SK3842001A3 - Pyrrolopyrimidines as protein kinase inhibitors (revised) - Google Patents

Abstract

Chemical compounds having structural formula (I) and physiologically acceptable salts and metabolites thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the kinases, whose activity is inhibited by these chemical compounds, are involved in immunologic, hyperproliferative, or angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyper proliferative disorders, rheumatoid arthritis, disorders of the immune system, transplant rejections and imflammatory disorders.

Description

Pyrolopyrimidines as protein kinase inhibitors (revised)

Related Applications

This application refers to U.S. application Ser. 60 / 100,832, filed Sep. 18, 1998; 60 / 100,833, filed Sep. 18, 1998; 60 / 100,834 filed September 18, 1998 and 60 / 100,946 filed September 18, 1998.

BACKGROUND OF THE INVENTION

There are at least 400 enzymes that are identified as kinases. These enzymes catalyze the phosphorylation of target protein substrates. Phosphorylation is usually a reaction of transfer of a phosphate group from ATP to a protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine / threonine kinases.

Phosphorylation reactions and reverse phosphatase reactions to tyrosine, dimeric and threonine residues are involved in innumerable cellular processes that underlie responses to a variety of intercellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. The protein kinase cascade is often involved in intercellular signal transduction and is required for the realization of these cellular processes. Because of their ubiquity in these processes, protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or located in the nucleus, often as components of enzyme complexes. In many cases, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process takes place in a cell.

Protein tyrosine kinases. Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins.

This post-translational modification of these substrate proteins, often the enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (see Schlessinger and Ulrich, 1992, Neuron 9: 383-391 for a review). Aberrant or excess PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inadequate immune system activation (e.g., autoimmune disorders), allograft rejection, and graft versus host disease. In addition, endothelial cell-specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process and are thus involved in promoting the progression of cancers and other diseases involving inadequate vascularization (e.g. diabetic retinopathy, coil neurovascularization due to age-related macular degeneration) , psoriasis, arthritis, premature retinopathy, infantile hemangiomas).

Tyrosine kinases can be of the receptor type (with extracellular, transmembrane and intracellular domains) or of the non-receptor type (completely intracellular).

Receptor tyrosine kinases (RTKs). RTKs represent a large family of transmembrane receptors with a variety of biological activities. At least nineteen (19) different RTK subfamilies are currently identified. The receptor tyrosine kinase (RTK) family includes receptors that are key to the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57: 433-478, 1988; Ullrich and Schlessinger, Ce // 61: 243- 254 (1990). The intrinsic function of RTKs is activated by ligand binding, which leads to phosphorylation of the receptor and multiple cellular substrates and consequently to a number of cellular responses (Ullrich and Schlessinger, 1990, Cell 61: 203-212). Thus, receptor tyrosine kinase-mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), usually followed by receptor dimerization, stimulation of intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. This creates binding sites for intracellular signal transduction molecules, and this leads to complexes with a spectrum of cytoplasmic signaling molecules that facilitate the respective cellular response. E.g. cell division, differentiation, metabolic effects, changes in the extracellular microenvironment), see Schlessinger and Ullrich, 1992, Neuron 9: 120.

Proteins with SH2 binding domains (src homology -2) or phosphotyrosine (PTB) bind activated tyrosine kinase receptors and their substrates with high affinity and propagate signals to the cell. Both of these domains recognize phosphotyrosine. (Fantl et al., 1992, Ce // 69: 413-423; Songyang et al., 1994, Mol. Cell. Biol. 14: 2777-2785; Songyang et al., 1993, Ce // 72: 767-778; and Koch et al., 1991, Science 252: 668-678, Shoelson, Curr Opin, Chem Biol (1997), 1 (2), 227-234, Cowburn, Curr Opin, Struct Biol (1997) 7 (6), 835-838. Several intracellular substrate proteins have been identified that associate with receptor tyrosine kinases (RTKs). They can be divided into two basic groups: (1) substrates having a catalytic domain; and (2) substrates which do not have such a domain, but which serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Ce // 72: 767-778). The specificity of the interactions between receptors or proteins and the SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in binding affinities between SH2 domains and amino acid sequences flanking phosphotyrosine residues at particular receptors correlate with observed differences in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72: 767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its expression and ligand availability patterns, but also by a number of downstream signal transduction pathways that are activated by a particular receptor as well as by the timing and duration of these stimuli. Phosphorylation thus provides an important regulatory step that determines the selectivity of signaling pathways obtained by specific growth receptors as well as differentiation of factor receptors.

Several receptor tyrosine kinases, such as FGFR-1, PDGFR, TIE-2 and c-Met, are reported to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. Cell Biol 129: 895-898, 1995). One such receptor tyrosine kinase, known as "fetal liver kinase 1" (FLK-1), is a member of the type III RTK subclass. An alternative term for human FLK-1 is "kinase insert domain-containing receptor" (KDR) (Terman et al., Oncogene 6: 1677-83, 1991). Another alternative designation for FLK-1 / KDR is "vascular endothelial cell growth factor receptor 2" (VEGFR-2) because it binds VEGF with high affinity. The murine version of FLK-1 / VEGFR-2 is also called NYK (Oelrichs et al., Oncogene 8 (1): 11-15, 1993). DNA encoding murine, rat and human FLK-1 was isolated and the nucleotide and encoded amino acid sequences were disclosed (Matthews et al., Proc. Natl. Acad. Sci. USA, 88: 9026-30, 1991; Terman et al., 1991 Terman et al., Biochem. Biophys. Res Comm. 187: 1579-86, 1992; Sarzani et al., supra; and Millauer et al., Cell 72: 835-846, 1993). Numerous studies, such as those reported by Millauer et al., Supra, suggest that VEGF and FLK-1 / KDR / VEGFR-2 are a ligand-receptor pair that plays an important role in vascular endothelial cell proliferation and vascular formation and branching, vasculogenesis and angiogenesis.

Another RKT subclass of type III designated "fms-like tyrosine kinase-1" (Flt-1) is related to FLK-1 / KDR (DeVries et al. Science 255; 989-991, 1992; Shibuya et al., Oncogene 5: 519-524 (1990). An alternative term for Flt-1 is "vascular endothelial cell growth factor receptor 1" (VEGFR1). To date, members of the FLK-1 / KDR / VEGFR-2 and FIH / VEGFR-1 subfamilies have been found as expression products on endothelial cells. These members of the subclasses are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-270, 1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with higher affinity than FLK-1 / KDR and is mitogenic to vascular endothelial cells (Terman et al., 1992, supra; Mustonen et al. Supra; DeVries et al. supra). Flt-1 is believed to be essential for endothelial organization during vascular development. Expression of Flt-1 is associated with early vascular development in mouse embryos and with neovascularization during wound healing (Mustonen and Alitalo, supra). Expression of Flt-1 in monocytes, osteoclasts and osteoblasts as well as in r

adult tissues such as kidney glomeruli suggest an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra).

As previously reported, new data suggest that VEGF plays a role in stimulating both normal and pathogenetic angiogenesis (Jakeman et al., Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and Treatment 36: 139-155). , 1995; Ferrara et al., Endocrine Reviews 18 (1); 4-25, 1997; Ferrara et al., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 209-232, 1997). In addition, VEGF has been implicated in controlling and improving vascular permeability (Connolly, et al., J. Biol. Chem. 264: 20017-20024, 1989; Brown et al., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 233269,1997). Various forms of VEGF resulting from alternative mRNA cleavage have been reported, including the Four forms described by Ferrara et al. (J. Cell Biochem. 47: 211-218, 1991). Both secreted and predominantly cell-associated VEGF types have been identified by Ferrara et al. supra and protein are known to exist in the form of disulfide linked dimers.

Recently, several related VEGF homologues have been identified. However, their roles in normal physiological and disease processes have not yet been explained. In addition, members of the VEGF family are often coexpressed with VEGF in several tissues and are generally capable of forming heterodimers with VEGF. This property is likely to alter receptor specificity and biological effects of heterodimers and further complicate the explanation of their specific functions, as illustrated below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159-164, 1998 and references cited therein).

Placental growth factor (PIGF) has an amino acid sequence that exhibits significant homology to the VEGF sequence (Park et al., J. Biol. Chem. 269: 25646-54, 1994; Maglione et al. Oncogene 8: 925-31, 1993). As with VEGF, various PIGF species are derived from alternative mRNA cleavage and the protein exists in dimeric form (Park et al., Supra). PIGF-1 and PIGF-2 bind to Flt-1 with high affinity, and PIGF-2 also intensively binds to neuropilin-1 (Migdal et al, J. Biol. Chem. 273 (35): 22272-22278), but none of these binds to FLK-1 / KDR (Park et al., supra). PIGF has been reported to potentiate both the vascular permeability and the mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (allegedly due to heterodimer formation) (Park et al., Supra).

VEGF-B is produced in two isoforms (167 and 185 residues), which also appear to bind Flt-1 / VEGFR-1. It may play a role in regulating extracellular matrix degradation, cell adhesion and migration through modulation of urokinase-type plasminogen activator expression and activity and plasminogen activator inhibitor 1 (Peppera, Proc. Natl. Acad. Sci. USA (1998), 95 (20): 11709 -11,714).

VEGF-C was originally cloned as a ligand for VEGFR-3 / Flt-4, which is primarily expressed by lymphatic endothelial cells. In its fully processed form, VEGF-C can also bind KDR / VEGFR-2 and stimulate endothelial cell proliferation and migration in vitro and angiogenesis in in vivo models (Lymboussaki et al, Am. J. Pathol. (1998), 153 (2)). Witzenbichler et al, Am J Pathol (1998), 153 (2), 381-394). Transgenic overexpression of VEGF-C causes proliferation and enlargement of only lymphatic vessels, while blood vessels remain unaffected. In contrast to VEGF, VEGF-C expression is not induced by hypoxia (Ristimaki et al, J. Biol. Chem. (1998), 273 (14), 8413-8418).

The most recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D is reported to bind and activate at least two VEGFRs, VEGFR-3 / FI-4 and KDR / VEGFR-2. It was originally cloned as a mitogen-inducible c-fos for fibroblasts and is most expressed in mesenchymal lung and skin cells (Achen et al., Proc. Natl. Acad. Sci. USA (1998), 95 (2), 548-553 and cited therein). references).

With respect to VEGF, it is claimed that VEGF-C and VEGF-D induce increases in vascular permeability in vivo in the Miles assay when injected into cutaneous tissue (PCT / US97 / 14696; WO98 / 07832, Witzenbichler et al., Supra). The physiological role and importance of these ligands in modulating vascular hyperpermeability and endothelial responses in tissues where they are expressed remains uncertain.

Recently, a virally encoded novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), has been emerging, which utilizes the receptor

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KDR / Flk-1 and has potent mitotic activity without the heparin binding domain (Meyer et al., EMBO J. (1999), 18 (2), 363-374; Ogawa et al., J. Biol. Chem. (1998), 273 ( 47), 31273-31282.). The VEGF-E sequences have 25% homology to mammalian VEGF and are encoded by the parapoxvirus Orpha virus (OV). This parapoxvirus, which affects sheep and goats and occasionally humans, generates lesions with angiogenesis. VEGF-E is a dimer of about 20 kDa with no base domain or affinity for heparin, but has a characteristic cysteine node motif present in all mammalian VEGFs and surprisingly found to possess the heparin-like potency and bioactivity of the VEGF165 isoform VEGF-A, ie both factors stimulate tissue factor (TF) release, proliferation, chemotaxis, and budding of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF165, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR), resulting in receptor autophosphorylation and a biphasic increase in free intracellular Ca ²⁺ concentrations, whereas VEGF-? E did not bind to VEGF receptor-1 (Flt-1).

Based on the emerging discoveries of other VEGF and VEGFR homologues and precedents for ligand and receptor heterodimerization, the actions of such VEGF homologs may include the formation of VEGF ligand heterodimers and / or receptor heterodimerization or binding to undiscovered VEGFR (Witzenbichler et al., Supra). Recent studies also suggest that neuropilin-1 (Migdal et al, supra) or VEGFR-3 / Flt-4 (Witzenbichler et al., Supra) or receptors other than KDR / VEGFR-2 may be involved in the induction of vascular permeability (Stacker , SA, Welcomed, A., Domagala, T., Nice, E., and Wilks, AF, Angiogenesis and Cancer Conference, Amer. Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40 S118-120 (1997).

Tie-2 (TEK) is a member of the recently discovered endothelial cell-specific receptor tyrosine kinase family, which is involved in critical angiogenic processes such as branching, budding, reshaping, maturation, and vascular stability. Tie-2 is the first mammalian receptor tyrosine kinase for which agonist ligands (e.g., Angiopoietin1 ('Ang1') that stimulate receptor autophosphorylation and signal transduction), as well as antagonist ligands (e.g.

r fi · r

Angiopoietin2 ("Ang2")). Knock-out and transgenic manipulation of Tie-2 expression and its ligands indicates that strict spatial and temporal control of Tie-2 signaling is essential for proper development of a new vasculature. The current model suggests that stimulation of Tie-2 kinase by Ang1 ligand is directly involved in the branching, budding and growth of new vessels and the enhancement and interaction of periendothelial support cells important in maintaining vessel integrity and inducing rest. The absence of Ang1 stimulation of Tie-2 or inhibition of Tie-2 autophosphorylation by Ang2, which is produced at high levels at vascular regression sites, may result in loss of vascular structure and matrix contacts, leading to endothelial cell death, particularly in the absence of growth or survival stimuli. . However, the situation is even more complicated since at least two additional Tie-2 ligands (Ang3 and Ang4) have recently been reported and the ability to heterooligomerize different agonist and antagonist angiopoietins and thereby modify their activity has been demonstrated. Thus, focusing on ligand-receptor Tie-2 interactions as an anti-angiogenic therapeutic approach is less preferred and a kinase inhibition strategy is preferred.

The soluble extracellular domain of Tie-2 ("ExTek") may act to disrupt tumor vasculature establishment in breast cancer xenograft and lung metastasis models, and in tumor-mediated ocular neovascularization. In vivo production at mg / ml levels of ExTek in rodents can be achieved by adenoviral infection for 7-10 days without adverse side effects. These results suggest that disruption of Tie-2 signaling pathways in normal healthy animals can be well tolerated. These Tie-2 inhibitory responses to ExTek may be due to ligand sequestration and / or generation of a non-productive full-length Tie-2 heterodimer.

Recently, significant up-regulation of Tie-2 expression has been found in the vascular synovial panus of human arthritic joints, consistent with the role in inadequate neovascularization. This finding suggests that Tie-2 plays a role in the progression of rheumatoid arthritis. Point mutations producing constitutively activated forms of Tie-2 have been identified in association with human g

venous malformations. Thus, Tie-2 inhibitors are useful in the treatment of such diseases and in other situations of inadequate neovascularization.

Non-receptor tyrosine kinases. Non-receptor tyrosine kinases are a collection of cellular enzymes that lack extracellular and transmembrane sequences. More than twenty-four non-receptor tyrosine kinases containing eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK) are currently identified. Currently, the Src subfamily of non-receptor tyrosine kinases contains the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src enzyme subfamily has been associated with oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bohlen, 1993, Oncogene 8: 2025-2031, which is hereby incorporated by reference.

Many tyrosine kinases, whether RTKs or non-receptor tyrosine kinases, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions including cancer, psoriasis, and other hyperproliferative diseases or hyperimmune responses.

Development of compounds for modulating PTK. In view of the supposed importance of PTKs for the control, regulation and modulation of cell proliferation, diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify "inhibitors" of receptor and non-receptor tyrosine kinases using a number of approaches including mutant ligands. Soluble receptors and antibodies (Application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Natl. Acad. Sci 90: 10705-09; Kim et al., 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al., Biochemistry 33: 10450-56; Takano, et al., 1993, Mol. Bio. Cell 4: 358A; Kinsella, et al. 1992, Exp. Cell Res. 199: 56-62 Wright, et al., 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; US Patent No. 5,330,992); Mariani, et al., 1994, Proc. Am.Assoc. Cancer Res. 35: 2268).

Recently, attempts have been made to identify small molecules that act as tyrosine kinase inhibitors. For example, bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO) have been described as tyrosine kinase inhibitors in general.

92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808). Styryl compounds (US Patent No. 5,217,999), styryl substituted pyridyl compounds (US Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1; Expert Opin. Ther. Pat. (1998), 8 (4)) : 475-478), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxyl compounds (PCT WO 92/21660) and benzylphosphoric acid compounds (PCT WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. Anilinocinolines (PCT WO97 / 34876) and quinazoline derivatives (PCT WO97 / 22596; PCT WO97 / 42187) have been described as inhibitors of angiogenesis and vascular permeability.

In addition, attempts have been made to identify small molecules that act as serine / threonine kinase inhibitors. For example, bis (indolylmaleimide) compounds have been described as inhibitors of particular PKC serine / threonine kinase isoforms whose signal transduction function is associated with altered vascular permeability in VEGF-related diseases (PCT WC97 / 40830; PCT WO97 / 40831).

Plk-1 kinase inhibitors

Plk-1 is a serine / threonine kinase that is an important regulator of cell cycle progression. It plays a critical role in the assembly and dynamic function of the mitotic spindle apparatus. Plk-1 and related kinases have also been shown to be closely involved in the activation and deactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of Plk-1 expression are associated with cell proliferation activities. They are often found in malignant tumors of various origins. Plk-1 inhibitors are expected to block cancer cell proliferation by disrupting processes involving mitotic spindles and inadequately activated cyclin-dependent kinases.

Cdc2 / Cyclin B kinase inhibitors (Cdc2 also known as cdk1)

Cdc2 / cyclin B is another serine / threonine kinase enzyme that belongs to the cyclin-dependent kinase (cdks) family. These enzymes are involved in the critical transition between different phases of cell cycle progression. It is believed that uncontrolled cell proliferation, which is a cancer criterion, is dependent upon increased cdk activities in these cells. Inhibition of increased cdk activities in cancer cells by cdc2 / cyclin B kinase inhibitors could suppress proliferation and may restore normal control of cell cycle progression.

Regulation of CDK activation is complex, but requires association of CDK with a member of the cyclin family of regulatory subunits (Draetta, Trends in Cell Biology, 3: 287289 (1993)); Murray and Kirschner, Nature, 339: 275-280 (1989); Solomon et al., Molecular Biology of the Cell, 3: 13-27 (1992)). Another level of regulation occurs through activation and deactivation of the phosphorylation of the CDK subunit (Draetta, Trends in Cell Biology, 3: 287-289 (1993)); Murray and Kirschner, Nature, 339: 275-280 (1989); Solomon et al., Molecular Biology of the Cell, 3: 13-27 (1992); Ducommun et al., EMBO Journal 10: 3311-3319 (1991); Gautier et al., Nature 339: 626-629 (1989); Gould and Nurse, Nature, 342: 39-45 (1989); Krek and Nigg, EMBO Journal, 10: 33313341 (1991); Solomon et al., Cell, 63: 1013-1024 (1990)). Coordinated activation and deactivation of various cyclin and CDK complexes is required for normal cell cycle progression (Pines, Trends in Biochemical Sciences, 18: 195-197 (1993); Sherr, Cell, 73: 1059-1065 (1993)). The critical transitions of G1-S and G2-M are controlled by activation of various cyclin and CDK activities. It is believed that both G1 cyclins D / CDK4 and cyclin E / CDK2 mediate the onset of phase S (Matsushima et al., Molecular & Cellular Biology, 14: 2066-2076 (1994); Ohtsubo and Roberts, Science, 259: 1908-1912 (1993); Quelle et al., Genes & Development, 7: 1559-1571 (1993); Resnitzky et al., Molecular & Cellular Biology, 14: 1669-1679 (1994)). Phase S progression requires cyclin A / CDK2 activity (Girard et al., Cell, 67: 1169-1179 (1991); Pagano et al., EMBO Journal, 11: 961-971 (1992); Rosenblatt et al., Proceedings of the National Academy of Science USA, 89: 2824-2828 (1992); Walker and Maller, Nature, 354: 314-317 (1991); Zindy et al., Biochemical & Biophysical Research Communications, 182: 1144-1154 (1992)) whereas activation of cyclin A / cdc2 (CDK1) and cyclin B / cdc2 is required for the onset of metaphase (Draetta, Trends in Cell Biology, 3: 287-289 (1993)); Murray and Kirschner, Nature, 339: 275-280 (1989); Solomon et al., Molecular Biology of the Cell, 3: 13-27 (1992); Girard et al., Cell, 67: 1169-1179 (1991); Pagano et al., EMBO Journal 11: 961-971 (1992); Rosenblatt et al., Proceedings of the National Academy of Science, USA, 89: 28242828 (1992); Walker and Maller, Nature, 354: 314-317 (1991); Zindy et al.,

Biochemical & Biophysical Research Communications, 182: 1144-1154 (1992)).

Therefore, it is not surprising that the loss of control of CDK regulation is a common event in hyperproliferative diseases and cancer. (Pines, Current Opinion in Cell

Biology, 4: 144-148 (1992); Lees, Current Opinion in Cell Biology, 7: 773-780 (1995); Hunter and Pines, Cell, 79: 573-582 (1994)).

Inhibitors of kinases involved in mediating or maintaining disease states are new therapies for these disorders. Examples of such kinases include, but are not limited to: (1) inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis, 3: 401-406 (1992); Courtneidge, Seminars in Cancer Biology, 5: 236-246 (1994); (Powis, Pharmacology & Therapeutics, 62: 57-95 (1994)) and cyclin-dependent kinases (CDKs) 1, 2 and 4 in cancer (Pines, Current Opinion in Cell Biology, 4: 144-148 (1992); Lees Current Opinion in Cell Biology, 7: 773-780 (1995); Hunter and Pines, Cell, 79: 573-582 (1994)), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger et al., (3) Inhibition of CDK5 and GSK3 kinases in Alzheimer's disease (Hosoi et al., Journal of Biochemistry (Tokyo), 117: 741-749 (1995)). Aplin et al., Journal of Neurochemistry, 67: 699-707 (1996), (4) inhibition of c-Src kinase in osteoporosis (Tanaka et al., Nature, 383: 528531 (1996), (5) GSK inhibition) -3 kinases in type 2 diabetes (Borthwick et al., Biochemical & Biophysical Research Communications, 210: 738-745 (1995), (6) inhibition of p38 kinase in inflammation (Badger et al., The Journal of Pharmacology and Experimental Therapeutics, 279: 1453-1461 (1996)), (7) inhibition VEGF-R 1-3 and TIE-1 and -2 kinases in diseases involving angiogenesis (Shawver et al., Drug Discovery Today, 2: 50-63 (1997)), (8) inhibition of UL97 kinase in viral infections ( He et al., Journal of Virology, 71: 405-411 (1997)), (9) inhibition of CSF-1R kinase in bone and hematopoietic diseases (Myers et al., Bioorganic & Medicinal Chemistry Letters, 7: 421-424 ( 1997) and (10) inhibition of Lck kinase in autoimmune diseases and transplant rejection (Myers et al., Bioorganic & Medicinal Chemistry Letters, 7: 417-420 (1997)).

In addition, it is possible that inhibitors of certain kinases are useful in the treatment of diseases where the kinase is not deregulated but is nevertheless important for maintaining the disease state. In this case, inhibition of kinase activity would act either as a treatment or as a remedy for these diseases. For example, many viruses, such as human papilloma virus, disrupt the cell cycle and female cells into phase S of the cell cycle (Vousden, FASEB Journal, 7: 8720879 (1993)). When cells are prevented from entering DNA synthesis after infection by a virus by inhibiting the essential phase with initiation of activities such as CDK2, this can disrupt the life cycle of the virus by preventing virus replication. This same principle can be used to protect normal body cells from the toxicity of cyclic specific chemotherapeutic agents (Stone et al., Cancer Research, 56: 3199-3202 (1996); Kohn et al., Journal of Cellular Biochemistry, 54: 44-452 ( 1994)). Inhibition of CDK 2 or 4 will prevent progression to cycle in normal cells and reduce the toxicity of cytotoxics that act in phase S, G2 or mitosis. In addition, it has been shown that CDK2 / cyclin E activity also regulates NFκB. Inhibition of CDK2 activity stimulates NF-κB-dependent gene expression, an event mediated through interactions with p300 co-activator (Perkins et al., Science, 275: 523-527 (1997)). NF-κB regulates genes involved in inflammatory responses (such as hematopoietic growth factors, chemokines, and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology, 12: 141-179 (1994)) and can be involved in suppressing apoptotic signals in cell (Beg and Baltimore, Science, 274: 782-784 (1996); Wang et al., Science, 274: 784-787 (1996); Van Antwerp et al., Science, 274: 787-789 (1996)) . Thus, inhibition of CDK2 can suppress apoptosis induced by cytotoxic drugs by a mechanism that includes NF-κB. Thus, this suggests that inhibition of CDK2 activity may also be useful in other cases where NF-κB regulation plays a role in the etiology of the disease. Another example can be taken from fungal infections: Aspergillosis a common infection in immune-compromised patients (Armstrong, Clinical Infectious Diseases, 16: 1-7 (1993)). Inhibition of Aspergillus Cdc2 / CDC28 or Nim A kinases (Osmani et al., EMBO Journal, 10: 2669-2679 (1991); Osmani et al., Cell, 67: 283-291 (1991)) can cause developmental arrest or death of fungi thereby improving the therapeutic outcome for patients with these infections.

It is therefore desirable to identify potent small compounds that specifically inhibit signal transduction and cell proliferation by modulating the activity of receptor and non-receptor tyrosines and serine / threonine kinases to regulate abnormal or inadequate cell proliferation, differentiation or metabolism. In particular, the identification of methods and compounds that specifically inhibit tyrosine kinase function that is essential for angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates and macromolecular matrix extravasation and matrix deposition as well as related diseases would be beneficial. SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

and pharmaceutically acceptable salts thereof.

In formula I, ring A is a six-membered aromatic ring or a five- or six-membered heteroaromatic ring. Ring A is optionally substituted with one or more of the following: substituted or unsubstituted aliphatic, halogen, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR ⁴ R ⁵ , -C (O) ₂ H, OH, substituted or unsubstituted alkoxycarbonyl, -C (O) ₂ -haloalkyl, substituted or unsubstituted alkylthioether, substituted or unsubstituted alkylsulfoxide, substituted or unsubstituted alkylsulfone , substituted or unsubstituted arylthioether, substituted or unsubstituted arylsulfoxide, substituted or unsubstituted arylsulfone, substituted or unsubstituted alkylcarbonyl, -C (O) -haloalkyl, substituents an unsubstituted or unsubstituted aliphatic ether; substituted or unsubstituted aromatic ether;

L is one of the following linkers: L is -O-; -WITH-; -S (O) -; -S (O) ₂ -; -N (R) -; N (C (O) OR) -; -N (C (O) R) -; -N (SO ₂ R); _-CH2 O-; -CH ₂ S-; -CH ₂ N (R) -; -CH (NR) -, CH ₂ N (C (O) R)) -; -CH ₂ N (C (O) OR) -; -CH ₂ N (SO ₂ R) -; -CH (NHR) -; -CH (NHC (O) R) -; CH (NHSO ₂ R) -; -CH (NHC (O) OR) -; CH (OC (O) R) -; - CH (OC (O) NHR) -; -CH = CH-; -C (= NOR) -; -WHAT)-; .-CH (OR) -; -C (O) N (R) -; -N (R) C (O) -; -N (R) S (O) -; -N (R) S (O) ₂ -; -0C (O) N (R) -, - N (R) C (0) N (R) -; -NRC (O) O-; S (O) N (R) -; S (O) ₂ N (R) -; N (C (O) R) S (O) -; N (C (O) R) S (O) ₂ -; -N (R) S (O) N (R) -; -N (R) S (O) ₂ N (R) -; -C (O) N (R) C (O) -; S (O) N (R) C (O) -; -S (O) ₂ N (R) C (O) -; -OS (O) N (R) -; -OS (O) ₂ N (R) -; -N (R) S (O) O-; N (R) S (O) ₂ O-; -N (R) S (O) C (O) -; -N (R) S (O) ₂ C (O) -; SON (C (O) R) -; -SO ₂ N (C (O) R) -; N (R) SON (R) -; -N (R) SO ₂ N (R) -; -C (O) O-; -N (R) P (OR ') O-; -N (R) P (OR ') -; N (R) P (O) (OR ') O-; -N (R) P (O) (OR ') -; -N (C (O) R) P (OR ') O-; -N (C (O) R) P (OR ') -; N (C (O) R) P (O) (OR ') O- or -N (C (O) R) P (OR') -, wherein R and R 'are each independently -H, acyl, substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, or substituted or unsubstituted cycloalkyl; or R and R 'are each independently -H, acyl, substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, or substituted or unsubstituted cycloalkyl.

Alternatively, L is -R ^b N (R) S (O) ² -, -R ^b N (R) P (O) -, or -R ^b N (R) P (O) 0 -. R _b is an alkylene group, taken together with the sulfonamide, phosphinamide or phosphonamide group to which it is attached, to form a five- or six-membered ring fused to ring A.

Alternatively, L is represented by one of the following structural formulas:

Λ / -} Λ λ Λ ϊ Λ

Ν-P Ν-P Ν-Ρ-Ο

R85-O

R85-O

R85-O

Ν-Ρ

-}

R85-Q \ ⁰

R85 \ ⁰

R85 or

R ⁸⁵ taken together with the phosphinamide or phosphonamide is a 5-, 6- or 7-membered aromatic, heteroaromatic or heterocycloalkyl ring.

In formula IR ¹ , a substituted aliphatic group, substituted cycloalkyl, substituted bicycloalkyl, substituted cycloalkenyl, optionally substituted aromatic group, optionally substituted heteroaromatic group, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl, optionally substituted heterobicycloalkyl, optionally substituted alkylamindo, and optionally substituted alkylamindo and -S (O) ₂ -alkyl or optionally substituted -S (O) ₂ -cycloalkyl, -C (O) -alkyl or optionally substituted -C (O) alkyl.

R ¹ may be substituted with one or more substituents. R ¹ is preferably substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, substituted or unsubstituted, substituted or unsubstituted aliphatic ether, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, rc. '. ,,.

substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aryloxycarbonyl, -OH, substituted or unsubstituted aminocarbonyl, oxime, substituted or unsubstituted azabicycloalkyl, heterocycloalkyl, oxo, aldehyde, substituted or unsubstituted alkyl, unsubstituted, or unsubstituted alkylsulfonyl unsubstituted heterobicycloalkyl, cyano, -NH ₂ , alkylamino, ureido, thioureido, and -BE.

B is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatics, substituted or unsubstituted heteroaromatics, alkylene, aminoalkyl, alkylenecarbonyl or aminoalkylcarbonyl.

E is substituted or unsubstituted azacycloalkyl, substituted or unsubstituted azacycloalkylcarbonyl, substituted or unsubstituted azacycloalkylsulfonyl, substituted or unsubstituted azacycloalkylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroaryl, or unsubstituted aryl sulfonamido, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted ureido, substituted or unsubstituted thioureido, or substituted or unsubstituted aryl.

However, when R ^{1 is an} aliphatic group or a cycloalkyl, R ¹ is not exclusively substituted by one or more substituents selected from the group consisting of hydroxyl and lower alkyl ethers. In addition, heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl and the aliphatic group is not substituted exclusively by one or more aliphatic groups.

In formula IR ² , -H, substituted or unsubstituted aliphatic, substituted or unsubstituted cycloalkyl, halogen, -OH, cyano, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, unsubstituted heteroaralkyl, -NR ⁴ R ⁵ , or -C (O) NR ⁴ R ⁵ .

In formula IR ³ , a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocycloalkyl.

In formula IR ⁴ , R ⁵ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or substituted or unsubstituted heteroaromatic group.

Alternatively, R ⁴ and R ^{5 are} independently -H, azabicycloalkyl, heterocycloalkyl, substituted or unsubstituted alkyl, or YZ.

Y is selected from the group consisting of -C (O) -, - (CH ₂ ) _p -, -S (O) ₂ -, -C (O) O-, SO ₂ NH-, -CONH-, (CH ₂ ) _P 0-, - (CH ₂ ) _p NH-, - (CH ₂ ) _p S-, - (CH ₂ ) _p S (O) - and - (CH ₂ ) _p S (O) ₂ -;

p is an integer from 0 to about 6.

Z is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

j is an integer from 0 to 6.

However, when L is -CH ₂ NR-, -C (O) NR- or -NRC (O) - and R ³ is azacycloalkyl or azaheteroaryl, j is 0. In addition, when L is -O- and R ³ is phenyl, j is 0.

The compounds of this invention are useful as serine / threonine and tyrosine kinase inhibitors. In particular, the compounds of the invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, particularly cancer and the process of angiogenesis. For example, some of these compounds are inhibitors of receptor kinases such as KDR, Flt-1, FGFR, PDGFR, c-Met, TIE2, or IGF-1-R. Since some of these compounds are anti-angiogenic, they are important agents for inhibiting the progression of disease states where angiogenesis is an important component. Certain compounds of the invention are effective as inhibitors of such serine / threonine kinases as PKCs, erk, MAP kinase, MAP kinase kinase, MAP kinase kinase kinase, cdks, Plk-1 or Raf-1. These compounds are useful in the treatment of cancer and hyperproliferative diseases. In addition, certain compounds are potent inhibitors of non-receptor kinases, such as those of the Src family (e.g., lck, blk and lyn), Tec, Csk, Jak, Map, Nik, and Syk. These compounds are useful in the treatment of cancer, hyperproliferative diseases and immunological diseases.

Certain compounds of the invention are selective TIE-2 kinase inhibitors that may be anti-angiogenic (particularly in combination with one or more VEGFR inhibitors) or pro-angiogenic when used in the presence or in conjunction with a VEGF-related stimulus. In this way, such inhibitors may be used in promoting therapeutic angiogenesis to treat, for example, ischemia, heart attack or occlusion, or to promote wound healing.

The present invention provides a method of inhibiting the kinase activity of tyrosine kinases and serine / threonine kinases comprising administering a compound represented by formula I for this kinase at a concentration sufficient to inhibit the enzymatic activity of the kinase.

The present invention further encompasses the use of these compounds in pharmaceutical compositions with a pharmaceutically effective amount of the compounds described above and a pharmaceutically acceptable carrier or vehicle. These pharmaceutical compositions can be administered to individuals to slow or stop the angiogenesis process in angiogenesis-assisted diseases or to treat edema, effusions, exudates or ascites and other conditions associated with vascular hyperpermeability. Certain pharmaceutical compositions may be administered to individuals for the treatment of cancer and hyperproliferative disorders by inhibiting serine / threonine kinases such as cdk, Plk-1, erk, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The values of the substituents in the first preferred group of compounds of formula I are given below.

L is preferably -N (R) S (O) ₂ -, -S (O) ₂ N (R) -, -N (R) C (O) -, -C (O) N (R) -, or -ABOUT-.

R ³ is preferably substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazole, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted, substituted or unsubstituted quinoline, substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanyl, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted, substituted or unsubstituted, substituted or unsubstituted, substituted or unsubstituted substituted or unsubstituted substituted benzoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline, substituted or unsubstituted quinoxaline, substituted or unsubstituted indole or substituted or unsubstituted pyrazole. R ³ may also alternatively be a substituted or unsubstituted aliphatic group or a substituted or unsubstituted alkenyl, provided that L is -SN (R) -, -S (O) N (R) -, -S (O) ₂ N (R) -, -N (R) S-, -N (R) S (O) -, -N (R) S (O) ₂ -, -N (R) SN (R ') -,

-N (R) S (O) N (R ') - or -N (R) S (O) ₂ N (R') -;

In one embodiment, R ^{3 is} substituted or unsubstituted phenyl.

R ³ may be substituted with one or more substituents. Preferred substituents for R ³ are F, Cl, Br, I, CH ₃ , NO ₂ , OCF ₃ , OCH ₃ CN, CO ₂ CH _3, CF ₃ t-butyl, pyridyl, substituted or unsubstituted oxazolyl, triphases

- r fi · P rrfr, KT. r. Substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, ethyl, -S- (substituted or unsubstituted) , -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -CíOjNR'R ^9, R ^c and CH ₂ oR ^c.

R ^f , R ⁹ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or substituted or unsubstituted heteroaromatic group.

Alternatively, R ^f and R ^{9 are} each independently a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.

R ^c is hydrogen or substituted or unsubstituted alkyl or substituted or unsubstituted aryl; -W- (CH 2) t -NR ^d R ^e , -W- (CH 2) _t -O-alkyl, -W (CH ₂ ), -S-alkyl or -W- (CH ₂ ) _t -OH.

t is an integer from 0 to about 6.

W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR ^k -.

R ^k is -H or alkyl.

R ^d , R ^e and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterobicyclic group.

Alternatively, R ^d and R ® are each independently -H, alkyl, alkanoyl or -KD.

K is -S (O) ₂ -, -C (O) -, -C (O) NH-, -C (O) ₂ - or a direct bond.

D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, unsubstituted aminocycloalkyl, COOR 'or substituted or unsubstituted alkyl.

R ¹ is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.

More preferred substituents for R ₃ are F, Cl, Br, I, cyano, nitro, OCF ₃ , CH _3, and CF ₃ .

Ring A is preferably substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted indole. In one embodiment, Ring A is substituted or unsubstituted phenyl.

Ring A may be substituted with one or more substituents. Preferred substituents for ring A are F, Cl, Br, I, CH ₃ , NO ₂ , OCF ₃ , OCH ₃ , CN, CO ₂ CH ₃ , CF ₃ , t-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, -S- (substituted or unsubstituted aryl), -S- (substituted or unsubstituted) , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -C (O) NR ^f R ⁹ , R ^c and CH ₂ OR ^C. R ^f , R ⁹ and R ^c are as defined above.

Ring A is more preferably substituted with F, Cl and nitro.

R ² is preferably hydrogen.

In one embodiment, R ^{1 has the} formula

Ka) m is an integer from 0 to about 3.

In another embodiment, R ^{1 has the} formula

O ⁰ _{CH2) t}

NR 8 R 9 (b) m and have the same meaning as previously defined. R ⁸ , R ⁹ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicyclic alkyl group. R ⁸ and R ⁹ are alte. native each independently -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² . Y ₂ is -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, (CH ₂ ) _q O -, - _{(CH2) q} NH-, (CH,) _q S-, - _{(CH2) q} S (O) - or - (CH _{2) q} S (O) ₂ -. q is an integer from 0 to 6. Z ² is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

In another embodiment, R ^{1 has the} formula (CH ₂ ) _s

(CH ₂ ) _t

NR 8 R 9 (c) m, t, R ⁸ and R ⁹ are as defined above, s is an integer from 0 to 6. q is an integer from 0 to about 6. R ⁷⁷ is -OR ⁷⁸ or -NR ⁷⁹ R ⁸⁰ . R ⁷⁸ is -H or a substituted or unsubstituted aliphatic group. R ⁷⁹ , R ^80, and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl group, or substituted heterobicyclic alkyl group. R ⁷⁹ and R ⁸⁰ are each independently -H, azabicycloalkyl, heterocycloalkyl or -Y ³ -Z ³ . Y ³ is selected from the group consisting of -C (O) -, -

(CH ₂ ) n S (O) - and - (CH ₂ ) _q S (O) ₂ -. Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

In another embodiment, R ^{1 has the} formula 1 (d) v is an integer from 1 to about 3. R ¹⁰ is -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² . Y ² and Z ² are as defined above.

In another embodiment, R ^{1 has the} formula

P »

Γ Γ r r r

R 10 I (e) and R ¹⁰ are as defined above. R ¹¹ represents one or more substituents selected from the group consisting of hydrogen, hydroxy, oxo, substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl, and substituted or unsubstituted aralkyl, provided that the carbon atoms adjacent to the nitrogen atom are not substituted with a hydroxyl group.

In another embodiment, R ^{1 has the} formula

N

N

R10

kf)

R ¹⁰ is as defined above.

r

In another embodiment, R ^{1 has the} formula

r is an integer from 1 to about 6. R ⁸ and R ⁹ are as defined above.

In another embodiment, R ^{1 has the} formula

l (h)

R ⁸ , R ⁹ and t are as defined above, w is an integer from 0 to about 4. u is 0 or 1. R ¹² is hydrogen or substituted or unsubstituted alkyl.

In another embodiment, R ^{1 has the} formula

Ki, w, t, R ¹⁰ and R ¹² are as defined above.

In another embodiment, when R ¹ is 1 (g) or 1 (H), R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl group of formula

u is as defined above. R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently lower alkyl or hydrogen. Alternatively, at least one pair of substituents R ¹³ and R ¹⁴ ; R ¹⁵ and R ¹⁶ ; R ¹⁷ and R ¹⁸ ; or R ¹⁹ and R ²⁰ together are an oxygen atom. Alternatively, at least one of R ¹³ and R ¹⁵ is cyano, CONHR ²¹ , COOR ²¹ , CH ² OR ²¹ or CH ² NR ²¹ (R ²² ). R ²¹ , R ²² and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl group, or substituted heterobicyclic alkyl group. R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ Z ³ ; Y ³ and Z ³ are as defined above. X is -O-, -S-, -SO-, -SO 2 -, -CH 2 -, CH (OR ²³ ) - or NR ²³ . R ²³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH 2, -C (O) R ²⁴ , or -C (O) OR ²⁴ . R ²⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.

In another embodiment, R ⁸ , R ^9, and the nitrogen atom together form a heterocycloalkyl of formula

t, R ²¹ and R ²² are as defined above. R ²⁵ and R ²⁶ are each independently hydrogen or lower alkyl. R ²⁵ and R ²⁶ are alternatively taken together with an oxygen atom, i being an integer from 1 to about 6.

In another embodiment, R ⁸ , R ^9, and the nitrogen atom together form a heterocycloalkyl of formula

N

ΖΔ, (CH ₂ ) i

R 27 is as defined above. R ²⁷ is CH ₂ OH, C (O) NR ²⁴ R ²⁸ or COOR ²⁴ . R ²⁴ and R ²⁸ are as defined above.

In another embodiment, R ⁸ , R ^9, and the nitrogen atom together form a heteroaromatic group of the formula

N,

R29

R ²⁹ is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, carboxylic acid, cyano, C (O) OR ^30, CH 2 OR ^30, CH 2 NR ²¹ R ²² or C (O) NR ²¹ R ^22nd R ³⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl or heterocycloaryl. R ²¹ and R ²² are as defined above.

In another embodiment, at least one of R ⁸ and R ⁹ is of formula Y ³ -D, wherein D has the formula

Y ³ is as defined above, x is 0, 1 or 2. T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ²⁴⁾ - or -N (R ²⁴⁾ -. R ²⁴ is as defined above.

In another embodiment, at least one of R ⁸ and R ⁹ is of the formula Y ³ -N (R ³¹ ) R ³² ; Y ³ is as defined above. R ³¹ and R ³² are each independently substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted cyanoalkyl. Alternatively, R ³¹ and R ³² together with the nitrogen atom form a five- or six-membered heterocycloalkyl, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl.

In another embodiment, when R ¹ is 1 (e), Z ² is of formula N (R ³⁵ ) R ³⁶ . R ³⁵ and R ³⁶ are each independently hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl.

In another embodiment, when R ¹ is 1 (e), Z ² is of the formula

X1 — X1 / \ • ^N \ X ^x '

R37 p »

Each X ¹ is independently CH or N. R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted .

In another embodiment, when R ¹ is 1 (e), Z ² is of the formula

R 37g is an integer from 0 to about 3. T is as defined above. R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl.

In another embodiment, when R ¹ is 1 (e), Z ² is of the formula

R 37 g and R ³⁷ are as defined unsubstituted aralkyl.

In another embodiment, when R ¹ is 1 (e), Z ² is of the formula

R37

T, g and R ³⁷ are as defined above.

In another embodiment, when R ¹ is 1 (e), Z ² is of the formula

R ³⁷ is as defined above. R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, perhaloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl.

In another embodiment, R ^{1 has the} formula

u is as defined above. R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ are each independently methyl or hydrogen. Alternatively, at least one pair of substituents R ³⁹ and R ⁴⁰ ; R ³⁶ and R ³⁷ ; R ³⁸ and R ³⁹ . R ⁴⁰ and R ⁴¹ are alternatively taken together with an oxygen atom. R ⁴⁷ is H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² . Y ² and Z ² are as defined above. R ⁴⁷ has an alternative formula

y is 0 or 1. R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ and R ⁵⁵ are each independently methyl or hydrogen. Alternatively, at least one pair of substituents R ⁴⁸ and R ⁴⁹ ; R ⁵⁰ and R ⁵¹ ; R ⁵² and R ⁵³ ; or R ⁵⁴ and R ⁵⁵ together are an oxygen atom. R ⁵⁶ is -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ . Y ³ and Z ³ are as defined above.

In another embodiment, R ^{1 has the} formula

e, f, h, u and u are independently 0 or 1. R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ and R ⁶⁶ are each independently methyl or hydrogen. Alternatively, at least one pair of substituents R ⁵⁷ and R ⁵⁸ ; R ⁵⁹ and R ⁶⁰ ; R ⁶¹ and R ⁶² ; or R ⁶³ and R ⁶⁴ together are an oxygen atom. R ⁶⁷ is H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² . Y ² and Z ² are as defined above. R ⁶⁷ has an alternative formula rr

d is 0 or 1. R ⁶⁸ , R ⁸⁹ , R ⁷⁰ , R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ and R ⁷⁵ are each independently lower alkyl or hydrogen. Alternatively, at least one pair of substituents R ⁸⁸ and R ⁸⁹ ; R ⁷⁰ and R ⁷¹ ; R ⁷² and R ⁷³ . R ⁷⁴ and R ⁷⁵ together are an oxygen atom. R ⁷⁸ is -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ . Y ³ and Z ³ are as defined above.

