in mice:
A / J mice free of specific pathogens (male, 5 weeks old) must be acclimatized for seven days before the start of the experiment. The animals are then randomly distributed into several groups based on their body weights. Animals should be administered intranasal poly (1: C) -LMW (poly-IC; 1 mg / mL, 40 pL) twice a day for 3 times under anesthesia with 3% isoflurane. Animals should be treated with the test compound intranasally (35 pL of solution in 50% DMSO / PBS) 2hr before each treatment of poly-1: C. Twenty-four hours after the last challenge of poly-1: C, animals are anesthetized, the trachea must be cannulated and BALF must be collected. The concentrations of alveolar macrophages and neutrophils in BALF should be determined using a blood cell counter and adjusted to 1 * 106 cells / ml. The differential count is calculated manually. Forty microliters of the cell suspension are centrifuged using cytospin 3 to prepare a cell smear. The cell smear is stained with a blood staining solution for differentiation and microscopically observed to identify eosinophils according to morphological characteristics. The number of each cell type among 300 white blood cells in the cell smear is determined and will be expressed as a percentage, and the number of neutrophils and macrophages in each BALf must be calculated.
Although the invention has been described here with reference to particular embodiments, it should be understood that those embodiments are merely illustrative of the principles and applications of the present invention. It should, therefore, be understood that numerous modifications can be made to the illustrative modalities and that other arrangements can be designed without departing from the spirit and scope of the present invention as described above. It is intended that the attached claims define the scope of the invention and that the methods and structures within the scope of these claims and their equivalents are thus covered.
All publications and patents and / or patent applications cited in this application are hereby incorporated by reference to the same extent as if each individual publication or patent application were individually and specifically indicated to be incorporated by reference here.