As used herein, aromatic groups include carbocyclic rings (e.g. benzyl and cinamyl) and fused polycyclic aromatic rings (e.g. naphthyl and 1,2,3,4-tetrahydronaphthyl). Aromatic groups are also referred to herein as aryl.

Heteroaromatic groups as used herein include heteroaryls (e.g., thienyl, pyridyl, pyrazole, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furans, pyrroles, imidazoles, pyrazoles, triazoles, pyrimidines, pyrazines, thiazoles, isoxazoles, isothiazoles, tetrazoles or tetrazoles). heteroaryls in which the carbocyclic aromatic ring, carbocyclic non-aromatic ring or heteroaryl is fused to one or more other heteroaryls (e.g., benzo (b) thienyl, benzimidazole, indole, tetrahydroindole, azaindole, indazole, quinoline, imidazopyridine, purine, pyrrolo [2, 3-d] pyrimidine, pyrazolo [3,4-d] pyrimidine) and N-oxides thereof.

Aralkyl, as used herein, is an aromatic substituent that is attached to the compound by an aliphatic group of one to about six carbon atoms.

Heteroaralkyl as used herein is a heteroaromatic substituent which is attached to the compound by an aliphatic group of one to about six carbon atoms.

Heterocycloalkyl as used herein is a non-aromatic ring having 3 to 8 atoms and containing at least one heteroatom, for example nitrogen, oxygen or sulfur.

Acyl as used herein is -C (O) NR ^X R ^Z , -C (O) OR ^X , -C (O) R ^X , wherein R ^x and R ^z are independently -H, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.

As used herein, aliphatic groups include linear, branched or cyclic C _r C ₈ hydrocarbons which are completely saturated or which contain one or more units of unsaturation. "Lower alkyl" is a saturated aliphatic group having 1 to 6 carbon atoms.

The compounds of formula I may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartarates [e.g. (+) - Tartrate, (-) - Tartrate or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

Certain compounds of formula I having acid substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts, and arginine salts. These salts can be prepared by methods known to those skilled in the art.

Certain compounds of formula I and salts thereof may exist in more than one crystalline form, and the present invention includes each crystalline form and mixtures thereof.

Certain compounds of formula I and salts thereof may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

r r

Certain compounds of formula I may contain one or more chiral centers and exist in various optically active forms. When the compounds of formula I contain a single chiral center, these compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, for example racemic mixtures. Enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; forming diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selectively reacting one enantiomer with an enantiomer-specific reagent, for example by enzymatic esterification; or by gas-liquid or liquid chromatography in a chiral medium, for example on a chiral support, for example a silica with a bound chiral ligand, or in the presence of a chiral solvent. It will be appreciated that when the desired enantiomer is converted to another chemical entity by one of the separation procedures described above, an additional step is required to release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active agents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral center, it may exist in diastereomeric forms. The pairs of diastereomers may be separated by methods known to those skilled in the art, for example by chromatography or crystallization, and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereomer of the compounds of Formula I and mixtures thereof.

Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and / or geometric isomer of the compounds of formula I and mixtures thereof.

Certain compounds of formula I may exist in various stable conformational forms, which may be separable. Torsional asymmetry due to limited rotation about an asymmetric single bond due to, for example, spherical hindrance or ring tension may allow separation of different conformers. The present invention includes each conformational isomer of the compounds of Formula I and mixtures thereof.

Certain compounds of formula I may exist in zwitterionic form, and the present invention includes each zwitterionic form of the compounds of formula I and mixtures thereof.

Preferred compounds of the present invention include:

C / s-5- (4-phenoxyphenyl) -7- (4-pyrolidinocyklohex-1-yl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine

7rans-5- (4-phenoxyphenyl) -7- (4-pyrolidinocyklohex-1-yl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine

C / s-5- (4-phenoxyphenyl) -7- (4-piperidinocyklohex-1-yl) -7 H -pyrrolo [2 _L 3d] pyrimidin-4-ylamine hydrochloride of trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyklohex-1-yl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine

7irans-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine

C / s-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine

5- (4-Phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride

5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) 7H-pyrrolo [2 ₁ 3-d] pyrimidin-4-ylamine dihydrochloride

C / 's-7- [4- (4-isopropyl) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine

77´ans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine r '-

Cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amino-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

Cis -7 - [- 4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trans-7- [4] - (4-ethyl-piperazin) cyclohexyl] -5- (4-phenoxyphenyl) -7 / 7-pyrrolo [2,3djpyrimidin-4-amine

Cis-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trismaleate

7-trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trismaleate

Cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine trismaleate

7rans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trismaleate

Cis-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt

Trans-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) 7H-pyrrolo [2,3-d] pyrimidin-4-amine dimalate salt

C / s-7- [4- (dimethylamino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3d] pyrimidin-4-amine dimaleate salt

Trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyklohexyl) -7 H -pyrrolo [2 _L 3-d | pyrimidin-4-amine dimaleate salt

7rans-5- (4-Phenoxyphenyl) -7- (4-tetrahydro-1H-1-pyrrolylcyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dimalate salt

Cis -5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7 H -pyrrolo [2,3- b] pyrimidin-4-amine trimaleate salt

7ra / 7S-5- (4-Phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine trimaleate salt

7- [3- (4-methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trimaleate

7irans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 / - / - pyrrolo [2,3dJpyrimidin-4-amine

Trans -7- [3- (4-Methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate trans-7- [3- (4-methylpiperazino) cyclohexyl] - 5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-hydrochloride cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H- pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-b] pyrimidin-4-amine trihydrochloride

7-trans-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c] pyrimidin-4-amine trimaleate

N-benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} 2-methoxyphenyl) carbamate trimaleate

7-trans-Benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate

7rans-N 1- (4- {4-amino-7- [4- (4-nnetylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) benzamide

Trans - N 1 - (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) benzamide trimaleate

C / s-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide

7rans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide c / s- N 1 - (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate salt frans- / 1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ _2,1- d] pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate c / s 2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7A7-pyrrolo [2 ₁ 3d] pyrimidin-5-yl-phenoxy) -6 - [(3-methoxypropyl) amino] benzonitrile trimaleate trans-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 / 7-pyrrolo [2,3-d] pyrimidin-5-yl-phenoxy) -6 - [(3-methoxypropyl) amino cis-2-Amino-6- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl-phenoxy) -benzonitrile trimaleate trans- 2-Amino-6- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl-phenoxy) benzonitrile trimaleate cis -2- (4- 4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d | pyrimidine n-5-ylphenoxy) -6 - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate trans-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2] 3dlpyrimidin-5-ylphenoxy) -6 - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate cis -2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H) - trans-2- (4-4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [N-pyrrolo [2,3-b] pyrimidin-5-ylphenoxy) -6- (2-pyridylsulfanyl) benzonitrile trimaleate] 2,3d] Pyrimidin-5-yl-phenoxy) -6- (2-pyridylsulfanyl) benzonitrile trimalate cis-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7 trans - 5- (2-Methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- b] pyrrolo [2,3-b] pyrimidin-4-amine trimaleate cis-Pyrimidin-4-amine trimaleate cis-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-Fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate

N1-4- [4-amino-7- (1-benzyl-4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide

N1-4- [4-amino-7- (1-benzyl-4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide

N1-4- [4-amino-7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide

N1-4- [4-amino-7- (1-formyl-4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide

N1 - [4- (4-amino-7-1 - [(1-methyl-1H-4-imidazolyl) sulfonyl] -4-piperidyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) - 2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimalate

N1- [4- (4-amino-7-1 - [(1,2-dimethyl-1H-4-imidazolyl) sulfonyl] -4-piperidinyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) - 2-fluoro-phenyl] -4-fluoro-1-benzenesulfonamide

N1- [4- (4-amino-7-1 - [(1,3-dimethyl-1H-5-pyrazolyl) carbonyl] -4-piperidinyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) - 2-fluoro-phenyl] -4-fluoro-1-benzenesulfonamide

N 1 (4-f4-amino-7- [1- (2-pyridylcarbonyl) -4-piperidinyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1 -benzenesulfonamide

N1-4- (4-amino-7- {4- [1- (1-methylpiperidin-4-yl) piperidinyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl}) - 2-phenyl-4 trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluoro-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate -5-yl} -2-fluorophenyl) -5-chloro-2-thiophenesulfonamide benzenesulfonamide trimalate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- ( 4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimalate cis cis-1- (4- {4-amino) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate cis / N- 1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo o [2,3d] Pyrimidin-5-yl-2-fluorophenyl) -2,5-difluoro-1-benzenesulfonamide trimaxate-trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) trans-N-4- (4- (4-Amino-7-) -7-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide trimaleate Trans-N-1- ([4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate 4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,3 _l 4-trifluoro-1 - cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) benzenesulfonamide trimaleate -2 N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-nitro-1-benzenesulfonamide trimaleate cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-fluorophenyl) -2-fluoro-1-benzenesulfonamide -yl} -2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimalate cis cis-1- (4- {4-amino-7- [4- (4-mee) tlpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimalate cis-N-1- (4- {4-amino- 7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate cis-N-1- (4 - {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate cis with N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -5-chloro-2 cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ _2,1- d] pyrimidin-5-yl} -2-fluorophenyl) -thiophenesulfonamide dimalate - 4-Bromo-2,6-difluoro-1-benzenesulfonamide trimalate cis cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine -5-yl} -2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimalate cis cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate c / with N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro- 1-Benzenesulfonamide trimaleate cis -1-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2- N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2 _l 3d] fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl]) -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimalate cis-N-1- (4- {4-amino-7- [ 4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate cis-N-1- (4- { 4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -4-bromo-2-fl Fluoro-1-benzenesulfonamide trimaleate rr rtr

c / with N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -5-bromo Cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-thiophenesulfonamide trimaleate ) '2,4-dichloro-1-benzenesulfonamide Cis / with N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2 _I, 3d] pyrimidine-5 N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-) -yl} -2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide trimaleate pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide trimaleate cis-N-4- (4- {4-amino-7- [4] - (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate cis-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2 ₁ 3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate C / P-'l- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2, 5-dichloro- Cis-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluoro-1-thiophenesulfonamide trimaleate Fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate cis-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate cis-4- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4- sulfonamide trimaleate cis -4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2]) 3d] pyrimidin-5-yl} -2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimalate cis cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) (cyclohexyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate cis-1- (4- {4-amino-7- [4]) - (4-methylpiperazin o) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2 _L 3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide Cis / with N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) - (2-nitrophenyl) trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) methanesulfonamide trimaleate -2 trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-nitro-1-benzenesulfonamide trimaleate (S) -N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine-fluorophenyl) -2-fluoro-1-benzenesulfonamide -5-yl} -2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimale trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2- trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-chloro-1-benzenesulfonamide trimaleate Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} fluorophenyl) -3-fluoro-1-benzenesulfonamide 2S-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H) -2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate pyrrolo [2 _l 3d] pyrimidin-5-yl} -2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate trans-N 1- (4- {4-amino-7- [4- Trans-N-1- (4- {4-Amino-7-methyl-piperazino) -cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate - [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate trans (7S-N-1-) (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-flu trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] orthophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl) pyrimidin-5-yl} -2-chlorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trans-N-1- (4- {4-amino-7- [4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate frans-N-1- (4- { 4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -5-bromo-2-thiophenesulfonamide trimaleate trans-N-1 - (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,4-dichloro-1- trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) benzenesulfonamide trimaleate -2 Trans-N-1- (4- {4-amino-7- [4- (4-methyl) -benzoic acid), 30,4-trichloro-1-benzenesulfonamide trimaleate trans-N-4- (4- {4-amino-2-thiophenesulfonamide) -piperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate trans-N- 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dichloro-1 trans-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2 ₁ 3d] pyrimidin-5-yl} -2-fluorophenyl) -thiophenesulfonamide trimaleate - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate trans-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2]) ₁ 3d] pyrimidin-5-yl} -2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimethanate-N-4- (4- {4-amino-7- [ 4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate trans- N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2- Fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate trans / 7S-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4] Trans - N-1- (4- {4-amino-4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate trans-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluoro-phenyl) - (2- nitrophenyl) methanesulfonamide trimaleate

The compounds of the invention have anti-angiogenic properties. These anti-angiogenic properties are due, at least in part, to inhibition of protein tyrosine kinases essential for angiogenic processes. For this reason, these compounds can be used as active agents against such disease states as arthritis, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia / reperfusion after injury, peptic healing, peptic healing, peptic healing, peptic healing Helicobacter-related, viral-induced angiogenic disorders, fractures, Crow-Fukas syndrome (POEMS), preeclampsia, menometrorrhagia, feline typhoid, rubeosis, neovascular giaucoma and retinopathy such as those associated with diabetic retinopathy or non-retinopathy associated with retinopathy degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative diseases such as thyroid hyperplasia (especially Grave disease) and cysts (e.g. ovarian tree hypervascularity characteristic of polyvarial syndrome syndrome) Stein-Leventhal syndrome) and polycystic kidney disease, as such diseases require vascular cell proliferation for growth and / or metastasis.

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Furthermore, some of these compounds may be used as anti-burn agents, chronic lung disease, slaughter, polyps, anaphylaxis, chronic and allergic inflammation, delayed type hypersensitivity, ovarian overstimulation syndrome, cerebral edema associated with brain tumor, high altitude or trauma hypoxia-induced cerebral or pulmonary edema, ocular and macular edema, ascites, glomerulonephritis and other diseases where the manifestation of the disease is vascular hyperpermeability, effusions, exudates, protein extravasation or edema. These compounds will also be useful in the treatment of diseases in which protein extravasation results in the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g., keloid, fibrosis, cirrhosis and carpal canal syndrome). Increased VEGF production potentiates inflammatory processes such as monocyte enhancement and activation. The compounds of the invention will also be useful in the treatment of inflammatory disorders, for example inflammatory bowel disease (IBD) and Crohn's disease.

VEGFs are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and edema formation. Indeed, vascular hyperpermeability and edema, which are associated with the expression or administration of many other growth factors, appear to be mediated through VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia leads to significant upregulation of VEGF in numerous tissues, therefore situations involving heart attack, occlusion, ischemia, anemia or disturbance of the circulatory system typically elicit responses that are mediated by VEGF / VPF. Vascular hyperpermeability, associated edema, altered transendothelial exchange, and macromolecular extravasation, which is often accompanied by diapedesis, can lead to excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Therefore, the hyperpermeability mediated by VEGF can significantly contribute to disorders with these etiological features.

Since blastocyst implantation, placental development, and embryogenesis are dependent on angiogenesis, certain compounds of the invention are useful as contraceptives and anti-fertility agents.

It is believed that the above disorders are mediated to a large extent by protein tyrosine kinase activity including KDR / VEGFR-2 and / or Flt1 / VEGFR-1 and / or TIE-2 tyrosine kinase. By inhibiting the activity of these tyrosine kinases, the progression of these disorders is inhibited since the component of angiogenicity or vascular hyperpermeability of the disease state is greatly limited. The action of certain compounds of the invention in view of their selectivity for specific tyrosine kinases results in minimization of side effects that would occur if less selective tyrosine kinase inhibitors were used. Certain compounds of the invention are also potent inhibitors of FGFR, PDGFR, c-Met and IGF-1-R. These receptor kinases can potentiate, directly or indirectly, angiogenic and hyperproliferative responses in various disorders, therefore inhibition thereof may prevent disease progression.

The compounds of the invention have inhibitory activity against protein kinases. That is, these compounds modulate signal transduction by protein kinases. The compounds of the invention inhibit protein kinases from the serine / threonine and tyrosine kinase classes. In particular, these compounds selectively inhibit the activity of KDR / FLK-1 / VEGFR-2 tyrosine kinases. Certain compounds of the invention also inhibit the activity of other tyrosine kinases such as the FIM / VEGFR-1, Tie-2, FGFR, PDGFR, IGF-1R, c-Met, Src subfamily kinases, such as Lck, Src, Fins, yes, etc. In addition, some of the compounds of the invention significantly inhibit serine / threonine kinases such as PKC, MAP kinases, erk, CDKs, Plk-1 or Raf-1, which play an essential role in cell proliferation and cell cycle progression. The potency and specificity of the generic compounds of the invention to a particular protein kinase can often be varied and optimized by varying the nature, number and arrangement of substituents (ie, R ¹ , R ² , R ³ , A and ring 1) and conformational constraints. In addition, metabolites of certain compounds may also have significant protein kinase inhibiting activity.

The compounds of this invention, when administered to an individual in need of such compounds, inhibit vascular hyperpermeability and edema formation in those individuals. These compounds act as believed to inhibit the activity of KDR tyrosine kinase, which is involved in the process of vascular hyperpermeability and edema formation. KDR tyrosine kinase can also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase or VEGFR-2 tyrosine kinase. KDR tyrosine kinase is activated when vascular endothelial growth factor (VEGF) or another activating ligand (such as VEGF-C, VEGF-D, VEGF-E, or HIV Tat protein) binds to the KDR tyrosine kinase receptor, which lies on the surface of vascular endothelial cells . Upon such activation of KDR tyrosine kinase, vascular hyperpermeability occurs and fluid enters the bloodstream through the vessel walls into the interstitial spaces, forming an edema area. This response is often accompanied by diapedesis. Similarly, excess vascular hyperpermeability can disrupt normal molecular exchange through the endothelium in critically important tissues and organs (e.g., lungs and kidneys), causing macromolecular extravasation and deposition. Following this acute response to KDR simulation, which is believed to facilitate the subsequent angiogenic process, prolonged stimulation of KDR tyrosine kinase leads to proliferation and chemotaxis of vascular endothelial cells and formation of new vessels. By inhibiting KDR tyrosine kinase activity by either blocking the production of activating ligand, blocking binding of activating ligand to the KDR tyrosine kinase receptor, preventing dimerization and transphosphorylation of the receptor, inhibiting the enzymatic activity of KDR tyrosine kinase (by inhibiting the phosphorylation function of the enzyme), or al., Cancer Res. 58. 278-1284 (1998) and references cited therein), hyperpermeability as well as associated extravasation, subsequent edema formation and matrix deposition, and angiogenic responses can be inhibited and minimized.

One group of preferred compounds of the invention has the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt-1 tyrosine kinase activity (Flt-1 tyrosine kinase is also referred to as VEGFR-1 tyrosine kinase). Both KDR tyrosine kinase and Flt-1 tyrosine kinase are activated by binding VEGF to KDR tyrosine kinase receptors and Flt-1 tyrosine kinase receptors, respectively. Certain preferred compounds of the invention are unique because they inhibit the activity of one VEGF receptor tyrosine kinase (KDR), which is activated by activating ligands, but does not inhibit other receptor tyrosine kinases, such as Flt-1, which are also activated by certain activating ligands. In this way, certain preferred compounds of the invention are therefore selective in their tyrosine kinase inhibitory activity.

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In one embodiment, the present invention provides a method for treating a protein kinase-mediated condition in a patient comprising administering to the patient a therapeutically or prophylactically effective amount of one or more compounds of Formula I.

"Protein kinase-mediated condition" means a medical condition, for example, a disease or other undesirable physical condition, genesis or progression of which at least partially depends on the activity of at least one protein kinase. For example, the protein kinase may be a protein-tyrosine kinase or a protein-serine / threonine kinase.

The patient to be treated can be any animal and preferably is a mammal, such as a pet or cattle. More preferably, the patient is a human.

A "therapeutically effective amount" is an amount of a compound of Formula I or a combination of two or more of such compounds that inhibits, in whole or in part, the progression of the condition or at least partially ameliorates one or more symptoms of the condition. The therapeutically effective amount may also be an amount prophylactically effective. The amount that is therapeutically effective will depend on the size and sex of the patient, the condition being treated, the severity of the condition, and the desired outcome. For a given patient, the therapeutically effective amount can be determined by methods known to those skilled in the art.

The method of the present invention is useful in the treatment of protein kinase-mediated conditions, for example any of the conditions described above. In one embodiment, the protein kinase-mediated condition is characterized by undesired angiogenesis, edema, or stromal deposition. The condition may be one or more ulcers, for example ulcers caused by bacterial or fungal infections, Morren ulcers and ulcerative colitis. The condition may also be caused by a microbial infection such as Lyme disease, sepsis, septic shock or infections caused by Herpes simplex, Herpes Zoster, human immunodeficiency virus, protozoa, toxoplasmosis or parapoxvirus; angiogenic diseases such as von Hippel Lindau disease, polycystic kidney disease, pemphigoid, Paget's disease and psoriasis; reproductive disease such as endometriosis, ovarian overstimulation syndrome, preeclampsia or menometrorrhagia; fibrotic and edemic conditions, for example, sarcosidosis, fibrosis, cirrhosis, thyroiditis, systemic hyperviscosity syndrome, Osler-Weber-Rendu's disease, chronic occlusive pulmonary disease, asthma and burn-related edema, trauma, radiation, stroke, hypoxia or ischemia; or an inflammatory / immunological condition, for example systemic lupus, chronic inflammation, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis and graft rejection. Suitable protein kinase mediated conditions include sickle cell anemia, osteoporosis, tumor-induced hypercalcemia, and bone metastases. Other protein kinase-mediated conditions that can be treated by the method of the present invention include ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, papilla excision, chronic retinal detachment, postoperative detachment of the retina, , Stargardt's disease and Eales' disease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also useful in the treatment of cardiovascular diseases such as atherosclerosis, restenosis, vascular occlusion and carotid obstruction disease.

The compounds of the present invention are also useful in the treatment of cancer-related indications such as solid tumors, sarcomas (in particular Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignant diseases including leukemia and lymphoma, tumor-induced pleural or periural effusion ascites.

The compounds of the present invention are also useful in the treatment of CrowFukas Syndrome (POEMS) and diabetic conditions such as giaucoma, diabetic retinopathy and microangiopathy.

The Src, Tec, Jak, Map, Csk, NFkB, and Syk kinase families play a central role in the regulation of immune function. The Src family currently includes Fyn, Lck, Fgr, Fes, Lyn,

Src, Yrk, Fyk, Yes, Hck, and Blk. The Syk family is currently understood to include only Zap and Syk. The TEC family includes Tec, Btk, Rlk, and Itk. The Janus family of kinases is involved in the transmission of growth factor and pro-inflammatory cytokine signals across several receptors. Although BTK and ITK, members of the Tec kinase family, play a less well understood role in immunobiology, their modulation by an inhibitor may prove therapeutically beneficial. The Csk family is currently understood to include only Csk and Chk. RIP, IRAK-1, IRAK-2, NIK, p38 MAP kinases, Jnk, IKK-1 and IKK-2 are involved in signaling pathways for key, inflammatory-promoting cytokines such as TNF and IL-1. Because of their ability to inhibit one or more of these kinases, the compounds of Formula I may function as immunomodulatory agents useful for maintaining allografts, treating autoimmune diseases, and treating sepsis and septic shock. By their ability to regulate the migration or activation of T lymphocytes, B lymphocytes, heparinocytes, monocytes and neutrophils, these compounds could be used to treat such autoimmune diseases and sepsis. Prevention of transplant rejection, either host versus solid organ implant or implant versus host bone marrow, is limited by the toxicity of currently available immunosuppressive agents and an effective drug with an improved therapeutic index would be beneficial. Gene-based experiments have shown a substantial role for Src in the biology of osteoclasts, the cells responsible for bone resorption. The compounds of formula I, through their ability to regulate Src, may also be useful in the treatment of osteoporosis, Paget's disease, tumor-induced hypercalcemia, and in the treatment of bone metastases.

Several protein kinases have been shown to be proto-oncogenic. Chromosome cleavage (at the Itk kinase cleavage point on chromosome 5), translocation as in the case of the Abl gene with BCR (Philadelphia chromosome), truncation in cases such as c-Kit or EGFR, or mutation (e.g. Met) results in the formation of dysregulated proteins from proto-oncogenic to oncogenic products. In other tumors, oncogenesis is driven by the interaction of autocrine or paracrine ligand / growth factor receptors. Members of the src kinase family are typically involved in signal transduction, thereby potentiating oncogenesis and may themselves become oncogenes by overexpression or mutation. By inhibiting the protein kinase activity of these proteins, the disease process can be disrupted. Vascular restenosis may include FGF and / or PDGF-assisted proliferation of smooth muscle cells and endothelium. Ligand stimulation of FGFR, PDGFR, IGF1-R and c-Met in vivo is pro-angiogenic and potentiates angiogenesis-dependent diseases. Inhibition of FGFr, PDGFr, c-Met or IGF1-R kinase activities individually or in combination may be an effective strategy for inhibiting these events. Compounds of Formula I that inhibit the kinase activity of normal or aberrant c-kit, c-met, c-fms, src, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, IGF1-R and other receptor or cytosolic tyrosine family members kinases may be valuable in the treatment of benign and neoplastic proliferative diseases.

In many pathological conditions (e.g., solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inadequate ocular neovascularization, psoriasis and atherosclerosis), the progression of the disease depends on persistent angiogenesis. Polypeptide growth factors often produced by diseased tissue or related inflammatory cells and their corresponding endothelial cell-specific receptor tyrosine kinases (e.g., KDR / VEGFR-2, FK-1 / VEGFR-1, Tie-2 / Tek and Tie) are essential for stimulation endothelial cell growth, migration, organization, differentiation, and establishment of the necessary new functional vasculature. Due to the vascular permeability factor activity in VEGF in mediating vascular hyperpermeability, VEGF stimulation of VEGFR kinase is also thought to play an important role in the formation of tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusions, delayed type hypersensitivity reactions and edema dysfunction, trauma, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), post-cardiopulmonary hypotension, and bypass-related hyperpermeability and ocular edema resulting in glauco-neo-vascular disease or glaucoma. In addition to VEGF, recently identified VEGF-C and VEGF-D and virally encoded VEGF-E or HIV-Tat proteins can also cause vascular hyperpermeability responses by stimulating VEGFR kinase. KDR / VEGFR-2 and / or Tie-2 are also expressed in a selected hematopoietic stem cell population. Certain members of this population are pluripotent in nature and can be stimulated by growth factors to differentiate into endothelial cells and participate in vasculogenetic angiogenic processes. For this reason, they have been called endothelial progenitor cells (EPC) (J. Clin. Investig. 103: 1231-1236 (1999)). In some progenitors, Tie-2 may play a role in their enhancement, adhesion, regulation and differentiation (Blood, 4317-4326 (1997)). Certain compounds of Formula I capable of blocking the kinase activity of endothelial cell-specific kinases could therefore inhibit the progression of a disease involving these situations.

Vascular destabilization of the antagonist ligand Tie-2 (Ang2) is believed to induce an unstable "plastic" state in the endothelium. In the presence of high levels of VEGF, a strong angiogenic response may occur; however, in the absence of VEGF or VEGF-related stimulus, clinically clear vessel regression and endothelial apoptosis may occur (Genes and Devel. 13: 1055-1066 (1999)). Analogously, a Tie-2 kinase inhibitor may be propangiogenic or anti-angiogenic in the presence and absence of a VEGF-related stimulus, respectively. Tie-2 inhibitors can therefore be used with suitable proangiogenic stimuli, for example VEGF, to promote therapeutic angiogenesis in situations such as wound healing, heart attack and ischemia.

The compounds of Formula I, or salts thereof, or pharmaceutical compositions containing a therapeutically effective amount thereof, can be used to treat protein kinase mediated conditions, for example, benign and neoplastic proliferative diseases and immune system disorders as described above. Such diseases include, for example, autoimmune diseases such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g., kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers such as lung, breast, stomach, bladder, colon, pancreas, ovaries, prostate and rectal cancer and hematopoietic cancer (leukemia and lymphoma), and diseases involving inadequate vascularization such as diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration and infantile hemangiomas in man. In addition, such inhibitors may be useful in the treatment of disorders including VEGF-mediated edema, ascites, effusions and exudates, including, for example, macular edema, cerebral edema, acute lung injury, and adult respiratory distress syndrome (ARDS).

The compounds of the present invention may also be useful in the prophylaxis of the above diseases.

It is believed that the above disorders are mediated to a large extent by protein tyrosine kinase activity involving VEGF receptors (e.g., KDR, Flt-1 and / or Tie-2). By inhibiting the activity of these receptor tyrosine kinases, the progression of these disorders is inhibited since the component of the angiogenicity of the disease state is greatly limited. The action of the compounds of the invention in view of their selectivity for specific tyrosine kinases results in minimization of side effects that would occur if less selective tyrosine kinase inhibitors were used.

According to another aspect, the present invention provides compounds of formula I as defined above for use as medicaments, in particular as inhibitors of protein kinase activity, for example tyrosine kinase activity, serine kinase activity and threonine kinase activity. According to another invention, the present invention provides the use of compounds of formula I as defined above in the manufacture of a medicament for use in inhibiting protein kinase activity.

The following definitions apply in this application:

"Physiologically acceptable salts" are those salts which retain the biological activity and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as sulfonic acid , carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like.

"Alkyl" means a saturated aliphatic hydrocarbon including linear and branched groups having 1 to 6 carbons or cyclic hydrocarbons having 3 to 6 carbons.

"Alkoxy" means an O-alkyl group wherein alkyl is as defined above.

Pharmaceutical formulations

The compounds of the present invention may be administered to a human patient alone or in pharmaceutical compositions where they are mixed with suitable carriers or vehicles at doses that treat or ameliorate vascular hyperpermeability, edema, and associated disorders. Mixtures of these compounds may also be administered to the patient in simple formulations or in suitably formulated pharmaceutical compositions. A therapeutically effective dose is an amount of the compound or compounds sufficient to prevent or ameliorate inadequate neovascularization, progression of hyperproliferative diseases, edema, VEGF-associated hyperpermeability and / or VEGF-related hypotension. Techniques for formulation and administration of the compounds of the present application can be found in "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, latest edition.

Routes of administration

Suitable routes of administration may be, for example, oral, eye drops, rectal, transmucosal, topical or intestinal administration; parenteral administration including intramuscular, subcutaneous, intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injection.

Alternatively, the compound may be administered topically instead of systemically, for example, by injecting the compound directly into the edematous site, often in a depot or sustained release formulation.

Additionally, the drug may be administered by a targeted drug delivery system, for example, in a liposome coated with an endothelial cell specific antibody.

Composition and formulation

The pharmaceutical compositions of the present invention may be manufactured in a known manner, e.g. by conventional mixing, dissolving, granulating, dragee-making, crushing, emulsifying, occluding or lyophilizing processes.

Thus, pharmaceutical compositions for use according to the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising vehicles and excipients which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Adequate formulation depends on the route of administration chosen.

For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution or physiological buffer. For transmucosal administration, penetrants appropriate to the barrier are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated simply by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions and the like for oral ingestion by the treated patient. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid vehicle, optionally grinding the obtained mixture and processing the mixture of granules after adding suitable excipients, if necessary, to obtain tablets or dragee cores. Suitable vehicles are, in particular, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, for example sodium alginate, may be added.

The dragee cores are coated with suitable coatings. Concentrated sugar solutions may be used for this purpose, which may optionally include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablet or dragee coatings to identify or characterize various combinations of active compound doses.

Pharmaceutical preparations which can be used orally include two-piece capsules made of gelatin as well as soft, glued capsules made of gelatin and a plasticizer, for example glycerol or sorbitol. The two-part capsule may contain the active ingredients in admixture with a filler, for example lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, for example, fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are preferably administered in the form of an aerosol spray from a pressurized container or a nebulizer using a suitable dialysis medium, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a metered dose valve. Capsules and cartridges e.g. of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be in unit dosage form, e.g. in ampoules or in multi-dose containers with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of active compounds may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water before use.

The compounds may also be formulated in rectal compositions, for example, suppressors or retention intestines, e.g. containing conventional suppressor bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as a deposited preparation. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, as a poorly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. The solvent system may be a VPD solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar polysorbate 80 and 65% w / v polyethylene glycol 300, made up to volume with absolute ethanol. The VPD solvent system (VPD: 5W) consists of VPD diluted 1: 1 with 5% dextrose in aqueous solution. This solvent system also dissolves hydrophobic compounds and itself has low toxicity when administered systemically. The ratios of the solvent system may naturally vary considerably without impairing the solubility and toxicity characteristics. In addition, the identity of the components of the solvent system may also vary: for example, other low toxic nonpolar surfactants may be used instead of polysorbate 80; the fractional size of the polyethylene glycol may vary; other biocompatible polymers can replace polyethylene glycol, e.g. polyvinylpyrrolidone; and other dextrose substitutes may be other sugars or polysaccharides.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may also be used. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide may also be used, albeit at the cost of higher toxicity. In addition, the compounds may be delivered by sustained release systems, for example, semipermeable bases of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are introduced and are known to those skilled in the art. Sustained-release capsules, depending on their chemical nature, can release the compounds for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, other strategies for protein stabilization may be used.

The pharmaceutical compositions may also contain suitable solid or gel carriers or vehicles. Examples of such carriers or vehicles include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Many of the compounds of the invention can be administered as salts with pharmaceutically compatible contraions. Pharmaceutically compatible salts can be formed with many acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to have greater solubility in aqueous or other protic solvents compared to the corresponding free base forms.

r ·

Effective doses

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent the development or alleviation of existing symptoms of the subject being treated. Determining effective amounts is an essential task for those skilled in the art.

For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially based on cellular assays. For example, the dosage can be formulated in cell and animal models to achieve a range of circulating concentrations that includes IC ₅₀ as determined in cellular assays (ie, the concentration of test compound that achieves half the maximal inhibition of a given protein kinase activity). In some cases, it is desirable to determine IC ₅₀ in the presence of 3-5% serum albumin, since such determination approximates the effects of plasma protein binding to the compound. Such information can be used to more accurately determine useful doses in humans. In addition, the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that can be safely achieved in plasma.

A therapeutically effective dose is an amount of a compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. to determine the maximum tolerated dose (MTD) and ED ₅₀ (effective dose for 50% maximum response). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between MTD and ED ₅₀ . Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration

administration. The exact formulation, route of administration, and dosage can be selected by the particular physician taking into account the patient's condition. (See, e.g., Fingl et al., 1975, in The Pharmacological Basis of Therapeutics, Chapter 1, p. 1). In the treatment of crises, an acute bolus or infusion approaching MTD may be required to achieve a rapid response.

The amount and dose interval can be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain the effects of kinase modulation or minimal effective concentration (MEC). The MEC will vary with each compound, but can be estimated based on in vitro data, e.g. based on the concentration required to achieve 50-90% inhibition of protein kinase using the assays described herein. The dosages required to achieve the MEC will depend on the characteristics of the individual and the route of administration. However, HPLC or biological assays may be used to determine plasma concentrations.

Dose intervals can also be determined using the MEC value. Compounds should be administered using a regimen that maintains plasma levels above MEC for 10 90% of the time, preferably between 30-90% and most preferably between 50-90% until symptom relief is achieved. In the case of local administration or selective uptake, the effective local concentration may not be related to the plasma concentration.

The amount of composition administered will, of course, depend upon the subject being treated, the weight of the subject, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician.

wrapping

The compositions may, if desired, be presented in a pack or dispenser which may contain one or more unit dosage forms containing the active ingredient. For example, the pack may consist of metal or plastic foil, for example a blister pack. The package or dispenser may be accompanied by instructions for administration. It is also possible to prepare compositions comprising

The Pβ compound of the invention formulated in a compatible pharmaceutical carrier, placed in a suitable container and labeled for the treatment of the indicated condition.

In some formulations, it may be advantageous to use the compounds of the present invention in the form of particles of very small size, such as those obtained by wet milling.

The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. As used herein, the term "active compound" refers to any compound of the invention, but particularly any compound that is the end product of one of the preceding examples.

(a) Capsules

In the preparation of the capsules, 10 parts by weight of the active compound and 240 parts of lactose can be deagregated and mixed. The composition may be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound.

(b) Tablets

Tablets may be prepared from the following ingredients.

Weight parts Active compound 10 lactose 190 Maize starch 22 polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, lactose and a portion of the starch may be deagregated, mixed and the resulting mixture may be granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate can be mixed with magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to obtain tablets each containing a unit dose or part of a unit dose of the active compound.

c) Enteric coated tablets

Tablets may be prepared as described under (b) above. The tablets may be enteric coated in a conventional manner with a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in a 1: 1 mixture of ethanol and dichloromethane.

(d) Supervisors

For the preparation of the suppressors, 100 parts by weight of the active compound in 1300 parts by weight of the triglyceride base of the suppressors can be used, and the mixture can be formed into the suppressors, each containing a therapeutically effective amount of the active ingredient.

In the compositions of the present invention, the active compound may, if desired, be combined with other compatible pharmacologically active ingredients. For example, the compounds of the invention may be administered in combination with one or more pharmaceutical compositions that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signaling, inhibit vascular hyperpermeability, reduce inflammation or inhibit or prevent or neovascularization. The compounds of the invention may be administered prior to, after or concurrently with the additional pharmaceutical composition, depending on which route of administration is appropriate. These additional pharmaceutical compositions include, but are not limited to, anti-oedemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt / PTB inhibitors, IGF1R inhibitors, PKC inhibitors, and PI3 kinase inhibitors. The compounds of the invention and the additional pharmaceutical compositions act either additively or synergistically. Thus, administration of a combination of agents that inhibit angiogenesis, vascular hyperpermeability, and / or inhibit edema formation may provide greater relief from the deleterious effects of hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than administration of one of the compounds alone. Combinations with antiproliferative or cytotoxic chemotherapy or radiation are contemplated for the treatment of malignant disorders.

The present invention also includes the use of Compound I as a medicament.

Another aspect of the present invention provides the use of a compound of formula I or a salt thereof in the manufacture of a medicament for the treatment of vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and / or immune system disorders in mammals, particularly humans.

The present invention also provides a method of treating vascular hyperpermeability, inadequate neovascularization, proliferative diseases, and / or immune system disorders, comprising administering to a mammal, particularly a human, in need thereof, a therapeutically effective amount of a compound of Formula I.

The in vitro potency of compounds to inhibit these protein kinases can be determined by the procedures described below.

The potency of the compounds can be determined by the amount of inhibition of phosphorylation of the exogenous substrate, e.g. synthetic peptide (Z. Songyang et al., Nature, 373: 536-539) by the test compound as compared to the control.

Production of KDR tyrosine kinase using baculovirus system:

The coding sequence for the human KDR intracellular domain (aa789-1354) was generated by PCR using cDNA isolated from HUVEC cells. The poly-His6 sequence was also introduced at the N-terminus of this protein. This fragment was cloned into the pVL1393 transfection vector at the Xba 1 and Not 1 sites. Recombinant baculovirus (BV) was generated by cotransfection with the BaculoGold transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western analysis. For protein production, SF-9 cells were cultured in SF-900-II medium at 2 x 10 6 / ml and infected at 0.5 plaque forming units per cell (MOI). Cells were harvested 48 hours after infection.

Cleaning DRC

SF-9 cells expressing (His) ₆ KDR (aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X- 100, 1 mM PMSF, 10 µg / ml aprotinin, 1 µg / ml leupeptin) per cell pellet from 1 L cell culture. The lysate was centrifuged at 19,000 rpm. in a Sorval SS-34 rotor for 30 minutes at 4 ° C. The cell lysate was applied to a 5 ml NiCl ₂ chelating sepharose column, equilibrated with 50 mM HEPES, pH

7.5, 0.3 M NaCl. The KDR was eluted with the same buffer containing 0.25 M imidazole. Column fractions were analyzed by SDSPAGE and an ELISA assay (below), which measures kinase activity. The purified KDR was exchanged into 25 mM HEPES buffer, pH 7.5, 25 mM NaCl, 5 mM DTT and stored at -80 ° C.

Production and purification of human Tie-2 kinase

The coding sequence for the human Tie-2 intracellular domain (aa775-1124) was generated by PCR using cDNA isolated from the human placenta as a template. The poly-His ₆ sequence was introduced at the N-terminus and this construct was cloned into the pVL 1939 transfection vector at the Xba 1 and Not 1 sites. Recombinant BV was generated by cotransfection with the BaculoGold transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western analysis. For protein production, SF-9 insect cells were cultured in SF-900-II medium at 2 x 10 6 / ml and infected at an MOI of 0.5. Purification of His-labeled kinase used in screening was analogous to KDR.

Production and purification of human Flt-1 tyrosine kinase

The baculovirus expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. The nucleotide sequence encoding poly-His6 was located 5 'to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated by PCR using cDNA libraries isolated from HUVEC cells. The histidine residues allowed affinity purification of the protein as a method analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a multiplicity of 0.5 and harvested 48 hours after infection.

Source of EGFR Tyrosine Kinase

EGFR was purchased from Sigma (Cat. No. E-3641; 500 units / 50 μΙ) and the EGF ligand was purchased from Oncogene Research Products / Calbiochem (Cat. No. PF011-100).

ZAP70 Expression

The baculovirus expression vector used was pVL1393. (Pharmingen, Los Angeles, CA.) The nucleotide sequence encoding amino acids M (H) 6 of LVPR ₉ S n F was located 5 'to the region encoding the entire ZAP70 (amino acids 1-619). The nucleotide sequence encoding the region encoding ZAP70 was generated by PCR using cDNA libraries isolated from Jurkat immortalized T lymphocytes. Histidine residues allowed affinity purification of the protein (vide infra). The LVPR ₉ S bridge forms a recognition sequence for proteolytic cleavage by thrombin, allowing removal of the affinity tag from the enzyme. SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours after infection.

Extraction and purification of ZAP70

SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 µg / ml leupeptin, 10 µg / ml aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a HiTrap chelating sepharose column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. The fusion protein was eluted with 250 mM imidazole. The enzyme was stored in a buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.

Source of protein kinase

Lck, Fyn, Src, Blk, Csk and Lyn, and truncated forms thereof, can be obtained commercially (e.g., from Upstate Biotechnology Inc. (Saranac Lake, NY) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.

ELISA (Enzyme Linked Immunosorbent Assay) for PTK

Enzyme linked immunosorbent assay (ELISA) was used to detect and measure the presence of tyrosine kinase activity. ELISAs were performed according to known protocols as described, for example, in Volier, et al., 1980, EnzymeLinked Immunosorbent Assay, In: Manual of Clinical Immunology, 2d ed., Edited by Rose and Friedman, p. 359-371 Am. Soc. of Microbiology, Washington, D.C.

The protocol was adapted to determine activity with respect to a specific PTK. Preferred protocols for conducting ELISA experiments are exemplified below. Adaptation of these protocols to determine compound activity for other members of the receptor PTK family as well as non-receptor tyrosine kinases is an essential task for those of skill in the art. A universal PTK substrate (e.g., random poly (Glu ₄ Tyr) copolymer, molecular weight 20,000-50,000) was used with the ATP (typically 5 μΜ) at concentrations approximately twice the apparent Km in the assay to determine inhibitor selectivity.

To test the inhibitory effect of the compounds of the invention on KDR, Flt1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, Blk, Csk, Src, Lyn, Fyn and ZAP70 tyrosine kinase activity, used the following procedure:

Buffers and solutions:

PGTPols (Glu, Tyr) 4: 1

Store the powder at -20 ° C. Dissolve the powder in phosphate buffered saline (PBS) to a 50 mg / ml solution. Store 1 ml aliquots at -20 ° C. For plate preparation, dilute to 250 µg / ml in Gibco PBS.

Reaction Buffer: 100 mM Hepes, 20 mM MgCl ₂ , 4 mM MnCl ₂ , 5 mM DTT, 0.02% BSA, 200 μΜ NaVO ₄ , pH 7.10

ATP: Store 100 mM aliquots at -20 ° C. Dilute to 20 μΜ in water

Wash Buffer: PBS with 0.1% Tween 20

Antibody dilution buffer: 0.1% bovine serum albumin (BSA) v

PBS

TMB Substrate: mix TMB substrate and 9: 1 peroxide solutions immediately prior to use or use K-Blue Substrate from Neogen

Stop solution: 1 M phosphoric acid

Approach

1. Preparation of the plate:

Dilute a stock solution of PGT (50 mg / ml, frozen) in PBS to 250 µg / ml. Add 125 μΙ per well of Corning modified high-affinity flat bottom ELISA plates (Corning # 25805-96). Add 125 μΙ PBS to empty wells. Cover with adhesive tape and incubate overnight at 37 ° C. Wash with 1 x 250 μΙ wash buffer and dry for about 2 hours in a 37 ° C dry incubator.

Store the coated plates in a sealed bag at 4 ° C until use.

2. Tyrosine kinase reaction:

- Prepare inhibitor solutions at 4-fold concentration in 20% DMSO in water.

- Prepare the reaction buffer

- Prepare the enzyme solution so that the required units are in 50 μί, eg. for DRC make up to 1 ng / μΙ for a total of 50 ng per well in reactions. Store on ice.

- Add 4x ATP solution to 20 μΜ of 100 mM stock solution in water. Store on ice.

- Add 50 μΙ of enzyme solution per well (usually 5-50 ng of enzyme per well depending on specific kinase activity)

- Add 25 μΙ 4x inhibitor

- Add 25 μΙ 4x ATP for inhibitor test

- Incubate for 10 minutes at room temperature

- Stop the reaction by adding 50 μΙ 0.05 N HCl per well

- Wash plate ** Final concentrations for reaction: 5 μΜ ATP, 5% DMSO

3. Binding of antibodies

- Dilute 1 mg / ml aliquot of PY20-HRP (Pierce) (phosphotyrosine antibody) to 50 ng / ml in 0.1% BSA in PBS by two-step dilution (100 x then 200 x) ·

- Add 100 μΙ Ab per well. Incubate for 1 hour at room temperature. Incubate for 1 hour at 4 ° C.

- Wash the plate 4 times

4. Color reaction

- Prepare the TMB substrate and add 100 μΙ per well

- Monitor OD at 650 nm until 0.6

- Stop with 1 M phosphoric acid. Shake on the plate reader.