权利要求:
Claims (8)
[0001]
1. Compound, characterized by the fact that it is selected from: 2- (6-Amino-9H-purin-9-yl) methyl) -3- (3-fluorophenyl) -5-methoxy-4H-chromen-4-one; 2 - ((4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -3- (3-fluorophenyl) -5-methoxy -4H-chromen-4-one; 2 - ((4-amino-3- (3-fluor-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2 - (((4-amino-3- (3-fluoro-5-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; 2 - (((4-amino-3- (3-fluoro-5-hydroxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (+) - 2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one; (-) - 2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5 - fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (+) - 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (-) - 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (1 H-pi razol-4-i) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-f I uor-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (6-amino-9H-purin-9-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) -5-fluorine-3- phenyl-4H-chromen-4-one; 2- (1 - (4-amino-3- (benzofuran-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i) eti I) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluoren i I) -4 H - chromen-4-one; (+) - 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluoren i I ) -4 H-chromen-4-one; (-) - 2- (1 - (4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluorine ni I ) -4 H-chromen-4-one; 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) -5-fluorine-3- (1H-pyrazol-4-yl) -4H-chromen-4-one; 2- (1- (4-amino-3- (3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl ) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (3-isopropyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) - 5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (3-fluorine-4- (P> Per'din-4-yloxy) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl ) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (3-fluoro-4- (2-hydroxyethylamino) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluorine-4 - (> soProP ', aminoXenyl) "1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine -3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (4- (dimethylamino) -3-fluorophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluor-4-morpholinophenyl ) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - ( 4-amino-3- (2-methyl-1 H-benzo [d] imidazol-5-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-fluorine-4- (4-methylpiperazin-1-i I) fe ni I) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4- (dimethylamino) -1 H-pyrazolo [3,4-d] pyrimidin-1-i) ethyl (I) -5-fluor-3- (3-fluorophen) - one; 2- (1 - (4- amino-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (4-fluoren i) -4 H-chromen-4-one; 2 - (1 - (4-amino-3- (4- (difluoromethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3- ( 4-f luorfenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorfeml) -1 H-pyrazolo [3,4-d] piπmidin-1 - yl) ethyl) -5-fluoro-3- phenyl-4H-chromen-4-one; 2- (1 - (4-ammo-3-methyl-1 H-pyrazolo [3,4-d] piπmidin-1-i I) ethyl I) -5-fluor-3- (3-fluoren 11 ) - 4H-chromen-4-one; 2- (1 - (4-amino-3-ethyl-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluorine i) - 4H-chromen-4-one; 2- (1 - (4-amino-3-isopropyl-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluorophenyl) - 4H-chromen-4-one; 2- (1 - (4-ammo-3- (benzo [b] thiophen-2-yl) -1 H-pyrazolo [3,4-d] pinmidin-1 -i I) eti I) -5-f I uor- 2 - „-,« «.« no-, “K" - “K" - .. fluor-3- (3-fluorfeml) -4H-chromen-4-one 4-methylbenzenesulfonate; 2- (1 - (4-amino-3- (3-methyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5 - fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate; 2- (1- (4-amino-3- (4- (1-benzhydrylazetidin-3-yloxy) -3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2 ^ 1 ^ 4 "to ^ 2 ° '3' ^ fluor'4'tnfluormetoxlfeni'1H'pirazoo3'4'dpinmidin'1 'il) ethyl) -5-fluor-3- (3-fluorfeml) -4H-chromen -4-one; 2- (1 - (4-amino-3- (3-fluoro-4- (oxetan-3-yloxy) phenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl ) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (d- (4-amino-34piiTolidin-1-yl) -1H-pyrazolo [3,4-d ] pinirnidin-1-yl) ethyl) -5-fluor-3- (3-fluoreml) -4H-chromen-4-one; N- (4- (4-amino-1 - (1 - (5-fluorine- 3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3,4-d] pyrimidin-3-yl) phenyl) isobutyramide; 2- (1 - ( 4-amino-3- (4-isobutylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3- (3-fluorophenyl) -4H- chromen-4-one; 2- (1 - (4-amino-3- (4-isopropoxy-3-methylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) eti I) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 24144-arnino-3- (4- (5,6-dihydro-4H-1 3-oxazin-2-yl) phenyl ) -1H-pyrazolo [3,4-d] pinmidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; pyrazolo [3,4-d] pinmidin -3-yl) -N-methylbenzenesulfonamide, pyrazolo [3,4-d] pyrimidin-3-yl) -2-fluor-N-isoprop ilbenzamide, 2- (1- (4-amino-3- (4- (5- (methylamino) -1,3,4-thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4- d] pinmidin -1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; N- (4- (4-ammo-1 - (1 - (5-fluor-3- (3-fluorfeml) -4-oxo-4H-chromen-2-yl) ethyl) -1 H- Pirszoio [3.4- dipinm> ain-3-ii) -N-> soe.opi! b8nzenosuiionsmide pyrazolo [3,4-d] pinmidin-3-yl) -N-cyclopropylbenzenesulfonamide; 2- (1 - (4-amino-3- (2-isopropoxypyrimidin-5-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) - Müor ^ uorfeniHH-chromen ^ at; (R) / (S) -2- (1 - (4-amino-3- (3-fluor-4-morfohnophenyl) -1 H-pyrazolo [3,4-d] pinmidin-1 - yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3,4-d ] pyrimidin-3-yl) benzenesulfonamide; methyl 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3,4- d] pyrimidin-3-yl) thiophene-2-carboxylate; 2- (1 - (4-amino-3- (5-methylthiophen-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (1 H-pyrrolo [2,3-b] pyridi n-5-i I) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; methyl 4- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3,4- d] pyrimidin-3-yl) -3-fluorbenzoate; 2- (1- (9H-purin-6-ylamino) propyl) -5-fluorine-3-phenyl-4H-chromen-4-one; 2- (1 - (4-amino-3- (3-hydroxyprop-1-in I) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluorine-3 - (3-fluorophenyl) -4H-chromen-4-one; (S) / (R) -2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one 4-methylbenzenesulfonate; (+) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (R) / (S) -2- (1 - (4-amino-3- (3-fluor-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (4-methoxy-3,5-dimethylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) - 5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (4- (methoxymethyl) phenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluorine-3- ( 3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (imidazo [1,2-a] pyridin n-6-i I) -1 H-pyrazolo [3,4-d] pyrimidin-1 -i I) ethyl I) - 5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; tert-butyl (5- (4-amino-1 - (1 - (5-fluor-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazole [3 , 4-d] pyrimidin-3-yl) furan-2-yl) methylcarbamate; 2- (1 - (4-amino-3- (2,4-dimethylthiazol-5-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (5- (morpholinomethyl) thiophen-2-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3 - (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (4- (5-amino-1,3,4-thiadiazol-2-yl) phenyl) -1H-pyrazolo [3,4-d] pinmidin-1-yl ) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; (-) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (1,3-dimethyl-1 H-indazol-6-yl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) - 5 -fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 5-fluor-3- (3-fluorfeml) -4H-chromen-4-one; N- (4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazole [3, 4-d] pyrimidin-3-yl) -2-fluorophenyl) isobutyramide; N- (4- (4-amino-1 - (1 - (5-fluorine-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazole [3, 4-d] pyrimidin-3-yl) -2-fluorophenyl) acetamide; 2- (1 - (4- (dimethylamino) -3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one; ... S-íliJor-S-ll-IS-p-SuoM-isopropoxyenill-i-morpholium-IH-piraiololS.a-aipininidin- IH-pyrazoloISd-dlpinmidm-S-illíeriIpsobutiramids, «« .PM (S) / ( R) -2- (1 - (4-amino-3- (3-fluor-4-isopropoxyfeml) -1 H-pyrazolo [3,4-d] pinmidin-1 - ™ Rb2i ("<)«. H. .poW3. «pBp, 1HK ~ ^., yl) ethyl) -5-fluor-3- (3-fluorfeml) -4H-chromen-4-one camphorsulfonate; 2- (1 - (4-amino-3- ( 4- (difluoromethoxy) -3-fluorophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (1H-pyrazol-4-yl) -4H-chromen -4-one; 2- (1 - (4-amino-3- (3-fluor-4-morfohnofeml) -1 H-pyrazolo [3,4-d] pinmidin-1 -i I) eti I) -5 - .. fluor-3- (4-fluorfeml) -4H-chromen-4-one; (S) -2- (1 - (4-amino-3- (3-fluor-4-isopropoxyphenyl) -1 H- pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor-3- (4-fluorophenyl) -4H-chromen-4-one; (R) -2- (1 - (4-amino -3- (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro-3- (4-fluorophenyl) -4H-chromen-4 -one; (S) -2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorfeml) -1 H-pyrazolo [3,4-d] piπmidin-1 - yl) ethyl) -5-fluorine-3- (4-fluorophenyl) -4H-chromen-4-one; (R ) -2- (1 - (4-amino-3- (4- (difluormethoxy) -3-fluorfeml) -1 H-pyrazolo [3,4-d] piπmidin-1 - yl) ethyl) -5-fluor- 3- (4-fluorophenyl) -4H-chromen-4-one; 2- (1 - (4- (dimethylamino) -3- (3-fluor-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; 5-fluorine-2- (1- (3- (3-fluorine-4-morpholinophenyl) -4- (methylamino) -1H-pyrazolo [3,4-dlplri ^ dip-1-) l) θlll) -3- (3-fluorfθp !!) - 4H-cromβp-4-ops; (S) -2- (1 - (4-amino-3- (3-fluor-4-isopropoxyfeml) -1 H-pyrazolo [3,4-d] piπmidin-1 - .w∞PMK ^ π ^ p. ^ w 3 «Wpo« .n <). 