- Read OD immediately at 450 nm

Optimal incubation times and enzyme reaction conditions vary slightly with the enzyme preparations and are determined empirically for each dose.

For Lck, 100 mM MOPSO, pH 6.5, 4 mM MnCl ₂ , 20 mM MgCl ₂ , 5 mM DTT, 0.2% BSA, 200 mM NaVO ₄ were used as reaction buffer under analogous assay conditions.

The compounds of formula I may have therapeutic utility in the treatment of diseases involving identified, including but not limited to, as yet unidentified protein tyrosine kinases that are inhibited by compounds of formula I. All of the compounds disclosed herein significantly inhibit either FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, Blk, Lyn or Src at concentrations of 50 micromoles or less. Certain compounds of the invention also significantly inhibit other tyrosine or serine / threonine kinases, such as cdc2 (cdk1) at concentrations of 50 micromoles or less.

Source Cdc2

Human recombinant enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA, USA) or purified from known natural or recombinant sources using conventional methods.

»R

Test Cdc2

The protocol attached to the purchased reagents with minor modifications was used.

Briefly, the reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 3 (commercial buffer) supplemented with fresh 300 μΜ ATP (31 pCi / ml) and 30 pg / ml history type lllss in final concentrations. A reaction volume of 80 μΙ containing enzyme units was run for 20 minutes at 25 ° C in the presence or absence of inhibitor. The reaction was terminated by the addition of 120 μΙ 10% acetic acid. The substrate was separated from the unincorporated label by applying the mixture to phosphocellulose paper and washing three times for 5 minutes with 75 mM phosphoric acid. Counts were measured with a beta counter in the presence of liquid scintillant.

Certain compounds of the present invention significantly inhibit cdc2 at concentrations below 50 μΜ.

Source of PKC kinase

The catalytic PKC subunit can be obtained commercially (Calbiochem).

PKC kinase assay

A radioactive kinase assay was used according to a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3: 166, 1220-1227 (1990)). Briefly, all reactions were performed in a kinase buffer consisting of 50 mM Tris-HCl pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 100 μΜ ATP, 8 μΜ peptide, 5% DMSO and ³³ P ATP (8 Ci / mM). Compound and enzyme were mixed in a reaction vessel and the reaction was initiated by the addition of a mixture of ATP and substrate. After completion of the reaction by adding 10 μΙ of Stop Buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture was applied to phosphocellulose filters. The loaded samples were washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. The incorporation of the radiolabel was quantified by liquid scintillation counting.

The source of the erk2 enzyme

Recombinant mouse enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA, USA) or purified from known natural or recombinant sources using conventional methods.

Test of erk2 enzyme

Briefly, the reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl ₂ (commercial buffer) supplemented with fresh 100 μΜ ATP (31 pCi / ml) and 30 μΜ myelin basic protein under conditions recommended by the supplier. Reaction volumes and assay method for incorporating radioactivity were as described for the PKC (vide supra) assay.

In vitro models for T cell activation

Upon activation by mitogen or antigen, secretion of IL-2, a growth factor that promotes their subsequent proliferative phase, is induced in T lymphocytes. Therefore, either IL-2 production from primary T cell proliferation or appropriate T cell lines can be measured to replace T cell activation. Both of these assays are well described in the literature and their parameters are well documented (Current Protocols in Immunology, vol. 2, 7.10.1-7.11.2).

Briefly, T lymphocytes can be activated by co-culture with allogeneic stimulatory cells as a process called a unidirectional mixed lymphocyte response. Responder and stimulator peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) according to the manufacturer's instructions. Stimulator cells are mitotically inactivated by mitomycin C (Sigma) or gamma irradiation. Responder and stimulator cells are co-cultured at a two to one ratio in the presence and absence of the test compound. Typically, 10 ⁵ responders are mixed with 5 x 10 ⁴ stimulators and plated (volume 200 μΙ) in a round bottom microtiter plate (Čostar Scientific). Cells are cultured in RPMI 1640 supplemented with either heat-inactivated bovine serum (Hyclone Laboratories) or combined human AB serum from male donors, 5 x 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO. The cultures are pulsed with 0.5 µCi of ³ H thymidine (Amersham) one day before separation (mostly day three).

Cultures were separated (Betaplate harvester, Wallac) and isotope absorption was evaluated by liquid scintillation (Betaplate, Wallac).

The same culture system can be used to assess T cell activation by measuring IL-2 production. Eighteen to twenty-four hours after initiation of culture, supernatants are discarded and IL-2 concentrations are measured by ELISA (R and D Systems) according to the manufacturer's instructions.

fn vivo models of T lymphocyte activation

The in vivo efficacy of the compounds can be tested in animal models known to directly measure T lymphocyte activation or for which T lymphocytes have been shown to be effectors. T lymphocytes can be activated in vivo by ligation of the constant portion of the T lymphocyte receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB / c mice are given 10 µg of anti-CD3 Ab intraperitoneally two hours before exsanguination. Animals intended to receive the test compound are administered a single dose of the compound one hour before anti-CD3 Ab administration. Serum levels of the pro-inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), indicators of T lymphocyte activation, are measured by ELISA. A similar model utilizes in vivo preparation of lymphocytes with a T specific antigen, for example KLH (keyhole limpet hemocyanin) followed by secondary in vitro exposure of lymph node cells to the same antigen. As before, measurement of cytokine production is used to assess the activation status of cultured cells. Briefly, C57BL / 6 mice are immunized subcutaneously with 100 µg of KLH emulsified in complete Freund's adjuvant (CFA) on day zero. Animals are first administered the compound one day before immunization and then on days one, two and three after immunization. The draining lymph nodes are harvested on day 4 and their cells are cultured at 6 x 10 ⁶ per ml in tissue culture medium (RPMI 1640 supplemented with heat-inactivated fetal bovine serum (Hyclone Laboratories) 5 x 10 ^-5 M 2-mercaptoethanol and 0.5 % DMSO) twenty-four and forty-eight hours. Culture supernatants are then evaluated for autocrine growth factor T lymphocyte growth factor (IL-2) and / or IFN-γ levels by ELISA.

Lead compounds can also be tested in animal models of human disease. Examples of these are experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models that mimic aspects of human multiple sclerosis have been described in both rat and mouse (reviewed by FASEB J. 5: 2560-2566, 1991; mouse model: Lab. Invest. 4 (3): 278, 1981; rodent model: J Immunol 146 (4): 1163-8 (1991). Briefly, mice or rats are immunized with an emulsion of myelin basic protein (MBP) or its neurogenic peptide derivatives and CFA. Acute disease can be induced by the addition of bacterial toxins, for example bordetella pertussis. Relapsing / relapsing disease is induced by adoptive transfer of T lymphocytes from MBP / peptide immunized animals.

CIA can be induced in DBA / 1 mice by immunization with type II collagen (J. Immunol: 142 (7): 2237-2243). Mice develop symptoms of arthritis as early as 10 days after challenge with the antigen and can be scored up to ninety days after immunization. In both the EAE and CIA models, the compound can be administered either prophylactically or at the time of disease onset. Effective drugs should reduce severity and / or incidence.

Certain compounds of the invention that inhibit one or more angiogenic receptor PTKs and / or protein kinase as lck involved in mediating inflammatory responses may reduce the severity and incidence of arthritis in these models.

Compounds can also be tested in mouse allografts - either cutaneous (reviewed in Ann. Rev. Immunol., 10: 333-58, 1992; Transplantation: 57 (12): 1701-17D6, 1994) or cardiac (Am. J. Anat. : 113: 273 (1963). Briefly, full thickness skin grafts are transplanted from C57BL / 6 mice to BALB / c mice. The grafts can be checked for rejection daily starting at day six. In a neonatal mouse heart transplant model, neonatal hearts are transplanted ectopically from C57BL / 6 into adult CBA / J mouse ears. Hearts begin to beat four to seven days after transplantation and rejection can be assessed visually using an autopsy microscope by observing the cessation of beating.

t r

Cell receptor PTK assays

The following cellular assay was used to determine the level of activity and effect of various compounds of the present invention on KDR / VEGFR2. Similar receptor PTK assays using a specific ligand stimulus can be constructed in a similar manner for other tyrosine kinases using techniques known in the art.

VEGF induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC) as measured by Western Blots:

1. HUVEC cells (combined from multiple donors) were purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer's instructions. Only the early passages (3-8) were used for this test. Cells were cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complete EBM medium (Clonetics).

2. To evaluate compound inhibitory activity, cells were trypsinized and seeded at 0.5-1.0 x 10 ⁵ cells / well in each well of 6-well group plates (Costar; Cambridge, MA).

3. 3-4 days after seeding, the plates were 90-100% confluent. Medium with

I was removed from all wells, cells were rinsed with 5-10 ml PBS and incubated for 1824 h with 5 ml EBM base medium without additions (i.e. serum fasting).

4. Serial dilutions of inhibitors were added to 1 ml of EBM medium (25 μΜ, 5 μΜ or 1 μΜ final concentration) to the cells and incubated for one hour at 37 ° C. Human recombinant VEGF ₁₆₅ (R&D Systems) was then added to all wells in 2 ml EBM medium at a final concentration of 50 ng / ml and incubated at 37 ° C for 10 minutes. Control cells, untreated or treated with VEGF only, were used to assess background phosphorylation and induction of phosphorylation by VEGF.

All wells were then washed with 5-10 ml cold PBS containing mM sodium orthovanadate (Sigma) and cells were lysed and scraped in 200 μΙ RIPA buffer (50 mM Tris-HCl) pH 7, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA) containing inhibitors (PMSF 1 mM, aprotinin 1 pg / ml, pepstatin 1 pg / ml, leupeptin 1 pg / ml, sodium vanadate 1 mM, sodium fluoride 1 mM) and 1 pg / ml ml Chase (all chemicals from Sigma Chemical Company, St. Louis, MO). The lysate was centrifuged at 14,000 rpm for 30 min to remove the nuclei.

Equal amounts of proteins were then precipitated by adding cold (20 ° C) ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. The pellets were reconstituted in a sample of Laemli buffer containing 5% mercaptoethanol (BioRad; Hercules, CA) and boiled for 5 min. The proteins were resolved by polyacrylamide gel electrophoresis (6%, 1.5 mm Novex, San Deigo, CA) and transferred to a nitrocellulose membrane using a Novex system. After blocking with bovine serum albumin (3%), the protein was probed overnight with anti-DRDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 ° C. . After washing and incubating for 1 hour with HRP-conjugated F (ab) ₂ goat anti-rabbit or goat anti-mouse IgG, the bands were visualized using an emission chemiluminescence (ECL) system (Amersham Life Sciences, Arlington Height, IL).

Certain examples of the present invention significantly inhibit cell VEGF-induced KDR tyrosine kinase phosphorylation at concentrations of less than 50 μΜ.

In vivo model of uterine edema

This assay measures the ability of a compound to inhibit the acute increase in uterine weight in mice that occurs within the first few hours after estrogen stimulation. This early onset of uterine weight increase is known to be due to edema due to increased uterine vasculature permeability. Cullinan-Bove and Koss (Endocrinology (1993), 133: 829837) showed a close temporal relationship between estrogen-stimulated uterine edema and increased expression of VEGF mRNA in the uterus. These results were confirmed by the use of a neutralizing monoclonal antibody on VEGF, which significantly reduced the acute weight gain of the uterus after estrogen stimulation (WO

97/42187). Thus, this system can serve as a model for the in vivo inhibition of VEGF signaling and related hyperpermeability and edema.

Materials: All hormones were purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to the supplier's instructions.

Vehicle components (DMSO, Cremaphor EL) were purchased from Sigma (St. Louis, MO).

Mice (Balb / c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in a pathogen-free facility in accordance with the guidelines of the Institutional Care and Animal Use Committee.

method:

Day 1: Balb / c mice received (i.p.) an intraperitoneal injection of 12.5 units of pregnant mare's serum gonadotrophin (PMSG).

Day 3: Mice received 15 units of human chorionic gonadotrophin (hCG) i.p.

Day 4: Mice were randomized into groups of 5-10. Test compounds were administered i.p., i.v. or p.o. routes depending on solubility and vehicle at doses of 1 to 100 mg / kg. The vehicle control group received vehicle only and the two groups were untreated.

Thirty minutes later, the experimental, vehicle, and 1 of the untreated groups received an ip injection of 17-estradiol (500 µg / kg). After 2-3 hours, the animals were sacrificed by CO ₂ inhalation. After a central incision, each uterus was isolated and removed by cutting just below the neck and attaching the uterine tubes to the fallopian tubes. The adipose and connective tissue were carefully removed so as not to damage the integrity of the uterus before weighing (wet weight). Fluids were removed from the uteri by compressing copper with two sheets of filter paper with a glass liter bottle filled with water. Uterines were weighed after blotting. The difference between wet weight and blotted weight was taken as the uterine fluid content. The mean fluid content of the treated groups was compared to the untreated or vehicle treated groups. Significance was determined by Student's test. The unstimulated control group was used to monitor the estradiol response.

The results show that certain compounds of the present invention inhibit edema formation when administered systemically by different routes.

Certain compounds of the invention that are inhibitors of angiogenic receptor tyrosine kinases may also be active in the Matrigel implant model of neovascularization. The Matrigel neovascularization model involves the formation of new blood vessels within a pure "marble" extracellular matrix implanted subcutaneously, which is induced by the presence of a pro-angiogenic tumor cell-producing factor (for examples see Passaniti, A., et al, Lab. Investig. (1992), 67 ( 4), 519-528, Anat Rec (1997), 249 (1), 63-73, Int J. Cancer (1995), 63 (5), 694-701, Vasc Biol (1995), 15 (11), 1857-6. This model preferably runs for 3-4 days and ends with a macroscopic visual or visual scoring of neovascularization, microscopic determination of microvessel density or quantification of hemoglobin (Drabkin method) after removal of the implant versus controls from animals not treated with inhibitors. Alternatively, the model may utilize bFGF or HGF as a stimulus.

Certain compounds of the present invention that inhibit one or more oncogenic, proto-oncogenic or proliferation-dependent protein kinases or angiogenic receptor PTKs also inhibit the growth of primary mouse, rat, or human xenograft tumors in mice, or inhibit metastasis in mouse models.

DETAILED DESCRIPTION OF THE INVENTION

Processes for preparing compounds of Formula I will now be described. These processes form a further aspect of the present invention. These processes are preferably carried out at atmospheric pressure.

Compounds of formula I may be prepared by condensing a compound of formula

(II) wherein R ¹ , R ² , R ³ , L and ring A are as defined above, with formamide at a temperature in the range of 50 to 250 ° C optionally in the presence of a catalyst, for example 4-dimethylaminopyridine.

Compounds of formula I may be prepared by reacting a compound of formula (III)

wherein R ^x is bromine or iodine, with one of the following compounds: R ₃ B (OH) ₂ , R ₃ Sn (CH ₃ ) ₃ or a compound represented by formula IV

R 3 (CH ₂₎ j

or r *

Wherein R ³ is as defined above, in the presence of a catalyst, for example a palladium metal compound, e.g. Pd _{(PPh3) 4th}

Compounds of formula I in which R ¹ represents alkyl or aralkyl may be prepared by alkylation of a compound of formula (V)

wherein R ² and R ³ are as defined above, with a compound of formula R ¹ X ', wherein R ¹ represents alkyl or aralkyl and X' represents a leaving group, for example halogen, mesyloxy or tozyloxy.

Compounds of formula I in which R ¹ represents an optionally substituted cyclic ether, for example tetrahydrofuryl or tetrahydropyranyl, may be prepared by alkylation of a compound of formula VI

wherein R ² and R ³ are as defined above, with a compound of formula R ¹ X ¹ , wherein X ¹ is as defined above, and R ¹ is an optionally substituted cyclic ether.

Compounds of formula I in which R ¹ represents a cyclic ether, for example tetrahydrofuryl or tetrahydropyranyl, optionally substituted with formyl, may be prepared by alkylating a compound of formula VI with a compound R'X in which R ¹ represents a cyclic ether substituted with a formyl group protected by a method known (See, e.g., Tet. Letts. 30 (46): 6259-6262 (1989) followed by deprotection. Compounds in which R ¹ represents a cyclic ether such as tetrahydrofuryl or tetrahydropyranyl, substituted (e.g. optionally substituted amino) methyl, may be prepared by reductive amination of a compound wherein R ¹ represents a cyclic ether substituted with formyl.

Compounds of formula I wherein R ¹ is optionally substituted furyl, thienyl, or pyrrolyl may be prepared by reacting 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine with a suitable heteroaryl boronic acid in the presence of a copper salt catalyst such as copper acetate in the presence of a solvent for reactants, e.g. a halogenated solvent, e.g. dichloromethane, in the presence of a desiccant, e.g. 4A molecular sieves, in the presence of an organic base, e.g. triethylamine or pyridine, at a temperature in the range of 0-50 ° C, preferably at room temperature. (For conditions see Tet. Letts. (1998), 39: 2942-2944 and references cited therein. This work is hereby incorporated by reference.) These compounds can be formulated by methods known to those skilled in the art to obtain compounds in which R ¹ represents furyl, thienyl or pyrrolyl substituted with formyl. The formyl group in these compounds can be productively aminated by methods known to those skilled in the art to provide compounds wherein R ¹ is furyl, thienyl or pyrrolyl substituted with aminomethyl groups. Alternatively, intermediates in which R ¹ represents furyl, thienyl or pyrrolyl may be subjected to a Mannich reaction to give intermediates in which R ¹ represents furyl, thienyl or pyrrolyl substituted with an aminomethyl group.

Compounds of formula I may be prepared by reaction of a compound of formula VII

(VII) wherein R ¹ , R ² , R ³ , L and ring A are as defined above and R ^y represents a leaving group such as halogen or phenoxy with an ammonia or an ammonium salt such as ammonium acetate at a temperature in the range of 15 250 ° C, preferably in a pressure vessel.

The compounds of formula I in which R ² represents chloro, bromo or iodo may be prepared by reaction of a compound of formula VIII

(VIII) wherein R ¹ , R ³ L and ring A are as defined above, with a halogenating agent, for example an iodinating agent, e.g. N-bromosuccinimide, or a chlorinating agent, e.g. N-chlorosuccinimide.

Compounds of formula I in which -LR ³ represents -NHC (O) R ³ may be prepared by reaction of a compound of formula IX

(IX) wherein R ¹ , R ² and ring A are as defined above and Y is a protected amine, with a compound of formula R ³ COR ^X in which R ^x represents a leaving group such as chlorine. Alternatively, compounds of formula IX in which Y represents a halogen such as chlorine may be reacted with a compound of formula R ³ COR ^X and the product reacted with ammonia to give a compound of formula I. Analogous methods may be used to prepare compounds of formula I in which -LR ³ is -NRSO ² R ³ . Analogous methods can be used to prepare a compound of formula I wherein -LR ³ is -NRCO 2 -R ³ or -NRCONR '. R and R 'are as defined above.

Compounds of formula I wherein -LR ³ is -OSO ₂ - may be prepared by reacting a compound of formula X

wherein R ¹ , R ² and ring A are as defined above, with a compound of formula R ⁴ SO ₂ R ^x .

Compounds of formula I may then be prepared from such intermediates according to Scheme 2 or the alternative of Scheme 2 described below.

Compounds of formula II may be prepared according to Scheme 1, wherein IPA is propan-2-ol.

r »

R3- _(CH2) j

1) NaOCH ₂ CH ₃ / CH ₃ CH ₂ OH

2) NCCH ₂ CN / NaOCH ₂ CH ₃ , CH ₃ CH ₂ OH, 50 ° C

It will be apparent to those skilled in the art that compounds of Formula I may be converted to other compounds of Formula I by known chemical reactions. For example, alkoxy can be cleaved to form hydroxyl, nitro groups can be reduced to amines, amines can be acylated or sulfonylated, and N-acyl compounds can be hydrolyzed to amines. Compounds of formula I in which -L- is S can be oxidized to produce compounds of formula I in which -L- is SO and SO _{2 by} methods known to those skilled in the art.

r r

Compounds of formula III are commercially available or can be prepared by methods known to those skilled in the art.

Compounds of formula V wherein R ² is hydrogen can be prepared according to Scheme 2. The amino group can be protected from the final step and then deprotected after the final step of Scheme 2 by methods known to those skilled in the art. Compounds of formula V in which R ² is other than hydrogen can be prepared by analogous methods (see J. Med. Chem. (1990), 33, 1984).

+ R 3 - (CH ₂ ) j

B (OH) ₂

Alternatively, the (ring A) -LR ³ may be joined prior to the amination in Scheme 2. Alternatively, prior to carrying out either process is present and R ¹ as defined above.

Compounds of formula VII in which R ^y is -Cl can be prepared according to Scheme 3.

Scheme 3

Compounds in which (ring A) -LR ³ is absent can be prepared according to Scheme 4 and as described in J. Med. Chem., (1988), 31: 390 and references cited therein. Compounds in which (ring A) -LR ³ is other than hydrogen can be prepared by analogous methods.

Scheme 4

Compounds of formula VII may be prepared by synthesis of a 5-iodo compound in a manner analogous to that described for the preparation of compounds of formula V.

R ¹ can be modified as shown in Schemes 5 and 6. P in Schemes 5 and 6 represents a protecting group.

Scheme 5

ABOUT

Scheme 6

\

It will be apparent to those skilled in the art that when a substituent is identical or similar to a functional group that has been modified in one of the above processes, these substituents will require protection from initiation of the process followed by deprotection. Otherwise, competitive side reactions will occur. Alternatively, processes other than those described above may be used in which the substituent does not interfere. Examples of suitable protecting groups and methods for their addition and removal can be found in the textbook " Protective Groups in Organic Synthesis, T.W. Green, John Wiley & Sons, 1981. For example, suitable protecting groups for amines are formyl or acetyl.

The following synthesis examples were carried out according to the general preparation procedures described above:

Example 1: Benzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

a) Tetrahydro-2H-4-pyranyl trifluoromethanesulfonate. Pyridine (1.7 mL, 20.97 mmol) was added to a solution of tetrahydro-2H-4-pyranol (2 mL, 20.97 mmol) in dichloromethane (16 mL). The flask was immersed in an ice water bath and trifluoromethanesulfonic anhydride (3.6 mL, 20.97 mmol) in dichloromethane (7 mL) was added dropwise over 10 minutes. After 20 minutes, the reaction mixture was filtered and the solid was washed with a minimal amount of dichloromethane. The combined filtrate was washed with water, 1.0 N HCl, water and brine. The organic layer was dried (MgSO ₄ ) and filtered. The solvent was evaporated to give tetrahydro-2H-4-pyranyl trifluoromethanesulfonate. ¹ H NMR (CDCl ₃ ) δ 1.99 (m, 2H), 2.11 (m, 2H),

3.58 (m, 2H), 3.96 (m, 2H), 5.17 (m, 1H). .

b) 4-chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine. 4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (3.0 g, 10.73 mmol) was added in small portions to a solution of sodium hydride (0.891 g, 22.2 mmol) in Ν, Ν -dimethylformamide (40 mL) at 0 ° C. After the addition was complete, the ice water bath was removed and the resulting mixture was stirred for 30 minutes. Tetrahydro-2H-4-pyranyl trifluoromethanesulfonate was added and the reaction mixture was stirred at ambient temperature for 24 hours. The mixture was poured into ice water (100 mL) and the solid collected by filtration and purified by recrystallization to give 4-chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine . ¹ H NMR (CDCl ₃ ) δ 2.06 (m, 2H), 3.63 (m, 2H), 4.16 (m, 2H), 5.00 (m, 1H), 7.45 (s, 1H), 8.61 (s, 1H). LC / MS (MH < ^{+ &gt}; = 364)

c) tert-Butyl N- (4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. tert-Butyl N- [2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate (1.66 g, 4.75 mmol) in water degassing by sonication under vacuum for 1 minute. 4-Chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine (1.1 g, 3.17 mmol), tetrakis (triphenylphosphine) palladium (0) (0, 22 g, 0.19 mmol), sodium carbonate (0.8 g, 7.60 mmol) and 1,2-dimethoxyethane (30 mL) were added to the aqueous mixture. The resulting suspension was degassed again for 2 minutes and then heated to 85 ° C for 24 hours. The reaction mixture was cooled to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed and dried (MgSO 4). The solid was purified by flash column chromatography on silica using a 7: 3 mixture of heptane and ethyl acetate as the mobile phase to give tert-butyl N- (4 (4-chloro-7)). tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. ^1H-NMR _(CDCl3) δ 1.55 (s, 9H), 2.10 (m, 4H), 3.66 (m, 2H);

3.92 (s, 3H), 4.16 (m, 2H), 5.05 (m, 1H), 7.06 (m, 2H), 7.14 (s, 1H), 7.32 (s (1H),

8.13 (br. D, J = 8Hz, 1H), 8.64 (s, 1H). LC / MS (MH < ^{+ &gt}; = 459)

d) 4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyaniline. A solution of 10% trifluoroacetic acid in dichloromethane (50 mL) was added to tert-butyl N- (4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl)) -2-methoxyphenyl) carbamate at 0 ° C. After 20 minutes, the ice water bath was removed and the resulting solution was stirred at room temperature for 4 hours. The solvent was removed and the residue was dissolved in dichloromethane. Saturated sodium carbonate solution was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried (MgSO 4, filtered and concentrated. The solid was purified by passing through a plug of silica gel with heptane / ethyl acetate (3: 2) as the mobile phase to give 4- (4-chloro-7- tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyaniline ¹ H NMR (CDCl ₃ ) δ 2.09 (m, 4H), 2.51 (br, s, NH ₂ ),

3.66 (m, 2H), 3.91 (s, 3H), 4.16 (m, 2H), 5.05 (m, 1H), 6.79 (d, J = 8 Hz, 2H), 6.93 (d, J = 8Hz, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 8.63 (s, 1H). LC / MS (MH ⁺ = 359) ^m / z

e) 5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine. Ammonium hydroxide (25 mL) was added to a solution of 4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyaniline (0.73 g) , 2.03 mmol) in dioxane (25 mL) in a pressure vial. The pressure vial was sealed and heated to 122 ° C for 2 days. The vial was cooled to ambient temperature and the solvent was evaporated. Ethyl acetate was added and the organic layer was washed, dried (MgSO ₄ ), filtered and concentrated to give 5- (4-amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin-4-amine. ¹ H NMR (DMSO-d ₆ ) δ 1.87 (m, 2H), 2.11 (m, 2H), 3.52 (m, 2H), 3.79 (s, 3H), 3.99 ( m, 2H)

4.87 (m, 3H), 6.02 (br, s, NH _2), 6.73 (d, J = 8 Hz, 2H), 6.77 (d, J = 8 Hz, 1H), 6 88 (s, 1H); 7.33 (s, 1H); 8.10 (s, 1H). LC / MS (MH < ^{+ &gt}; = 340)

f) Benzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. Benzyl chloroformate (16 μΙ, 0.110 mmol) was added dropwise to a stirred solution of 5- (4-amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 mL) and dichloromethane (0.7 mL) under nitrogen at 0 ° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was purified by preparative TLC using dichloromethane / methanol (95: 5) as eluent to give benzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2]). (3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. Δ NMR (CDCl ₃ ) δ 2.07 (m, 4H), 3.65 (m, 2H), 3.9 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H) 5.23 (s, 2H), 6.96 (s, 1H), 7.03 (s, 1H), 7.08 (d, J = 8Hz, 1H), 7.42 (m, 6H) )

8.20 (br, s, J = 8Hz, 1H), 8.32 (s, 1H). LC / MS (MH + = 474).

Example 2: Neopentyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate.

Neopentyl chloroformate (13 μΙ, 0.110 mmol) was added dropwise to a stirred solution of 5- (4-amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 mL) and dichloromethane (0.7 mL) under nitrogen at 0 ° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was purified by preparative TLC using dichloromethane / methanol (95: 5) as eluent to give neopentyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2]). (3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. ¹ H NMR (CDCl ₃ ) δ 1.00 (s, 3H), 2.07 (m, 4H), 3.65 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H), 5.18 (s, 2H), 6.97 (s, 1H), 7.03 (s, 1H), 7, 07 (d, J = 8Hz, 1H), 7.25 (s, 1H), 8.19 (br, s, J = 8Hz, 1H), 8.33 (s, 1H). LC / MS (MH + = 454).

Example 3: Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (100 mg, 0.294 mmol) was dissolved in dichloromethane (2 mL) . Pyridine (2 mL) was added followed by phenylchloroformate (44 μΙ, 0.353 mmol). After stirring for 3 hours, an additional 44 μΙ of phenyl methanesulfonyl chloride was added and the reaction stirred overnight. The solvent was removed and the residue was purified by preparative LC / MS to give phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (52 mg, 0.113 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.09 (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 ( m, 1H), 5.24 (s, 2H), 7.09 (m, 3H), 7.23 (m, 4H), 7.41 (m, 2H), 7.62 (s, 1H), 8.20 (bd, J = 7.80 Hz, 1 H),

8.33 (s, 1 H). LC / MS MH < ^{+ &gt}; = 460.

Example 4: Tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate 4-nitrophenyl tetrahydro-2H4-pyranyl carbonate

Tetrahydro-2H-4-pyranol (1.0 mL, 10.5 mmol) was mixed with 4-methylmorpholine (2.0 mL) in dichloromethane (20 mL). To the reaction mixture was slowly added 4-nitrochloroformate (1.98 g, 9.82 mmol). After stirring for 5 hours, the reaction mixture was diluted with dichloromethane. The organic layer was washed with water, 1.0 N HCl, saturated sodium bicarbonate, brine, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by flash column chromatography using ethyl acetate / heptane (4: 1) as the mobile phase to give 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate (1.5 g, 5.62 mmol). ¹ H NMR (CDCl ₃ -d) δ

1.87 (m, 2H), 2.06 (m, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m, 1H), 7.40 (d J = 9.0 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H).

a) Tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate. 5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (57 mg, 0.168 mmol) and 4-nitrophenyl tetrahydro-2H- 4-Pyranyl carbonate (90 mg, 0.336 mmol) was mixed in pyridine (1 mL). After stirring for 5 hours, an additional 90 mg of 4r trophenyl tetrahydro-2H-4-pyranyl carbonate was added and the reaction mixture was stirred for 2 days. The reaction mixture was heated at 70 ° C for 2 hours. The solvent was removed and the residue was purified by preparative thin layer chromatography to give tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidine) -5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.064 mmol). ¹ H NMR (CDCl ₃ -d) δ 1.78 (m, 4H), 2.08 (m, 4H), 3.60 (m, 4H), 3.94 (s, 3H), 3.97 ( m, 2H), 4.15 (m, 2H);

4.98 (m, 2H), 5.23 (s, 2H), 6.78 (s, 1H), 7.04 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H 8.16 (bd, J = 7.90 Hz, 1H), 8.33 (s, 1H). LC / MS MH < ^{+ &gt}; = 468.

Example 5 :, 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

a) 4-Nitrophenyl (3-pyridylmethyl) carbonate. 4-Nitro chloroformate (2.49 g, 12.3 mmol) in dichloromethane (20 mL) was cooled in an ice water bath. 3-Pyrides, methanol (1.0 mL, 10.3 mmol) and 4-methylmorpholine (2.0 mL, 18.5 mmol) were added slowly. After 20 minutes, the ice water bath was removed and the reaction was allowed to warm to room temperature. Ethyl acetate was added 30 minutes later and the reaction mixture was filtered. The filtrate was washed with water, saturated sodium bicarbonate, brine, dried over MgSO ₄ , filtered and evaporated to give a dark brown solid which was recrystallized from ethyl acetate and heptane to give 4-nitrophenyl- (3-pyridylmethyl) carbonate (1, 2). 52 g, 5.54 mmol). ¹ H NMR (CDCl 3) δ 7.38 (m, 3H), 7.79 (m, 1H), 8.28 (d, J = 9.09 Hz, 2H), 8.65 (m, 1H), 8.72 (s, 1H).

b) 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate. 5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol) was dissolved in dichloromethane (0.7 ml). Pyridine (0.7 mL) was added followed by 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol). After heating at 100 ° C overnight, the solvent was removed and the residue was purified by preparative LC / MS to give 3-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrole) [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.08 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.15 (m, 2H), 4.96 ( m, 1H), 5.26 (s, 2H), 5.54 (bs, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J = 8) 2Hz, 1H), 7.35 (m, 2H), 7.79 (d, J = 7.8Hz, 1H), 8.15 (m, 1H), 8.29 (s, 1H), 61 (s, 1 H), 8.71 (s, 1 H). LC / MS MH + = 475

c) 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride. 3-Pyridylmethyl N [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol) was dissolved in ethyl acetate (2.0 mL). 1.0 N HCl in ether (1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 3-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2 -methoxyphenyl] carbamate hydrochloride (13 mg, 0.25 mmol). 1 H NMR (DMSO-d ₆ ) δ 1.91 (m, 2H), 2.17 (m, 2H), 3.54 (m, 2H), 3.87 (s, 3H), 4.03 (m (2H), 4.97 (m, 1H), 5.23 (s, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.51 ( m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.95 (m, 1H), 8.42 (s, 1H), 8.60 (s, 1H), 8.71 (s, 1H), 8.82 (s, 1H). LC / MS MH < ^{+ &gt}; = 475.

Example 6: 2-Morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (25 mg, 0.054 mmol) was mixed with 2-morpholino-1-ethanol (0.1 mL) in pyridine (0.7 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to give 2-morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine-5). -yl) -2-methoxyphenyl] carbamate (24 mg, 0.048 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.2 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 2-morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride (24 mg, 0.045 mmol). ¹ H NMR (DMSO-d _e) δ 1.88 (m, 2H), 2.16 (m, 2H), 3.55 (m, 8 H), 3.90 (s, 3H), 4.03 ( m, 4H), 4.49 (m, 2H);

4.92 (m, 1H); 7.07 (m, 1H); 7.15 (s, 1H); 7.65 (bs, 2H); 7.84 (s, 1H); 8.45 (s) (1H),

8.75 (s, 1H). 10.95 (bs, 1H). LC / MS MH + = 497.

Example 7: (4-Bromo-1,3-thiazol-5-yl) methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5) yl) -2-methoxyphenyl] carbamate.

a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde. 1,3-Thiazolane-2,4-dione (3.52 g, 30 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed with dimethylformamide (2.56 mL, 34 mmol). The mixture was then heated at 75 ° C for 1 hour and 5 hours at 100 ° C. After cooling to room temperature, the mixture was added to ice water (500 mL) and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate, dried over MgSO ₄ , filtered and evaporated to give a brown solid which was washed with petroleum ether. Evaporation of the solvent gave 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). Ή NMR (CDCl ₃ -d) δ 9.90 (s, 1H).

b) (2,4-Dibromo-1,3-thiazol-5-yl) methanol. 2,4-Dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol) was dissolved in methanol (70 mL) at 0 ° C. Sodium borohydride (0.244 g, 6.42 mmol) was added in small portions. The ice water bath was removed in 10 minutes and the reaction mixture was stirred at room temperature overnight. The solvent was removed and saturated ammonium chloride was added. 1.0 N NaOH was added to adjust the pH to 10. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash column chromatography to give (2,4-dibromo-1,3-thiazol-5-yl) methanol (0.946 g, 3.47 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.11 (bs, 1 H) δ 4.79 (s, 2H).

c) (4-Bromo-1,3-thiazol-5-yl) methanol. (2,4-Dibromo-1,3-thiazol-5-yl) methanol (0.94 g, 3.44 mmol), sodium carbonate trihydrate (1.34 g) and palladium on carbon (10%, 0.07) g) were combined in methanol (33 mL). The resulting mixture was hydrogenated at 60 psi for 2 days. The solid was filtered through a pad of celite. The solvent was evaporated and the residue was purified by flash column chromatography to give (4-bromo-1,3-thiazol-5-yl) methanol (0.32 g, 2.78 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.29 (bs, 1H) 4.86 (s, 2H),

8.72 (s, 1 H).

d) (4-Bromo-1,3-thiazol-5-yl) methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-) yl) -2-metoxyfenyljkarbamát. Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (28 mg, 0.061 mmol) was mixed with (4- bromo-1,3-thiazol-5-yl) methanol (50 mg, 0.434 mmol) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give (4-bromo-1,3-thiazol-5-yl) methyl N- [4- (4-amino-7-tetrahydro-2H-) - 4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2metoxyfenyljkarbamát. ¹ H NMR (CDCl 3) δ 2.07 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H),

4.13 (m, 2H), 4.98 (m, 1H), 5.35 (s, 1H), 5.40 (s, 2H), 6.97 (s, 1H), 7.04 (s 1 H, 7.09 (m, 1 H), 7.35 (s, 1 H), 8.17 (s, 1 H), 8.32 (s, 1 H), 8.78 (s, 1 H). LC / MS MH < ^{+ &gt}; = 481.

Example 8: Tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with tetrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to give tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine-5). -yl) -2-methoxyphenyl] carbamate (14 mg, 0.031 mmol). ¹ H NMR (CDCl 3) δ 2.07 (m, 6H), 3.66 (m, 2H), 3.96 (m, 7H), 4.13 (m, 2H),

4.98 (m, 1H), 5.26 (s, 2H), 5.40 (m, 1H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d J = 8.2 Hz, 1H), 7.26 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H). LC / MS MH < ^{+ &gt}; = 455.

Examples 9 and 10: 1,3-Dioxan-5-yl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2 -metoxyfenyljkarbamát

1,3-Dioxolan-4-ylmethyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with glycerol formaldehyde (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to give tetrahydro-3-furanyl N- [4- (4-amino-797 tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d]). pyrimidin-5-yl) -2-methoxyphenyl] carbamate (2 mg, 0.004 mmol). ¹ H NMR (CDCl 3) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.92 (m, 3H), 4.07 (m, 6H), 4.79 (m 1H, 4.83 (d, J = 6.3Hz, 1H), 4.96 (m, 1H), 5.04 (d, J = 6.3Hz, 1H), 6.15 (vbs, 2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.53 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.22 (s) s, 1H). LC / MS MH ⁺ = 471 and 1,3-dioxolan-4-ylmethyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) (2-Methoxyphenyl) carbamate (6.0 mg, 0.013 mmol). 1 H NMR (CDCl 3) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.75 (m, 1H),

3.92 (m, 3H), 4.03 (m, 1H), 4.13 (m, 1H), 4.34 (m, 2H), 4.94 (s, 1H), 4.97 (m, 1H) ), 5.10 (s, 1H), 5.32 (bs, 2H), 6.97 (s, 1H), 7.03 (m, 2H), 7.06 (d, J = 8.2) Hz, 1H), 7.38 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H). LC / MS MH < ^{+ &gt}; = 471.

Example 11: 2-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with 2-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine) -5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol). 1 H NMR (DMSO-d ₆ ) δ

1.92 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.89 (s, 3H), 4.02 (m, 2H), 4.91 (m, 1H) ), 5.23 (s, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.37 (m, 1H), 7.53 (d J = 7.8 Hz (1H), 7.87 (m, 3H), 8.42 (s, 1H), 8.57 (d, J = 4.2 Hz, 1H), 8.85 (s , 1H). LC / MS MH < ^{+ &gt}; = 475.

Example 12: 4-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine) -5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 4-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl ] carbamate hydrochloride (12 mg, 0.023 mmol). ^{@ 1} H NMR (DMSO-d6) _.delta

1.91 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (m, 1H) )

5.34 (s, 2H), 7.06 (d, J = 8.2 Hz, 1H), 7.16 (s, 1H), 7.73 (m, 1H), 7.81 (m, 1H), 7.87 (s, 1H), 8.46 (s, 1H), 8.76 (d, J = 5.6 Hz, 1H), 9.05 (s, 1H). LC / MS: MH < ^{+ &gt}; = 475.

Example 13: (5-Methyl-3-isoxazolyl) methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2- methoxyphenyl] carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl) methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give (5-methyl-3-isoxazolyl) methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [ 2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (18 mg, 0.038 mmol). H 1 H NMR (CDCl 3) δ 2.06 (m, 4H), 2.44 (s, 3H), 3.64 (m, 2H),

3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12 (s, 1H), 6.95 (s, 1H) 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21 (s, 1H). LC / MS: MH < ^{+ >} 479.

Example 14: [(2S) -5-Oxotetrahydro-1 H-2-pyrrolyl] methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidine-5) yl) -2-methoxyphenyl] carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with (5S) -5 (hydroxymethyl) tetrahydro-1 H -2-pyrrolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl N- [4- (4-amino-7-tetrahydro-2H-4-) pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (10 mg, 0.021 mmol), 1 H NMR (CDCl 3) δ 1.90 (m, 1H), 2, 06 (m, 4H), 2.34 (m, 1H), 2.41 (m, 2H), 3.64 (m, 2H), 3.94 (s, 3H), 4.04 (m, 2H) 4.14 (m, 2H); 4.98 (m, 1H); 5.33 (m, 3H); 6.10 (s, 1H);

6.98 (s, 1H), 7.04 (s, 1H), 7.09 (m, 1H), 7.31 (s, 1H), 8.11 (bs, 1H), 8.32 (s , 1H). LC / MS: MH + 481.

Example 15: 4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

a) tert-Butyl N- (4- (hydroxymethyl) phenyl) carbamate. (4-Aminophenyl) methanol (1.23 g, 10 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) were mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred overnight at room temperature. Ethyl acetate was added and the organic layer was washed with water, 1.0 N HCl, saturated sodium carbonate, water, brine, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by flash column chromatography with ethyl acetate and heptane (2: 3) to give tert-butyl N- (4 (hydroxymethyl) phenyl) carbamate (2.16 g, 9.67 mmol). ¹ H NMR (CDCl 3) δ 1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5 Hz, 2H), 7.36 (d, 8.5 Hz, 2H).

b) 4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (51 mg, 0.111 mmol) was mixed with tert-butyl N- (4- (hydroxymethyl) phenyl) carbamate (119 mg) in pyridine (0.8 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 4-aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine) (5-yl) -2-methoxyphenyl) carbamate (9 mg, 0.015 mmol). ¹ H NMR (CDCl 3) δ 1.52 (s, 1H), 2.08 (m, 4H), 3.65 (m, 2H), 3.90 (s, 3H), 4.14 (m (2H), 4.97 (m, 1H), 5.17 (s, 2H), 5.37 (bs, 1H), 6.55 (s, 1H), 6.95 (s, 1H), 7 .03 (s, 1H), 7.06 (m, 1H), 7.31 (s, 1H), 7.38 (m, 3H), 8.16 (bs, 1H), 8.30 (s, 1H). LC / MS: MH + 589.

Example 16: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 ml). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 μΙ, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. Solid ·

100 was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxy-phenyl] -benzamide (64). mg, 0.144 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.12 (m, 4H), 3.67 (m, 2H), 3.99 (s, 3H), 4.17 (m, 2H), 4.99 ( m, 1H), 7.03 (s, 1H), 7.04 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.53 (m, 3H), 7, 94 (d, J = 7.8Hz, 1H), 8.33 (s, 1H), 8.58 (s, 1H), 8.63 (d, J = 8.2Hz, 1H). LC / MS: MH < ^{+ &gt}; = 444

Example 17: N 2 - [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] -2-pyridinecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 ml). Pyridine (2.0 mL) was added followed by 2-pyridinecarbonyl chloride hydrochloride (63 mg, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide ( 84 mg, 0.189 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.12 (m, 4H), 3.67 (m, 2H), 4.03 (s, 3H),

4.14 (m, 2H), 5.00 (m, 1H), 5.37 (s, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.14 (d) J = 8.2 Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70 (d, J = 8.2 Hz) 1 H, 10.62 (s, 1 H). LC / MS: MH < ^{+ &gt}; = 445.

Example 18: N5- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1,3-dimethyl-1 Η-5-pyrazolecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 ml). Pyridine (2.0 mL) was added followed by 2-pyridinecarbonyl chloride hydrochloride (63 mg, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N5- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1 3-dimethyl-1H-5-pyrazolecarboxamide (30 mg, 0.065 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.11 (m, 4H),

2.32 (s, 3H), 3.66 (m, 2H), 3.99 (s, 3H), 4.13 (m, 2H), 4.17 (s, 3H), 4.99 (m (1H),

5.22 (bs, 2H), 6.46 (s, 1H), 7.03 (s, 1H), 7.07 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H) ), 8.33 (2.2, 2H), 8.49 (d, J = 8.2 Hz, 1H). LC / MS: MH < ^{+ &gt}; = 462.

101

Example 19: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2,2-dimethylpropanamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1). , 5 ml). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2 2-dimethylpropanamide (27 mg, 0.064 mmol). ¹ H NMR (CDCl ₃ -d) δ 1.35 (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H),

3.96 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H), 5.46 (bs, 2H), 6.98 (s, 1H), 7.04 (s) 1 H, 7.07 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49 (d, J = 8.2 Hz) , 1H). LC / MS: MH + = 424.

Example 20: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1-cyclopentanecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 ml). Pyridine (1.5 mL) was added followed by 1-cyclopentanecarbonyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2 2-dimethylpropanamide (33 mg, 0.076 mmol). ¹ H NMR (CDCl ₃ -d) δ 1.66 (m, 2H), 1.81 (m, 2H), 1.95 (m, 4H), 2.06 (m, 4H), 2.77 ( m, 1H), 3.65 (m, 2H), 3.94 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.37 (bs, 2H), 6.98 (s, 1H), 7.03 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H) 8.49 (d, J = 8.2Hz, 1H). LC / MS: MH + = 437.

Example 21: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -3-phenylpropanamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 ml). Pyridine (1.5 mL) was added followed by 3-phenylpropanoyl chloride (37 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent and the residue were removed

102 was dissolved in 1 ml DMSO, methanol (1 ml) was added and a precipitate formed. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2 2-dimethylpropanamide (7 mg, 0.015 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.07 (m, 4H), 2.75 (m, 2H), 3.09 (m, 2H), 3.65 (m, 2H),

3.88 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.97 (bs, 2H), 6.93 (s, 1H), 7.05 (m) , 2H),

7.26 (m, 5H), 7.70 (s, 1H), 8.24 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H). LC / MS: MH < ^{+ &gt}; = 472.

Example 22: 5- (4-Phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

a) Tosyl chloride (12.0 g) was added portionwise to a mixture of 3-hydroxy-tetrahydro-furan (5.0 g) in pyridine (100 mL) at 0 ° C under nitrogen with stirring. The mixture was stirred at 0 ° C for 2 hours and then warmed to ambient temperature. The mixture was stirred at room temperature for 72 hours. The mixture was cooled to 0 ° C and 5 M hydrochloric acid (200 mL) was added. The mixture was extracted with ethyl acetate, and the combined ethyl acetate extracts were washed with 2M hydrochloric acid and then brine, then dried, filtered and evaporated to give 3-tosyloxy-tetrahydrofuran as an oil.

b) Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added to a solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (906 mg) and dimethylformamide (30 ml) ) under stirring under nitrogen. The mixture was stirred for 30 minutes and a solution of 3- (tosyloxy) tetrahydrofuran (750 mg) in dimethylformamide (10 mL) was added with stirring. The mixture was stirred and heated to 95 ° C for 18 hours and then evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried and evaporated to give a gummy residue which was triturated with ether and filtered to give 5- (4-phenoxyphenyl) -7 (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] Pyrimidin-4-ylamine 1.1. Mp 196-196.5 ° C.

Example 23: 5- (4-Phenoxyphenyl) -7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Similar to Example 1, 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine was reacted with 4-tosyloxytetrahydropyran to give (after column flash).

103 chromatography) of 5- (4-phenoxyphenyl) -7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p. 193-193.5 ° C.

Example 24: 4-amino-5- (4-phenoxyphenyl) -7- [4- (N-tert-butoxycarbonyl) tetrahydroisoxazolyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

a) Di-tert-butyl dicarbonate (4.56 g) was added to a solution of 4-hydroxy-tetrahydroisoxazole (2.4 g) and triethylamine (4.2 g) in tetrahydrofuran (100 mL) with stirring at 0 ° C under nitrogen. The mixture was stirred at room temperature for 72 hours and then filtered. The filtrate was evaporated under reduced pressure to give N- (tert-butoxycarbonyl) -4-hydroxytetrahydroisoxazole as an oil which was used directly in the next section of this example.

b) The product from a) (3.6 g) above was stirred in pyridine (50 ml) at 0 ° C under nitrogen and then tosyl chloride (3.62 g) was added portionwise at 0 ° C with stirring. The mixture was stirred at 0 ° C for 1 hour and then allowed to warm to ambient temperature over 18 hours. The pyridine was removed under reduced pressure and ethyl acetate (50 mL) and citric acid (50 mL of a 1 M solution in water) were added. The organic layer was separated and washed with 1 M citric acid solution and then brine, dried, filtered and evaporated to give an oil which was purified by flash column chromatography using petroleum ether, m.p. in. 40-60 ° C containing 20-30% ethyl acetate as the mobile phase. Appropriate fractions were collected and combined to give N- (tert-butoxycarbonyl) -4-tosyloxy-tetrahydroisoxazole, m.p. 63-65 ° C.

c) A solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (1.0 g) in dimethylformamide (40 ml) was added dropwise to a sodium hydride suspension (0.145) with stirring. g 60% dispersion in mineral oil) in dimethylformamide (60 ml) with stirring under nitrogen at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and then the product of b) (1.25 g) was added with stirring. The mixture was heated to 100 ° C for 3 hours and then cooled to ambient temperature, quenched with water and extracted with ethyl acetate to give an oil. The oil was triturated with ethyl acetate, and the resulting solid was collected by filtration to give 4-amino-5- (4-phenoxyphenyl) -7- [4- (N-tert-butoxycarbonyl) tetrahydroisoxazolyl] -7H-pyrrolo [2, m.p. 3-d] pyrimidin-4-ylamine, mp.1.162-163 ° C.

104

Example 25: 5- (4-Phenoxyphenyl) -7- (4-tetrahydroisoxazolyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride

The product of Example 3 (0.29 g) was dissolved in dichloromethane (8 mL) and stirred at 0 ° C while trifluoroacetic acid (2.0 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. The pH of the mixture was adjusted to basic with sodium bicarbonate solution and extracted with dichloromethane to give an oil which was purified by flash column chromatography using ethyl acetate and then ethyl acetate with methanol (9: 1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was dissolved in ethyl acetate and ethereal hydrogen chloride (3.0 mL of 1 M solution) was added. The resulting solid was collected by filtration, washed with ether and dried under vacuum at 45 ° C for 2 hours to give 5- (4-phenoxyphenyl) -7- (4-tetrahydroisoxazolyl) -7H-pyrrolo [2,3-d] - pyrimidin-4-ylamine dihydrochloride, 1.1. 208 ° C (dec.).

Example 26: 4-Chloro-5-iodo-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine

a) 4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (5.0 g) was added to a mixture of sodium hydride (0.79 g of a 60% dispersion in mineral oil) in dimethylformamide (100 ml) ) with stirring at 0 ° C under nitrogen. The mixture was stirred until hydrogen evolution ceased. At 0 ° C, 3-tosyloxytetrahydrofuran (4.65 g) was added and the mixture was then heated to 90 ° C. The mixture was stirred at this temperature for 2 hours and then at room temperature overnight. Water (100 mL) was carefully added and the mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine, m.p. Mp 184-186 ° C.

b) A mixture of 4-iodophenol (25.0 g), 2-fluorobenzaldehyde (14.14 g), potassium carbonate (31.5 g) and dimethylformamide (500 ml) was heated to 120 ° C under nitrogen with stirring for 15 hours . The mixture was cooled to ambient temperature and filtered. Water (500 mL) was added to the filtrate and the mixture was extracted with ethyl acetate to give a solid which was triturated with hot hexane (500 mL). The mother liquor was decanted from the gum residue and cooled. The solid that precipitated was collected by filtration to give 2- (4-iodophenoxy) benzaldehyde,

1.1. 84.5-86 ° C.

105

c) Toluene (250 mL) was degassed and then purged with nitrogen for 30 minutes. To this toluene was added 2- (4-iodophenoxy) benzaldehyde (6.46 g), hexamethyldicine (10.0 g) and tetrakis (triphenylphosphine) palladium (0) (1.4 g). The mixture was heated to reflux under nitrogen with stirring for 7 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by flash column chromatography on silica using 3% ethyl acetate in petroleum ether, m.p. in. 40-60 ° C as the mobile phase to give 2- (4-trimethylstannylphenoxy) benzaldehyde as an oil.

d) A mixture of (c) (1.80 g), (b) (1.76 g), tris (dibenzylideneacetone) dipalladium (228 mg), triphenylarzine (383 mg) and dimethylformamide (75 ml) was heated to 65 ° C. under nitrogen with stirring for 70 hours. The mixture was cooled to ambient temperature and quenched with water. The mixture was extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using increasing amounts of ethyl acetate from 30-50% in petroleum ether m.p. in. 40-60 ° C as a mobile phase to give a solid which was triturated with diethyl ether and filtered to give 2 - [(4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [2])). 3-d] pyrimidin-5-yl) phenoxy] benzaldehyde as a solid.

e) The product of d) (360 mg) was dissolved in methanol (5 ml) and sodium borohydride (65 mg) was added with stirring at 0 ° C. The mixture was warmed to room temperature and stirred at this temperature for 1 hour. The reaction was quenched by addition of dilute sodium hydroxide solution and then evaporated under reduced pressure to give a residue which was extracted with ethyl acetate to give 2 - [(4- (4-chloro-7- (3-tetrahydrofuryl) 7H-pyrrolo)). [2,3-d] pyrimidin-5-yl-phenoxy] benzyl alcohol.

f) A mixture of the product of e) (280 mg), 1,4-dioxane (15 ml) and concentrated aqueous ammonia solution (15 ml, density 0.88) was heated to 120 ° C in a pressure vessel for 20 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate and methanol (9: 1) as the

106 mobile phase to give 2 - [(4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3d] pyrimidin-5-yl) phenoxy) benzyl alcohol as a glassy solid with m.p. 92-96 ° C.

Example 27: 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -N, N-diethylbenzylamine

a) Sodium triacetoxyborohydride (264 mg) was added to a mixture of 2 - [(4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy) benzaldehyde (330 mg) and diethylamine (121 mg) in 1,2-dichloroethane in an ampoule (5 mL), and the vial was closed with a whisper, stirred at room temperature for 20 hours and quenched with saturated aqueous sodium bicarbonate (5 mL). was extracted with ethyl acetate to give 2- [4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -N, N-diethylbenzylamine.

b) A mixture of the product of a) (280 mg), concentrated aqueous ammonia solution (10 ml, density 0.88) and 1,4-dioxane (10 ml) was heated to 120 ° C in a pressure vessel for 16 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried, filtered and evaporated to give an oil which was purified by flash column chromatography using ethyl acetate and methanol as mobile phase to afford 2- [4- (4-amino-7). - (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -N, N-diethylbenzylamine, m.p.

Example 28: 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -benzonitrile

a) A mixture of 2-fluorobenzonitrile (28.8 g), 4-bromophenol (36.9 g), potassium carbonate (58.9 g) and dimethylformamide (30 ml) was heated to 120 ° C under stirring under nitrogen for 5 hours. The mixture was allowed to stand overnight at ambient temperature and then partitioned between ethyl acetate and water. The organic layer was separated, washed, dried and evaporated to give an oil which solidified on standing. The solid was triturated with petroleum ether, m.p. in. 40-60 ° C and filtered to give 2- (4-bromophenoxy) benzonitrile.

b) A mixture of the product of part a) (5.57 g), hexamethyldicin (10.0 g), tetrakis (triphenylphosphine) palladium (0) (1.4 g) and degassed toluene (250 ml) was heated to 110 ° C. with stirring under nitrogen for 4.5 hours. The mixture was allowed to stand r * r * r * r * r

107 H 'j.

hours at ambient temperature and then filtered through a pad of silica. The layer was washed with ethyl acetate and the combined filtrates were evaporated to dryness. The residue was purified by silica flash column chromatography using petroleum ether of m.p. in. 40-60 ° C and diethyl ether (2%) with an increase of 5% as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 2- (4-trimethylstannylphenoxy) benzonitrile.

c) A mixture of 4-chloro-5-iodo-7- (3-tetrahydrofuryl) pyrrolo [2,3-d] pyrimidine (1.8 g, prepared as described in Example 5) and the product of part b) (1.23) g) were reacted and then treated as in Example 5d) to give 2- (4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl)) ) -phenoxy] -benzonitrile.

d) A mixture of the product of (c) (470 mg), concentrated aqueous ammonia (33 ml, density 0.880) and 1,4-dioxane (33 ml) was heated together in a pressure vessel at 120 ° C for 18 hours and then treated similarly to in Example 5 to give 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzonitrile, m.p. Mp 201-203 ° C.

Example 29: 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo (2,3-d] pyrimidin-5yl) phenoxy] benzaldehyde

a) As in Example 2, 3-tosyloxytetrahydrofuran (1.84 g) was reacted with 5- (4-benzyloxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (2.9 g) using hydride sodium (0.30 g of a 60% dispersion in mineral oil) and dimethylformamide (40 mL) except that the mixture was heated at 90 ° C for 4.5 hours to give

5- (4-Benzyloxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as a solid.

b) A mixture of the product of part a) (6.0 g), 10% palladium on charcoal (3.0 g)

g), ammonium formate (4.9 g) and ethanol (500 ml) were heated on a steam bath with stirring under nitrogen for 2 hours. The mixture was cooled and filtered and the solvent was evaporated. The filtrate was concentrated to half volume and filtered to give a solid which was identified as 4- [4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol 1.1. 257-259 ° C.

108

c) A mixture of 4- [4-amino-7- (3-tetrahydrofuryl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -phenol (2.55 g), 2-fluorobenzaldehyde (1.07 g), potassium carbonate ( 2.13 g) and dimethylformamide (80 mL) was heated to 120 ° C with stirring under nitrogen for 5 hours, cooled to room temperature, quenched with water and extracted with ethyl acetate to give 2- [4- ( 4-amino-7- (3-tetrahydrofuryl) 7H-pyrrolo [2 ₁ 3-d) pyrimidin-5-yl) phenoxy] benzaldehyde, 1.1.185 -187 ° C.

Example 30: 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] tetrahydrofuran-3-ol

Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added to a solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (902 mg) and dimethylformamide (30 mL) under stirring under nitrogen. The mixture was stirred for 30 minutes, 3,6-dioxabicyclo [3.1.0] hexane (300 mg) was added and the mixture was heated to 80 ° C. The mixture was allowed to stand for 64 hours and then evaporated under reduced pressure. The residue was triturated with water leaving an oily gum. Ether was added and the mixture was stirred rapidly for 30 minutes to give a solid which was collected by filtration and washed with methanol. The solid was discarded. An additional solid was obtained from the filtrate, which was recrystallized from ethanol to give 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] tetrahydrofuran-3-ol , 1.1. 234.5-235.5 ° C.

Example 31: 5- [4- (2-Morpholinomethyl-phenoxy) -phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

A mixture of 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde (0.15 g), morpholine (64 mg), triacetoxyborohydride sodium (117 mg) and 1.2 dichloroethane (5 mL) were stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was filtered through a EMPORE® filter cartridge. The filtrate was evaporated, the residue was dissolved in dichloromethane (5 mL), polymer-bound tris (2-aminoethyl) amine (0.3 g) and 2 drops of glacial acetic acid were added and the mixture was stirred at ambient temperature overnight. The polymer was collected by filtration, washed with dichloromethane and then methanol. The combined organic filtrates were evaporated under reduced pressure to give an oil which was triturated with diethyl ether and ethyl acetate with heating to dissolve the solid and then the solution was cooled in ice and filtered to give 5- (4- (2r) • er

109 [eta] (morpholinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p.

Example 32: 5- [4- (2-Piperidinomethyl-phenoxy) -phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Similar to Example 10, 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d) pyrimidin-5-yl) phenoxy] benzaldehyde (0.15 g) was reacted with piperidine ( 63 mg) to give 5- [4- (2-piperidinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine, m.p. 76 - 78 ° C (glass foam).

Example 33: 5- {4- [2- (2-Methoxyethyl) aminomethylphenoxy] phenyl} -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Similar to Example 10, 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d) pyrimidin-5-yl) phenoxy] benzaldehyde (0.15 g) and 2- methoxyethylamine (56 mg) to give 5- {4- [2- (2-methoxyethyl) aminomethylphenoxy] phenyl} -7- (3-tetrahydrofuryl) 7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, 1.1 . 66 - 68 ° C (glass foam).

Example 34: 4 - [(4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzyl alcohol)

a) Similar to Example 9, 4- [4-amino-7- (3-tetrahydrofuryl) 7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol was reacted with 4-fluorobenzaldehyde to give 4- (4- (4-amino-7- (3-tetrahydrofuryl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde.

b) The product of a) (0.35 g) was dissolved in methanol (10 ml) and to this solution was added sodium borohydride (32 mg) at 0 ° C. The mixture was warmed to room temperature and stirred at room temperature for 10 minutes. 1,2-Dichloroethane (4 mL) was added to improve solubility. The mixture was stirred at ambient temperature for 18 hours, glacial acetic acid (1 ml) was added and the mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The ethyl acetate layer was separated, dried, filtered and evaporated to give 4 [(4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5yl) phenoxy] benzyl alcohol). Mp 92-95 ° C.

t> 110

Example 35: 5- [4- (4-Fluorophenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine

A mixture of 4- [4-amino-7- (3-tetrahydrofuryl-7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol (0.59 g), 4-fluorophenylboronic acid (0.56 g), copper acetate (0.36 g), triethylamine (1.01 g), dichloromethane (20 ml) and activated ground molecular sieves 4 (0.5 g) were stirred under nitrogen in a dry atmosphere for 64 hours. a pre-rinsed layer of silica and eluted with dichloromethane (200 mL), then ethyl acetate (250 mL), and finally ethyl acetate with methanol 9: 1 (250 mL). with methanol as the mobile phase to give 5- [4- (4-fluorophenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, mp 198-199 ° C.

Example 36: 5- [4- (4-Morpholinomethyl-phenoxy) -phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Similar to Example 10, a mixture of 4- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde (336 mg) and morpholine (146) was reacted. mg) to give 5- [4- (4-morpholinomethylphenoxy) -phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, 1.1. Mp 142-144 ° C.

Example 37: 5- [4- (3-Morpholinomethyl-phenoxy) -phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino

a) A mixture of 4- [4-amino-7- (3-tetrahydrofuryl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -phenol (0.297 g) was treated with 3-formylphenylboronic acid similar to Example 14 to give 3 - [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde.

b) The product of part a) (100 mg) and morpholine (44 mg) were reacted with similar reagents and conditions as described in Example 10 to give 5- [4- (3-morpholinomethylphenoxy) phenyl] -7- (3). (tetrahydrofuryl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine, 1.1. Mp 83-85 ° C.

111

Example 38: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (2- (4-pyridyl) ethylamino) benzonitrile

A mixture of 4- [4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -phenol (0.517 g), 2-fluoro-6- (2- (4) (pyridinyl) ethylamino) benzonitrile (0.42 g), potassium carbonate (0.48 g) and dimethylformamide (20 mL) was heated at 120 ° C under nitrogen for 8 hours. The mixture was allowed to cool, diluted with water and then extracted with ethyl acetate to give a solid which was recrystallized from ethyl acetate and the obtained solid was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate with methanol (9: 1, 8: 1). 1,4: 1) to give 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3d] pyrimidin-5-yl) phenoxy] -6- (2- (4-pyridyl) ethylamino) -benzonitrile, 1.1. Mp 212-213 ° C.

Example 39: 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-imidazol-1-yl) propylaminobenzonitrile

4- [4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl-phenol (0.49 g), 2-fluoro-6- (3-imidazole-1- yl) propylaminobenzonitrile, potassium carbonate (0.45 g) and dimethylformamide were reacted similar to Example 17 to give 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d]) pyrimidin-5-yl) phenoxy] -6- (3-imidazol-1-yl) propylaminobenzonitrile, 1.1. 110 ° C (glass foam).

Example 40: 4-Amino-6-bromo-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine

a) A mixture of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (302 mg) was dissolved in dimethylacetamide (10 mL) and dichloromethane (50 mL) and then N- was added. bromosuccinimide (178 mg) in dichloromethane (10 mL). The mixture was allowed to stir at room temperature for 16 hours. The mixture was evaporated under reduced pressure, the residue was triturated with water and the resulting solid collected by filtration and dried to give 4-amino-6-bromo-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] Pyrimidine, 1.1. Mp 282-283 ° C.

b) A mixture of the product of a) (1.14 g) in dry dimethylformamide (30 ml) was stirred under nitrogen while sodium hydride (120 mg of a 60% dispersion in mineral oil) was added. This was followed by 3-tosyloxy-tetrahydrofuran (0.8 g) in dimethylformamide (10 mL). The mixture was heated at 90 ° C overnight. The mixture was evaporated under reduced pressure, the residue was triturated with water and the solid obtained

112 was collected by filtration and dried to give a solid which was purified by dissolving in ethanol, adding water to turbidity and filtering. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by flash column chromatography on silica to give 4-amino-6-bromo-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3] -d] pyrimidine, 1.1. 205-206 ° C.

Example 41: 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-methoxypropylamino) benzonitrile

As in Example 17, 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (0.65 g), 2-fluoro-6- (3-methoxypropylamino) benzonitrile (0.15 g) was heated under nitrogen. 46 g), potassium carbonate (0.61 g) and dimethylformamide (40 mL) at 120 ° C for 8 hours to yield 2- [4- (4 amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [ 2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-methoxypropylamino) benzonitrile, m.p.

Example 42: 2- [4- (4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzonitrile

a) A mixture of 5- (4-benzyloxyphenyl) -7- (tetrahydropyran-4-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine (2.83 g), 10% palladium on carbon (1.41) g), ammonium formate (2.31 g) and ethanol (250 ml) were heated to reflux under nitrogen with stirring for 1.5 hours. The mixture was cooled to ambient temperature, filtered, and the filtrate cooled and filtered. The filtrate was evaporated to give solid 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol.

b) A warm solution of 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl] phenol (0.082 g) in dimethylformamide (3.4 ml) was added to the mixture 2fluorobenzonitrile (80 mg) and potassium carbonate (76 mg) in an ampoule. The vial was flushed with nitrogen and sealed. The mixture was shaken at 120 ° C for 6 hours and then allowed to cool to ambient temperature over 16 hours. The mixture was diluted with water (11 mL) and extracted with ethyl acetate to give 2- [4- (4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzonitrile, m.p. t. 125 ° C (softening).

Examples 43-48 were prepared in a similar manner to the previous example by reacting 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5e-e.

113:; J · j yl yl yl yl yl yl yl yl yl yl yl j j yl yl yl yl yl yl j j j j j yl j j j j j j j j j j Reactions were monitored for starting material consumption and heated for an appropriate period of time.

Example 49: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-imidazol-1-yl) propylaminobenzonitrile from 2-fluoro-6- (3- (imidazol-1-yl) propylamino) -benzonitrile.

Example 50: 2- (4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy) -6- (2-morpholinoethoxy) benzonitrile, 1.1.110 ° C (glass), from 2-fluorobenzonitrile.

Example 51: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (2- (4-pyridyl) ethylamino) benzonitrile, 1.1. 120-123 ° C (glass), from 2-fluoro-6- (2- (4-pyridyl) ethylamino) benzonitrile.

Example 52: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy) -6- (3-methoxypropylamino) benzonitrile, m.p. 205-207 ° C, from 2-fluoro-6- (3-methoxy-propylamino) -benzonitrile.

Example 53: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-fluorobenzonitrile, m.p. 216-217 ° C, from 2,5-difluorobenzonitrile.

Examples 54-101

General method

Doses of the amines listed in Table 1 (9 mol equivalents relative to the ester used weighing from 47.5 mg to 184.5 mg) were weighed into separate vials and methanol (1 mL) was added to each. A solution of ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-ylacetate (1 mol equivalent) in a mixture of methanol and triethylamine (4 ml, methanol to triethylamine ratio 23) The reaction mixtures were shaken at 60-65 ° C for 36 hours Methanol and triethylamine were removed under reduced pressure at 50 ° C for 3 hours and water (3 ml) was added to each vial followed by dichloromethane The vials were shaken for 15 seconds and then allowed to stand for 18 hours The mixtures were poured into EMPORE® extraction disc inserts (10 mm / 6 mL) and the dichloromethane phases separated and evaporated at 50 ° C for 3 hours. During processing, it was observed that solids were separated in the vials for 18 hours

114 phase. The aqueous layer in each liner was then extruded with compressed air. Dichloromethane (4 mL) was added to each extraction pad. Each filtrate was evaporated under reduced pressure at 50 ° C for 3 hours. The desired products were either found in the original dichloromethane extract when indicated as being present in the liquid, or found in the insoluble solid phase and referred to as being found in the solid phase. Some products were found in both phases. These phases are shown in Table 1.

Each sample was analyzed by LCMS and the target ion was detected in each case. The retention time for each product is shown in Table 1. The conditions used are shown below.

Column: Mobile phase: Conditions: (Gradient)

flow rate:

BDS c18 hypersil (100 x 2.1 mm).

0.1 M NH ₄ OAc [pH 4.55]: MeCN (gradient see below). 10-100% MeCN over 8 minutes.

100% MeCN for 1 minute.

100-10% MeCN over 2 minutes.

(Total analysis time 11 min.) Ml / min (no MS cleavage).

250-320 nm

Wavelength range: Injection volume: 20 μΙ. MS

Method: APCI11H.

Ionization of APcI + ve / -ve.

Weight range: 100-700 m / z.

Tapered stress:.

Similar to Examples 54-101, the amines listed in Table 2 were reacted with ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propionate to give The processing conditions and analysis conditions were identical to those used for Examples 54-101. In each case, the target ion was found by LCMS.

115

Table 1

Amín č. Title phase RT / min product 54 ethanolamine solid 3.44 55 DL-2-amino-1-propanol solid 3.58 56 1-amino-2-propanol solid 3.56 57 2-methoxyethylamine fluid á 3.78 53 3-amino-1-propanol both 3.50 59 (S) - (+) - 2-Amino-1-propanol both 3.58 60 (R) - (-) - 1 -Amino-2-propanol both 3.56 61 Ν, Ν-dimethylethylenediamine both 3.31 62 (+/-) - 2-amino-1-butanol solid 3.77 63 1-amino-2-butanol both 3.77 64 3-amino-1,2-propanediol solid 3.32 65 (S) -3-amino-1,2-propanediol solid 3.32 66 (R) -3-amino-1,2-propanediol solid 3.32 67 1-methylpiperazine both 3.28 68 N, N-dimethyl-1,3-propanediamine fluid á 3.29 69 N2, N2-dimethyl-1,2-propanediamine both 3.37 70 1-dimethylamino-2-propylamine fluid á 3.44 71 DL-2-Amino-3-methyl-1-butanol solid 3.98 72 N- {2- [1- (N-Morpholine) -1-oxo] ethyl} piperazine fluid á 3.56 73 2-Amino-2-methyl-1-propanol both 3.86 74 2-amino-2-methyl-1,3-propanediol both 3.49

v t

116

Amín č. Title phase RT / min product 45 2- (2-aminoethoxy) ethanol both 3.47 76 1- (2-Aminoethyl) pyrrolidine fluid á 3.40 77 N-methylhomopiperazine fluid á 3.32 78 1-amino-1-cyclopentanemethanol both 4.16 79 2-aminocyclohexanol solid 3.98 80 N, N-diethylethylenediamine fluid á 3.44 81 N- (3-Hydroxypropyl) ethylenediamine both 3.24 82 2 - ((2-aminoethyl) thio) ethanol both 3.69 83 2- (2-aminoethyl) pyridine fluid á 3.89 84 3- (2-aminoethyl) pyridine fluid á 3.79 85 N- (3-Aminopropyl) imidazole fluid á 3.37 86 1- [2- (N-Morpholine) ethyl] piperazine fluid á 3.39 87 2- (Aminomethyl) -1-ethyl-pyrrolidin both 3.48 88 1- (2-Aminoethyl) piperidine both 3.49 89 1-Pyrolidínpropánamín fluid á 3.37 90 (R) - (+) - 2-aminomethyl-1-ethylpyrrolidine both 3.48 91 4- (2-Aminoethyl) morpholine both 3.39 92 3-diethylaminopropylamino both 3.43 93 N, N-Dimetylneopentándiamín both 3.47 94 Ethyl 1-piperazinecarboxylate liquid -: - 4.34

117

Amín č. Title phase RT / min product á 95 2- (Aminomethyl) -2-ethyl-1,3-propanediol both 3.69 96 1- (3-Aminopropyl) -2-pyrrolidinone both 3.68 97 1-Piperidínpropylamín fluid á 3.46 98 4- (3-Aminopropyl) morpholine fluid e and 3.33 99 N, N-diisopropylethylenediamine fluid á 3.59 100 N, N-bis (3-aminopropyl) methylamine fluid á 3.03 101 Tris (2-aminoethyl) amine fluid á 3.01

Prepared compounds are listed below.

Example 54: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-hydroxy-ethyl) -acetamide

Example 55: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxy-prop-2-yl) -acetamide

Example 56: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-hydroxy-propyl) -acetamide

Example 57: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-methoxy-ethyl) -acetamide

Example 58: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (3-hydroxy-propyl) -acetamide

118

Example 59: (S) -4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxy-prop-2-yl) -acetamide

Example 60: (R) -4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- (2-hydroxypropyl) acetamide

Example 61: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl-N- [2- (N, N-dimethylamino) ethyl] acetamide

Example 62: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxy-but-2-yl) -acetamide

Example 63: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl-N- (2hydroxybutyl) acetamide

Example 64: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- (2,3-dihydroxypropyl) acetamide

Example 65: (S) -4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2,3-dihydroxy-propyl) -acetamide

Example 66: (R) -4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2,3-dihydroxy-propyl) -acetamide

Example 67: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl-N, N- (3azapentametylén) acetamide

Example 68: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (N, N-dimethylamino) -propyl] -acetamide

Example 69: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [1- (N, N-dimethylamino) -prop-2-yl] -acetamide

119

Example 70: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (N, N-dimethylamino) -propyl] -acetamide

Example 71: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxy-3-methyl-but-2-yl) -acetamide

Example 72: 7- {2- [4- (2-Morpholino-2-oxoethyl) piperazin-1-yl] -2-oxoethyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Example 73: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxy-3-methyl-prop-2-yl) -acetamide

Example 74: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (1,3-dihydroxy-2-methyl-prop-2-yl) -acetamide

Example 75: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (2-hydroxy-ethoxy) -ethyl] -acetamide

Example 76: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2 (pyrrolidin-1-yl) -ethyl] -acetamide

Example 77: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N ₁ N- (3-azahexamethylene) -acetamide

Example 78: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [1 (hydroxymethyl) cyclopentyl] acetamide

Example 79: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-hydroxy-cyclohexyl) -acetamide

120 J '

Example 80: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (N, N-diethylamino) -ethyl] -acetamide

Example 81: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (3-hydroxy-propylamino) -ethyl] -acetamide

Example 82: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (2-hydroxy-ethylthio) -ethyl] -acetamide

Example 83: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (pyridine)]

2-yl) ethylacetamide

Example 84: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- [2- (pyridin

3-yl) ethyl] acetamide

Example 85: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [3 (imidazol-1-yl) -propyl] -acetamide

Example 86: 7- {2- [4- (2-Morpholinoethyl) piperazin-1-yl] -2-oxoethyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 ylamine

Example 87: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (methyl-pyrrolidin-2-yl) -methyl-acetamide

Example 88: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-piperidinoethyl) -acetamide

Example 89: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- [3- (pyrrolidin-1-yl) -propyl] -acetamide

Example 90: (R) -4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- (Netylpyrolidin-2-yl) methylacetamide

121

Example 91: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-morpholinoethyl) -acetamide

Example 92: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- [3- (N, Ndietylamino) propyl] acetamide

Example 93: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (N, N-dimethylamino) -2,2-dimethylpropyl] acetamide

Example 94: 7- [2- (4-Ethoxycarbonylpiperazin-1-yl) -2-oxoethyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrinnidin-4-ylamine

Example 95: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [2,2-bis (hydroxymethyl) butyl-acetamide

Example 96: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (2-pyrrolidinon-1-yl) -propyl] -acetamide

Example 97: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl-N- (3piperidinopropyl) acetamide

Example 98: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (3-morpholinopropyl) -acetamide

Example 99: 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl N- (3-hydroxy-1-methylprop-2-yl) acetamide

Example 100: 4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (N-3-aminopropyl-N-methyl) aminopropyl] acetamide

122

Example 101: 4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- [N-bis (2-amino-ethyl) -amino-ethyl] -acetamide

Table 2

Amín č. Title phase RT / min product 102 ethanolamine both 3.68 103 DL-2-amino-1-propanol both 3.78 104 1-Amino-2-propanol both 3.31 105 2-methoxyethylamine both 4.08 106 3-Amino-1-propanol both 3.73 107 (S) - (+) - 2-Amino-1-propanol both 3.78 108 (R) - (-) - 1 -Amino-2-propanol fluid á 3.81 109 Ν, Ν-dimethylethylenediamine fluid á 3.50 110 (+/-) - 2-amino-1-butanol both 3.96 111 1-amino-2-butanol both 4.06 112 3-amino-1,2-propanediol both 3.52 113 (S) -3-amino-1,2-propanediol both 3.53 114 (R) -3-amino-1,2-propanediol both 3.53 115 N, N-dimethyl-1,3-propanediamine fluid á 3.47 116 N2, N2-dimethyl-1,2-propanediamine fluid á 3.57 117 1-dimethylamino-2-propylamine fluid á 3.67 118 DL-2-Amino-3-methyl-1-butanol both 4.15 119 2- (2-aminoethylamino) ethanol fluid á 3.40

123

Amín č. Title phase RT / min product 120 2-Amino-2-methyl-1-propanol both 4.17 121 2-amino-2-methyl-1,3-propanediol both 3.76 122 2- (2-aminoethoxy) ethanol fluid á 3.71 123 1- (2-Aminoethyl) pyrrolidine both 3.61 124 1-Amino-1-cyclopentanethanol both 4.48 125 2-aminocyclohexanol both 4.19 126 N, N-diethylethylenediamine both 3.68 127 N- (3-hydroxypropyl) ethylenediamine both 3.42 128 2 - ((2-aminoethyl) thio) ethanol fluid á 3.94 129 2- (2-Aminoethyl) pyridine fluid á 4.13 130 3- (2-aminoethyl) pyridine both 4.05 131 N- (3-Aminopropyl) imidazole fluid á 3.58 132 2- (2-aminoethylamino) -1-methylpyrrolidine both 3.56 133 2- (Aminomethyl) -1-ethylpyrrolidine both 3.70 134 1- (2-Aminoethyl) piperidine both 3.70 135 1-Pyrolidínpropánamín both 3.60 136 (R) - (+) - 2-aminomethyl-1-ethylpyrrolidine both 3.70 137 4- (2-Aminoethyl) morpholine both 3.63 138 3-diethylaminopropylamino both 3.64 139 N, N-Dimetylneopentándiamín both 3.68 140 2- (Aminomethyl) -2-ethyl-1,3-propanediol both 3.94 141 1- (3-Aminopropyl) -2-pyrrolidinone fluid 3.91

124

Amín č. Title phase RT / min product and 142 1-Piperidínpropylamín both 3.70 143 4- (3-Aminopropyl) morpholine fluid á 3.53 144 Ν, Ν-diisopropylethylenediamine fluid á 3.86 145 N, N-bis (3-aminopropyl) methylamine solid 3.21 146 Tris (2-aminoethyl) amine both 3.17

Example 102: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxy-ethyl) -propanamide

Example 103: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-prop-2-yl) -propanamide

Example 104: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxy-propyl) -propanamide

Example 105: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-methoxy-ethyl) -propanamide

Example 106: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-hydroxy-propyl) -propanamide

Example 107: (S) -1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-prop-2-yl) -propanamide

Example 108: (R) -1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxy-propyl) -propanamide f.

Example 109: 1 - [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl] -N- [2- (N, N-dimetylaminoJetyljpropánamid

Example 110: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxybut-2-yl) -propanamide

Example 111: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxy-butyl) -propanamide

Example 112: 1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl] -N- (2,3-dihydroxypropyl) propanamide

Example 113: (S) -1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl] -N- (2,3-dihydroxypropyl) propanamide

Example 114: (R) -1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2 ₁ 3-dihydroxypropyl) propanamide

Example 115: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3 (N, N-dimethylamino) -propyl] -propanamide

Example 116: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2 (N, N-dimethylamino) -propyl] -propanamide

Example 117: 1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _l 3-d] pyrimidin-7-yl] -N- [1- (N, N-dimethylamino) prop-2- yl] propanamide

Example 118: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-3-methyl-but-2-yl) -propanamide

Example 119: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxy-ethylamino) -ethyl] -propanamide

126

Example 120: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-2-methyl-prop-2-yl) -propanamide

Example 121: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1,3-dihydroxy-2-methyl-prop-2-yl) propanamide

Example 122: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxy-ethoxy) -ethyl] -propanamide

Example 123: 1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl] -N- [2- (pyrrolidin-1-yl) ethyl] propanamide

Example 124: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [1 (hydroxymethyl) cyclopentyl] propanamide

Example 125: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxy-cyclohexyl) -propanamide

Example 126: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2 (N, N-diethylamino) -ethyl] -propanamide

Example 127: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (3-hydroxy-propylamino) -ethyl] -propanamide

Example 128: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxy-ethyl-thio) -ethyl] -propanamide

Example 129: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2 (pyrid-2-yl) -ethyl] -propanamide

127

Example 130: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2 (pyrid-3-yl) -ethyl] -propanamide

Example 131: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3 (imidazol-1-yl) -propyl] -propanamide

Example 132: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N-methyl-pyrrolidin-2-yl) -ethyl] propanamide

Example 133: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N - [(N-methyl-pyrrolidin-2-yl) -methyl] -propanamide

Example 134: 1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-7-yl] -N- (2-piperidinoethyl) propanamide

Example 135: 1- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _l 3-d] pyrimidin-7-yl] -N- [3- (pyrrolidin-1-yl) propyl] propanamide

Example 136: (R) -1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N [(N-ethyl-pyrrolidin-2-yl)] methyl] propanamide

Example 137: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-morpholinoethyl) -propanamide

Example 138: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3 (N, N-diethylamino) -propyl] -propanamide

Example 139: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3 (N, N-dimethylamino) -2,2] dimethylpropyl] propanamide

Example 140: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [ _2,1- bis (hydroxymethyl) butyl] propanamide

128

Example 141: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (2-pyrrolidinon-1-yl) -propyl] -propanamide

Example 142: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-piperidinopropyl) -propanamide

Example 143: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-morpholinopropyl) -propanamide

Example 144: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2 (N, N-di-isopropylamino) -ethyl] propanamide

Example 145: 1- [Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (N-3-aminopropyl-N-methyl) aminopropyl] propanamide

Example 146: 1- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -N- [Nbis (2-aminoethyl) aminoethyl] propanamide

Example 147: 2- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -butyrolactone

a) 4-Amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 _L 3-d] pyrimidine (1.0 g) was added to a mixture of sodium hydride (0.158 g of 60% dispersion in mineral oil) in dimethylformamide ( 70 ml) with stirring under nitrogen at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and then α-bromo-γ-butyrolactone (0.60 g) in dimethylformamide (6 mL) was added dropwise with stirring at 0 ° C. The mixture was stirred at room temperature for 18 hours and then quenched with water (100 mL). The mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give 2- [4aminO '5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -Y-butyrolactone as an oil which was used directly b).

b) Ν, Ν-Dimethylethylenediamine (5.0 ml) was added to a mixture of the product of a) (1.2 g) and pyridin-2-one (50 mg) in toluene (100 ml). The mixture was heated for 2 hours

129

100 ° C and then evaporated to dryness under reduced pressure. The residue was suspended in ethyl acetate and washed with water. The organic extracts were then extracted with 5 M hydrochloric acid (3 x 50 mL), the acidic extracts were washed with ethyl acetate, adjusted to basic with 6 M sodium hydroxide solution at 0 ° C and then back extracted with ethyl acetate and then with dichloromethane. The combined organic extracts were dried, filtered and evaporated to an oil which was crystallized from ethyl acetate / ether to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7]. -yl] -4-hydroxy-N- [2-dimethylamino) ethyl] butyramide, m.p.

Example 148: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propionate

Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added to the mixture

4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (906 mg) in dry dimethyformamide (30 mL) and the mixture was stirred under nitrogen for 30 minutes at room temperature. A solution of ethyl 2-bromopropionate (543 mg) in dry DMF (10 mL) was added dropwise over 10 minutes via syringe. The mixture was stirred at room temperature for 2 hours and then allowed to stand for 18 hours. The mixture was evaporated under reduced pressure, the residue was washed with water and the obtained solid was triturated with ether and filtered to give ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propionate, 1.1. Mp 139-140 ° C.

Example 149: N- (2-dimethylaminoethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl) propionamide

A mixture of ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propionate (425 mg), N, N-dimethylethylenediamine (2 ml) and methanol (20 ml) ) was heated at reflux for 18 hours with carbon dioxide evolution. The mixture was cooled and filtered, the filtrate was diluted with water (50 mL) and stirred with ether. The mixture was allowed to stand for 18 hours and the precipitated solid was collected by filtration, washed with water and then ether and dried to give N- (2-dimethylaminoethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) propionamide, m.p.

Example 150: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetate

A mixture of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (906 mg), sodium hydride (120 mg of a 60% dispersion in mineral oil) and dry

130 dimethylformamide (30 mL) was stirred at room temperature under nitrogen for 30 minutes. With stirring, ethyl bromoacetate (0.5 g) in dimethylformamide (10 mL) was added at 0-5 ° C over 5 minutes. The mixture was stirred at room temperature for 30 minutes and then allowed to stand for 18 hours. The mixture was evaporated under reduced pressure and the residue was triturated with water and ether. The resulting solid was collected by filtration, washed with water and then with ether to give ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] acetate, m.p. 161-161.3 ° C.

Examples 151-156

General method

Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetate (194 mg) was heated to 62 ° C and stirred with 10 mol equivalents of the respective of the amine listed below in methanol (12 mL) for 18 hours to give the following compounds after workup:

Example 151

N- [2-hydroxyethyl-1,1-di (hydroxymethyl)] - 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide, m.p. t. 222 DEG-223 DEG C. with decomposition, from 2-hydroxyethyl-1,1-di (hydroxymethyl) ethylamine.

Example 152

N- [2- (piperazin-1-yl) ethyl] -2- [4-amino-5- [4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide, m.p. 138-140 ° C, from 2- (piperazin-1-yl) ethylamine.

Example 153

N- (2-morpholinoethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide, mp.1.164-165 ° C, from 2-morpholinoethylamine.

Example 154

N- [3- (1-imidazole) propyl] -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] acetamide, m.p. C, from 3- (1-imidazolyl) propylamine.

Example 155

N- (N-ethylpyrrolidin-2-ylmethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide, 1.1.122 - 122.5 ° C, from 1- (N-ethylpyrrolidin-2-yl) methylamine.

131

Example 156

N - [- 2 (2-hydroxyethoxy) ethyl] -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide; 147 ° C, from 2- (2-hydroxyethoxy) ethylamine.

Example 157: 2- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -propionic acid

A mixture of ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propionate (201 mg), aqueous potassium hydroxide solution (4 mL of a 2 M solution) and methanol ( 20 ml) was heated to reflux for 1 hour. The mixture was concentrated under reduced pressure to about 5 mL and then diluted with water (30 mL). The mixture was filtered while hot, the filtrate was cooled and then acidified with dilute acetic acid until precipitation no longer occurred. The mixture was heated on a hotplate until the gel obtained became a finely powdered solid. This solid was collected by filtration to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] propionic acid, m.p. 239.5-241 ° C.

Example 158: Ethyl 4- [4-amido-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] butyrate

A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (1.5 g) was dissolved in DMF (30 ml) and sodium hydride (0.22 g 60%) was added. dispersion in mineral oil) and then ethyl 4-bromobutyrate (1.08 g) in DMF (15 mL) similar to Example 95 to give ethyl 4- [4-amido-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3d] pyrimidin-7-yl] butyrate, 1.1. Mp 104-104.5 ° C.

Example 159: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] carboxamide

Similar to Example 97, 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine (1.0 g), sodium hydride (1.032 g of a 60% dispersion in mineral oil) were reacted together. -bromoacetamide (0.55 g) and dimethylformamide (50 mL) to give a solid after work-up which was recrystallized from isopropanol to give ethyl 2- [4 amino-5- (4-phenoxyphenyl) -7H-pyrrolo [ 2,3-d] pyrimidin-7-yl] carboxamide, m.p. t. 232-233 ° C.

i r

132

Example 160: 2- [4-Amino-5- (4-phenoxy-phenyl) -pyrrolo [2,3-d] pyrimidin-7-yl] -2-methyl-propionamide

4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (200 mg) was dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (1.5 ml), sodium hydroxide (0.158 g) was added at room temperature and the mixture was stirred for 15 minutes. 2-Bromo-2-methylpropanamide (0.5 g) was added and the mixture was stirred vigorously for 18 hours at room temperature under an anhydrous atmosphere, then additional 2-bromo-2-methylpropanamide (0.15 g) was added and stirring was continued for another 24 hours. . Water (3 mL) was added to the reaction mixture along with dilute hydrochloric acid (5 M) to adjust the pH to 0. The suspension was added to water (60 mL) and allowed to stand at room temperature for 18 hours. The solid was collected by filtration, washed well with water and dried under high vacuum at 50 ° C. The solid was purified by reverse phase preparative HPLC. Appropriate fractions were collected, combined and extracted with dichloromethane. Evaporation of dichloromethane gave 2- [4-amino-5- (4-phenoxyphenyl) pyrrolo [2,3-d] pyrimidin-7-yl] -2-methylpropionamide, m.p. Mp 227-228 ° C.

Example 161: 4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] -N- (2-dimethylamino-ethyl) -butyramide

A mixture of ethyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] butyrate (100 mg) in 30 mL of methanol was heated to reflux with 0.6 ml of 2-dimethylaminoethylamine for 18 hours. The mixture was evaporated under reduced pressure and the residue was heated with 2-dimethylaminoethylamine (10 mL) in a steam bath for 18 hours. Excess amine was evaporated under reduced pressure. Water was added to the residue and the mixture was filtered to give 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin7-yl] N- (2-dimethylaminoethyl) butyramide .

Examples 162, 163 and 164 were prepared in a similar manner to Example 108 by reacting the same ester with the appropriate amine.

Example 165

4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] -N- [3- (1-imidazolyl) propyl] butyramide from 3- (1-imidazolyl) ) propylamine.

133

Example 166

4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] -N- (2-morpholinoethyl) butyramide from 2-morpholinoethylamine.

Example 167

4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] -N- (3-morpholinopropyl) butyramide from 3-morpholinopropylamine.

Preparation of starting materials

a) 7-t-butylamine (15 ml) was added with stirring to a solution of 2-bromo-4'-phenoxyacetophenone (12.7 g, prepared by bromination of 4'-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture was heated at 80 ° C for 3 hours. The mixture was cooled to 0 ° C and concentrated hydrochloric acid (10 mL) was added. The suspension was stirred at room temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g), m.p. Mp 210-212 ° C.