2.l, ^^ 5-fluor-3- (4-fluorophenyl) -2- (1- (6- (4-methylpiperazin-1-yl) -9H-puπn -9-yl) ethyl) -4H-one; 2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen -4- one; 5-fluorine-3- (3-fluorophenyl) -2- (1 - (3- (3-methyl-1 H-indazol-6-yl) -4-morpholino-1 H-pyrazole [3 , 4-d] pyrimidin-1-yl) ethyl) -4H-chromen-4-one; 2- (1 - (4-amino-3- (3-chloro-4-morfohnofeml) -1 H-pyrazole [3 , 4-d] piπmidin-1 -i I) ethyl I) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (+) - 2- (1 - (4-ammo- 3- (4-isopropoxy-3-methylphenyl) -1 H-pyrazolo [3,4-d] piπmidin-1 - yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4- (-) - 2- (1 - (4-amino-3- (4-isopropoxy-3-methylphenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5- fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (S) / (R) -5-fluorine-2- (1- (3- (3-fluorine-4-isopropoxyphenyl) -4- morpholino-1H-pyrazolo [3,4- 2- (1 - (4-ammo-3- (3-chloro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] piπmidin-1 -i I) eti I) - 2-, | 4-.W ... S41p «.l3— 2- (1 - (4-ammo-3- (3-fluor-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-d] piπmidin-1 -i I) ethyl I) -5-pyrazole [3, 4-d] piπmidin-3-yl) isoindohn-1-one; 2- (1 - (3- (4-acetyl-3-fluorophenyl) -4-amino-1 H-pyrazolo [3,4-d] pyrimidin-1-i I) ethyl I) -5-f uor- SO-fluorophenylHH-chromen ^ -one; 5-fluor-3- (3-fluorophenyl) -2- (1- (6- (4-methylpiperazin-1-yl) -9H-puπn-9-yl) ethyl) -4H-chromen-4-one; (S) -2- (1 - (4-amino-3- (3-chloro-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluor- 3- (3-fluorophenyl) -4H-chromen-4-one; (R) -2- (1 - (4-amino-3- (3-chloro-4-morpholinophenyl) -1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) ethyl) -5-fluoro- 3- (3-fluorophenyl) -4H-chromen-4-one; N- (3- (4-amino-1 - (1 - (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl) -1 H-pyrazolo [3, 4-d] pyrimidin-3-yl) phenyl) methanesulfonamide; (S) -2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one; (R) -2- (1- (6- (dimethylamino) -9H-purin-9-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-2-one; 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluorine-3- (2-fluorophenyl) -4H-cronnen-4-one; 2- (1- (4-amino-3- (4-ethoxy-3- (trifluormethyl) phenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluor-3- (3-fluorophenyl) -4H-chromen-4-one; 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) propyl) -5-fluoro-3- (3- fluorfenyl) -4H-chromen-4-one; (S) -5-fluorine-3- (3-fluorophenyl) -2- (1- (2-methoxy-9H-purin-6-ylamino) ethyl) -4H-chromen-4-one; (R) -5-fluorine-3- (3-fluorophenyl) -2- (1- (2-methoxy-9H-purin-6-ylamino) ethyl) -4H-chromen-4-one; (S) / (R) -5-fluorine-2- (1- (2-fluorine-9H-purin-6-ylamino) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one; (S) / (R) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5 -methyl-3-phenyl-4H-chromen-4-one; 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluoro-3-o-tolyl-4H-chromen-4-one; and pharmaceutically acceptable salts thereof.
[0002]
2. Compound according to claim 1, characterized by the fact that the compound of formula I is 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazole [3, 4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one or a pharmaceutically acceptable salt thereof.
[0003]
3. Compound according to claim 1, characterized by the fact that the compound of formula I is (+) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one or a pharmaceutically acceptable salt thereof.
[0004]
Compound according to claim 1, characterized by the fact that the compound of formula I is (-) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluorine-3- (3-fluorophenyl) -4H-chromen-4-one or a pharmaceutically acceptable salt thereof.
[0005]
Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
[0006]
A compound according to any one of claims 1 to 5, characterized in that it is for use in the treatment of a disease or disorder associated with PI3-K selected from leukemia, pulmonary neutrophilia, inflammation, arthritis and inflammatory diseases pulmonary.
[0007]
7. Compound according to claim 6, characterized by the fact that the disease, disorder or condition associated with PI3K is selected from chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, chronic bronchitis, inflammatory bowel disease, allergic rhinitis, lupus erythematosus and ulcerative colitis, hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hematopoietic tumors of myeloid lineage, acute myeloid leukemias, chronic myeloid leukemias, myeloid multiple myelosis refractory, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma.
[0008]
8. Compound according to claim 6, characterized by the fact that the disease, disorder or condition associated with PI3-K is selected from chronic obstructive pulmonary disease, asthma, Chronic Lymphocytic Leukemia (CLL); Acute Myeloid Leukemia (AML); and Multiple Myeloma (MM).

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-03-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-11-05| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-02-27| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-07-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 04/05/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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IN1542CH2011|2011-05-04|

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IN1542/CHE/2011|2011-05-04|

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IN81CH2012|2012-01-09|

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IN81/CHE/2012|2012-01-09|

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PCT/US2012/036594|WO2012151525A1|2011-05-04|2012-05-04|Novel compounds as modulators of protein kinases|

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