1) 4'-Phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g) was added in one portion to sodium ethoxide (prepared by dissolving sodium (93 mg) in ethanol (50 ml)) and stirred at 40 ° C for 30 minutes under nitrogen.

2) Sodium (331 mg) in ethanol (50 mL) was dissolved in a separate flask and malononitrile (858 mg) was added. The solution was stirred at room temperature for 5 minutes and to this solution was added a solution of the 4'-phenoxy-2- (tert-butylamino) acetophenone obtained in part (1) in one portion, with the precipitation of sodium chloride. The resulting mixture was heated at 50 ° C for 3 hours and 2 hours at 80 ° C. The solvent was evaporated under reduced pressure and the resulting oil was partitioned between water and ethyl acetate. The organic phase was separated, dried and evaporated to give a black solid. This solid was dissolved in hot ethanol and triturated with water to give 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert-butyl) pyrrole.

b) A mixture of 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert-butyl) pyrrole (1.9 g), formamide (30 ml) and 4-dimethylaminopyridine (10 mg) was heated to 180 ° C for 6 hours. The mixture was cooled to ambient temperature and water was added, whereupon a dark solid precipitated. This solid was collected by filtration, washed with water, rt

134 was then boiled in ethanol and the insoluble matter was collected by filtration hot and dried. The solid was purified by preparative HPLC on a silica column using dichloromethane, propan-2-ol and ethanol 98: 1: 1 as the mobile phase to give 7-tert-butyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (4 amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine), mp 157-158 ° C. ¹ H NMR (d 6 DMSO) δ 8.15 (1H, s), 7.50-7.35 (4H, m), 7.30 (1H, s), 7.15 (1H, t), 10 (4H, m), 6.05 (2H, br s), 1.75 (9H, s).

c) A mixture of 4-amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid ( 55 ml of 48% solution) was heated to reflux for 18 hours under nitrogen. The mixture was allowed to cool and the solid was collected by filtration. This solid was washed with methanol and then ether to give 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide, m.p. t. Mp 288-292 ° C. The hydrobromide salt was converted to the free base by heating with dilute sodium hydroxide solution (100 mL 5% w / v) and ethanol (60 mL) with stirring and removal of ethanol by distillation. The mixture was cooled and the solid collected by filtration and washed well with water to give 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p. t. 272 ° C.

Example 168: 7-Cyclopentanesulfonyl-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Sodium hydride (0.132 g of a 60% dispersion in mineral oil) was added to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (1.0 g) and dimethylformamide (30 ml). ) under stirring under nitrogen. The mixture was stirred for 30 minutes and cyclopentanesulfonyl chloride (0.558 g, prepared as described in J.O. C. 1952, 17, 1529-1533) in dry dimethylformamide (5 mL) was added dropwise. The mixture was allowed to stand for 72 hours and then evaporated under reduced pressure. The residue was triturated with water and filtered to give a solid which was washed well with water, stirred with ethyl acetate, and filtered. The filtrate was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. The appropriate fractions were collected and evaporated to give 7-cyclopentanesulfonyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p. Mp 188-188.5 ° C.

135

Example 169: 5- (4-Phenoxy-phenyl) -7- (8-phthalimidooktyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (906 mg) and dimethylformamide (30 ml) under stirring. stirring under nitrogen. The mixture was stirred under nitrogen for 30 minutes and N- (8-bromoctyl) phthalimide (1.4 g) in dimethylformamide (5 mL) was added. The mixture was stirred at room temperature for 18 hours and then partitioned between water and ethyl acetate. The ethyl acetate layer was separated and purified by flash column chromatography using ethyl acetate as the mobile phase to give 5- (4-phenoxyphenyl) -7- (8-phthalimidooktyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p. Mp 85-86 ° C.

Example 170: 7- (8-Amino-octyl) -5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride dihydrate

A mixture of 5- (4-phenoxyphenyl) -7- (8-phthalimidooktyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (1.0 g), hydrazine hydrate (1.0 ml) and ethanol (40 ml) ) was heated at reflux for 2 hours with carbon dioxide evolution. The mixture was allowed to cool for 18 hours and the precipitated solid was collected by filtration and discarded. The filtrate was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, dried, and a solution of concentrated hydrochloric acid in isopropanol was added dropwise until precipitation no longer occurred. The mixture was allowed to stand overnight, the mother liquor was decanted and the semi-solid residue was triturated with ethyl acetate to give 7- (8-aminoctyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4- ylamine dihydrochloride dihydrate, m.p.

Example 171: N- {2- [4-amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-ethyl] -phthalimide

In a similar manner to Example 468 but with additional heating at 90 ° C for 3 hours, 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was reacted with 2-bromomethylphthalimide to give N - {2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] ethyl} phthalimide, m.p.

~ r

136 ^¾ ''

Example 172: 7- (2-aminoethyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-4-ylamine hydrochloride

Similar to Example 469, the product of the previous example was hydrazine hydrate to give 7- (2-aminoethyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine hydrochloride, 1.1.284 - 285 ° C.

Example 173: 7-Isobutyryl-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Isobutyryl chloride (1.8 g) was added dropwise to a mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (4.32 g), dry dimethylformamide (200 mL) and dry pyridine (2 mL) with stirring under nitrogen at 20 ° C. The mixture was stirred at room temperature for 1 hour and evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, dried and evaporated and the residue was recrystallized from toluene to give 7-isobutyryl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, 1.1.160,5 - 161 ° C.

Example 174: 5- (4-Phenoxy-phenyl) -7- (1,4-dioxaspiro [4.5] decan-8-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine

Sodium hydride (0.26 g of a 60% dispersion in mineral oil) was added to the mixture

5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (1.94 g) and dimethylformamide (50 mL) at room temperature with stirring. The mixture was stirred until hydrogen evolution ceased and then 8-tosyloxy-1,4-dioxaspiro [4.5] decane (2.0 g, prepared as described in US 4,360,531 from 1,4-dioxaspiro [4,5]) was added. decan-8-one (prepared according to J. Med. Chem. 1992, 2246)). The mixture was heated at 120 ° C for 5 hours under nitrogen, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the residue purified by flash column chromatography on silica with ethyl acetate and then ethyl acetate with increasing amounts of methanol up to methanol. 6% to give 5- (4-phenoxyphenyl) -7- (1,4-dioxaspiro [4,5] decan-8-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, m.p. mp 193-194 ° C.

Example 175: 4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexanone

The product of the previous example (500 mg), acetone (20 ml) and 3 M hydrochloric acid (10 ml) were stirred under nitrogen at room temperature.

137 minutes. The mixture was then heated at 60 ° C for 1 hour and the acetone was then removed under reduced pressure. The pH of the residue was adjusted with aqueous 5 M sodium hydroxide solution and the residue was then extracted with ethyl acetate and the resulting solid was triturated with diethyl ether and filtered to give 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3] -d] pyrimidin-7-yl] cyclohexanone, 1.1. Mp 252-254 ° C.

Examples 176 and 177: cis -5- (4-phenoxyphenyl) -7- (4-morpholinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-5- (4- phenoxyphenyl) -7- (4-morpholinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

Sodium triacetoxyborohydride (42 mg) and glacial acetic acid (18 mg) were added to the product of the previous example (120 mg) and morpholine (31 mg) in 1,2-dichloroethane. The mixture was stirred at 40 ° C for 2 hours and then another portion of morpholine (0.15 g) and sodium triacetoxyborohydride (0.21 g) was added. The mixture was stirred at room temperature for 20 hours and quenched with saturated aqueous bicarbonate solution. The mixture was filtered through a EMPORE® filter cartridge and the filtrate was extracted with 3 M hydrochloric acid. The acidic extracts were adjusted to basic pH with 5M sodium hydroxide solution, extracted with dichloromethane and the residue was purified by silica chromatography to give cis5- (4-phenoxyphenyl) -7- (4-morpholinocyclohex-1-yl) -7H -pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-5- (4-phenoxyphenyl) -7- (4-morpholinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine .

Examples 178 and 179: cis-7- (4-N-ethoxycarbonyl) piperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and trans 7- (4-N-ethoxycarbonyl) -piperazine-1-yl-cyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine

In a similar manner to the previous example, 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexanone (0.4 g from 1.0 g 40% pure) and 1-ethoxycarbonylpiperidine (158 mg) were reacted together in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 mL) containing glacial acetic acid (60 mg) to give (after workup and chromatography) cis-7- (4N- trans (7- (4-N-ethoxycarbonyl) piperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine and trans-7- (4-N-ethoxycarbonyl) piperazin-1-ylcyclohexyl ) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine.

138

Example 180: 2- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -pyridine-3-carbonitrile

5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (906 mg) was treated with 2-chloronicotinonitrile (510 mg) in the presence of sodium hydride (150 mg) in dimethylformamide (30 mL) ) at 100 ° C for 5 hours to give 2- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-7-yl] pyridine-3-carbonitrile, mp 242 242.5 ° C (after treatment).

Example 181: 7- [3- (Aminomethyl) pyrid-2-yl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dimalate

The product of the previous example (468 mg), ethanol saturated with ammonia (200 ml) and Raney nickel (2 ml) were shaken under hydrogen at 26 bar at 80 ° C for 6 hours and then allowed to stand at room temperature for 68 hours. The mixture was filtered and the residue washed well with ethanol. The filtrate was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and filtered. Maleic acid (135 mg) dissolved in ethyl acetate (20 mL) was added portionwise to the filtrate until no more precipitate formed. The mixture was heated and decanted from a small amount of gummy residue. The gum was further heated with ethyl acetate and decanted. The combined ethyl acetate extracts were cooled and the precipitated solid was collected by filtration to give 7- [3- (aminomethyl) pyrid-2-yl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine- 4-Ylamine dimalate, 1.1. Mp 131-134 ° C.

Example 182: 3- [4-amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -8-methyl-8-azabicyclo [3.2.1] octane

Sodium hydride (168 mg of a 60% dispersion in mineral oil) was added to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (770 mg) in dimethylformamide (30 mL). Under nitrogen, 3-mesyloxy-8-methyl-8-azabicyclo [3.2.1] octane (900 mg, prepared as described in JACS 1958, 80, 4679) in dimethylformamide (10 mL) was added under stirring. The mixture was heated at 75 ° C for 5 hours and allowed to stand at room temperature for 7 days. The solvent was evaporated under reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the obtained residue was purified by flash column chromatography on silica using ethyl acetate with methanol (50:50) as the mobile phase to separate the starting materials and then with ethyl acetate, methanol and triethylamine (5). : 5: 1) as a mobile phase to pr

139 eluted the product. The appropriate fractions were combined and evaporated and the resulting solid was triturated with ether and filtered to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] - 8-methyl-8-azabicyclo [3.2.1] octane, 1.1. Mp 238-250 ° C.

Examples 183 and 184: cis-7- (N-methylhomopiperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] prymidin-4-ylamine and trans-7- (N methylhomo-piperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] prymidin-4-ylamine

In a similar manner to Examples 176 and 177, 4- [4 amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexanone (0.4 g from 1.0 g 40) was reacted together. N-methylhomopiperazine (114 mg), sodium triacetoxyborohydride (296 mg), glacial acetic acid (60 mg) and 1,2-dichloroethane (15 mL). After filtration, the filtrate was evaporated and the residue was purified by silica chromatography to afford cis-7- (N-methylhomopiperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] prymidin-4-ylamine and trans-7- (N-methylhomo-piperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] prymidin-4-ylamine.

Examples 185 and 186: cis-7- (N-methylpiperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7-pyrrolo [2,3-d] prymidin-4-ylamine and trans-7- (N- methylpiperazin-1-yl-cyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] prymidin-4-ylamine

In a similar manner to the previous example, Nmethylpiperazine (100 mg) was reacted with the same amounts of cyclohexanone derivative and other reagents to give cis-7- (N-methylpiperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7-pyrrolo [2,3-d] prymidin-4-ylamine and trans -7- (N-methylpiperazin-1-ylcyclohexyl) -5- (4-phenoxy-phenyl) -7-pyrrolo [2,3-d] prymidin-4-ylamine .

Example 187: 3- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentan-1-one

A mixture of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentan-1-ol (100 mg), activated manganese dioxide (500 mg), and of dichloromethane (100 mL) was stirred at room temperature for 18 hours to give a solution of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentane- 1-one in dichloromethane which was used in the following example.

140

Example 188: cis-7- (3-morpholinocyclopent-1-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine and trans-7- (3-morpholinocyclopent- 1-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

To the solution obtained in the previous example were added morpholine (45 mg) followed by sodium triacetoxyborohydride (151 mg) and glacial acetic acid (47 mg). The mixture was stirred at room temperature under nitrogen for 18 hours while the dichloromethane was evaporated. Tetrahydrofuran (100 mL) was added and the mixture was stirred for an additional 8 hours. The mixture was worked up to give cis-7- (3-morpholinocyclopent-1-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-7- ( 3morfolinocyklopent-1-yl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine.

Example 189: 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl) cyclopentyl N- (2-morpholinoethyl) carbamate hydrochloride

a) To a solution of 3- (4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl) cyclopentanol (20 mg) in dichloromethane (1 mL) was added at 0 ° C N-methylmorpholine (7 mL) and the mixture was stirred for 20 minutes. The cooling bath was removed, 4-nitrophenyl chloroformate (12.5 mg) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate, and brine. The organic solution was dried over magnesium sulfate and evaporated to give the crude product.

b) The crude product of a) in dichloromethane (2 ml) was added to 2-morpholinoethylamine (0.2 ml) and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried, filtered and evaporated and the obtained crude product was purified by preparative HPLC to give 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl) cyclopentyl N- (2-morpholinoethyl) carbamate.

c) The product of b) was dissolved in ethyl acetate (2 ml) and hydrogen chloride was bubbled through the solution for 2 minutes. A precipitate formed and stirring was continued for another 10 minutes. The solvent was evaporated and water was added to dissolve the solid phase. Lyophilization afforded 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl) cyclopentyl N- (2-morpholinoethyl) carbamate hydrochloride as a solid.

r ι ·

141

Example 190: 3- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentyl-2-amino-acetate hydrochloride

a) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentanol (50 mg, 0.129 mmol) and N-tert-butoxycarbonylglycine (34 mg, 0.194 mmol) were combined in N, N-dimethylformamide (1 mL). 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) and 4-dimethylamino pyridine (16 mg, 0.129 mmol) were added. The resulting mixture was stirred under nitrogen at room temperature for 24 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried (MgSO 4, filtered and evaporated. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 3- [4-amino-5- (4-phenoxyphenyl) 1 H -pyrrolo [2,3- d] pyrimidin-7-yl] cyclopentyl-2 - [(tert-butoxycarbonyl) amino] acetate The structure was confirmed by ¹ H NMR.

b) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-2 - [(tert-butoxycarbonyl) amino] acetate (39 mg, 0.072 mmol) ) was dissolved in ethyl acetate (2.5 mL). Hydrogen chloride was bubbled through the solution for 1 minute. The flask was sealed and the solution stirred for an additional 30 minutes. Diethyl ether was added and a precipitate formed. This solid was collected by filtration to give 3- [4 amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-2-aminoacetate hydrochloride. The structure was confirmed by ’H NMR and LC / MS (MH + = 444).

Example 191: 3- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentyl (2S) -2-amino-3-methyl-butanoate hydrochloride

a) (2S) -1 - [(tert-Butoxycarbonyl) amino] -2-methylbutanoic acid anhydride and 2,5-dioxo-2,5-dihydro-1H-1-pyrrolecarboxylic acid (114 mg, 0.362 mmol) was added to solution 3 - [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol (66 mg, 0.171 mmol) in dichloromethane (1 mL). The resulting mixture was stirred under nitrogen at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed, dried (MgSO 4, filtered and evaporated. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 3- [4-amino-5- (4-phenoxyphenyl)] -7H142 pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3-methylbutanoate The structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 586).

b) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl- (2S) -2 - [(tert-butoxycarbonyl) amino] -3- methyl butanoate (35 mg, 0.060 mmol) was dissolved in ethyl acetate (2.5 mL). Hydrogen chloride was bubbled through the solution for 5 minutes. The flask was sealed and the solution stirred for an additional 30 minutes. Diethyl ether was added and a precipitate formed. This solid was collected by filtration to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl (2S) 2-amino-3 -butanoate hydrochloride. The structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 486).

Example 192: 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl) cyclopentyl N- (2-morpholinoethyl) carbamate hydrochloride

a) N-Methylmorpholine (0.007 mL, 0.062 mmol) was added dropwise to a solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 mL) with stirring under nitrogen at 0 ° C. After 20 minutes, the ice water bath was removed and the mixture was allowed to warm to ambient temperature. 3- [4 amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol (20 mg, 0.052 mmol) was added to the mixture and the resulting solution was stirred for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-dlpyrimidin-7-yl] cyclopentyl- (4-nitrophenyl) carbonate. The structure was confirmed by ¹ H NMR.

b) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl (4-nitrophenyl) carbonate (0.052 mmol) in dichloromethane (1 mL) was added to was added to 2-morpholinoethylamine (0.2 mL). The resulting mixture was stirred under nitrogen at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed, dried (MgSO ₄ ), filtered and evaporated. The solid was purified by preparative HPLC to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-N (2-morpholinoethyl) carbamate . The structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 543).

143

c) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-N- (2-morpholinoethyl) carbamate (10 mg, 0.018 mmol) was dissolved in ethyl acetate (2.5 mL). Hydrogen chloride was bubbled through the solution for 2 minutes, and a precipitate formed. The flask was closed and the solution stirred for an additional 10 minutes. The solid was collected by filtration to give 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) cyclopentyl-N- (2-morpholinoethyl) carbamate hydrochloride. The structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 543).

Preparation of starting materials

a) tert-Butylamine (15 ml) was added with stirring to a solution of 2-bromo-4'-phenoxyacetophenone (12.7 g, prepared by bromination of 4'-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture was heated at 80 ° C for 3 hours. The mixture was cooled to 0 ° C and concentrated hydrochloric acid (10 mL) was added. The suspension was stirred at room temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g), m.p. Mp 210-212 ° C.

b) (1) 4'-Phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g) was added in one portion to sodium ethoxide (prepared by dissolving sodium (93 mg) in ethanol (50 ml)) and the mixture was stirred at 40 ^° C for 30 minutes under nitrogen.

(2) Sodium (331 mg) in ethanol (50 mL) was dissolved in a separate flask and malononitrile (858 mg) was added. The solution was stirred at room temperature for 5 minutes and to this solution was added a solution of the 4'-phenoxy-2- (tert-butylamino) acetophenone obtained in part (1) in one portion, with the precipitation of sodium chloride. The resulting mixture was heated at 50 ° C for 3 hours and 2 hours at 80 ° C. The solvent was evaporated under reduced pressure and the resulting oil was partitioned between water and ethyl acetate. The organic phase was separated, dried and evaporated to give a black solid. This solid was dissolved in hot ethanol and triturated with water to give 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert -butyl) pyrrole.

c) A mixture of 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert -butyl) pyrrole (1.9 g), formamide (30 ml) and 4-dimethylaminopyridine (10 mg) was added. was heated at 180 ° C for 6 hours. The mixture was cooled to ambient temperature and water was added, followed by r β

A dark solid precipitated. This solid was collected by filtration, washed with water, then boiled in ethanol and the insoluble matter was collected by filtration hot and dried. The solid was purified by preparative HPLC on a silica column using dichloromethane, propan-2-ol and ethanol 98: 1: 1 as the mobile phase to give 7-tert-butyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (4 amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine), mp 157-158 ° C. ¹ H NMR (d 6 DMSO) δ 8.15 (1H, s), 7.50-7.35 (4H, m), 7.30 (1H, s), 7.15 (1H, t), 10 (4H, m), 6.05 (2H, br s), 1.75 (9H, s).

d) A mixture of 4-amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid ( 55 ml of 48% solution) was heated to reflux for 18 hours under nitrogen. The mixture was allowed to cool and the solid was collected by filtration. This solid was washed with methanol and then ether to give 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide, m.p. t. Mp 288-292 ° C. The hydrobromide salt was converted to the free base by heating with dilute sodium hydroxide solution (100 mL 5% w / v) and ethanol (60 mL) with stirring and removal of ethanol by distillation. The mixture was cooled and the solid collected by filtration and washed well with water to give 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine.

e) A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (600 mg), tetrakis (triphenylphosphine) palladium (40 ml) and dry dimethylsulfoxide (30 ml) was stirred under A solution of cyclopentadiene monoepoxide (200 mg) in tetrahydrofuran (10 mL) was added via nitrogen in an ice-water bath and a syringe under nitrogen at 0 ° C. The mixture was stirred at ambient temperature (excluding light) for 66 hours, then tetrahydrofuran was removed under reduced pressure and water was added to the residue. The mixture was allowed to stand for 18 hours, extracted with ethyl acetate, and the obtained residue was purified by flash column chromatography on silica using ethyl acetate and industrial methanol (9: 1) as mobile phase to give 4- [4-amino-5- (4-phenoxyphenyl)]. -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopent-2-enol as an oil. The structure was confirmed by ¹ H NMR and mass spectra.

f) 4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol (110 mg) was hydrogenated in ethanol (20 mL) with gaseous hydrogen at

145 re atmospheric pressure using 10% palladium on carbon (50 mg) as a catalyst. The catalyst was removed by filtration and the filtrate was evaporated to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol as an oil. The structure was confirmed by ¹ H NMR and mass spectra.

Example 193: cis-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine

7irans-5- (4-phenoxyphenyl) -7- (4-pyrolidinocyklohex-1-yl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine

To a stirred suspension of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclohexanone (2.34 g, 5.9 mmol) in 1,2-dichloroethane (250 mL) was added under a nitrogen atmosphere pyrrolidine (1.25 g, 17.6 mmol) and glacial acetic acid (1.00 mL, 17.6 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion and the resulting mixture was stirred for 70 hours. The mixture was extracted with 2 M aqueous hydrochloric acid (2 x 200 mL). The combined extracts were washed with dichloromethane (300 mL), basified with 12.5 M aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 200 mL). The combined extracts were dried over sodium sulfate and purified by Biotage 40S column chromatography using a mixture of ethyl acetate and triethylamine (95: 5) and ethyl acetate, triethylamine and methanol (85: 10: 5) as the mobile phase to afford cis-5- (4-Phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as an off-white solid (0.65 g, 1.4 mmol), m.p. 101 104 ° C, LC / MS Hypersil BDS c18 (100x

2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min): MH ⁺ 454 tr = 3.56 min and trans-5- (4-phenoxyphenyl) -7- (4- pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as an off-white solid (0.93 g, 2.1 mmol), m.p. 183-185 ° C, LC / MS (Hypersil BDS) c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min): MH ⁺ 454, t r = 3.68 minutes rp

146

Example 194: cis-5- (4-Phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine hydrochloride

7rans-5- (4-phenoxyphenyl) -7- (4-piperidinocyklohex-1-yl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine

To a stirred suspension of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclohexanone (2.34 g, 5.9 mmol) in 1,2-dichloroethane Piperidine (1.50 g, 17.6 mmol) and glacial acetic acid (1.00 mL, 17.6 mmol) were added under a nitrogen atmosphere and the resulting mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion and the resulting mixture was stirred for 70 hours. The mixture was extracted with 2 M aqueous hydrochloric acid (2 x 200 mL). The combined extracts were washed with dichloromethane (300 mL), basified with 12.5 M aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 200 mL). The combined extracts were dried over sodium sulfate and purified by Biotage 40S column chromatography using ethyl acetate with triethylamine (95: 5) as the mobile phase to afford cis-5 (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1). -yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.23 g) as a clear oil, LC / MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1 M ammonium acetate (acetonitrile, 10-100% acetonitrile over 8 min) MH ⁺ 468 tr = 3.67 minutes and trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2] 3djpyrimidin-4-ylamine as an off-white solid (193 mg, 0.4 mmol), mp 192-195 ° C, LC / MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min), MH ⁺ 468, t r = 3.71 minutes

Example 195

Cis-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine was dissolved in ethyl acetate (50 ml), diluted with diethyl ether (50 mL) and 1 M hydrogen chloride solution was added until a precipitate no longer formed. The resulting solid was collected and recrystallized from absolute ethanol to give cis-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidine-4- Ylamine hydrochloride as a colorless solid (75 mg, 0.2 mmol), mp 185-189 ° C.

f Example 196: 7rans-7- (4-Dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine

C / s-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ylamine

To a stirred solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclohexanone (3.24 g, 8.1 mmol) in dichloromethane (1000 mL) N-methylpiperazine (1.20 g, 12.0 mmol) and glacial acetic acid (0.69 mL, 12.0 mmol) were added under a nitrogen atmosphere and the resulting solution was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (1.70 g, 8.0 mmol) was added in one portion and the resulting solution was stirred for 6 hours. The addition was repeated in equal amounts and the resulting solution was stirred for 70 hours. The solution was extracted with 2 M aqueous hydrochloric acid (2 x 300 mL). The combined extracts were washed with dichloromethane (300 mL), basified with aqueous 0.880 ammonia solution and extracted with ethyl acetate (3 x 250 mL). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and purified by Biotage 40M column chromatography using ethyl acetate, methanol and triethylamine (8: 1: 1) as mobile phase to give cis-7- (4-dimethylaminocyclohexyl) - 5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as an off-white solid (220 mg, 0.5 mmol) mp 180-182 ° C, LC / MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min), MH ⁺ 428, t, = 3.43 minutes

The column was washed with ethyl acetate with methanol and triethylamine (4: 1: 1, 500 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) and purified by Biotage 40M column chromatography using dichloromethane with methanol (9: 1 to 7: 3) to give trans-7- (4-dimethylamino-cyclohexyl) -5- (4-phenoxyphenyl). ) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as an off-white solid (320 mg, 0.75 mmol), mp 207.5-210 ° C, LC / MS: Hypersil BDS c18 ( 100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10 100% acetonitrile over 8 min), MH ⁺ 428, t _r = 3.48 minutes

R - (+) - 4- [4-amino-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7 H -pyrrolo [2,3djpyrimidín.

148

Example 197: 4 - {(S) -tetrahydrofuran-3-yl} toluenesulfonate

To a solution of (S) -3-hydroxytetrahydrofuran (2.0 g, 23 mmol) in pyridine (40 mL) at 0 ° C was added tosyl chloride (4.8 g, 25 mmol) portionwise. The solution was stirred for 1 hour at 0 ° C and overnight at room temperature. The pyridine was evaporated in vacuo and the residue partitioned between EtOAc and saturated aqueous citric acid (200 mL each). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were dried (sodium sulfate), filtered and evaporated to give an oil (4.5 g, 85%). ¹ H NMR (CDCl _3, 250 MHz): 7.78 (2H, d), 7.35 (2H, d), 5.12 (1H, m), 3.76 3.93 (4H, m), 2 45 (3H, s), 2.01-2.20 (2 H, m).

To a stirred suspension of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (4.83 g, 16 mmol) in N, N-dimethylformamide (80 mL) was added 60% sodium hydride under a nitrogen atmosphere. in mineral oil (0.75 g, 19 mmol) and the mixture was stirred at room temperature for 30 minutes. To the obtained dark solution was added a solution of 4 - {(S) -tetrahydrofuran-3-yl} toluenesulfonate (4.20 g, 18 mmol) in N, N-dimethylformamide (20 mL) in 2 mL aliquots. The resulting solution was stirred at room temperature for 30 minutes and then at 95 ° C for 18 hours. The solution was allowed to cool to room temperature and then poured into ice-water (200 mL). The aqueous phase was extracted with dichloromethane (3 x 200 mL). The combined organic extracts were washed with water (4 x 150 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was heated with dichloromethane (1000 mL) until a solution was obtained, cooled to room temperature and purified by Biotage 40M column chromatography using ethyl acetate with triethylamine (95: 5) and then ethyl acetate with triethylamine and methanol (90: 5: 5). as mobile phase to give R - (+) - 4- [4 amino-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine as an off-white solid ( 4.35 g, 12 mmol), mp 165-166 ° C, LC / MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min MH ⁺ 373, t _r = 4.44 minutes. [α] _D ^{+ 20} · ⁵ ± 0.6 (dichloromethane, 22.6 ° C)

Example 198: 5- (4-Phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine N-tert-butoxycarbonylpiperidinol

To a solution of N-tert-butoxycarbonylpiperidone (10.0 g, 50 mmol) in MeOH (100 mL) at 0 ° C was added portionwise sodium borohydride (1.9 g, 50 mmol). Mix

149 was stirred at 0 ° C for 1 hour and then at room temperature for 20 hours. The reaction was quenched with 2 N NaOH (20 mL), the solvent was evaporated and the residue was partitioned between ethyl acetate and water (100 mL each). The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were extracted with brine and water (1 x 100 mL each). After drying (Na ₂ SO ₄ ), filtration and concentration, N-tert-butoxycarbonylpiperidinol was obtained as a colorless oil (10.5 g, 100%). Rt in 20% EtOAc / hexane = 0.05 (immersion in KMnO ₄ solution). IR (thin layer): 3428, 2939, 1693 cm ^-1

Example 199: tert-Butyl 4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate

To a solution of N-tert-butoxycarbonylpiperidinol (10.5 g, 0.052 mol) in pyridine (150 mL) at 0 ° C under nitrogen was added portionwise tosyl chloride (9.94 g, 0.052 mol). The mixture was stirred at 0 ° C for 2 hours. After warming to room temperature, it was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between citric acid solution (1 M, 100 mL) and ethyl acetate (200 mL). The acidic layer was extracted with ethyl acetate (1 x 100 mL) and the combined organic extracts were washed with citric acid solution (1 M, 2 x 100 mL), brine (100 mL) and water (100 mL). The solution was dried (Na ₂ SO ₄ ), filtered and evaporated to an oil which was purified by flash column chromatography using 10% EtOAc with cyclohexane and then 15% EtOAc with cyclohexane to give tert-butyl-4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate as a white solid (11.0 g, 60%) Rf in 20% EtOAc / cyclohexane = 0.17. ¹ H NMR (CDCl ₃ , 250 MHz): δ 7.79 (2H, d), 7.34 (2H, d), 4.67 (1H, m), 3.58 (2H, m), 3, 27 (2H, m), 2.45 (3H, s), 1.59-1.83 (4H, m), 1.43 (9H, s)

Example 200: tert-Butyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] -1-piperidinecarboxylate

To a solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (2.0 g, 6.6 mmol) in dry DMF (100 mL) under nitrogen at 0 ° C was added. NaH (0.264 g of 60% dispersion, 6.6 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Tert-Butyl 4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate (2.34 g, 6.6 mmol) was added and the resulting solution was heated at 95 ° C for 72 hours. The reaction was quenched by careful addition of water (150 mL). Extracted with EtOAc (3 x 100 mL) and washed with water (4 x 100 mL) and brine (2 x 100 mL). The organic solution was dried (Na ₂ SO ₄ ), filtered and evaporated and the resulting solid adsorbed onto

150 silica and purified by flash column chromatography on silica gel with EtOAc and then 5% MeOH / EtOAc as eluent to give tert-butyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-piperidinecarboxylate (1.0 g, 31%) as a white solid with m.p. 168.5 to 169.5 ° C, _Rf 10% EtOAc / MeOH 0.4. ¹ H NMR (d ₆ DMSO, 250 MHz): δ 8.14 (1H, s), 7.38-7.49 (5H, m), 7.07-7.23 (5H, m),

6.14 (2H, bs), 4.76 (1H, m), 4.11 (2H, m), 2.93 (2H, m), 1.92-2.02 (4H, m), 1 43 (9H, s). C ₂₈ H ₃₁ O ₃ N _S (485.2430). IR (KBr disk): 3059, 1695, 1588, 1235 cm &^lt; -1 & gt ^;.

Example 201: 5- (4-Phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylanine

To a solution of tert-butyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-piperidinecarboxylate (0.69 g, 1.4 mmol) in dry CH ₂ Cl ₂ (25 mL) at 0 ° C was added TFA (5 mL). The solution was stirred at room temperature for 20 hours and the solvent was evaporated. NaOH solution (5 N, 10 mL) was added and the resulting suspension was extracted with EtOAc (3 x 50 mL). Wash with brine (1 x 50 mL). Drying, filtering and concentrating gave a solid which was triturated with diethyl ether and filtered to give 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine (433258) as a white solid (500 mg, 91%). T. t. Mp 209-211 ° C. Rt in 1: 1 EtOAc: MeOH = 0.1. ¹ H NMR (d ₆ DMSO, 250 MHz) 8.13 (1H, s),

7.36-7.48 (4H, m), 7.29 (1H, s), 7.04-7.16 (5H, m), 5.80 (2H, bs), 4.64 (1H, s); m), 3.10 (2H, m), 2.80 (1H, bs), 2.67 (2H, m), 1.94 (4H, m). Mass Spec C ₂₃ H ₂₃ ON ₅ (385.1902). IR (KBr disk): 3278, 1620, 1585, 1490, 1245 cm ^-1

Example 202: 5- (4-Phenoxyphenyl) -7- (4-piperidyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine dihydrochloride

To 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (433258) (200 mg) in EtOAc / MeOH (15 mL, 1: 1) A solution of HCl in ether (1.0 M, 3 mL) was added. The resulting white precipitate was filtered under a stream of nitrogen and dried under vacuum for 6 hours to give 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride (1.4 hydrate) as a white solid (120 mg), 1.1. 304 ° C (dec.). 1 H NMR (D ₂ O, 250 MHz) 8.48 (1H, s), 7.69 (1H, s), 7.50-7.58 (4H, m), 7.18-7.34 (5H) m), 5.16 (1H, m), 3.81 (2H, d), 3.46 (2H, m),

2.49 (4 H, m). IR (KBr disk): 3937, 1657.1231 cm ^-1

151 et al

Example 203: tert-Butyl 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] -1-pyrrolidinecarboxylate

N-tert-butoxycarbonyl pyrrolidin-3-ol

To a solution of pyrrolidin-3-ol (10.0 g, 0.11 mol) in dichloromethane (200 mL) was added triethylamine (22.2 g, 30.5 mL, 0.22 mol) followed by di- tert- butyl dicarbonate (28.8 g, 0.13 mol) at 0 ° C. After warming to room temperature, it was stirred at room temperature overnight. The reaction was quenched by the addition of aqueous citric acid (150 mL) and the organic layer was washed with water, brine and again with water (1 x 100 mL each). The organic layer was dried (sodium sulfate), filtered and evaporated to give tert-butoxycarbonylpyrrolidin-3-ol (20.0 g, 93% crude product) as a golden oil.

Example 204: tert-Butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate

To a solution of N-tert-butoxycarbonylpyrrolidin-3-ol (19.8 g, 0.106 mol) in pyridine (200 mL) at 0 ° C under nitrogen was added portionwise tosyl chloride (22.3 g, 0.117 mol). The mixture was stirred at 0 ° C for 2 hours, warmed to room temperature, and stirred at room temperature overnight. The pyridine was evaporated in vacuo and the residue partitioned between EtOAc and saturated aqueous citric acid (200 mL each). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were dried (sodium sulfate), filtered and evaporated to an oil which was purified by flash column chromatography on silica gel using 10% EtOAc / cyclohexane as eluent to give F40. -85 got oil. This oil was dissolved in a small amount of cyclohexane with dimethyl ether (5: 1, 50 mL), cooled, and the flask walls were scraped with a spatula to induce crystallization. The resulting solid was filtered to give tert-butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate (10.5 g, 29%) as a white solid. Rt in EtOAc / cyclohexane = 0.13. ¹ H NMR (CDCl ₃ , 250 MHz): 7.79 (2H, d), 7.35 (2H, d), 5.04 (1H, m), 3.43 (4H, m), 2.46 (3H, s), 2.03 2.20 (2H, bm), 1.43 (9H, s)

To a solution of 4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidine (2.0 g, 6.6 mmol) in dry DMF (120 mL) under nitrogen at 0 C was ^much NaH (0.264 g of 60% dispersion, 6.6 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Tert-Butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate (2.25 g, 6.6 mmol) was added portionwise and the mixture was heated at 95 ° C for 72 hours.

152

The reaction was quenched with water and extracted with EtOAc (4 x 100 mL). The combined organic solutions were washed with water (4 x 100 mL) and brine (2 x 100 mL). The organic layers were dried (sodium sulfate), filtered and evaporated to give a solid which was dissolved in EtOAc / MeOH and adsorbed onto silica. Purification by column chromatography on silica gel with 5% MeOH / EtOAc as eluent afforded tert-butyl 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine-7] in F17-25. -yl] -1-pyrrolidinecarboxylate (1.0 g, 32%) as a white solid with m.p. 168-170 ° C, R, 9: 1 EtOAc: MeOH = 0.46. 1 H NMR (d ₆ DMSO, 250 MHz): 8.17 (1H, s), 7.38-7.50 (5H, m), 6.19 (2H, bs), 5.31 (1H, m) 3.77 (1H, m), 3.42-3.60 (3H, m), 2.38 (2H, m), 1.40 (9H, s). Mass Spectrum 471.2250 (C ^ NNs). IR (KBr disk): 3130, 1663, 1585, 1404, 1245 cm ^{@ -1}

Example 205: 5- (4-Phenoxy-phenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine

To a solution of tert-butyl 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-pyrrolidinecarboxylate (0.8 g, 1.7 mmol) in dichloromethane (25 mL) at 0 ° C was added trifluoroacetic acid (5 mL). The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 20 hours. The solvent was evaporated and dilute NaOH solution (5 N, 10 mL) was added. The resulting solution was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (1 x 75 mL). The organic solution was dried (sodium sulfate), filtered and evaporated in vacuo to give 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo (2,3-d] pyrimidin-4-ylamine in white solid (0.5 g, 79%) mp 182-184 ° C, R, in 1: 1 EtOAc: MeOH = 0.15 ¹ H NMR (d ₆ DMSO, 250 MHz): 8.14 (1H, s), 7.37-7.50 (5H, m), 7.05-7.18 (5H, m), 6.14 (2H, bs), 5.23 (1H, m), 3.09 - 3.27 (2H, m), 2.83 - 2.98 (2H, m), 2.19 - 2.33 (1H, m), 1.88 - 2.01 (1H, m Mass Spec 371.1758 (C ₂₂ H ₂₁ ON ₅ ) IR (KBr disk): 3106, 1585, 1489, 1232 cm ^-1

Example 206: 5- (4-Phenoxyphenyl) -7- (3-pyrrolidinyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine dihydrochloride

To a solution of 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (200 mg) in EtOAc / MeOH (2: 1, 20 mL) was added a solution HCl in ether (1.0 M, 3 mL) and the resulting precipitate was filtered under nitrogen to give 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4 -ylamine dihydrochloride (0.4

153 hydrate) as a white solid (190 mg) 1.1. 298 ° C (dec.). IR (KBr disk): 2909, 1658, 1249 cm ^-1

Example 207: 7-Perhydro-1-pyrrolizinyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3, d] pyrimidin-4-amine dihydrochloride salt

(a) perhydro-1-pyrrolizinol

Prepared by: Schnekenburger J, Briet E, Árch. Pharm. (Wienheim) 310,152-160 (1977).

b) perhydro-1-pyrrolizinyl methanesulfonate

A mixture of perhydro-1-pyrrolizinol (0.5 g, 3.94 mmol) and triethylamine (0.60 g, 5.91 mmol) in dichloromethane (10 mL) was stirred at 0 ° C under a nitrogen atmosphere. Methanesulfonyl chloride (0.68 g, 5.91 mmol) was added, the mixture was allowed to warm to room temperature and stirred for 8 hours. Saturated aqueous ammonium chloride solution (10 mL), dichloromethane (25 mL), and saturated aqueous sodium bicarbonate solution (10 mL) were added. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a residue. Purification by flash chromatography on silica gel using heptane / ethyl acetate (1: 3) as eluent gave perhydro-1-pyrrolizinyl methanesulfonate (0.54 g): 1 H NMR (DMSO-d ₆ , 400 MHz) δ 4.96 ( m, 1H), 3.61 (m, 1H), 2.9-3.3 (m, 6H), 2.35 (m, 1H), 1.55-2.25 (m, 6H).

c) 7-Perhydro-1-pyrrolizinyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3, d] pyrimidin-4-amine dihydrochloride salt

A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.49 g, 1.62 mmol) and 60% sodium hydride in oil (100 mg, 2.43 mmol) ) in DMF was stirred at room temperature for 15 minutes under a nitrogen atmosphere. The mixture was heated at 100 ° C for 18 hours and then cooled to room temperature. An additional 60% sodium hydride in oil (100 mg, 2.43 mmol) was added and heating was continued for an additional 2 hours. The mixture was cooled to ambient temperature and the solvents were removed under reduced pressure. The residue was partitioned between water (10 mL) and dichloromethane (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was purified by preparative C-18 RP HPLC and the obtained 150 mg of white solid was dissolved in ethyl acetate (10 mL) and 1 N hydrogen chloride in dimethyl ether was added to give 7154 perhydro-1-pyrrolizinyl-5- (4-phenoxyphenyl). ) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt as a white solid: ¹ H NMR (DMSO-d _6, 400MHz) δ 8.52 (s, 1H), 7.95 (s (1H), 7.02-7.58 (m, 1H), 5.38 (m, 1H, 4.40 (m, 1H), 1.9-3.9 (m, 10H); (Hypersil HS) C18, 5 µm, 100 A, 250 x 4.6 mm, 25-100% acetonitrile 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.62 min, MS: MH ⁺ 412.

Example 208: 7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt

(a) 2-methylperhydrocyclopenta [c] pyrrol-5-ol

Prepared by: Bohme H, Setiz G, Arch. Pharm. (Wienheim) 301,341 (1968).

b) 4-chloro-5-iodo-7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine

To a mixture of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (0.38 g, 1.36 mmol), 2-methylperhydrocyclopenta [c] pyrrol-5-ol (0.23 g, 1, 63 mmol) and triphenylphosphine (0.71 g,

2.72 mmol) in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (0.474 g, 2.72 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica using dichloromethane: methanol (8: 2) as the mobile phase to give 4-chloro-5-iodo-7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine (0.25 g): ¹ H NMR (DMSO-d ₆ , 400MHz) δ 8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s (2H), 5.36 (m, 1H), 2.88 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2 0.06-2.02 (m, 4H); TLC (dichloromethane / methanol 8: 2) Rf = 0.29; RP-HPLC (Hypersil HS C18, 5 µm, 100A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 6.50 min; MS: MH ^{@ +} 403.

c) 7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt

A mixture of 4-chloro-5-iodo-7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine (0.25 g, 0.622 mmol), 4-phenoxyphenylboronic acid (0) , 16 g, 0.746 mmol), tetrakis (triphenylphosphine) palladium (0.043 g, 0.037 mmol) and carbonate

155 sodium (0.172 g, 1.62 mmol) was heated in a mixture of ethylene glycol dimethyl ether (8 mL) and water (4 mL) at 90 ° C for 18 hours under a nitrogen atmosphere. The mixture was allowed to cool to ambient temperature and the solvents were removed under reduced pressure. The residue was partitioned between water (10 mL) and dichloromethane (30 mL). The layers were separated and the organic solution was dried over magnesium sulfate, filtered, and the filtrate was concentrated to a residue (0.354 g) under reduced pressure. The material was dissolved in 1,4-dioxane (10 mL) and concentrated (28%) ammonium hydroxide (10 mL). The mixture was heated in a sealed vial at 120 ° C for 20 hours and then cooled to room temperature. The solvents were evaporated under reduced pressure and the residue was purified by flash column chromatography on silica using dichloromethane / methanol 7: 3 as eluent to give 7- (2-methylperhydrocyclopenta [c] pyrrol-5-yl) -5- (4-phenoxyphenyl) ) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.05 g): ¹ H NMR (DMSO-d ₆ , 400 MHz) shows two peak groups corresponding to the cis and trans isomers of the desired compound δ 10.6-10, 8 (bs, 1 H),

8.49 (s, 1H), 6.99-7.98 (m, 11H), 5.39 and 5.48 (m, 1H), 2-3.8 (m, 10H); F 454098: RP-HPLC (Hypersil HS C18, 5: m, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.53 min; MS: MH + 426. 7- (2-Methylperhydrocyclopent [c] pyrrol-5-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt was prepared by dissolving the free base in 10 ml of 1 N hydrochloric acid and lyophilization.

Example 209: Cis and trans-7- [4- (N-tert-butoxycarbonyl-1S, 4S-2,5-diaza [2,2,1] heptanyl) cyclohexyl] -5- (4-phenoxyphenyl) -7H pyrrolo [2,3-d] pyrimidin-4-amine

To a suspension of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1cyclohexanone (0.67 g, 1.68 mmol) in dichloroethane (40 mL). t-butyl (1S, 4S) - (-) 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (1.0 g, 5.04 mmol) and glacial acetic acid (0 mL) were added (30 g, 5.04 mmol) at room temperature for 1 hour. Then Na (OAc) ₃ BH (0.46 g, 2.17 mmol) was added and the mixture was stirred at 80 ° C for 8 days. To the cooled reaction solution was added a solution of NaHCO ₃ (0.377 g, 10.08 mmol) in water (15 mL), and the mixture was stirred for 15 minutes. The layers were separated and the organic layer was washed with water and brine (3 x 100 mL each). The aqueous layer was extracted with CH ₂ Cl ₂ , the organic layers were combined, dried (MgSO 4, filtered and concentrated. Solid 156 was purified by silica gel column chromatography, (2 L, 6% MeOH in CH ₂ Cl ₂ then 2110%). MeOH / 5% NH ₄ OH in CH ₂ Cl ₂ ) to give:

Example 210: cis-7- [4- (N-tert-butoxycarbonyl-1S, 4S-2,5-diaza [2,2,1] heptanyl) cyclohexyl] -5- (4-phenoxyphenyl) -7H -pyrrolo [2,3-d] pyrimidin-4-amine (605 mg, 64%) ¹ H NMR (d ₆ DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.49 (4H, m), 7.32 (1H, m), 7.07-7.17 (5H, m), 6.09 (2H, bs), 4.63 (1H, m), 4.15 ( 1H, m), 3.30-3.70 (2H, m), 3.03-3.08 (2H, m), 2.80-2.90 (1H, m), 2.70-2, 75 (1H, m), 2.29-2.35, (1H, m), 2.09-2.21 (1H, m), 1.81-1.93 (4H, m), 1.60 1.80 (4H, m), 1.39 (9H, m). HPLC / MS: Perkin Elmer Pecosphere C18, 3 µΜ, 33 x 4.6, 3.5 mL / min 100-100% 50 mM ammonium acetate in acetonitrile over 4.5 minutes, C ₃₆ H ₄₄ N ₆ O ₃ ( 581.2), 95%.

Example 211: 7rans-7- [4- (N-tert-butoxycarbonyl-1S, 4S-2,5-diaza [2,2,1] heptanyl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [ 2,3-d] pyrimidin-4-amine (183 mg, 20%) ¹ H NMR (d ₆ DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.47 (5H, m), 7.15 7.17 (1H, m), 7.07-7.11 (4H, m), 6.10 (2H, bs), 4.62 (1H, m), 4.1- 4.2 (1 H, m),

3.71 (1H, bs), 3.03 (2H, m), 2.35 (2H, m), 1.93-2.01 (6H, m), 1.60-1.68 (2H , m),

1.40 (9 H, s). HPLC / MS Perkin Elmer Pecosphere C18, 3 µΜ, 33 x 4.6, 3.5 mL / min 100-100% 50 mM ammonium acetate in acetonitrile over 4.5 minutes, C ₃₀ H ₃₆ N ₆ O (581, 2), 99%.

Example 212: N - {1- [4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexyl} -N 1, N 2, N 2 - 7-trans-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} N1, N2 trimethyl-1,2-ethanediamine trimaleate salt , N2-trimethyl-1,2-ethanediamine trimaleate salt

A mixture of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1cyclohexanone (1.0 g, 2.51 mmol), Ν, Ν, Ν'-trimethylethylenediamine (0.77 g, 7.54 mmol) and acetic acid (0.45 g, 7.54 mmol) in 1,2-dichloroethane (50 mL) was stirred at ambient temperature under nitrogen atmosphere for 30 minutes. Sodium triacetoxyborohydride (0.69 g, 3.26 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. Water (20 mL) and sodium bicarbonate (1.26 g,

15.1 mmol), the mixture was stirred for one hour, filtered through a pad of celite and washed with dichloromethane (75 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using dichloromethane with methanol (7: 3) as eluent to afford cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H]. -pyrrolo [2,3d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2-trimethyl-1,2-ethanediamine (0.442 g) and teans-N1 {4- [4-amino-5- (4- phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2trimethyl-1,2-ethanediamine (0.336 g). Cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2-trimethyl-1,2 -ethanediamine (0.44 g, 0.909 mmol) was dissolved in warm ethyl acetate (100 mL) and maleic acid (0.32 g, 2.73 mmol) in ethyl acetate (30 mL) was added. The resulting salt formed an oily residue on the bottom and walls of the flask. The supernatant was decanted and the residue dissolved in water and lyophilized to yield cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl]. ] cyclohexyl} -N1, N2, N2-trimethyl-1,2-ethanediamine trimaleate salt (0.55 g): ¹ H NMR (DMSO-d ₆ , 400MHz) δ 8.22 (s, 1H), 7.41 -7.50 (m, 5H), 7.08-7.19 (m, 5H), 6.5 (bs, 2H), 6.15 (s, 6H), 4.78 (m, 1H), 3.28 (m, 2H), 3.00 (m, 2H), 2.80 (m, 1H), 2.79 (s, 6H), 2.50 (s, 3H), 2.19 (s) m, 2H), 1.99 (m, 2H);

1.78 (m, 4H); RP-HPLC (Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) ζ = 9.27 min; MS: MH + 485.

7rans-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2-trimethyl-1,2 -ethane diamine trimaleate salt was prepared from the free base in the same manner: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.20 (s, 1H),

7.41-7.48 (m, 5H), 7.08-7.19 (m, 5H), 6.45 (bs, 2H), 6.15 (s, 6H), 4.62 (m, 1H), 2.9-3.3 (m, 5H), 2.74 (s, 6H), 2.56 (s, 3H), 1.9-2.2 (m, 6H), 1.73 (m, 2H); RPHPLC (Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.17 min; MS: MH + 485.

The following compounds were prepared in a similar manner to cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2 , N2trimetyl-1,2-ethanediamine

Example 214: cis-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine ¹ H NMR (d ₆ DMSO, 400 MHz) ): δ 8.13 (1H, s), 7.39 - 7.50 (4H, m), 7.28 (1H, s), 7.07-7.16 (5H, m), 6.08 (2H, bs), 4.67 (1H, m), 2.49-2.67 (9H, m), 2.06-2.16

158 (5Η, m), 1.70-1.72 (2H, m), 1.53-1.59 (2H, m), 0.97 (d, J = 6.5 Hz, 6H). Mass spectrum C ₃₁ H ₃₈ N ₆ O (511.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25 - 100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.817 min, 99% TLC: R, 90% CI / Cl / MeOH = 0.30 (visible under UV).

Example 215: trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine

Ή NMR (d ₆ DMSO, 400 MHz): δ 8.13 (1H, s), 7.40-7.47 (5H, m), 7.08 7.18 (5H, m), 6.08 ( 2H, bs), 4.53 (1H, m), 2.45-2.55 (9H, m), 2.17-2.20 (1H, m),

1.86-1.96 (6H, m), 1.44-1.49 (2H, m), 0.97 (d, J = 5.5 Hz, 6H). Mass spectrum C ₃₁ H ₃₈ N ₆ O (511.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.367 min, 91% TLC: R, 90% CH 3 Cl 2 / MeOH = 0.21 (visible under UV).

Example 216: cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

Ή NMR (d ₆ DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.50 (4H, m), 7.27 (1H, s), 7.07-7, 11 (5H, m), 6.09 (2H, bs), 4.68 (1H, m), 3.42 (2H, t, J = 5.9 Hz), 3.22 (3H, s) 2.43-2.55 (9H, m), 2.03-2.16 (6H, m), 1.60-1.71 (2H, m), 1.52-1.59 (2H, m). Mass spectrum C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.317 min, 95% TLC: R, 90% CH ₂ Cl ₂ / MeOH = 0.22 (visible under UV).

Example 217: Trans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) 7 H -pyrrolo [2,3- c] pyrimidin-4-amine ¹ H NMR (d ₆ DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.47 (5H, m), 7.07 7.16 (5H, m), 6.09 (2H , bs), 4.55 (1H, m), 3.36-3.42 (2H, m), 3.23 (3H, s), 2.33 2.55 (11H, m), 1, 90-1.96 (6H, m), 1.44-1.47 (2H, m). Mass spectrum C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25 100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.200 min, 99%, TLC: R, 90% CH ₂ Cl ₂ / MeOH = 0.31 (visible under UV).

159

Example 218: cis -7 - [- 4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine ¹ H NMR (d ₈ DMSO) , 400 MHz): δ 8.23 (1H, s), 7.41 - 7.49 (4H, m), 7.07 7.17 (6H, m), 6.57 (2H, bs), 6.20 (5H, s), 4.77 (1H, m), 2.04-2.13 (8H, m), 1.62 1.77 (5H, m), 1.21 (3H, t). HPLC (Waters delta pack C18, 150 x 3.9 mm; 5-95% acetonitrile - 0.1 M ammonium acetate over 30 min, 1 mL / min) t _r = 13.851.100%.

trans -7- [4- (4-ethyl-piperazin) cyclohexyl] -5- (4-phenoxyphenyl) -7 / - / - pyrrolo [2,3-dJpyrimidin4-amine

¹ H NMR (d ₆ DMSO, 400 MHz): δ 8.19 (1H, s), 7.40-7.47 (4H, m), 7.19 (1H, m), 7.08- 7.19 (5H, m), 6.40 (2H, bs), 6.18 (6H, s), 4.95 (1H, m), 3.17 (2H, bs),

2.98 (2H, bs), 2.69 (2H, bs), 1.94-2.01 (8H, m), 1.54-1.57 (2H, d, J = 7.5 Hz) .

1.17 (3 H, t). HPLC (Waters delta pack C18, 150 x 3.9 mm; 5-95% acetonitrile 0.1 M ammonium acetate over 30 min, 1 mL / min) t _r = 13.701, 96%.

The following compounds were prepared as salts in a similar manner to trans-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} N1, N2 , N2-trimethyl-1,2-ethanediamine trimaleate salt:

Example 219: cis-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine trismaleate

Ή NMR (d ₆ DMSO, 400 MHz): δ 8.23 (1H, s), 7.40-7.49 (5H, m), 7.07-7.19 (5H, m), 6.55 (2H, bs), 6.16 (6H, s), 4.74 (1H, m), 3.26 (6H, bs), 2.04-2.49 (13H, m), 1.63 1.75 (5H, m), 1.25 (d, J = 6.6 Hz, 6H). Mass spectrum C ₃₁ H ₃₈ N ₆ O (511.1). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.967 min, 99% .

Example 220: trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trismaleate ¹ H NMR (d ₆ DMSO, 400 MHz): δ 8.20 (1H, s), 7.40-7.65 (5H, m), 7.08 7.19 (5H, m), 6.46 (2H, bs), 6, 14 (6H, s), 4.60 (1H, m), 2.50-3.45 (17H, m), 1.95 2.02 (5H, m), 1.56-1.59 ( 2H, m), 1.20 (d, J = 6.5 Hz, 6H). Mass spectrum C ₃₁ H ₃₈ N ₆ O (511.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25 100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.733 min, 90%.

160

Example 221: cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine trismaleate 1 H NMR (d ₆ DMSO, 400 MHz): δ 8.23 (1H, s), 7.41-7.49 (5H, m), 7.07 7.19 (5H, m), 6.55 (2H, bs), 6.16 (6H, s), 4.75 (1H, m), 3.62 (2H, m), 3.30 (3H, s),

3.17 (6H, bs), 2.50 (9H, m), 2.02-2.16 (5H, m), 1.74 (5H, m). Mass spectrum C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.750 min, 99% .

Example 222: 7rans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trismaleate 1 H NMR ( d ₆ DMSO, 400 MHz): δ 8.21 (1H, s), 7.41-7.48 (5H, m), 7.08 7.17 (5H, m), 6.53 (2H, bs), 6.17 (6H, s), 4.61 (1H, m), 3.45 (3H, s), 2.50-3.56 (19H, m), 1.99-2.08 (6H, m), 1.64 (2H, m). Mass spectrum C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC: (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 N ammonium acetate over 10 min, 1 mL / min) t _r = 7.383 min, 99% .

Example 223: cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N2, N2-dimethyl- 7rans-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} N2, N2-dimethyl 1,2-ethanediamine trimaleate salt -1,2-ethanediamine monomalate salt

Cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N2, N2-dimethyl-1,2 - ethanediamine trimaleate salt: 1 H NMR (DMSO-d ₆ , 400 MHz) δ 8.19 (s, 1H), 7.40-7.49 (m, 5H), 7.08-7.19 (m, 5H), 6.35 (bs, 2H), 6.13 (s, 6H), 4.78 (m, 1H), 3.15-3.45 (m, 5H), 2.74 (s, 6H) 1.80-2.25 (m, 8H); RP-HPLC (Hypersil CPS, 5 µL, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.90 min; MS: MH + 471.

Example 224: trans -N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N2, N2-dimethyl-1, 2-ethanediamine monomalate salt 1 H NMR (DMSO-d ₆ , 400MHz) δ 9.5 (bs, 1H), 8.26 (s, 1H), 7.41 - 7.55 (m, 5H), 08-7.19 (m, 5H), 6.7 (bs, 2H), 6.16 (s, 2H), 4.63 (m, 1H), 3.12-3.55 (m, 5H) 2.85 (s, 3H), 2.27 (m, 2H), 1.99-2.05 (m, 4H), 1.67-1.75 (m, 2H); RP-HPLC (Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.6 min; MS: MH + 471.

161: ':

r * *

Example 225: cis-7- (4 - {[3- (1H-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] 7-pyrimidin-4-amine trimaleate salt 7ansan-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] | pyrimidin-4-amine dimalate salt

Example 227: cis-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7,7-pyrrolo [2,3-d] pyrimidine -4-amine trimaleate salt ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.78 (bs, 1H), 8.48 (bs, 2H), 8.18 (s, 1H),

7.66 (s, 1H), 7.55 (s, 1H), 7.41-7.49 (m, 5H), 7.08-7.19 (m, 5H), 6.33 (bs, 2H);

6.12 (s, 6H), 4.78 (m, 1H), 4.27 (t, 2H), 2.99 (m, 3H), 1.8-2.25 (m, 10H); RPHPLC (Hypersil CPS, 5 μιτι, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 9.07 min; MS: MH ^{@ +} 508.

Example 228: trans-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine dimaleate salt ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.76 (bs, 1H), 8.51 (bs, 2H), 8.18 (s, 1H),

7.66 (s, 1H), 7.55 (s, 1H), 7.40-7.47 (m, 5H), 7.08-7.21 (m, 5H), 6.3 (bs, 2H), 6.11 (s, 4H), 4.60 (m, 1H), 4.26 (t, 2H), 3.14 (m, 1H), 2.97 (m, 2H), 1, 9-2.25 (m, 8H), 1.53-1.61 (m, 2H); RP-HPLC (Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.72 min; MS: MH ^{@ +} 508.

Example 229: cis-7- [4- (dimethylamino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine dimalate salt 1 H NMR (DMSO-d6, 400MHz) δ 9.06 (bs, 1H), 8.2 (s, 1H), 7.41 - 7.50 (m, 5H), 7.08 - 7.19 (m, 5H), 6.4 ( bs, 2H), 6.13 (s, 4H), 4.83 (m, 1H), 3.34 (m, 1H),

2.88 (s, 6H), 2.10-2.17 (m, 4H), 1.88-1.99 (m, 4H); RP-HPLC (Hypersil HS ΟΙ 8.5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.38 min; MS: MH ⁺ 428;

Example 230: 7ra / 7S-5- (4-Phenoxyphenyl) -7- (4-piperidinocyclohexyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine dimalate salt 1 H NMR (DMSO-d ₆ , 400) MHz) δ 8.92 (bs, 1H), 8.18 (s, 1H), 7.4-7.5 (m, 5H), 7.08-7.19 (m, 5H), 6.3 (bs, 2H), 6.13 (s, 4H), 4.63 (m, 1H), 3.15-3.5 (m, 3H), 2.9-3.1 (m, 2H), 1.16-2.18 (m, 14H); RP-HPLC (Hypersil HS C-18, 5µm, 100A,

162

250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.98 min; MS: MH + 468.

Trans-5- (4-Phenoxyphenyl) -7- (4-tetrahydro-1 H -1-pyrrolylcyclohexyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine dimalate salt ¹ H NMR (DMSO-d) _6.4 , 400MHz) δ 9.54 (bs, 1H), 8.18 (s, 1H), 7.40 - 7.47 (m, 5H), 7.08 - 7.18 (m, 5H), 6 3 (bs, 1H), 6.12 (s, 4H), 4.63 (m, 1H), 3.1-3.55 (m, 5H), 2.24 (m, 2H), 2, 00 (m, 6H), 1.86 (m, 2H), 1.67 (m, 2H); RP-HPLC (Hypersil HS C18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.82 min ; MS: MH + 454.

Example 231: cis-7- [4- (4-methyl-1,4-diazepan-1-yl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 1-trans-7- [4- (4-methyl-1,4-diazepan-1-yl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidine- amine dihydrochloride salt 4-amine dihydrochloride salt

Cis-7- [4- (4-methyl-1,4-diazepan-1-yl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.7 (d, 1H), 11.38 (d, 1H), 8.57 (s, 1H), 8.34 (d, 1 H), 7.42-7.51 (m, 4H), 7.03 7.20 (m, 5H), 4.93 (m, 1H), 4.7 (bs, 2H), 3, 4 - 3.99 (m, 9H), 2.8 (s, 3H), 1.86-2.57 (10H); RP-HPLC (Hypersil HS C-18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7, 67 min; MS: MH + 497.

Trans-7- [4- (4-methyl-1,4-diazepan-1-yl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt: ¹ 1 H NMR (DMSO-d ₆ , 400 MHz) δ 11.94 (d, 1H), 11.52 (d, 1H), 8.56 (s, 1H), 7.8 (s, 1H), 7, 42-7.51 (m, 4H), 7.107.20 (m, 5H), 4.76 (1H, m), 3.2-4.0 (m, 9H), 2.80 (s, 3H) 1.78-2.4 (m, 10H); RPHPLC (Hypersil HS C-18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 7.42 min ; MS: MH + 497.

163

Example 232: cis -5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt

7rans-5- (4-Phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7 H -pyrrolo [2,3- c] pyrinnidine-4amine trimaleate salt

a) cis-trans-tert-Butyl 4- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclohexyl} -1-piperazinecarboxylate

Example 233: cis-tert-butyl 4- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclohexyl} -1-piperazinecarboxylate: ¹ 1 H NMR (DMSO-d ₆ , 400 MHz) δ

8.14 (s, 1H), 7.3-7.5 (m, 6H), 7.07-7.16 (m, 5H), 6.1 (bs, 2H), 4.69 (m, 1H), 3.2-3.4 (4H, m), 2.38 (m, 4H), 2.0-2.25 (m, 5H), 1.5-1.8 (m, 4H) 1.41 (s, 9H); RPHPLC (Hypersil HS C-18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 13.60 min .

trans-tert-Butyl 4- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] cyclohexyl} -1-piperazinecarboxylate: ¹ H NMR (DMSO-) d ₆ , 400 MHz) δ 8.13 (s, 1H),

7.40-7.47 (m, 6H), 7.08-7.16 (m, 5H), 6.1 (bs, 2H), 4.55 (m, 1H), 3.34 (m, 4H),

2.35-2.51 (m, 3H), 1.89-1.99 (m, 6H), 1.38-1.49 (m, 4H), 1.39 (s, 9H); RPHPLC (Hypersil HS C-18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 10.40 min ..

b) cis -5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt

To cis-tert-butyl 4- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] cyclohexyl} -1-piperazinecarboxylate (1.85) g, 3.27 mmol) was added a 20% solution of trifluoroacetic acid in dichloromethane (60 mL) and the mixture was stirred at room temperature for 30 minutes. The solvents were removed under reduced pressure, the residue was partitioned between dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic solution was dried over magnesium sulfate, filtered, and the filtrate was evaporated to a residue (1.55 g). A portion of this material (1.0 g, 2.15 mmol) was dissolved in warm ethyl acetate (220 mL) and maleic acid (0.75 g, 0.44 mmol) in warm ethyl acetate (75 mL) was added. The mixture was cooled to room temperature and the solid collected by filtration and dried to give cis-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4- amine trimaleate salt (1.15 g) as a white solid: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ

164

8.5 (bs, 1H), 8.23 (s, 1H), 7.41-7.51 (m, 5H), 7.08-7.19 (m, 5H), 6.65 (bs, 2H), 6.16 (s, 6H), 4.74 (m, 1H), 1.16-3.2 (m, 17H); RP-HPLC (Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.63 min; MS: MH + 469.

c) trans-5- (4-Phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7? 7 -pyrrolo [2,3- d] pyrimidin-4-amine trimaleate salt ¹ H NMR (DMSO-d ₆ , 400MHz) δ 8.22 (s 1 H, 7.41-7.51 (m, 5H), 7.08 7.19 (m, 5H), 6.6 (bs, 2H), 6.16 (s, 6H), 4.58 (m, 1H), 1.4-3.2 (m, 17H); RPHPLC (Hypersil HS C-18, 5 µm, 100 A, 250 x 4.6 mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 10 min, 1 mL / min) t _r = 8.08 min ; MS: MH ^{@ +} 469.

Example 234: 7- [3- (4-Methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate

3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentan-1-ol (2.14 g, 0.0055 mol) in 1 L dichloromethane was stirred with 12 g of active manganese dioxide for 5 hours, filtered and fresh manganese dioxide (8 g) was added to the filtrate. After an additional 17 hours of stirring, the mixture was filtered and used directly in the next step. HPLC / MS showed starting material and 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclopentanone, 62.7% t _r 4.38 minutes. The dichloromethane solution was stirred with 1.0 g of N-methylpiperazine (0.01 mol) and acetic acid (0.6 g, 0.01 mol) for 15 minutes and sodium triacetoxyborohydride (0.89 g, 0.0042 mol) was added. . After 2 hours, 1.0 g of N-methylpiperazine, 0.6 g of acetic acid and 0.89 g of sodium triacetoxyborohydride were added and the mixture was stirred for 17 hours. After a further addition of 2.0 g of N-methylpiperazine, 1.2 g of acetic acid and 1.2 g of sodium triacetoxyborohydride and stirring for 3 days, a mixture was obtained which was evaporated under reduced pressure. Water (200 ml) and 6 M hydrochloric acid (50 ml) were added to the residue, the mixture was washed with ethyl acetate (which was discarded) and the pH was adjusted to basic with excess ammonia. The mixture was extracted with ethyl acetate and the extract was dried (sodium sulfate), purified by flash chromatography in 9: 1 ethyl acetate: ethanol to remove impurities, and then 8: 1: 1 ethyl acetate: ethanol: triethylamine to elute the product. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and a solution of maleic acid in ethyl acetate was added to give 7- [3- (4-methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) 165

7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-maleate (444395) as 1,4 solvate with ethyl acetate after drying at 80 ° C under reduced pressure (0.95 g, 0.001 mol) 1.1. 168-170 ° C (dec.).

Example 235: [4- (4-Amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] (phenyl) methanol

Sodium borohydride (0.052 g, 0.0013 mol) was added to a solution of [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] (phenyl) methanone (0, 1 g, 0.00026 mol) in tetrahydrofuran (4 mL) followed by addition of Amberlyst-15 H ⁺ . The mixture was stirred at ambient temperature under nitrogen for 15 min, filtered through a pad of celite and the solvent was removed under reduced pressure. The residue was purified by preparative RP-HPLC (Rainin, Hypersil C18, 8 µm, 100 A, 25 cm; 5% -85% acetonitrile-0.1% ammonium acetate over 20 min, 21 mL / min) to give [ 4- (4-Amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] (phenyl) methanol (0.005 g, 0.000013 mol):

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.12 (s, 1H), 7.31 (m, 10H), 6.01 (br, 2H),

5.91 (d, 1H), 5.75 (d, 1H), 5.06 (m, 1H), 2.10 (br, 2H), 1.88 (br, 4H), 1.67 (br, 2H)

RP-HPLC (Delta Pak C18, 5 µm, 300 A, 15 cm; 5% -85% acetonitrile 0.1 M ammonium acetate over 20 min, 1 mL / min) R, 16.74 min. MH ⁺ 385

Example 236: 7rans-7- [3- (4-Methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine trimaleate

To trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (1.30 g, 0.0027 mol) in 300 mL warm A solution of maleic acid (0.94 g, 0.0081 mol) in 100 mL of ethyl acetate was added to ethyl acetate and the mixture was allowed to cool. The colorless solid was collected, washed with ethyl acetate and dried to constant weight at 90 ° C / 3 mbar to give 1.85 g (0.0022 mol) of trans-7- [3- (4-methylpiperazino) cyclohexyl] -5 - (4-Phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine tri-maleate solvated with 0.18 mol of ethyl acetate, 1.1. 189 ° C (dec.).

166

Example 237: trans-7- [3- (4-Methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine trihydrochloride

Trans / 7S-7- [3- (4-Methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine (0.36 g, 0.00075 mol) in 25 mL of warm isopropanol was added a solution of 0.225 mL of 12 M hydrochloric acid (0.0027 mol) in 2 mL of isopropanol and the suspension was briefly heated to boiling and then the volatiles were evaporated under reduced pressure. The obtained colorless solid was dried to constant weight at 84 ° C / 5 mbar to obtain trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] ] pyrimidin-4-amine trihydrochloride (444626) solvated with 1 mol of water and 0.25 mol of isopropanol (0.25 g, 0.0004 mol) m.p. t. 304 - 306 ° C (dec.).

Example 238: cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo-2,3-d] pyrimidin-4-amine trimaleate salt

Cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine (1.45 g, 0.0030 mol) in ethyl acetate with 1.05 g (0.0091 mol) of maleic acid gave, after drying to constant weight at 90 ° C / 3 mbar, a colorless solid. 2.15 g of cis-7- [3- (4-methylpiperazino) cyclohexyl] -5 (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt solvated with O, 14 mol of ethyl acetate and 0.5 mol of water (0.0025 mol), 1.1. 186 ° C (dec.).

Example 239: cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7,77-pyrrolo [2,3-c] pyrimidin-4-amine trihydrochloride

Cis-7- [3- (4-Methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine 0.80 g (0.0017 mol) in isopropanol was added 0.5 mL of 12 M hydrochloric acid (0.006 mol). The resulting solid was filtered to give cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine trihydrochloride as a hygroscopic solid that was dried to constant weight at 80 ° C / 3 mbar. (0.75 g, 0.0011 mol) 1.1. 224.5 - 226.5 (dec.).

Example 240: trans-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] 7 H -pyrrolo [2,3- c] pyrimidin-4-amine trimaleate

A mixture of 3-phenoxytoluene (2.5 g, 0.0136 mol) and N-bromosuccinimide (2.54 g, 0.0142 mol) was stirred in acetonitrile (20 mL) for 2.5 hours under a nitrogen atmosphere.

167

The solvent was evaporated under reduced pressure. Carbon tetrachloride was added to the residue and the resulting solid was collected by filtration. The filtrate was concentrated to give 4-bromo-3-methylphenyl phenyl ether as a yellow oil (3.5 g, 0.0133 mol):

1 H NMR (Chloroform-d, 400 MHz) δ 7.45 (d, 1H), 7.33 (m, 2H), 7.12 (t, 1H), 7.00 (d, 2H), 6, 89 (s, 1H), 6.71 (d, 1H), 2.34 (s, 3H) RP-HPLC (Hypersil C18, 5 µm, 250 x 4.6 mm; 25% -100% in 23 min with 0.1 M ammonium acetate, 1 mL / min) R, 14.72 min.

A mixture of 4-bromo-3-methylphenyl phenyl ether (1.7 g, 0.00646 mol), diborpinpinol ester (2.0 g, 0.00775 mol), [1,1'bis (diphenylphosphino) ferrocene] dichloropalladium complex with dichloromethane (1: 1) (0.16 g, 0.00019 mol) and potassium acetate (1.9 g, 0.01938 mol) in N, N-dimethylformamide (65 mL) was heated at 80 ° C under a nitrogen atmosphere for 22 hours. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. Dichloromethane was added to the residue and the resulting solid was collected by filtration through a pad of celite. The filtrate was concentrated to a black mixture which was purified by flash chromatography on silica using a mixture of ethyl acetate and n-heptane (3:97) as the mobile phase to give 3-methyl-4- (4,4,5,5-tetramethyl-1). 3,2-dioxaborolan-2-yl) phenyl phenyl ether (1.05 g, 0.00338 mol):

1 H NMR (Chloroform-d, 400 MHz) δ 7.73 (d, 1H), 7.33 (m, 2H), 7.08 (t, 1H), 7.01 (d, 2H), 6, 79 (d, 2H), 2.51 (s, 3H), 1.34 (s, 12H) TLC (ethyl acetate / n-heptane = 3: 97) _Rf 0.28

A mixture of 4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidine (20 g, 47.7 mmol) and 6 N HCl ( aq) (60 mL, 360 mmol) in tetrahydrofuran (120 mL) and acetone (600 mL) was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and 6 N HCl (aq) (20 mL), tetrahydrofuran (60 mL) and acetone (300 mL) were added to the mixture. The mixture was stirred under nitrogen at room temperature for 4.5 hours. The solvent was removed under reduced pressure and the yellow residue was washed with water to give 4- (4-chloro-5-iodo7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-cyclohexanone (12.3 g). , 32.7 mmol). RP-HPLC

168 (Hypersil C18, 5 µm, 250 x 4.6 mm; 25% -100% over 15 min with 0.05 M ammonium acetate, 1 mL / min) R, 10.20 min.

A mixture of 4- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-cyclohexanone (5.6 g, 14.9 mmol) and N-methylpiperazine (3, 3 mL, 29.8 mmol), acetic acid (2.6 mL,

44.7 mmol), and trimethyl orthoformate (9.9 mL, 89.4 mmol) in dichloroethane (100 mL) was stirred at ambient temperature under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (14.2 g, 67.05 mmol) was added and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine and dichloromethane (2:98) and then methanol, triethylamine and dichloromethane (2: 3: 95) as the mobile phase to give trans-4-chloro- 5-Iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidine (1.7 g, 3.7 mmol). ¹ H NMR (DMSO-d _6, 400 MHz) 8.63 (s, 1H), 8.12 (s, 1H), 4.63 (br, 1H), 2.15 (s, 3H), 1.94 (br, 6H), 1.45 (br, 2H) RP-HPLC (Hypersil C18, 5 µm, 250 x 4.6 mm; 25% -100% over 15 min with 0.05 M ammonium acetate, 1 mL r / min), 6.17 min.

7rans-4-Chloro-5-iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidine (0.89 g, 1.9 mmol) in concentrated ammonium hydroxide (40 mL) and dioxane (40 mL) was heated to 120 ° C in an autoclave for 18 hours. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give trans-5-iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.35 g, 0, 8 mmol). RP-HPLC (Hypersil C18, 5 µm, 250 x 4.6 mm; 25% -100% over 15 min with 0.1 M ammonium acetate, 1 mL / min) R, 4.01 min. MS: MH ^{@ +} 441

169

Trans-5-Iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-4-amine (0.347 g, 0.000788 mol), 3-methyl-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl phenyl ether (0.27 g, 0.000867 mol), tetrakis (triphenylphosphine) palladium (0.054 g, 0.000047 mmol) and carbonate sodium (0.209 g, 0.00197 mol) in N, N-dimethylformamide (15 mL) and water (10 mL) was heated at 80 ° C under a nitrogen atmosphere for 16 hours. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine with dichloromethane (5:95) and then methanol, triethylamine and dichloromethane (3: 5: 92) as the mobile phase to give trans-5- (2). -methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.376 g, 0.000757 mol). 5- (2-Methyl-4-phenoxy-phenyl) -7- [4- (4-methyl-piperazino) -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.376 g, 0.000757 mol) was dissolved in refluxing ethanol (10 mL) and a preheated solution of maleic acid (0.264 g, 0.00227 mol) in ethanol (5 mL) was added. The mixture was refluxed for 15 minutes, cooled to ambient temperature and the precipitate was collected by filtration, washed with cold ethanol and dried to give trans-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino)]. -cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate (0.153 g, 0.000181 mol): ¹ H NMR (DMSO-d ₆ , 400 MHz) 8.22 (s, 1H), 7 42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s, 1H), 6.89 (d, 1H); 1H), 6.16 (s, 6H), 4.58 (m, 1H), 3.3 (br, 9H), 2.68 (s, 3H), 2.22 (s, 3H), 2, 01 (br, 6H), 1.57 (br, 2H) RP-HPLC (Hypersil C18, 5 µm, 250 x 4.6 mm; 25% -100% over 23 min with 0.1 M ammonium acetate, 1) ml / min) R t 7.30 min, MS: MH ⁺ 497

Example 241: 3- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentyl-2-amino-acetate hydrochloride

A mixture of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclopentanol (50 mg, 0.129 mmol), 2 - [(tert-butoxycarbonyl) amino acid acetic acid (34 mg, 0.194 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) and 4- (dimethylamino) pyridine (16 mg, 0.129 mmol) in DMF (1 mL) was stirred under nitrogen for 24 hours. The mixture was poured

170 into an ice-water mixture. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate as the mobile phase to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl] cyclopentyl-2- [ (tert-butoxycarbonyl) amino] acetate (39 mg, 0.072 mmol). HPLC: t _R = 19.22 min. (Delta-Pack, C-18, 5 µm, 300 A, 3.9 x 150 mm; 58% acetonitrile - 0.1 M ammonium acetate over 20 min, 1 mL / min)

3- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentyl-2 [(tert-butoxycarbonyl) -amino] acetate (39 mg, 0.072 mmol) was dissolved in ethyl acetate (2.5 mL). Hydrogen chloride was then bubbled through the solution for 3 minutes. The reaction mixture was stirred for an additional 30 minutes. Ether was added and the precipitate was collected by filtration under nitrogen to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] cyclopentyl-2-aminoacetate hydrochloride ( 39 mg) as a solid. ¹ H NMR (DMSO-d ₆ ) δ 2.20 (m, 5H), 2.67 (m, 1H), 3.83 (s, 2H), 5.25 (m, 1H), 5.31 ( m, 1H)

7.14 (m, 2H); 7.43 (m, 1H); 7.50 (m, 1H); 7.68 (m, 1H); 8.26 (bs, 2H); s, 1H). LC / MS: MH ⁺ = 444, t _r = 2.25 min, (Pecosfer, 3C-18, 3 µm, 4.6 x 33 mm; 0-100% acetonitrile - 0.1 M ammonium acetate over 5 min , 3.5 ml / min)

Example 242: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] cyclopentyl-N- (2-morpholinoethyl) carbamate hydrochloride

4- Nitrochloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 mL) was cooled in an ice water bath. 4-Methylmorpholine (7 µL, 0.062 mmol) was added slowly. After 20 minutes, the ice water bath was removed and the reaction was allowed to warm to room temperature. 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-7-yl) -1-cyclopentanol (20 mg, 0.052 mmol) was added and the reaction stirred for 4 days. The reaction mixture was diluted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate, brine, dried over MgSO ₄ , filtered and evaporated to give a yellow solid. A solution of this yellow material in dichloromethane (1 mL) was added to 2-morpholino-1-ethanamine (0.2 mL). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (3 times), brine, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by HPLC to give 3- [4-amino-17β] -P

5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-N- (2-morpholinoethyl) carbamate (17 mg, 0.031 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.08 (m, 4H), 2.43 (m, 7H), 2.73 (m, 1H), 3.29 (m, 2H), 3.67, (m, 4H), 5.28 (m, 5H), 7.09 (m, 6H),

7.40 (m, 4H); 8.30 (s, 1H). LC / MS: M-1 '= 543, t, = 2.13 min, (Pecosfer, 3C-18, 3 µm, 4.6 x 33 mm; 0-100% acetonitrile - 0.1 M ammonium acetate over 5 min) min, 3.5 mL / min).

3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-N- (2-morpholinoethyl) carbamate (10 mg, 0.0184 mmol) was dissolved in ethyl acetate (2.5 mL). Hydrogen chloride was then bubbled through the solution for 3 minutes. The reaction mixture was stirred for an additional 10 minutes. The precipitate was collected by filtration under nitrogen to give 3- [4 amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl-N- (2-morpholinoethyl) carbamate hydrochloride as white solid. ¹ H NMR (DMSO-d 6) δ 1.99 (m, 4H), 2.55 (m, 2H), 3.32 (m, 12H), 5.08 (m, 1 / 2H), 5.19 (m, 1 / 2H), 7.16 (m, 5H), 7.45, (m, 5H), 8.26 (s, 1H). LC / MS: MH ⁺ = 543, t r = 2.16 min, (Pecosfer, 3C-18, 3 µm, 4.6 x 33 mm; 0-100% acetonitrile - 0.1 M ammonium acetate over 5 min, 3.5 ml / min).

Example 243: 4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexanol

Sodium borohydride (500 mg, 13 mmol) was added in one portion to the stirred solution

4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] cyclohexan-1-one (780 mg, 2.0 mmol) in methanol (500 mL) The mixture was stirred under nitrogen for 1 hour and allowed to stand overnight. The solvent was removed under reduced pressure and the residue was partitioned between 2M aqueous sodium hydroxide solution (100 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2 x 100 mL). The combined organic extracts were washed with water (150 mL), dried over potassium carbonate, and purified by Biotage 40S column chromatography using ethyl acetate / triethylamine (98: 2 to 95: 5) and ethyl acetate / ethanol (95: 5) as the mobile phase to afford 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexanol was obtained as a white solid (750 mg, 1.9 mmol), m.p. 199-200 C. LC / MS: Hypersil BDS c18 (100 x 2.1 r ·

172 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile over 8 min), MH ⁺ 401, t _r = 4.12 min.

Example 244

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (100 mg, 0.294 mmol) was dissolved in dichloromethane (2 mL) . Pyridine (2ml) was added followed by phenylchloroformate (44 µΙ, 0.353 mmol). After stirring for 3 hours, an additional 44 μΙ of phenyl methanesulfonyl chloride was added and the reaction stirred overnight. The solvent was removed and the residue was purified by preparative LC / MS to give phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-one)]. yl) -2-methoxyphenyl] carbamate (52 mg, 0.113 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.09 (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 ( m, 1H), 5.24 (s, 2H), 7.09 (m, 3H), 7.23 (m, 4H), 7.41 (m, 2H), 7.62 (s, 1H), 8.20 (bd, J = 7.80 Hz, 1 H),

8.33 (s, 1 H). LC / MS MH < ^{+ &gt}; = 460.

Example 245

Tetrahydro-2H-4-pyranyl-N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate 4- nitrophenyl tetrahydro-2H-4-pyranyl carbonate

Tetrahydro-2H-4-pyranol (1.0 mL, 10.5 mmol) was mixed with 4-methylmorpholine (2.0 mL) in dichloromethane (20 mL). To the reaction mixture was slowly added 4-nitrochloroformate (1.98 g, 9.82 mmol). After stirring for 5 hours, the reaction mixture was diluted with dichloromethane. The organic layer was washed with water, 1.0 N HCl, saturated sodium bicarbonate, brine, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by flash column chromatography using a 4: 1 mixture of ethyl acetate and heptane as eluent to give 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate (1.5 g, 5.62 mmol). ¹ H NMR (CDCl ₃ -d) δ

1.87 (m, 2H), 2.06 (m, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m, 1H), 7.40 (d J = 9.0 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H).

173

a) Tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (57 mg, 0.168 mmol) and 4-nitrophenyl tetrahydro-2H- 4-Pyranyl carbonate (90 mg, 0.336 mmol) was mixed in pyridine (1 mL). After stirring for 5 hours, an additional 90 mg of 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate was added and the reaction mixture was stirred for 2 days. The reaction mixture was heated at 70 ° C for 2 hours. The solvent was removed and the residue was purified by preparative thin layer chromatography to give tetrahydro-2H-4-pyranyl-N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d]] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.064 mmol). ¹ H NMR (CDCl ₃ -d) δ 1.78 (m, 4H), 2.08 (m, 4H), 3.60 (m, 4H), 3.94 (s, 3H),

3.97 (m, 2H), 4.15 (m, 2H), 4.98 (m, 2H), 5.23 (s, 2H), 6.78 (s, 1H), 7.04 (s 1 H, 7.07 (d, J = 8.3 Hz, 1H), 8.16 (bd, J = 7.90 Hz, 1H), 8.33 (s, 1H). LC / MS MH + = 468.

Example 246

3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

a) 4-Nitrophenyl (3-pyridylmethyl) carbonate

4- Nitrochloroformate (2.49 g, 12.3 mmol) in dichloromethane (20 mL) was cooled in an ice water bath. 3-Pyridylmethanol (1.0 mL, 10.3 mmol) and 4-methylmorpholine (2.0 mL, 18.5 mmol) were added slowly. After 20 minutes, the ice water bath was removed and the reaction was allowed to warm to room temperature. Ethylacetate was added over 30 minutes of non-competition and the reaction mixture was filtered. The filtrate was washed with water, saturated sodium bicarbonate, brine, dried over MgSO ₄ , filtered and evaporated to give a dark brown solid which was recrystallized from ethyl acetate and heptane to give 4-nitrophenyl (3-pyridylmethyl) carbonate ( 1.52 g, 5.54 mmol). 1 H NMR (CDCl 3) δ 7.38 (m, 3H), 7.79 (m, 1H), 8.28 (d, J = 9.09 Hz, 2H), 8.65 (m, 1H) 8.72 (s, 1H).

b) 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (25 mg, 0.074 mmol) was dissolved in dichloromethane (0.7 ml).

174

Pyridine (0.7 mL) was added followed by 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol). After heating at 100 ° C overnight, the solvent was removed and the residue was purified by preparative LC / MS to give 3-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrol) [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.08 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H),

4.15 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 5.54 (bs, 2H), 6.97 (s, 1H), 7.04 (s) 1 H, 7.08 (d, J = 8.2 Hz, 1H), 7.35 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 8.15 (m 1 H, 8.29 (s, 1 H), 8.61 (s, 1 H), 8.71 (s, 1 H). LC / MS MH + = 475

c) 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol) was dissolved in ethyl acetate (2.0 mL). 1.0 N HCl in ether (1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 3-pyridylmethyl N - [4- (4-amino-7-tetrahydro-2 H -4-pyranyl-7 H) -pyrrolo [2,3- d] pyrimidin-5-yl) - 2-methoxyphenyl] carbamate hydrochloride (13 mg, 0.25 mmol). ¹ H NMR (DMSO-d ₆ ) δ 1.91 (m, 2H), 2.17 (m, 2H), 3.54 (m, 2H), 3.87 (s, 3H), 4.03 ( m, 2H), 4.97 (m, 1H), 5.23 (s, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7, 51 (m, 1H), 7.81 (d, J = 8.2Hz, 1H), 7.84 (s, 1H), 7.95 (m, 1H), 8.42 (s, 1H), 8.60 (s, 1 H), 8.71 (s, 1 H), 8.82 (s, 1 H). LC / MS MH + = 475.

Example 247

2-Morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (25 mg, 0.054 mmol) was mixed with 2-morpholino-1-ethanol (0.1 mL) in pyridine (0.7 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to give 2-morpholinoethyl N - [4- (4-amino-7-tetrahydro-2 H) -pyranyl-7 H -pyrrolo [2,3- d] Pyrimidin-5-yl) -2-methoxyphenyl] carbamate (24 mg, 0.048 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.2 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 2-morpholinoethyl N- [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-7 H) -pyrrolo [2,3- d] pyrimidine- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (24 mg, 0.045 mmol). ¹ H NMR (DMSO-d ₆ )

175 δ 1.88 (m, 2Η), 2.16 (m, 2H), 3.55 (m, 8H), 3.90 (s, 3H), 4.03 (m, 4H), 4.49 (m, 2H)

4.92 (m, 1H); 7.07 (m, 1H); 7.15 (s, 1H); 7.65 (bs, 2H); 7.84 (s, 1H); 8.45 (s) (1H),

8.75 (s, 1H). 10.95 (bs, 1H). LC / MS MH < ^{+ &gt}; = 497.

Example 248 (4-Bromo-1,3-thiazol-5-yl) methyl N- [4- (4-amino-7-tetrahydro-2 H -pyranyl-7 H) -pyrrolo [2,3- b] -djpyrimidin-5-yl) -2-methoxyphenyl] carbamate

a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde

1,3-Thiazolane-2,4-dione (3.52 g, 30 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed. or with dimethylformamide (2.56 mL, 34 mmol). The mixture was then heated at 75 ° C for 1 hour and 5 hours at 100 ° C. After cooling to room temperature, the mixture was added to ice water (500 mL) and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate, dried over MgSO ₄ , filtered and evaporated to give a brown solid which was washed with petroleum ether. Evaporation of the solvent gave 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). ¹ H NMR (CDCl ₃ d) δ 9.90 (s, 1H).

b) (2,4-Dibromo-1,3-thiazol-5-yl) methanol

2,4-Dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol) was dissolved in methanol (70 mL) at 0 ° C. Sodium borohydride (0.244 g,

6.42 mmol). The ice water bath was removed in 10 minutes and the reaction mixture was stirred at room temperature overnight. The solvent was removed and saturated ammonium chloride was added. 1.0 N NaOH was added to adjust the pH to 10. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash column chromatography to give (2,4-dibromo-1,3-thiazol-5-yl) methanol (0.946 g, 3.47 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.11 (bs, 1H), 4.79 (s, 2H).

c) (4-Bromo-1,3-thiazol-5-yl) methanol (2,4-Dibromo-1,3-thiazol-5-yl) methanol (0.94 g, 3.44 mmol), carbonate trihydrate sodium (1.34 g) and palladium on carbon (10%, 0.07 g) were combined in methanol (33 mL). The resulting mixture was hydrogenated at 60 psi for 2 days. The solid was filtered through a pad of celite. The solvent was evaporated and the residue was purified by column flash

176 chromatography gave (4-bromo-1,3-thiazol-5-yl) methanol (0.32 g, 2.78 mmol).

Δ NMR (CDCl ₃ -d) δ 2.29 (bs, 1H) 4.86 (s, 2H), 8.72 (s, 1H).

d) (4-Bromo-1,3-thiazol-5-yl) methyl N - [4- (4-amino-7-tetrahydro-2 H -pyranyl-7 H) -pyrrolo [2,3- c] / pyrimdin-5-yl) -2-methoxyphenyl] carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (28 mg, 0.061 mmol) was mixed with (4-bromo-1,3-thiazol-5-yl) methanol (50 mg, 0.434 mmol) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give (4-bromo-1,3-thiazol-5-yl) methyl] -N- [4- (4-amino-7-tetrahydro- 2H-4-pyranyl-7H-pyrrolo [2,3-Gf] pyrimidin-5-yl) -2metoxyfenyljkarbamát. ¹ H NMR (CDCl 3) δ 2.07 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H),

4.13 (m, 2H), 4.98 (m, 1H), 5.35 (s, 1H), 5.40 (s, 2H), 6.97 (s, 1H), 7.04 (s 1 H, 7.09 (m, 1 H), 7.35 (s, 1 H), 8.17 (s, 1 H), 8.32 (s, 1 H), 8.78 (s, 1 H). LC / MS MH < ^{+ &gt}; = 481.

Example 249

Tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) mixed with tetrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to yield tetrahydro-3-furanyl N - [4- (4-amino-7-tetrahydro-2 H -pyranyl-7 H -pyrrolo [2,3- b]). c] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (14 mg, 0.031 mmol). ¹ H NMR (CDCl 3) δ 2.07 (m, 6H), 3.66 (m, 2H), 3.96 (m, 7H), 4.13 (m, 2H),

4.98 (m, 1H), 5.26 (s, 2H), 5.40 (m, 1H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d J = 8.2 Hz, 1H), 7.26 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H). LC / MS MH < ^{+ &gt}; = 455.

177

Γ 9

Examples 250

1,3-Dioxan-5-yl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate

1,3-Dioxolan-4-ylmethyl / V- (4- (4-amino-7-tetrahydro-2 F / 4-pyranyl-7/7-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) mixed with glycerol formaldehyde (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC to yield tetrahydro-3-furanyl N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- c] pyrimidine- 5-yl) -2-methoxyphenyl] carbamate (2 mg, 0.004 mmol). ¹ H NMR (CDCl 3) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.92 (m, 3H), 4.07 (m, 6H), 4.79 (m 1H, 4.83 (d, J = 6.3Hz, 1H), 4.96 (m, 1H), 5.04 (d, J = 6.3Hz, 1H), 6.15 (vbs) (2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.53 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.22 (s, 1 H). LC / MS MH + = 471 and 1,3-dioxolan-4-ylmethyl-N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-dlpyrimidin-5-yl)) -2-methoxyphenyl) carbamate (6.0 mg, 0.013 mmol). ¹ H NMR (CDCl 3) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.75 (m, 1H),

3.92 (m, 3H), 4.03 (m, 1H), 4.13 (m, 1H), 4.34 (m, 2H), 4.94 (s, 1H), 4.97 (m, 1H) m, 1H), 5.10 (s, 1H), 5.32 (bs, 2H), 6.97 (s, 1H), 7.03 (m, 2H), 7.06 (d, J = 8) 2 Hz, 1H), 7.38 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H). LC / MS MH + = 471.

Example 251

2-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with 2-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative LC / MS to give 2-pyridylmethyl N - [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-7 H -pyrrolo [2]). 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 2-pyridylmethyl N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol). ¹ H NMR (DMSO-d ₆ )

178 δ 1.92 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.89 (s, 3H), 4.02 (m, 2H), 4.91 (m, 1 H),

5.23 (s, 2H); 7.05 (d, J = 8.2 Hz, 1H); 7.14 (s, 1H); 7.37 (m, 1H); 7.53 (d, J) = 7.8 Hz, 1H), 7.87 (m, 3H), 8.42 (s, 1H), 8.57 (d, J = 4.2 Hz, 1H), 8.85 (s, 1H) ). LC / MS MH < ^{+ &gt}; = 475.

Example 252

4- Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2 H) -4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was treated with 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N - [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-7) - pyrrole [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0 N HCl in ether (0.1 mL) was added slowly. The precipitate was collected by filtration under nitrogen to give 4-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate hydrochloride ( 12 mg, 0.023 mmol). 1 H NMR (DMSO-d ₆ ) δ

1.91 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (m, 1H) )

5.34 (s, 2H), 7.06 (d, J = 8.2Hz, 1H), 7.16 (s, 1H), 7.73 (m, 1H), 7.81 (m, 1H) 7.87 (s, 1H), 8.46 (s, 1H), 8.76 (d, J = 5.6 Hz, 1H), 9.05 (s, 1H). LC / MS: MH < ^{+ &gt}; = 475.

Example 253 (5-Methyl-3-isoxazolyl) methyl N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- c] pyrimidin-5-yl) -2- methoxyphenyl] carbamate

Phenyl N - [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-7 H -pyrrolo [2,3- c] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30) mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl) methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give (5-methyl-3-isoxazolyl) methyl N - [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-) - 7F-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (18 mg, 0.038 mmol). H 1 H NMR (CDCl 3) δ 2.06 (m, 4H), 2.44 (s, 3H), 3.64 (m, 2H),

3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12 (s, 1H), 6.95 (s, 1H) 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21 (s, 1H). LC / MS: MH < ^{+ >} 479.

179

Example 254 [(2S) -5-Oxotetrahydro-1 H-2-pyrrolyl] methyl N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl) 7 H -pyrrolo [2,3- d] pyrimidine-5 yl) -2-methoxyphenyl] carbamate

Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.065 mmol) was mixed with (5S) -5 (hydroxymethyl) tetrahydro-1H-2-pyrrolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative LC / MS to give [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl] -N- [4- (4-amino-7-tetrahydro-2H-4)]. -pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxy-phenyl] -carbamate (10 mg, 0.021 mmol). ¹ H NMR (CDCl 3) δ 1.90 (m, 1H), 2.06 (m, 4H), 2.34 (m, 1H), 2.41 (m, 2H), 3.64 (m , 2H),

3.94 (s, 3H), 4.04 (m, 2H), 4.14 (m, 2H), 4.98 (m, 1H), 5.33 (m, 3H), 6.10 (s (1H),

6.98 (s, 1H), 7.04 (s, 1H), 7.09 (m, 1H), 7.31 (s, 1H), 8.11 (bs, 1H), 8.32 (s, 1H); s, 1H). LC / MS: MH < ^{+ >} 481.

Example 255

4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-b] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

a) tert-Butyl N- (4- (hydroxymethyl) phenyl) carbamate (4-Aminophenyl) methanol (1.23 g, 10 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) were mixed with di / t -butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred overnight at room temperature. Ethyl acetate was added and the organic layer was washed with water, 1.0 N HCl, saturated sodium carbonate, water, brine, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by flash column chromatography with ethyl acetate and heptane (2: 3) to give tert-butyl N- (4- (hydroxymethyl) phenyl) carbamate (2.16 g, 9.67 mmol). ¹ H NMR (CDCl 3) δ 1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5 Hz, 2H), 7.36 (d,

8.5 Hz, 2H).

b) 4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- c] pyrimidin-5-yl) -2-methoxyphenyl) carbamate

Phenyl N - [4- (4-amino-7-tetrahydro-2 H - 4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (51 mg, 0.111 mmol) was treated with tert-butyl N- (4- (hydroxymethyl) phenyl) carbamate (119 mg) in pyridine (0.8 mL). The reaction mixture was stirred

180 was heated at 100 ° C overnight. The solvent was removed and the residue was purified by reverse phase preparative LC / MS to give 4-aminobenzyl-N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine-). 5-yl) -2-methoxyphenyl) carbamate (9 mg, 0.015 mmol). ¹ H NMR (CDCl 3) δ 1.52 (s, 1H), 2.08 (m, 4H), 3.65 (m, 2H), 3.90 (s, 3H), 4.14 (m (2H), 4.97 (m, 1H), 5.17 (s, 2H), 5.37 (bs, 1H), 6.55 (s, 1H), 6.95 (s, 1H), 7 .03 (s, 1H), 7.06 (m, 1H), 7.31 (s, 1H), 7.38 (m, 3H), 8.16 (bs, 1H), 8.30 (s, 1H). LC / MS: MH ⁺ 589;

Example 256 N- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -benzamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 ml). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 μΙ, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxy-phenyl] -benzamide (64). mg, 0.144 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.12 (m, 4H), 3.67 (m, 2H), 3.99 (s, 3H), 4.17 (m, 2H), 4.99 ( m, 1H), 7.03 (s, 1H), 7.04 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.53 (m, 3H), 7, 94 (d, J = 7.8Hz, 1H), 8.33 (s, 1H), 8.58 (s, 1H), 8.63 (d, J = 8.2Hz, 1H). LC / MS: MH < ^{+ &gt}; = 444

Example 257

A / 2- [4- (4-amino-7-tetrahydro-2 / -7-4-tetrahydropyranyl-7 / - / - pyrrolo [2,3-c /] pyrimidin-5-yl) -2-methoxyphenyl] -2 pyridinecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7,7-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2 , 0 mL). Pyridine (2.0 mL) was added followed by 2-pyridinecarbonyl chloride hydrochloride (63 mg, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give [1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-c] pyrimidin-5-yl) -2-methoxyphenyl] benzamide (84 mg, 0.189 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.12 (m, 4H), 3.67 (m, 2H), 4.03 (s, 3H),

4.14 (m, 2H), 5.00 (m, 1H), 5.37 (s, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.14 (d) , J = 8.2 • r

181

Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H), 10, 62 (s, 1 H). LC / MS: MH < ^{+ &gt}; = 445.

Example 258 / 75- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1,3-dimethyl-1 Η-5-pyrazolecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3d] pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 ml). Pyridine (2.0 mL) was added followed by 2-pyridinecarbonyl chloride hydrochloride (63 mg, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N - [4- (4-amino-7-tetrahydro-2 H -pyranyl-7 H -pyrrolo [2,3- c] pyrimidin-5-yl) - 2-methoxyphenyl] -1,3-dimethyl-1H-5-pyrazolecarboxamide (30 mg, 0.065 mmol). ¹ H NMR (CDCl ₃ -d) δ 2.11 (m, 4H),

2.32 (s, 3H), 3.66 (m, 2H), 3.99 (s, 3H), 4.13 (m, 2H), 4.17 (s, 3H), 4.99 (m 1H, 5.22 (bs, 2H), 6.46 (s, 1H), 7.03 (s, 1H), 7.07 (s, 1H), 7.12 (d, J = 8, 2 Hz, 1H), 8.33 (2.2, 2H), 8.49 (d, J = 8.2 Hz, 1H). LC / MS: MH < ^{+ &gt}; = 462.

Example 259

A / 1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2,2-dimethylpropanamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7,7-pyrrolo [2,3-c] pyrimidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL) ). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give [1- [4- (4-amino-7-tetrahydro-2H) -4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2- methoxyphenyl] -2,2-dimethylpropanamide (27 mg, 0.064 mmol). Δ NMR (CDCl ₃ -d) δ 1.35 (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H), 3.96 (s, 3H), 4.13 (m 2H, 4.97 (m, 1H), 5.46 (bs, 2H), 6.98 (s, 1H), 7.04 (s, 1H), 7.07 (d, J = 8, 2 Hz, 1 H), 8.15 (s, 1 H), 8.29 (s, 1 H), 8.49 (d, J = 8.2 Hz, 1 H). LC / MS: MH < ^{+ &gt}; = 424.

ŕ r

182

Example 260

A / 1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-pyrimidine-5-yl) -2-methoxyphenyl] -1-cyclopentanecarboxamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrrolidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 1-cyclopentanecarbonyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7,7-pyrrolo [2,3-c] pyrimidin-5-yl) -2-methoxyphenyl] - 2,2-dimethylpropanamide (33 mg, 0.076 mmol). 1 H NMR (CDCl ₃ -d) δ 1.66 (m, 2H), 1.81 (m, 2H), 1.95 (m, 4H), 2.06 (m, 4H),

2.77 (m, 1H), 3.65 (m, 2H), 3.94 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.37 (bs) , 2H),

6.98 (s, 1H), 7.03 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H) 8.49 (d, J = 8.2Hz, 1H). LC / MS: MH + = 437.

Example 261 / N- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -3-phenylpropanamide

5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL) . Pyridine (1.5 mL) was added followed by 3-phenylpropanoyl chloride (37 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 mL of DMSO, methanol (1 mL) was added and a precipitate formed. The solid was collected by filtration to give N - [4- (4-amino-7-tetrahydro-2H-4-pyranyl) -N-pyrrolo [2,3-d] pyrimidin-5-yl) -2 -methoxyphenyl] -2,2-dimethylpropanamide (7 mg, 0.015 mmol). 1 H NMR (CDCl ₃ -d) δ 2.07 (m, 4H), 2.75 (m, 2H), 3.09 (m, 2H), 3.65 (m, 2H),

3.88 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.97 (bs, 2H), 6.93 (s, 1H), 7.05 (m) , 2H),

7.26 (m, 5H), 7.70 (s, 1H), 8.24 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H). LC / MS: MH + = 472.

Examples 262-267 were synthesized using the following procedure:

To a mixture of cis -5- (4-amino-3-methoxyphenyl-7- [4- (4-methylpiperazino) cyclohexyl] 7 H -pyrrolo [2,3- d] pyrimidin-4-amine (0.25 g, 0.575 mmol), pyridine (2.5 mL) and dichloromethane (2.5 mL) were added the appropriate acid chloride (0.862 mmol) and the mixture was stirred at room temperature for 2 h.

183 was then stirred at ambient temperature under a nitrogen atmosphere for 1 hour. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase chromatography. Compound (280 mg, 0.460 mmol) was dissolved in hot ethyl acetate (25 mL), maleic acid (160 mg, 1.38 mmol) dissolved in ethyl acetate (10 mL) was added, allowed to cool to ambient temperature and then stirred 1 hour. The solid was collected by filtration and dried to give the title compound as the trimaleate salt. (370 mg).

The analytical RP-HPLC RTs shown in the table were obtained on a Hypersil HS C18 column ((5 µm, 100 A) 250 x 4.6 mm) using a linear gradient of 25-100% acetonitrile / 0.1 M ammonium acetate over 10 min at 1 ml / min. The retention time is indicated as "RT". Molecular masses of the mass spectrum are reported as "MH *".

Example 262 RT 6.62

MH + 576.3 Gradient a

184

RT7.7 ΜΗ * 608.2 Gradient a

RT 14.23 ΜΗ * 588.3 Gradient b

185

RT 6.85

MH ⁺ 540.2 Gradient a

Example 266 RT 8.15

MH ⁺ 608.2 Gradient a

186

Example 267 RT 8.15

MH ⁺ 642.3

General procedure for salt preparation:

Trans-benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) the carbamate was dissolved in ethyl acetate and maleic acid (280 mg) in ethyl acetate was added. The resulting solid was filtered under a stream of nitrogen and dried under vacuum for 4 hours to give cis -benzyl / N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H). -pyrrolo [2,3d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate salt (580 mg) as a cream solid. T. t. 158 ° C (dec.) ¹ H NMR (d ₆ DMSO, 400 MHz): 8.74 (1H, s), 8.27 (1H, s), 7.78 (1H, d), 7.35- 7.77 (5H, m), 7.10 (1H, s), 7.04 (1H, s), 6.16 (6H, s), 5.17 (2H, s), 4.74 (1H) , m), 3.82 (3H, s), 3.23 (5H, m), 2.78 (3H, s), 2.51 (3H, m), 2.41 (1H, s), 2 09 (4H, m); 1.70 (4H, m). HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 13.30 min, 94%.

The following salts were prepared in a similar manner. LCMS conditions are described below.

LCMS data: Perkin Elmer Pecosphere C18, 3 mM, 33 x 4.6, 3.5 mL / min 100-100% 50 mM ammonium acetate in acetonitrile over 4.5 minutes

187

188

structure Retention time MH ⁺ N H * -O about 2.64 481.2 ABOUT 7 O 0 to O 0 Θ O 0 chiral 2.7 481.2 -O N H * # 7 ABOUT 7 '' N O 0 F ^{η £} ΗΓΊ) ~ ^ο '0 e b Y about x

Example 268: cis-trans-N - 1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl-2-methoxyphenyl ) -3-phenylpropanamide

To 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7-yl] -1cyclohexanone (0.8 g, 2.3 mmol) in pyridine and dichloromethane (1: 2.5, 45 mL) was added hydrocinamyl chloride (0.57 g, 3.4 mmol) in dichloromethane (2 mL) at 0 ° C under a stream of nitrogen. The solution was stirred at 0 ° C for 2 hours. The reaction was quenched by the addition of saturated citric acid solution (50 mL) and the organic layer was washed with saturated aqueous citric acid solution (2 x 50 mL). It was dried, filtered and concentrated to give a brown foam (1.0 g). This was dissolved in dichloroethane (100 mL) and N-methylpiperazine (0.63 g, 6.3 mmol) and acid were added.

189 acetic (0.38 g, 6.3 mmol). Sodium triacetoxyborohydride (0.67 g, 3.15 mmol) was added in portions under nitrogen and the mixture was stirred at ambient temperature overnight. The reaction was quenched by addition of saturated NaHCO ₃ solution (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (sodium sulfate), filtered and evaporated to a residue which was purified by flash column chromatography on silica gel with dichloromethane / methanol (100/0 to 50/50 in 5% increments). The fractions corresponding to the faster moving material were combined to give cis- N 1 - (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidine-5). -yl-2-methoxyphenyl) -3-phenylpropanamide (0.26 g) as a glass. This was dissolved in ethyl acetate (5 mL) and maleic acid (160 mg) in ethyl acetate (2 mL) was added. The solid obtained was filtered to give cis / 1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c (1-pyrimidin-5-yl-2-methoxyphenyl)] ) -3-Phenylpropanamide trimaleate salt (260 mg) as a white solid Analytical LC / MS conditions: Column: Pecosphere, C18, 3 µm, 33 x 4.6 mm Eluent: 0% B / A to 100% B / A over 4.5 min (B: acetonitrile, A: 50 mM ammonium acetate buffer, pH 4.5), 3.5 mL / min (r, = 2.86 min, 568.4) ).

The fractions corresponding to the slower moving material were combined to give trans- N 1 - (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl) -3-phenylpropanamide (0.11 g) as a glassy substance. This was dissolved in ethyl acetate (5 mL) and a solution of maleic acid (68 mg) in ethyl acetate (2 mL) was added. The resulting solid was filtered to give trans- N - (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl-2-methoxyphenyl) -3 Phenylpropanamide trimaleate (94 mg) as a white solid. LC / MS analytical conditions: Column: Pecosphere, C18, 3 µm, 33 x 4.6 mm. Eluent: 0% B / A to 100% B / A over 4.5 min. (B: acetonitrile, A: 50 mM ammonium acetate buffer, pH 4.5), 3.5 mL / min. (R _t = 2.68 min, 568.2).

f p

190

4- [4-amino-5- (4-amino-3-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1cyclohexanone (2.25 g, 6.5 mmol), acid acetic acid (1.17 g, 19.5 mmol) and N-methylpiperazine (1.95 g, 19.5 mmol) were dissolved in dichloroethane (200 mL). Sodium triacetoxyborohydride (2.07 g, 9.75 mmol) was added in portions and the mixture was stirred at ambient temperature overnight. Saturated sodium bicarbonate solution (150 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water, dried (sodium sulfate), filtered and evaporated to a semi-solid which was purified by flash column chromatography on silica gel with CH ₂ Cl ₂ / methanol (0% MeOH to 50% MeOH in 5% increments). Fractions corresponding to the faster moving material were combined and evaporated to give cis-5- (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c] lpyrimidin-4-amine (1.2 g, 43%) as a cream. H NMR (d _e DMSO): δ 8.1 (1H, s), 7.11 (1 H, s), 6.87 (1H, s),

6.79 (1H, d), 6.05 (2H, bs), 4.80 (2H, bs), 4.64 (1H, m), 4.08 (1H, m), 3.82 (3H) , with),

3.17 (2H, m), 2.37 (6H, m), 2.21 (3H, s), 2.08 (4H, m), 1.70 (2H, m), 1.53 (2H) , m). HPLC (rt = 11.24 min, 97.6%).

The fractions corresponding to the slower moving material were combined and evaporated to give trans-5- (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] 7 H -pyrrolo [2,3- d] pyrimidin-4-amine (0.4 g, 14%) as a white solid. 1 H NMR (d 6 DMSO): δ 8.10 (1H, s), 7.26 (1H, s), 6.87 (1H, s), 6.77 (1H, d), 6.71 (1H, s), d), 6.05

191 (2H, s), 4.79 (2H, s), 4.52 (1H, m), 3.81 (3H, s), 3.35 (1H, m), 2.50 (5H, m) 2.31 (5H, m), 2.14 (1H, m), 1.97 (6H, m), 1.45 (2H, m). HPLC _(t R = 10.13 min, 97.9%).

To a solution of cis-5- (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (30 mg, 0.069 mmol) in pyridine (0.5 mL) was added the appropriate acid chloride (2 eq, 0.138 mmol). The vials were stoppered and shaken overnight on a rotary shaker. Two additional equivalents of acid chloride (0.138 mmol) were added in two portions (1 equivalent each) and the resulting mixtures were shaken again overnight. LCMS (Micromass column: Pecosphere, C18, 3 µm, 33 x 4.6 mm. Eluents: 0% B / A to 100% B / A over

4.5 min. (B: acetonitrile, A: 50 mM ammonium acetate buffer, pH 4.5),

3.5 ml / min) the obtained mixtures showed the presence of the product in all cases. The solutions were evaporated to dryness and the residue was redissolved in a small volume of DMF and purified by reverse phase preparative HPLC. The structures are listed below together with the relevant LCMS data.

Examples 269-293 were prepared by methods analogous to Example 268.

CH,

Example 269 RT 2.61 MH ⁺ 576.3

192

Example 270 RT 3.02 MH ⁺ 570.3

Example 271 RT 2.61 MH ⁺ 600.3 a

CH.

193

Example 272 RT 3.26 * 608.3

Example 273 RT 2.7.7 MH + 570.3 f * n

about. / about

CH,

Example 274 RT 2.78 MH + 558.4

194

9 ". (U o./o

Example 275 RT 3.00 MH * 574.3

Example 276 RT 2.76 570.3

195

CH,

Example 277 RT 3.26 MH ⁺ 608.3

Example 278 RT 2.94 MH ⁺ 570.3

196

Example 279 RT3.13 ΜΗ * 604.3

Example 280 RT 3.16 580.3

CN

CH, e r

197

Example 281 RT 2.68 MH ⁺ 565.3

Example 282 RT 2.90 MH ⁺ 585.3

CH,

Example 283 RT 2.84 MH * 585.3 • P

198

CH,

Example 284 RT 2.90 MH ⁺ 576.3

Example 285 RT 2.90 MH * 584.4

199

; n £

Example 286 RT 2.7.7 MH + 565.6

CH,

Example 287 RT 3.06 MH ⁺ 576.3

200

CH,

Example 288 RT 2.53 MH + 575.3

Example 289 RT 3.32 MH ⁺ 624.3

F

201

Example 290 RT 2.85 MH + 594.4

Example 291 RT 2.76 MH + 592.3

Example 292 RT 2.86 MH + 583.3

202

Q

CH,

CH,

Example 293 RT 2.29 MH + 508.3

General Synthesis for Examples 294-301:

Method A

A mixture of the appropriate piperazine (7.60 mmol), 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclohexanone (2.53 mmol) and glacial acetic acid (7.60 mmol) in 50 mL dichloroethane was stirred at room temperature for 1.5 h. Sodium triacetoxyborohydride (3.28 mmol) was added and the mixture was stirred at room temperature for 16 hours. A solution of 1.35 g of sodium bicarbonate in 50 ml of water was added and the reaction mixture was stirred for 1 hour. The organic portion was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to a brown oil. Purification by flash chromatography on silica gel afforded cis- and trans-7 - [(4-piperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amines.

Method B

A mixture of the appropriate pyrrolidine (7.53 mmol), 4- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7-yl] -1-cyclohexanone (2.51 mmol), and glacial acetic acid (7.35 mmol) in 45 mL dichloroethane was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.26 mmol) was added and the mixture was stirred at room temperature for 22 hours. A solution of 1.35 g of sodium bicarbonate in 50 ml of water was added and the reaction mixture was stirred for 1 hour. The organic portion was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to a brown oil.

203

- Γ I

Purification by flash chromatography on silica gel gave cis- and trans-7 - [(4-pyrrolidino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amines.

Salt formation

To a warm solution of pyrrolopyrimidine (2.48 mmol; from Method A or B above) in ethanol was added a solution of maleic acid (7.28 mmol) in ethanol. A white precipitate formed while cooling the solution to room temperature. The resulting solid was collected by filtration and dried under vacuum to give the desired trismalate salt.

The analytical RP-HPLC RT shown in the table was obtained on a Hypersil HyPurity Elite C18 column ((5 µm, 200 A) 250 x 4.6 mm) using a linear gradient of 25-100% acetonitrile / 0.1 M ammonium acetate over 10 min (gradient a) or 25 min (gradient b) at 1 mL / min.

RT 7.967 MH ⁺ 511.1 Gradient a

204

RT 7.383 Mbľ 527.2 Gradient a

Example 296 RT 13.941 MH + 497.1 Gradient b

205

RT 7.733 MH ⁺ 511.2 Gradient a

Example 298 RT 14.067 MH ⁺ 497.1 Gradient brf

206

RT 13.891 MH ⁺ 497.1 Gradient b

Example 300 RT 14.076 MH ⁺ 497.1 Gradient b

207 y

Example 301 RT 7.750 MH ⁺ 527.2 Gradient a

Example 302: Cis and trans 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-7-yl] -1-hydroxy-cyclohexylmethyl-cyanide

A solution of diisopropylamine (0.649 g, 0.0050 mol) in tetrahydrofuran (10 mL) was cooled to 0 ° C. A solution of 1.6 M n-butyl lithium (3.14 mL, 0.0050 mol) in hexanes was added dropwise while maintaining the temperature below 5 ° C. After the addition was complete, the mixture was stirred for an additional 20 minutes at 0 ° C. The mixture was cooled to -78 ° C and dry acetonitrile (0.175 g, 0.0043 mol) was added while maintaining the temperature to -70 ° C. After the addition was complete, the mixture was stirred for 20 minutes at -78 ° C and 4- [4 amino-5- (4-phenoxyphenyl) -7 / 7-pyrrolo [2,3-d] pyrimidin-7-yl] -1- (1-) was added. cyclohexanone (1.000 g, 0.0025 mmol) in tetrahydrofuran (10 mL) and hexamethylphosphoramide (10 mL) while maintaining the temperature below -70 ° C. After the addition was complete, the mixture was stirred at -78 ° C for 30 minutes and then at room temperature for 18 hours. The mixture was partitioned between dichloromethane and saturated aqueous ammonium chloride solution. The organic phase was washed with water and saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure

208 pressure and cis and trans isomers were separated by flash column chromatography on silica using dichloromethane and methanol (95: 5) as eluent to give the less polar 4- [4-amino-5- (4-phenoxyphenyl) -7W. -pyrrolo [2,3-dlpyrimidin-7-yl] -1-hydroxy-cyclohexylmethyl-cyanide (0.120 g, 0.00027 mol) and the more polar 4- [4-amino-5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-] d] pyrimidin-7-yl] -1-hydroxycyclohexylmethyl cyanide (0.170 g, 0.00038 mol):

Less Polar:

¹ H NMR (DMSO-d ₆ , 400MHz) δ 8.13 (s, 1H), 7.48 (d, 2H), 7.41 (t, 2H), 7.37 (s, 1H), 15 (t, 1H), 7.093 (d, 2H), 7.088 (d, 2H), 6.11 (b, 2H) 5.05 (s, 1H), 4.534.61 (m, 1H), 2.66 (s, 2H), 2.18 (q, 2H), 1.80 (t, 4H), 1.66 (t, 2H); RP-HPLC (Delta Pak C18, 5 µm, 300 A, 15 cm; 5% - 85% acetonitrile - 0.1 M ammonium acetate over 20 min, 1 mL / min) R, 15.90. MH * 440th

More polar: (Probably trans, aryl-axial, OH-axial) ¹ H NMR (DMSO-d ₆ 400 MHz) δ 8.13 (s, 1H), 7.63 (s, 1H), 7.48 (d, 2H), 7.41 (t, 2H), 7.15 (t, 1H), 7.11 (d, 2H), 7.08 (d, 2H), 6.11 (b, 2H) 5.22 (s, 1H), 4.62-4.67 (m, 1H), 2.98 (s, 2H), 1.82-1.99 (m, 6H), 1.65-1.73 (m , 2H); RP-HPLC (Delta Pak C18, 5 µm, 300 A, 15 cm; 5% - 85% acetonitrile - 0.1 M ammonium acetate over 20 min, 1 mL / min) R, 15.88. MH ^{@ +} 440.

Example 303: cis- and trans-5- (4-amino-3-fluorophenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine

a) tert-Butyl N- (4-bromo-2-fluorophenyl) carbamate

A solution of sodium bis (trimethylsilyl) amide (1.0 M solution in THF, 2.05 equiv, 270 mL, 270 mmol) was added dropwise to a solution of 4-bromo-2-fluoroaniline (24.78 g, 130.4 mmol) in THF (250 mL) over 15 min under nitrogen. After an additional 15 min, di-tert-butyl dicarbonate (1.2 equivalents, 34.12 g, 156.3 mmol) was added portionwise (note: a slight exothermic reaction was observed). The reaction mixture became highly viscous and was terminated in 4 hours (TLC analysis with EtOAc and heptane 1: 9 as eluent). The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO ₃ (150 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL) and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure.

209 i-P pressure. Purification by column chromatography using a 10% to 15% gradient

EtOAc: heptane gave tert-butyl N- (4-bromo-2-fluorophenyl) carbamate, light yellow waxy solid (30.0 g, 79%), 1 H NMR (400 MHz, CDCl ₃ ) 1.51 (9H, s), 7.22 (1H, m) and 7.24 (2H, m).

b) tert-Butyl N- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate

A solution of tert-butyl N- (4-bromo-2-fluorophenyl) carbamate (54.0 g, 0.186 mmol), N-s-pinacolatodiborane (1.2 equivalents, 56.8 g, 223.3 mmol), potassium acetate (3.0 equivalents, 54.7 g, 558 mmol) and PdCl ₂ (dppf) (0.03 equivalents, 4.65 g, 5.58 mmol) in degassed DMF (1 L) was heated to 80 ° C under nitrogen for 16 hours. The DMF was removed under reduced pressure and the obtained dark solid residue was dissolved in CH ₂ Cl ₂ (500 mL). Inorganic residues were separated by filtration through a pad of silica gel and the filtrate was purified by column chromatography using a 10% to 15% gradient of EtOAc in heptane to give the product as a yellow viscous oil which crystallized on standing to tert-butyl / N- [2-fluoro]. -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate (56.5 g, 92%), ¹ H NMR (400 MHz, CDCl ₃ ) 1.33 (12H, s), 1.53 (9H, s), 6.82 (1H, brs), 7.46 (1H, d, J 11 Hz), 7.55 (1H, br d), and 8.12 (1H, br), m / z 337.2 and RP-HPLC (5 to 100% CH ₃ CN in 0.1 N aqueous ammonium acetate over 15 at 1 mL / min on a Hypersil HyPurity column Elite (C18, 5 µm, 200 A, 250 x 4.6 mm) t, = 10.16 min, 90%.

c) tert-Butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2,3d] pyrimidin-5-yl] - 2-fluorophenylcarbamate

Suspension of 4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidine (31.18 g, 74.41 mmol), tert- butyl N- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate (1.5 equivalents, 37.6 g, 111.6 mmol) , sodium carbonate (2.5 equivalents, 19.72 g, 186 mmol) and Pd (PF ₃ ) ₄ (4 molar%, 3.44 g, 2.98 mmol) in DME (1.2 L) and degassed H ₂ O (230 mL) was heated at 80 ° C under nitrogen for 17 hours. Additional Pd catalyst (1 molar%, 86 g, 0.74 mmol) was added and the reaction continued to heat at 80 ° C for an additional 24 h when the reaction was complete (TLC analysis with EtOAc in heptane 3: 7 as eluent, Rf = 0). 7). The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (500 mL) and the inorganics were collected by filtration through a pad of celite. The filtrate was washed with 10% aqueous Na ₂ CO ₃ * P

210 (200 mL) and brine (200 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by column chromatography on silica gel with EtOAc in heptane 1: 2 gave tert-butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2] 3-d] pyrimidin-5-yl] -2-fluorophenylcarbamate as an off-white solid (21.0 g, 56%). ¹ H NMR (400 MHz, CDCl ₃ ) 1.55 (9H, s), 1.89 (4H, m), 2.07 (4H, m), 4.01 (4H, s), 4.89 (1H, m), 6.75 (1H, br s), 7.23 (1H, br s), 7.25 (1H, br s), 7.34 (1H, br s), br s), 8.14 (1H, br t) and 8.64 (1H, s) and RP-HPLC (5 to 100% CH ₃ CN in 0.1 N aqueous ammonium acetate over 15 min at 1 ° C). ml / min on a Hypersil HyPurity Elite C18 column, 5 µm, 200 A, 250 x 4.6 mm) t, = 10.48 min, 100%.

d) 5- (4-Amino-3-fluorophenyl) -7- (1,4-dioxaspiro [4,5] dec-8-yl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine

N, -4- [4-Chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7 H -pyrrolo [2,3- d] pyrimidine-5], a cloudy mixture -yl] -2-fluorophenylcarbamate (10.5 g, 20.92 mmol), aqueous ammonium hydroxide (28-30%, 100 mL) and dioxane (100 mL) were placed in a sealed vial at room temperature and then heated to room temperature. 120 ° C with stirring for 24 hours (TLC analysis with EtOAc: heptane 9: 1 as eluent). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (300 mL), washed with brine (2 x 150 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure and thoroughly dried to give 5- (4-amino- 3-fluorophenyl) -7- (1,4-dioxaspiro [4,5] dec8-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as a yellow solid (7.93 g, 99%) %). ¹ H NMR (400 MHz, d ₆ -DMSO) 1.74 (4H, m), 1.90 (2H, m), 2.06 (2H, m), 3.90 (4H, m) ), 4.64 (1H, m), 5.18 (2H, br s), 6.02 (2H, br s), 6.84 (1H, br), 6.97 (1H, br) , d), 7.08 (1H, d), 7.26 (1H, s) and 8.10 (1H, s) and m / z 384.2 (MH +).

e) 4- [4-amino-5- (4-amino-3-fluorophenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7-yl] -1cyclohexanone

M HCl (300 mL) was slowly added to a solution of 5- (4-amino-3-fluorophenyl) -7 (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2,3- d] pyrimidin-4-amine (18.49 g, 48.28 mmol) in acetone (800 mL) at 0 ° C and the obtained dark orange-brown solution was heated at 60 ° C for 4 hours (TLC analysis with 10% MeOH in CH ₂ CI ₂ ). The acetone was removed under reduced pressure and the pH of the acidic layer was adjusted to about 8 with saturated aqueous Na ₂ CO ₃ . The resulting precipitate was collected by filtration and thoroughly dried to give 4- [4-amino-5- (4-amino-3-fluorophenyl) -7H211 pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclohexanone as a light brown solid (12.67 g, 77%). A second crop was obtained from the standing solution (2.01 g, 12%).

1 H NMR (400 MHz, d ₆ -DMSO) 2.27 (2H, m), 2.30 (4H, br d), 2.73 (2H, m), 5.14 (1H)

H, m), 5.20 (2H, br s), 6.05 (2H, br s), 6.85 (1H, f), 6.97 (1H, dd), 7.06 (1H, dd),

7.35 (1H, s) and 8.12 (1H, s) and m / z 340.1 (MAT).

Example 304: cis-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4- Fluoro-1-benzenesulfonamide trimaleate

To a solution of 4- [4-amino-5- (4-amino-3-fluorophenyl) -7H-pyrrolo [2,3-d] pyrimidin-7yl] -1-cyclohexanone (1.0 g, 2.95 mmol) , N-methylpiperazine (3 equivalents, 0.885 g, 8.85 mmol, 0.98 mL) and glacial acetic acid (3 equivalents, 0.51 mL, 8.85 mmol) in dichloroethane (50 mL) under nitrogen were added triacetoxyborohydride sodium (1.3 equivalents, 0.81 g, 3.84 mmol). The solution was stirred for 18 hours, additional sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added and the reaction continued for another 48 hours. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The aqueous layer was further extracted with dichloromethane (4 x 100 mL) and the combined organic layers were dried over magnesium sulfate and evaporated to dryness to give a yellow foam (0.95 g). Purification by column chromatography on silica gel using a gradient of dichloromethane and methanol (9: 1 to 5: 1) afforded cis-5- (4-amino-3-fluorophenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7]. - / - pyrrolo [2,3-d] pyrimidin-4-amine, a faster moving component, as a cream solid (400 mg, 32%). ¹ H NMR (d ₆ DMSO, 400 MHz) 1.56 (3H, br t), 1.68 (2H, br d), 1.99 (5H, m), 2.20 (3H, s), 2 43 (7H, br m), 4.65 (1H, m), 5.20 (2H, s), 6.01 (2H, br s), 6.85 (1H, t, J = 9.6) Hz), 6.98 (1H, dd, J = 8.0 and 1.6 Hz), 7.10 (1H, dd, J = 12.4 and 1.6 Hz), 7.12 (1H, s) ), and 8.10 (1H, s) and RP-HPLC (10 to 90% CH ₃ CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL / min using a Waters Symmetry C18 column, 250 x 4, 6 mm) t _r = 8.619 min, 96%

A mixed fraction was obtained which contained both cis- and trans-isomers (440 mg, 50:50 mixture) and, in addition, the slower moving fraction contained trans-5- (4 amino-3-fluorophenyl) -7- [4- (4 -methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-4amine as a yellow solid (110 mg, 9%). 1 H NMR (d ₆ DMSO, 400 MHz) 1.94 (6H,

212

m), 2.17 (3H, s), 2.33 (7H, br m), 2.51 (3H, m), 3.28 (1H, m), 4.51 (1H, m), 5 18 (2H, s), 6.01 (2H, br s), 6.84 (1H, t), 6.96 (1H, dd), 7.04 (1H, dd), 7.30 (1H) , s) and

8.08 (1H, s) and RP-HPLC (10 to 40% CH ₃ CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL / min using a Waters Symmetry C18 column, 250 x 4.6 mm) t _r = 7.595 min, 97%

Example 305: trans-N- 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluorophenyl) -4 -fluoro-1-benzenesulfonamide trimaleate

4-Fluorobenzenesulfonyl chloride (45.9 mg, 0.236 mmol) was added to a solution of trans-5- (4-amino-3-fluorophenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidine Of 4-amine (100 mg, 0.236 mmol) in pyridine (2 mL) at 40 ° C. After 27 hours at 40 ° C, the reaction was complete and the mixture was concentrated under reduced pressure. Purification by silica gel column chromatography using 10% to 50% MeOH in dichloromethane as a gradient gave a colorless oil (0.78 mmol). The product was dissolved in ethanol and maleic acid (3 equivalents, 27 mg, 0.233 mmol) was added. The mixture was heated until homogeneous and trans-N1- (4- {4 amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluorophenyl) - 4-fluoro-1-benzenesulfonamide trimaleate crystallized upon cooling as a beige solid (37 mg, 17%), RP-HPLC (10-40% CH ₃ CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL / min on a Waters Symmetry C18 column, 250 x 4.6 mm) t _r = 14.528 min, 96% and m / z 582.0 (ΜΛΓ).

Example 306: cis-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4- cis- N - (4 {-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-) - Fluorophenyl) -4-fluoro-1-benzenesulfonamide was prepared using the same procedure as the trans- N 1 - (4 {-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] cyclohexyl] -7 H -pyrrolo [2,3- d] -d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide, except that the preparation was carried out on a scale of 3.36 mmol.

(400 mg, 32%), RP-HPLC (10 to 40% CH ₃ CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL / min on a Waters Symmetry C18 column, 250 x 4.6 mm) t _r = 15.232, 94% min and m / z = 582.1 (M -1).

213

Example 307: 5- (4-Amino-3-fluorophenyl) -7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

a) 7- (1-Benzyl-4-piperidyl) -4-chloro-5-iodo-7 H -pyrrolo [2,3- d] pyrimidine

Diethyl diazodicarboxylate (2.0 equivalents, 18.19 g, 41.2 mL, 104.8 mmol) was added dropwise over approximately 1 h to a solution of 4-chloro-3-iodopyrrolo [2,3-d] pyrimidine (14.55 g) , 52.4 mmol), 1-benzyl-4-hydroxypiperidine (3.0 equivalents, 30.06 g, 157.16 mmol) and triphenylphosphine (2.0 equivalents, 27.51 g, 104.8 mmol) in THF (730 mL) at room temperature under nitrogen. The reaction was complete after 72 h (TLC analysis using EtOAc: heptane 1: 1 as eluent, R f = 0.2). the reaction mixture was concentrated in vacuo and a 1: 4 mixture of ethyl acetate and heptane was added until a precipitate was observed in the clear solution. The precipitate was collected by filtration (Ph ₃ PO) and the filtrate was concentrated, dissolved in ethyl acetate (500 mL) and extracted with aqueous HCl (1 M, 3 x 200 mL). The combined acidic layers were made basic with aqueous NaOH (4 N) to pH 12, extracted into ethyl acetate (3 x 300 mL), dried (MgSO 4 and concentrated in vacuo. Purification by column chromatography using light petroleum ether (30-60 ° C) with ethyl acetate 5: 4 on silica gel yielded 2 major fractions, the first of which contained the product as a pale yellow crystalline solid, which was recrystallized from ethyl acetate to give 7- (1-benzyl-4-piperidyl) 4-chloro-5- iodo-7 H -pyrrolo [2,3- d] pyrimidine as a cream crystalline solid (5.7 g, 24%); 1 H NMR (400 MHz, CDCl ₃ ) 2.02 (4H, m), 2, 24 (2H, m), 3.06 (2H, br d), 3.58 (2H, s), 4.76 (1H, m), 7.27 (2H, m), 7.32 (3H, m), 7.49 (1H, s) and 8.60 (1H, s) and m / z = 452.8 (MET).

b) tert-Butyl N- [7- (1-benzyl-4-piperidyl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenylcarbamate

A suspension of 7- (1-benzyl-4-piperidyl) -4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (5.7 g, 12.6 mmol), tert-butyl N - [2 -fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate (1.5 equiv, 18.9 g, 6.38 mmol), sodium carbonate (2 , 5 equivalents, 3.34 g, 31.5 mmol) and Pd (PF ₃ ) ₄ (4 mol%, 0.58 g, 0.5 mmol) in DME (210 mL) and degassed water (37 mL) were added. was heated at 80 ° C under nitrogen for 17 h (TLC analysis with EtOAc: heptane 1: 1 as eluent). The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (400 mL) and washed with 10% aqueous Na ₂ CO ₃ (3 x 200 mL). The organic layer was dried (MgSO 4,

214 was concentrated and purified by column chromatography using ethyl acetate and heptane 1: 1 as eluent to give tert-butyl N-4- [7- (1-benzyl-4-piperidyl) -4-chloro-7H-pyrrolo [2,3- d] Pyrimidin-5-yl] -2-fluorophenylcarbamate as a white crystalline solid (5.2 g, 9.7 mmol, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) 1.55 (9H, s), 2.05 (4H, m), 2.24 (2H, m), 3.06 (2H, br d), 3, 60 (2H, s), 4.83 (1H, m), 7.25 (2H, m), 7.29 (1H, Zn), 7.33 (6H, m), 8.12 (1H, br) t) and 8.64 (1H, s).

c) 5- (4-Amino-3-fluorophenyl) -7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4amine

A mixture of tert-butyl N- [7- (1-benzyl-4-piperidyl) -4-chloro-7 H -pyrrolo [2,3- b] pyrimidin-5-yl] -2-fluorophenylcarbamate (5 , 2 g, 9.7 mmol), aqueous ammonium hydroxide (28-30%, 100 mL) and 1,4-dioxane (100 mL) were placed in a sealed vial at room temperature and heated to 120 ° C with stirring for 16 h, (TLC analysis using EtOAc as eluent). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (300 mL), washed with brine (2 x 200 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to a brown solid which was triturated with ether (about 50 mL). mL) to give 5- (4-amino-3-fluorophenyl) -7- (1-benzyl-4-piperidyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine as a cream solid (3). (0 g, 74%). ¹ H NMR (400 MHz, CDCl ₃ ) 2.06 (4H, m), 2.27 (2H, m), 3.06 (2H, m), 3.59 (2H, br s), 3.70 (2H, br s), 4.73 (1H, m), 5.12 (2H, s), 6.85 (1H, t), 7.01 (1H, s), 7.06 (1H, dd), 7.10 (1H, dd), 7.28 (2H, m), 7.34 (3H, m) and 8.31 (1H, s) and mp M.p. 141-142 ° C.

Example 308: N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] 2-fluorophenyl-4-fluoro-1- benzenesulfonamide

N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide (470981) was prepared using the same procedure as trans-N- [4- (4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7Hpyrrolo [2,3-d] pyrimidin-5-one)]. yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate except that the preparation was carried out on a scale of 6.96 mmol. (V) -4- [4-Amino-7- (1-benzyl-4-piperidyl) -7 H -pyrrolo [2,3- d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide was obtained as a cream solid (3.2 g 80%), m / z 575 (MH ⁺ ) and 1.1. 265-266 ° C.

215

Example 309: N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] 2-fluorophenyl-2,3-dichloro- 1-benzenesulfonamide

A / 1-4- [4-amino-7- (1-benzyl-4-piperidinyl) -7 H -pyrrolo [2,3-c / | pyrimidin-5-yl] -2-fluorophenyl-2,3-dichloro-1 -benzenesulfonamide was prepared in the same manner as above, on a scale of 5.04 mmol. The resulting N-1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-c] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide was obtained as a brown solid (1.0 g, 32%), m / z 625 (MH +) and RP-HPLC (5 to 85% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min at 1 ° C). ml / min on a Waters Delta pack 5 µm C18, 300 A, 150 x 3.9 mm) t _r = 14.963 min, 95%.

Example 310: N1-4- [4-amino-7- (4-piperidinyl) -7 H -pyrrolo [2 _L 3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide

A mixture containing N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide ( 2.40 g, 4.18 mmol), ammonium formate (10 equivalents, 41.8 mmol, 2.62 g), palladium on carbon (10%, 1.2 g) and ethanol (100 mL) were heated to reflux with vigorous stirring for 6 h, filtered and concentrated under reduced pressure. The solid obtained was partitioned between dichloromethane (50 mL) and water (50 mL). The brown solid that precipitated at the phase boundary was separated and analyzed as N 1 -4- [4-amino-7- (4-piperidyl) 7 H -pyrrolo [2,3- d] pyrimidin-5-yl] - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide (0.33 g), m / z 485 (MH +) and m.p. 238-239 ° C (dec.).

Example 311: N1-4- [4-amino-7- (1-formyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide

The procedure described for the preparation of N1-4- [4-amino-7- (4-piperidyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide was carried out in small scale (0.35 mmol), the combined organic layers from the work-up were separated, dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure to give a white oil which was purified by preparative HPLC (100% pH 4.5) 50 mM ammonium acetate to 100% CH ₃ CN over 8.5 minutes with a 1.5 minute hold at 25 ml / min on a Hypersil 5 µm BDS C18 column, 100 x 21.2 mm) to give (V1-4) - [4-amino-7- (1-formyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide as a white solid (50 mg) , 27%), m / z = 512.9 (MH +) and RP-HPLC (5 to 85% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min

216 at 1 ml / min on a Waters Delta pack 5 µm C18, 300 A, 150 x 3.9 mm) t _r =

13.091 min, 95%.

Example 312: N 1 - [4- (4-amino-7-1 - [(1-methyl-1H-4-imidazolyl) sulfonyl] -4-piperidyl-7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimalate

1-Methylimidazol-4-ylsulfonyl chloride (1.1 equivalents, 0.068 mmol, 12.3 mg) was added to a suspension of 5- (4-amino-3-fluorophenyl) -7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (30 mg, 0.062 mmol) and triethylamine (3 equivalents, 0.186 mmol, 26 µL) in dichloromethane (1 mL) and stirred at ambient temperature for 24 h. The reaction mixture was concentrated under reduced pressure, partitioned between dichloromethane (100 mL) and water (50 mL) and the aqueous layer was further extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel with 10% methanol in dichloromethane gave a waxy white solid (10 mg). Maleic acid (2 equivalents, 4 mg) in hot ethanol was added to the product and N - [4- (4-amino-7-1 - [(1-methyl-1 H -imidazolyl) sulfonyl] -4-piperidyl -7 H -pyrrolo [2,3- d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimalate salt crystallized upon cooling (10 mg), RP-HPLC (5 to 85) % CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min at 1 mL / min on a Waters Delta pack 5 µm C18, 300 A, 150 x 3.9 mm) t _r = 14.186 min, 100% am / z = 629 (MH +).

Example 313: N1- [4- (4-amino-7-1 - [(1,2-dimethyl-1H-4-imidazolyl) sulfonyl] -4-piperidyl-7H-pyrrolo [2,3-d] pyrimidine-5- yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide

Using the procedure for the synthesis of the free base N1- [4- (4-amino-7-1 [(1-methyl-1H-4-imidazolyl) sulfonyl] -4-piperidyl-7H-pyrrolo [2,3-d] pyrimidine -5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate was prepared N1- [4- (4-amino-71 - [(1,2-dimethyl-1H-4-imidazolyl) sulfonyl] -4 -piperidyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) 2-fluorophenyl] -4-fluoro-1-benzenesulfonamide as a cream solid (9 mg), 1.1. 217 218 ° C and m / z = 643.2 (MH +).

Example 314: N1- [4- (4-amino-7-1 - [(1,3-dimethyl-1H-5-pyrazolyl) carbonyl] -4-piperidyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide

1,3-Dimethylpyrazole-5-carbonyl chloride (1.5 equivalents, 14.8 mg, 0.093 mmol) was added to a stirred suspension of 5- (4-amino-3-fluorophenyl) -7- (1-benzyl-4-piperidyl) ) 217

7H-pyrrolo [2,3-d] pyrimidin-4-amine (30 mg, 0.062 mmol) and potassium carbonate (2 equivalents, 17.1 mg, 0.124 mmol) in N-methylpyrrolidinone (2 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the mixture was purified by silica gel column chromatography using 5% methanol in dichloromethane as eluent to give [1- [4- (4-amino-7-1 - [(1,3-dimethyl-1)]]. (7-5-pyrazolyl) carbonyl] -4-piperidyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide as a colorless glass (10 mg), RP- HPLC (100% pH 4.5 50 mM ammonium acetate to 100% CH ₃ CN over 4.5 minutes with 0.5 minute hold at 3.5 ml / min on a Perkin Elmer Pecosphere 3 pm C18 column (33 x 4, 6 mm)) t _r = 2.98 min, 96% m / z = 629 (MH +).

Example 315: N1- (4- {4-amino-7- [1- (2-pyridylcarbonyl) -4-piperidyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4 fluoro-1-benzenesulfonamide

N 1- (4- {4-amino-7- [1- (2-pyridylcarbonyl) -4-piperidinyl] -7 H -pyrrolo [2 _L 3d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro- 1-Benzenesulfonamide was prepared using the same procedure as N 1 - [4- (4-amino-7-1 - [(1,3-dimethyl-1H-5-pyrazolyl) carbonyl] 4-piperidyl-7 H -pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide, (12 mg), RP-HPLC HPLC (100% pH 4.5 50 mM ammonium acetate to 100% CH3 ₎ CN over 4.5 min with 0.5 min hold at 3.5 mL / min on a Perkin Elmer Pecosphere 3 µm C18 (33 x 4.6 mm) column) t, = 2.73 min, 98% am / z = 590.2 (MH +).

Example 316: N1-4- (4-amino-7- {4- [1- (1-methylpiperid-4-yl) piperidyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl}) - 2- Fluorophenyl 4-fluoro-1-benzenesulfonamide trimaleate

Sodium triacetoxyborohydride (28.1 mg, 0.134 mmol) was added to a solution of Λ / 1-4 [4-amino-7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide (50 mg, 0.103 mmol) and 1-methylpiperid-4-one (0.92 mL, 0.155 mmol) in glacial acetic acid (0.025 mL) and NMP (3 mL). The reaction mixture was stirred for 20 h at room temperature and then additional sodium triacetoxyborohydride (1.3 equivalents) was added. After an additional 24 h, the reaction was complete, the reaction mixture was concentrated in vacuo and partitioned between dichloromethane (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The aqueous layer was further extracted with dichloromethane (4 x 100 mL) and the combined organic layers were dried over magnesium sulfate and evaporated to dryness. Purification by column chromatography on silica gel using dichloromethane / methanol / ammonium hydroxide (78: 19: 3) as eluent gave the title compound as a white solid, m.p.

218 obtained a brown solid. The trimaleate salt was then formed by standard methods to give N - 1-4- (4-amino-7- {4- [1- (1-methylpiperid-4-yl) piperidyl] -7 H -pyrrolo [2,3- b] -d] pyrimidin-5-yl}) - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide trimaleate as a brown solid (45 mg, 75%), m / z 582 (MH +) and RP-HPLC (5) up to 85% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min at 1 mL / min on a Waters Delta pack 5 µm C18, 300 A, 150 x 3.9 mm) t _r = 10.658 min, 95% .

Example 317: N1-4- [4-amino-7- (4-oxo-cyclohexyl) -7 H -pyrrolo [2 _l 3-d] pyrimidin-5-yl] -2metoxyfenylbenzamid

a) To a solution of 4-chloro-5-iodo-7H-pyrrolo [2 ₁ 3-d] pyrimidine (25.0 g, 0.09 mol), 1,4-dioxaspiro [4,5] decan-8-ol (35.8 g, 0.0267 mol) and triphenylphosphine (46.7 g, 0.178 mol) in THF (1.2 L) were added diethyl azodicarboxylate (30.9 g, 0.178 mol) under nitrogen. The solution was stirred for 20 hours and most of the solvent was then evaporated (250 ml left). EtOAc (450 mL) was then added and the solid formed was filtered, washed with EtOAc (2 x 50 mL) and dried under reduced pressure to give 4-chloro-7- (1,4-dioxaspiro [4,5] dec). (8-yl) -5-iodo-7 H -pyrrolo [2,3- d] pyrimidine (22.5 g, 60%) as a cream solid. 1 H NMR (d ₆ DMSO, 400 MHz) 8.64 (1H, s), 8.10 (1H, s), 4.74 (1H, m), 3.90 (4H, m), 2.12 (2H, m), 1.91 (2H, m), 1.71-1.83 (4H, m). Rt in EtOAc: heptane 1: 4 = 0.12.

b) A solution of tert-butyl N- [2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate (8.2 g, 23.5 mmol) 1,4-Chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -5-iodo-7H-pyrrolo [2,3-d] pyrimidine (6.57 g, 15.7 mmol) ), tetrakistriphenylphosphine palladium (1.1 g, 0.93 mmol), sodium carbonate (4.16 g, 39.2 mmol) in dimethoxyethane (200 mL) and water (100 mL) were heated at 80 ° C for 20 hours under nitrogen. . The resulting solution was cooled to room temperature and partitioned between EtOAc (300 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organic layers were washed with water (1 x 150 mL). The organic portion was dried (sodium sulfate), filtered and evaporated to a solid residue. An attempt to dissolve in EtOAc / heptane (1: 4) resulted in a cream solid (2.5 g). The filtrate was adsorbed onto silica and purified by column chromatography on silica gel with heptane EtOAc 10: 1, heptane EtOAc 4: 1, heptane EtOAc 1: 1 and EtOAc heptane 4: 1. Appropriate fractions were combined to give a white solid

219 /../,/ which was triturated with heptane / EtOAc (5: 1) to give tert-butyl

N -4- [4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate in the form of solid (3.2 g), combined yield 71%.

1 H NMR (d ₆ DMSO, 400 MHz): 8.66 (1H, s), 7.93 (2H, m), 7.74 (1H, m), 7.19 (1H, s), 07 (1H, d), 4.81 (1H, m), 3.93 (4H, m), 3.91 (3H, s), 2.18 (2H, m), 1.99 (2H, m) 1.79 (4H, m), 1.48 (9H, s). HPLC (conditions: 5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 21.24 min, 100%.

c) tert -Butyl-4- [4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2,3-c] pyrimidin-5-yl] -2 -methoxyphenylcarbamate (5.7 g, 0.011 mol), concentrated ammonia solution (100 mL) and dioxane (100 mL) were heated in an autoclave at 120 ° C for 20 hours. The solvent was evaporated and the residue was reconstituted in EtOAc and water (250 mL / 100 mL). The organic layer was separated, dried (sodium sulfate), filtered and evaporated to give a solid which, according to HPLC (conditions: 5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) N-4- [4-amino-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate; - (4-amino-3-methoxyphenyl) -7- (1,4-dioxaspiro [4,5] dec-8-yl) 7H-pyrrolo [2,3-d] pyrimidin-4-amine 2: 1. The mixture was dissolved in acetone (200 mL) and HCl (5 N, 100 mL) was added dropwise over 0.5 h. The resulting solution was stirred overnight at room temperature and the solvent was then evaporated. The pH of the acidic solution was basified with 2 N NaOH (ice-cooling) and the solution was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (2 x 100 mL). A solid precipitated during the extraction process. This solid was filtered off and triturated in hot EtOAc / MeOH. Insoluble materials were filtered off, the filtrate was evaporated and the resulting solid was triturated with dimethyl ether and ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulfate), filtered and evaporated. The resulting solid was triturated with dimethyl ether and ethyl acetate (5: 1) and filtered to give 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidine -7-yl] -1-cyclohexanone as a yellow solid. (2.3 g, combined yield = 78%). 1 H NMR (d ₆ DMSO, 400 MHz): 8.17 (1H, s), 7.32 (1H, s), 6.88 (1H, s), 6.77 (1H, m), 6, 73 (1H, m), 6.71 (1H, m), 6.07 (2H, bs), 5.14 (1H, m), 3.81 (3H, s), 2.72 (2H, m) 1.35 (4H, m), 2.18 (2H, m).

r ~

220

HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r =

11.24 min, 95%.

d) To a solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7-yl] -1-cyclohexanone (0.105 g, 0, 3 mmol) in pyridine (2 mL) and dichloromethane (5 mL) was added benzoyl chloride (63 mg, 0.45 mmol) in dichloromethane (1 mL) at 0 ° C under nitrogen. The solution was stirred at 0 ° C for 2 hours and then quenched with water (5 mL). HCl (1 N, 40 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with water (1 x 30 mL). The organic layer was dried (sodium sulfate), filtered and evaporated to an oil, which was purified by flash column chromatography on silica gel using 2% -10% MeOH / EtOAc as eluent to afford (R) 1-4- [4-amino- 7- (4-Cyclohexyl) -7 H -pyrrolo [2,3- b] pyrimidin-5-yl] -2-methoxyphenylbenzamide as a white solid (0.130 g, 96%). T. t. 234-237'C. _Rf in 9: 1 EtOAc: MeOH = 0.30. HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t, = 14.82 min, 96%. 1 H NMR (d ₆ DMSO, 400 MHz): 9.43 (1H, s), 8.19 (1H, s), 7.94 (3H, m), 7.59 (4H, m), 7.18 (1H, s), 7.06 (1H, d, J = 8Hz), 6.18 (2H, bs), 5.20 (1H, m), 3.92 (3H, s), 2.76 (2H, m), 2.35 (4H, m), 2.22 (2H, m).

Example 318: Benzyl N-4- [4-amino-7- (4-oxocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate

To a solution of the obtained 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7-yl] -1-cyclohexanone (0.40 g, 1.15) mmol) in pyridine (5 mL) and dichloromethane (10 mL) was added benzyl chloroformate (0.29 g, 1.73 mmol) at -5 ° C under nitrogen. The temperature of the solution was allowed to rise to 0 ° C and the solution was stirred for 1 hour. The reaction was quenched by the addition of water (5 mL) and the solvent was evaporated. The residue was partitioned between EtOAc and water (100 mL each) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (sodium sulfate), filtered and evaporated to a solid which was triturated with EtOAc / Et ₂ O to give benzyl Λ -4- [4 amino-7- (4-oxocyclohexyl) -7H-pyrrolo]. [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate (0.28 g) as a yellow solid. T. t. 175-176 ° C. Rf in 9: 1 EtOAc: MeOH = 0.24. HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 16.69 min, 98%. ¹ H NMR (d ₆ DMSO, 400 MHz): 8.64 (1H, s), 8.17 (1H, s),

221 Γ

7.75 (1H, d, J = 8.4 Hz), 7.50 (1H, s), 7.36 (5H, m), 7.10 (1H, s), 7.02 (1H, s, d, J = 8

Hz), 6.15 (2H, bs), 5.19 (3H, m), 3.81 (3H, s), 2.72 (2H, m), 2.35 (4H, m), 2, 22 (2H,

m).

Example 319: N -benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2- methoxyphenyl) carbamate trimaleate a

7-trans-Benzyl N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate

To a solution of benzyl N- 4- [4-amino-7- (4-oxocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate (0.83 g, 1.74 mmol), N-methylpiperazine (0.52 g, 5.22 mmol) and glacial acetic acid (0.31 g, 5.22 mmol) in dichloroethane (100 mL) under nitrogen were added portionwise sodium triacetoxyborohydride (0.55 g, 2). , 61 mmol). The solution was stirred for 6 hours and then quenched with sodium hydroxide (2 N, 20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried (sodium sulfate), filtered and evaporated to an oil which was purified by flash column chromatography on silica gel with EtOAc, EtOAc with MeOH 9: 1, CH ₂ Cl ₂ and CH ₂ Cl ₂ with MeOH 9: 1 to give an oil in F20-25 (480 mg). This oil was dissolved in ethyl acetate and maleic acid (280 mg) in ethyl acetate was added. The resulting solid was filtered under a stream of nitrogen and dried under vacuum for 4 hours to give cis -benzyl / N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7). N - [pyrrolo [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate salt (580 mg) as a cream solid. T. t. 158 DEG C. (dec.). 1 H NMR (d ₆ DMSO, 400 MHz): 8.74 (1H, s), 8.27 (1H, s), 7.78 (1H, d), 7.35-7.77 (5H, m) ), 7.10 (1H s), 7.04 (1H, s), 6.16 (6H, s), 5.17 (2H, s), 4.74 (1H, m), 3, 82 (3H, s), 3.23 (5H, m), 2.78 (3H, s), 2.51 (3H, m), 2.41 (1H, s), 2.09 (4H, m) 1.70 (4H, m). HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t, = 13.30 min, 94%.

F28-45 gave a glassy foam (186 mg) which was dissolved in ethyl acetate (10 mL) and maleic acid (114 mg) in ethyl acetate (3 mL) was added. The resulting solid was filtered off under nitrogen and dried under vacuum for 4 hours to give trans -benzyl N - (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -) -. -pyrrolo [2,3-c (1-pyrimidin-5-yl) -2-methoxyphenyl) carbamate trimaleate salt (250 mg) as

222 creamy solid. T. t. Mp 146-148 ° C. HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 13.54 min, 94.6%. ¹ H NMR (d ₆ DMSO,

400 MHz): 8.72 (1H, s), 8.25 (1H, s), 7.77 (1H, d), 7.51 (1H, s), 7.35 (5H, m), 7 10 (1H, s), 7.04 (1H, d), 6.16 (6H, s), 5.17 (2H, s), 4.59 (1H, m), 3.86 (3H) s, 2.723.10 (11H, m), 2.50 (3H, s), 1.97 (6H, m), 1.56 (2H, m).

Example 320: 7 trans- N - (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 N 7 pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) benzamide

To a solution of N 1 -4- [4-amino-7- (4-oxocyclohexyl) -7 H -pyrrolo [2,3- d] pyrimidin-5-yl] -2-methoxyphenylbenzamide (1.2 g, 2.66 mmol), N- methylpiperazine (0.80 g, 7.98 mmol) and glacial acetic acid (0.48 g, 7.98 mmol) in dichloroethane (150 mL) under nitrogen were added portionwise sodium triacetoxyborohydride (0.85 g, 3.99) mmol). The solution was stirred overnight at room temperature and then quenched with sodium hydroxide (2 N, 20 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL) and the combined organic layers were dried (sodium sulfate), filtered and evaporated to a solid which was purified by flash chromatography on silica gel with dichloromethane followed by 5% MeOH / dichloromethane to 20% MeOH. in dichloromethane in 5% increments. F23-36 were combined and evaporated to give a cream solid (0.11 g) which was dissolved in EtOAc (10 mL) and a solution of maleic acid in EtOAc (5 mL) was added. The resulting fine solid was filtered under a stream of nitrogen to give trans - N - 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- c]] pyrimidin-5-yl} -2-methoxyphenyl) benzamide (0.108 g) as a cream solid. ¹ H NMR (d ₆ DMSO, 400 MHz): 9.48 (1H, s), 8.28 (1H, s), 7.97 (3H, m), 7.53-7.63 (4H, m) ), 7.18 (1H, s), 7.08 (1H, d), 6.85 (1H, bs), 6.16 (6H, s), 4.61 (1H, m), 3.92 (3H, s), 2.70-3.11 (11H, m), 2.01 (7H, m), 1.58 (2H, m). HPLC / MS (column = Pecosphere 3 C ₁₈ 3 microns, conditions = 100% 100 mM ammonium acetate to 100% acetonitrile in 5 min), t _r = 1.83 min, MH + = 540.8 rr

223 p '

Example 321: cis - 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) -3- phenylpropanamide and

ľrans-A / 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 / - / - pyrrolo [2,3djpyrimidin-5-yl} -2-methoxyphenyl) -3- phenylpropanamide

a) To a solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7H-pyrrolo [2,3-b] pyrimidin-7-yl] -1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0 ° C was added hydrocinamoyl chloride (0.57 g, 3.4 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0 ° C for 2 hours, allowed to warm to room temperature and quenched with saturated citric acid solution (50 mL). The organic layer was washed with saturated citric acid solution (2 x 50 mL), dried (sodium sulfate), filtered and evaporated to give Λ / 1- {4- [4-amino-7- (4-oxocyclohexyl) -7] - / - pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenyl} -3-phenylpropanamide (1.0 g, 92% yield of crude product) as a brown foam. ¹ H NMR (d ₆ DMSO, 400 MHz): 9.17 (1H, s), 8.18 (1H, s), 8.06 (1H, d), 7.51 (1H, s), 7 18-7.29 (6H, m), 7.09 (1H, m), 6.99 (1H, d), 6.21 (2H, bs), 5.18 (1H, m), 3, 88 (3H, s), 1.99-2.93 (12H, m). HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 14.48 min, 92.2%.

b) To a solution of 92% pure N - {4- [4-amino-7- (4-oxocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenyl} -3-phenylpropanamide (1, 0 g, 2.1 mmol), N-methylpiperazine (0.63 g, 6.3 mmol), acetic acid (0.38 g, 6.3 mmol) in dichloroethane (100 mL) was added portionwise under nitrogen with triacetoxyborohydride sodium (0.67 g, 3.15 mmol). The solution was stirred for 20 hours and then quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and evaporated to a residue which was purified by flash column chromatography on silica gel using dichloromethane to 50% MeOH in dichloromethane in 10% increments. F84-96 were combined and evaporated to give cis - N - (4- {4-amino-7 [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] Pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide (0.26 g) as a creamy glassy foam. HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 12.65 min, 95.2%. ¹ H NMR (d ₆ DMSO, 400 MHz): 9.17 (1H, s), 8.14 (1H, s), 8.05 (1H, d), 7.28

224 (5Η, m), 7.18 (1H, m), 7.10 (1H, s), 6.99 (1H, d), 6.11 (2H, bs), 4.67 (1H, s), m), 3.88 (3H, s), 2.90 (2H, m), 2.73 (2H, m), 2.50 (7H, m), 2.28 (3H, s), 2, Δ (3H, m), 1.71 (2H, m), 1.55 (2H, m). F121-138 were combined and evaporated to give trans-NI (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl) (2-Methoxyphenyl) -3-phenylpropanamide (0.11 g) as a white solid. HPLC: (5-95% CH ₃ CN in 0.1 N aqueous ammonium acetate over 20 min) t _r = 12.61 min, 96.2%. ¹ H NMR (d ₆ DMSO, 400 MHz): 9.16 (1H, s), 8.13 (1H, s), 8.04 (1H, d), 7.44 (1H, s), 7, 29 (4H, m), 7.18 (1H, m), 7.09 (1H, s), 6.97 (1H, d), 6.11 (2H bs), 4.53 (1H, m) ), 3.88 (3H, s), 2.93 (2H, m), 2.71 (2H, m), 2.50 (4H, m), 2.30 (5H, m), 2.14 (3H, s), 1.89 (6H, m), 1.46 (2H, m).

The general procedure for the preparation of substituted pyrrolopyrimidinarylsulfonamides is as follows:

A 0.19 M solution of 5- (4-amino-3-fluorophenyl) -7- [4- (4-methylpiperazino) cyclohexyl] 7H-pyrrolo [2,3-d] pyrimidin-4-amine in pyridine was added to one equivalent of substituted arylsulfonyl chloride. The mixture was heated to 45 ° C while shaking in the Incubator Shaker for 24 hours. The reaction mixture was purified by gravity assisted preparative RP-HPLC (Micromass / Gilson, Hypersil BDS C18, 5 µm, 100 x 21.2 mm; 100-100% ammonium acetate (0.05 M, pH 4.5) - acetonitrile in during 12.5 min, 25 mL / min).

Compounds synthesized by the above procedure include the following:

Name Rt in HPLC m / z in min

Example 322: 7rans- N -1- (4- {4-amino-7- [4- (4- 3.18,648.39 methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} 2-Fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate

604.03

Example 323: Trans-N-1- (4- {4-amino-7- [4- (4- 3.14-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl ) -5-chloro-2-thiophenesulfonamide benzenesulfonamide trimaleate r ·

225

Name Rt in HPLC in min

Example 324: 7rans-N-1- (4- {4-Amino-7- [4- (4- 3.07 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl ) -2-Chloro-4-fluoro-1-benzenesulfonamide benzenesulfonamide trimaleate

Example 325: 7rans-N-1- (4- {4-Amino-7- [4- (4-39-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl ) -2,3-Dichloro-1-benzenesulfonamide trimaleate

Example 326: cis-1- (4- {4-amino-7- [4- (4- 2.82 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl -2-Chloro-4-fluoro-1-benzenesulfonamide trimaleate

Example 327: cis-1- (4-4-amino-7- [4- (4- 2.66 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl-2-fluorophenyl) -2 6-difluoro-1-benzenesulfonamide trimaleate

Example 328: 7α-N-1- (4- {4-amino-7- [4- (4- 2.53 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2 -fluorophenyl) -2,6-difluoro-1-benzenesulfonamide trimaleate

Example 329: Trans-N-4- (4- {4-amino-7- [4- (4- 2.63 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl ) -2,1,3-Benzothiadiazole-4-sulfonamide trimaleate

Example 330: 7rans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino 2.87) cyclohexyl] -7 H -pyrrolo [2 ₁ 3-d] pyrimidin-5-yl} -2-fluoro-phenyl ) -2,3 _L 4-Trifluoro-1-benzenesulfonamide trimaleate m / z

616.1

632.12

616.2

600.3

600.3

622.1

618.1

226

Title

HPLC Rt m / z in min

Example 331: cis-1- (4- {4-amino-7- [4- (4- 3.13,609.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2- Fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate

Example 332: cis-1- (4- {4-amino-7- [4- (4- 2.89,582.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 Fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate

Example 333: cis-1- (4- {4-amino-7- [4- (4- 3.4 668 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2 -fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimaleate

Example 334: cis-1- (4- {4-amino-7- [4- (4- 3.04 632.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2- fluorophenyl) -2 _I, 6-dichloro-1-benzenesulfonamide trimaleate

Example 335: cis-1- (4- {4-amino-7- [4- (4- 2.94,598.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2- fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate

Example 336: cis-1- (4- {4-amino-7- [4- (4- 2.76,582.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 fluorophenyl) -3-fluoro-1-benzenesulfonamide dimalate

Example 337: cis-1- (4- {4-amino-7- [4- (4- 3.01,604.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2- fluorophenyl) -5-chloro-2-thiophenesulfonamide dimalate

Example 338: cis-1- (4- {4-amino-7- [4- (4- 3.38,718.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate

227

Name Rt in HPLC m / z in min

Example 339: cis-1- (4- {4-amino-7- [4- (4- 2.98 616.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate

Example 340: cis-1- (4- {4-amino-7- [4- (4- 3.02 690.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate

Example 341: cis-1- (4- {4-amino-7- [4- (4- 3.22,648.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate

Example 342: cis-1- (4- {4-amino-7- [4- (4- 2.97 600.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate

Example 343: cis-1- (4- {4-amino-7- [4- (4- 3.12 612.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate

Example 344: cis-1- (4- {4-amino-7- [4- (4- 3.02 623.2 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate

Example 345: cis-1- (4- {4-amino-7- [4- (4- 3.08 618.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- Fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimaleate

Example 346: cis-1- (4- {4-amino-7- [4- (4- 2.98 600.3 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate

228

Title

HPLC Rt m / z in min

Example 347: cis-1- (4- {4-amino-7- [4- (4- 3.13 660.2 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate

Example 348: cis-1- (4- {4-amino-7- [4- (4- 3.16,648.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- Fluorophenyl) -5-bromo-2-thiophenesulfonamide trimaleate

Example 349: cis-1- (4- {4-amino-7- [4- (4- 3.09 632.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,4-dichloro-1-benzenesulfonamide trimaleate

Example 350: cis-1- (4- {4-amino-7- [4- (4- 3.41,668.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,30,4-trichloro-1-benzenesulfonamide trimaleate

Example 351: cis-1- (4- {4-amino-7- [4- (4- 3.29 683.9 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide trimaleate

Example 352: cis-4- (4- {4-amino-7- [4- (4- 2.73,622.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate

Example 353: cis -4- (4- {4-amino-7- [4- (4- 2.8 606.1 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate

Example 354: cis-1- (4- {4-amino-7- [4- (4- 3.18,638 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,5-dichloro-1-thiophenesulfonamide trimaleate r P

229

Name Rt in HPLC in min

Example 355: cis -4- (4- {4-amino-7- [4- (4- 2.84 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl 1- (7-chloro-2 _L, 1,3-benzoxadiazole) -4-sulfonamide trimaleate

Example 356: cis-4- (4- {4-amino-7- [4- (4- 2.89 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl 1- (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate

Example 357: cis-N - 4- (4- {4-amino-7- [4- (4- 2.82 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2 Fluorophenyl) - (5-methyl-2 ₁ 1,3-benzothiadiazole) -4-sulfonamide trimaleate

Example 358: cis-N-4- (4- {4-amino-7- [4- (4- 2.82 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- Fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate

Example 359: cis-1- (4- {4-amino-7- [4- (4- 3.01 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl -3-Chloro-2-methyl-1-benzenesulfonamide trimaleate

Example 360: cis-1- (4- {4-amino-7- [4- (4- 2.81 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-fluorophenyl ) -2-Bromo-1-benzenesulfonamide trimaleate m / z

640.2

636.2

636.2

656.2

612

644.2

758.1

Example 361: cis-N-1- (4- {4-amino-7- [4- (4- 3.29 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2 _I, 5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate

230

Title

HPLC Rt m / z in min

Example 362: cis-1- (4- {4-amino-7- [4- (4- 2.77,632 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate

Example 363: cis-1- (4- {4-amino-7- [4- (4- 2.73,623.2 methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2- fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate

General synthesis

Method (a)

A mixture of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1cyclohexanone (1.0 g, 2.51 mmol), the corresponding amine (7). , 54 mmol) and acetic acid (0.45 g, 7.54 mmol) in 1,2-dichloroethane (50 mL) was stirred at ambient temperature under a nitrogen atmosphere for 30 minutes. Sodium triacetoxyborohydride (0.69 g, 3.26 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. Water (20 mL) and sodium bicarbonate (1.26 g, 15.1 mmol) were added to the mixture, and the mixture was stirred for one hour. The mixture was then filtered through a pad of celite and the pad was washed with dichloromethane (75 mL). The organic layer was extracted from the filtrate, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane.

Method (b)

Where appropriate, salts were prepared as follows:

The above amine (0.909 mmol) was dissolved in warm ethyl acetate (100 mL) and maleic acid (0.32 g, 2.73 mmol) in ethyl acetate (30 mL) was added. The resulting salt formed an oily residue on the bottom and walls of the flask. The supernatant was decanted and the residue dissolved in water and lyophilized to form a salt.

r p r. ·

231

Method (c)

The guanidines were prepared as follows. The amine (0.536 mmol) was dissolved in DMF (5 mL), cooled to -5 ° C and 1-H pyrazole-1-carbamide (95 mg, 0.644 mmol) was added followed by diisopropylethylamine (208 mg, 1.6 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours and then concentrated under reduced pressure. The mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was lyophilized and purified by RP-HPLC.

HPLC protocols:

1. RP-HPLC - Hypersil HyPurity Elite C18, 5mm, 200A, 250 x 4.6mm; 25-100% acetonitrile - 0.1 M ammonium acetate over 15 min, 1 mL / min.

2. RP-HPLC - Hypersil HyPurity Elite C18, 5mm, 200A, 250 x 4.6mm; 5-100% acetonitrile - 0.1 M ammonium acetate over 15 min, 1 mL / min.

If desired, protecting groups were used.

The following compounds were prepared by the methods described above:

Name Synthetic method HPLC RT (Min) (Log) m / z Other chemistry (/ WFF) Example 364: Cis-4- {4- [4-amino-5-c (4-phenoxyphenyl) -7H-pyrido [2,3- 14:56 511.7 d] pyrimidin-7-yl] cyclohexyl} -1-piperazinecarboximidamide (2) Example 365: Trans-4- {4- [4-amino- c 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- 14:25 511.7 d] pyrimidin-7-yl] cyclohexyl} -1 piperazinecarboximidamide (2) Example 366: Trans-7- (4- {methyl [2-a, b (2-pyridyl) ethyl] amino} cyclohexyl) - 8:55 519.6 5- (4-Phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine trimaleate (2)

232

Example 367: Cis-3 - ({4- [4-amino-5-a 10:21 472.6 Made (4-phenoxyphenyl) -7 H -pyrrolo [2,3- hydrolysis d] pyrimidin-7 (2) ester yl] cyclohexyl} amino) propanoic acid acid

Example 368: 3 - ({4- [4-amino-5- (4- a 6:33 472.6 Made phenoxyphenyl) -7 H -pyrrolo [2,3- hydrolysis d] pyrimidin-7 (1) ester

yl] cyclohexyl} amino) propanoic acid

Example 369: Ethyl cis-3 - ({4-14-a, b 10:42 500.6 amino-5- (4-phenoxyphenyl) -7 H pyrrolo [2,3-d] pyrimidine-7- (D yl] cyclohexyl} amino) propanoate

dimaleate

General synthesis

Method (d)

To a solution of sodium hydride (22 mg, 0.553 mmol) in THF (2 mL) was added the appropriate phosphonate (0.553 mmol) at 0 ° C and the resulting mixture was stirred at this temperature for 20 min and then at room temperature for 10 min. The reaction mixture was cooled to 0 ° C and 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimin-7-yl] cyclohexanone (200 mg, 0.503 mmol) was added. in THF (10 mL) and the resulting mixture was allowed to warm to ambient temperature and stirred for 16 h. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was further extracted into ethyl acetate (3 x 5 mL), and the combined organic layers were washed with water (3 x 5 mL), dried (MgSO 4, and concentrated under reduced pressure.

233 chromatography on silica gel (for intermediates) or RP-HPLC (for final compounds) gave the desired compounds.

Method (s)

Hydrogenations were performed as follows. A mixture of alkene (0.068 mmol) and 10% Pd / C (12 mg) in ethanol (18 mL) was stirred under hydrogen (4 atmospheres) for 14 hours. The solids were collected by filtration and the filtrate was concentrated in vacuo. Purification by RP-HPLC gave the final compound.

Method (f)

Reductions with lithium aluminum hydride were performed as follows. A mixture of the substrate (0.19 mmol), lithium aluminum hydride (40 mg, 1.07 mmol) in THF (5 mL) was stirred at room temperature for 16 hours. The title compound was obtained by Fieser treatment followed by purification by RP-HPLC.

HPLC conditions: RP-HPLC - Pecosphere 3 C18, 33 x 4.6 mm, 3 µm column, 0-100% acetonitrile - 0.1 M ammonium acetate over 5 min, flow rate 4 mL / min.

If desired, protecting groups were used.

Name Synthetic HPLC- m / z Other chemistry (Ml · /) method RT (Min) Example 370: {4- [4-Amino-5- (4-d phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7 yl] cyclohexylidene} methyl cyanide 3.1 422.5 Example 371: tert-Butyl 2- [4- [4-amino-d 5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-7 yljcyklohexylidénjacetát 3.97 497.1

P 234

Example 372: Ethyl 2- [4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexylidene acetate

Example 373: 2- [4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexylidene} acetate

3.56 469.0

2.69. 441.5 Made by hydrolysis of ethyl ester

Example 374: 7- [4- (2-Aminoethyl) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine

Example 375: 2- {4- [4-Amino-5- (4-phenoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclohexyl} -acetic acid

2.11 428.5 Made by reducing unsaturated cyanide with lithium aluminum hydride

2.64. 443.5 Produced by hydrogenation of unsaturated acid r 235

Claims (70)

PATENT CLAIMS 1. A compound of the following structural formula: N \ R 1 and pharmaceutically acceptable salts thereof, wherein: ring A is a six-membered aromatic ring or a five- or six-membered heteroaromatic ring which is optionally substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aliphatic, halogen, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR ⁴ R ⁵ , -C (O) ₂ H, -OH, substituted or unsubstituted alkoxycarbonyl, -C (O) ₂ -haloalkyl, substituted or unsubstituted alkylthioether, substituted or unsubstituted alkylsulfoxide, substituted or unsubstituted alkylsulfone, substituted or unsubstituted arylthioether, substituted or unsubstituted arylsulfoxide, substituted substituted or unsubstituted arylsulfone, substituted or unsubstituted alkyl carbonyl, -C (O) -haloalkyl, substituted or unsubstituted aliphatic ether, substituted or unsubstituted aromatic ether, carboxamido, tetrazolyl, trifluoromethylsulfonamido, trifluoromethylcarbonylamino, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl, substituted or unsubstituted arylamido, -NR ₉₅ C (O) R ₉₅₁ substituted 236, or unsubstituted styryl and a substituted or unsubstituted aralkylamido, wherein R _ss is an aliphatic group or an aromatic group; L is -O-; -WITH-; -S (O) -; -S (O) ₂ -; -N (R) -; -N (C (O) OR) -; -N (C (O) R) -; -N (SO ₂ R); _-CH2 O-; -CH ₂ S-; -CH ₂ N (R) -; -CH (NR) -; -CH ₂ N (C (O) R)) -; -CH ₂ N (C (O) OR) -; -CH ₂ N (SO ₂ R) -; -CH (NHR) -; -CH (NHC (O) R) -; -CH (NHSO ₂ R) -; -CH (NHC (O) OR) -; - CH (OC (O) R) -; - CH (OC (O) NHR) -; -CH-CH-; -C (= NOR) -; -WHAT)-; -CH (OR) -, - C (O) N (R) -; -N (R) C (O) -; -N (R) S (O) -; -N (R) S (O) ₂ -; -OC (O) N (R) -, - N (R) C (O) N (R) -; -NRC (O) O-; S (O) N (R) -; S (O) ₂ N (R) -; N (C (O) R) S (O) -; N (C (O) R) S (O) ₂ -; -N (R) S (O) N (R) -; -N (R) S (O) ₂ N (R) -; -C (O) N (R) C (O) -; S (O) N (R) C (O) -; -S (O) ₂ N (R) C (O) -; -OS (O) N (R) -; -OS (O) ₂ N (R) -; -N (R) S (O) O-; -N (R) S (O) ₂ O-; -N (R) S (O) C (O) -; -N (R) S (O) ₂ C (O) -; SON (C (O) R) -; -SO ₂ N (C (O) R) -; -N (R) SON (R) -; -N (R) SO ₂ N (R) -; -C (O) O-; -N (R) P (OR ') O-; -N (R) P (OR ') -; -N (R) P (O) (OR ') O-; -N (R) P (O) (OR ') -; -N (C (O) R) P (OR ') O-; -N (C (O) R) P (OR ') -; -N (C (O) R) P (O) (OR ') O- or -N (C (O) R) P (OR') -, wherein R and R 'are each independently -H, acyl, substituted or an unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted cycioalkyl; or L is -R ^b N (R) S (O) ₂ -, -R ^b N (R) P (O) -, or -R ^b N (R) P (O) O-, wherein R ^b is an alkylene group, which, taken together with the sulfonamide, phosphinamide or phosphonamide group to which it is attached, forms a five- or six-membered ring fused to ring A; or L is represented by one of the following structural formulas: 237 / -ί Λ Λ Λ ι Λ Ν-P Ν-Ρ-Ο N-P N-P I I N-P I I R85-O R85-O 1 I 1 R85-O 1 Λ ' N- | D \ ⁰ y # \ ⁰ Y / R85- < D 1 - R ⁸⁵ R85 ^U or wherein R ⁸⁵ taken together with the phosphinamide or phosphonamide is a 5-, 6- or 7-membered aromatic, heteroaromatic or heterocycloalkyl ring; R., is a substituted aliphatic group, substituted cycloalkyl, substituted bicycloalkyl, substituted cycloalkenyl, optionally substituted aromatic group, optionally substituted heteroaromatic group, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl, optionally substituted heterobicycloalkyl, optionally substituted alkylamido and optionally substituted, optionally-substituted, optionally-substituted, S (O) ₂ -alkyl or optionally substituted -S (O) ₂ -cycloalkyl, -C (O) -alkyl or optionally substituted -C (O) -alkyl, provided that when R ¹ is an aliphatic group or cycloalkyl , R ¹ is not exclusively substituted by one or more substituents selected from the group consisting of hydroxyl and lower alkyl ethers, provided that the heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl and that the aliphatic group is not substituted exclusively one or more aliphatic groups wherein one or more The substituents are selected from the group consisting of: substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aromatic ether, substituted or 238 unsubstituted aliphatic ether, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aryloxycarbonyl, -OH, substituted or unsubstituted amino, substituted or unsubstituted amino, , substituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted heterobicycloalkyl, cyano, -NH ₂ , alkylamino, ureido, thioureido and -BE; B is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatics, substituted or unsubstituted heteroaromatics, alkylene, aminoalkyl, alkylenecarbonyl or aminoalkylcarbonyl; E is substituted or unsubstituted azacycloalkyl, substituted or unsubstituted azacycloalkylcarbonyl, substituted or unsubstituted azacycloalkylsulfonyl, substituted or unsubstituted azacycloalkylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, unsubstituted aryl sulfonamido, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted ureido, substituted or unsubstituted thioureido, or substituted or unsubstituted aryl; R ² is -H, substituted or unsubstituted aliphatic, substituted or unsubstituted cycloalkyl, halogen, -OH, cyano, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted «« ««; r- 'r ^r ' yyyy '* Γ 239 ^{R 6 is} aralkyl, substituted or unsubstituted heteroaralkyl, -NR ⁴ R ⁵ or -C (O) NR ⁴ R ⁵ ; R ³ is a substituted or unsubstituted aliphatic group, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterocycloalkyl; provided that L is -SN (R) -, -S (O) N (R) -, -S (O) _2, N (R) -, -N (R) S-, -N (R) S, (O) -, N (R) S (O) _Z -, -N (R) SN (R ') -, -N (R) S (O) N (R') - or -N (R) S (O) ₂ N (R ') - when R ₃ is a substituted or unsubstituted aliphatic, substituted or unsubstituted alkenyl; provided that j is 0 when L is -O-, -CH ₂ NR-, -C (O) NR- or -NRC (O) - and R ³ is azacycloalkyl or azaheteroaryl; and j is 0 when L is -O- and R ³ is phenyl; R ⁴ , R ⁵ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or substituted or unsubstituted heteroaromatic group; or R ⁴ and R ⁵ are each independently -H, azabicycloalkyl, heterocycloalkyl, substituted or unsubstituted alkyl, or YZ; Y is selected from the group consisting of -C (O) -, - (CH ₂ ) _p -, -S (O) ₂ -, -C (O) O-, SO ₂ NH-, -CONH-, (CH ₂₎ ) _p O-, - (CH ₂ ) _p NH-, - (CH ₂ ) _p S-, - (CH ₂ ) _p S (O) - and (CH ₂ ) _p S (O) ₂ -; p is an integer from 0 to 6; Z is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, 240 substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; i is an integer from 0 to 6, provided that when R ¹ is a substituted or unsubstituted aromatic group, ring A is phenyl, L is C (O) i is zero, R ³ is not phenyl. A compound according to claim 1, wherein R ³ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazole, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydropyranyl unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxane, substituted or unsubstituted dioxolane, substituted or unsubstituted quinoline, substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted benzofiothieno, substituted or unsubstituted benzofuranan, unsubstituted benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxazole; substituted or unsubstituted benzoxazole; substituted or unsubstituted benzimidazole; substituted or unsubstituted benzoxadiazole; The compound of claim 2, wherein R ³ is substituted with one or more substituents selected from the group consisting of: F, Cl, Br, I, CH ₃ , NO ₂ OCF ₃ OCH ₃ , CN, CO ₂ CH ₃ , CF ₃ , t-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, 241 substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, -S- (substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl) substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -NR _f R _g , alkynyl, -C (O) NR ^f R ⁸ , R ^c and CH ₂ OR ^C ; R ^f , R ^f and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or substituted or unsubstituted heteroaromatic group; or R ^f and R ⁹ are each, independently, -H, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group; and R ^c is hydrogen or substituted or unsubstituted alkyl or substituted or unsubstituted aryl, -W- (CH 2) t -NR ^d R ^e , -W- (CH 2), -O-alkyl, -W- (CH ₂ ) _t -S alkyl, -W- (CH _{2) r} OH, or -W- (CH _{2) r} oR _t; t is an integer from 0 to 6; W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR ^k -; R ^k is H or alkyl; and R ^d , R ^e and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterobicyclic group; or R ^d and R ® are each independently -H, alkyl, alkanoyl or -KD; K is -S (O) ₂ -, -C (O) -, -C (O) NH-, -C (O) ₂ - or a direct bond; 242 D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, unsubstituted aminocycloalkyl, COOR ¹ or substituted or unsubstituted alkyl; and R ¹ is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. The compound of claim 3, wherein R ³ is substituted or unsubstituted phenyl. The compound of claim 1, wherein ring A is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted indole. The compound of claim 5, wherein ring A is substituted with one or more substituents selected from the group consisting of: F, Cl, Br, I, CH ₃ , NO ₂ OCF ₃ OCH ₃ , CN, CO ₂ CH ₃ , CF ₃ , t-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -NR _g R, alkynyl, -C (O) NR ^{* 6 * 9,} R ^c, and CH ₂ OR ^C ; 243 r r r · R ^f , R ⁹ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or substituted or unsubstituted heteroaromatic group; or R 1 and R ⁹ are each independently -H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aromatic group; and ^Rc is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, -W- (CH 2) ^d R FNR ^e, -W- (CH2) _t -Oalkyl, -W- (CH _{2) t} -S-alkyl , W (CH _{2) t} OH, or -W- (CH _{2) t} -OR '; t is an integer from 0 to 6; W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR ^k -; R ^k is H or alkyl; and R ^d , R ^e and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic group; or R ^d and R ^e are each independently -H, alkyl, alkanoyl or -KD; K is -S (O) ₂ -, -C (O) -, -C (O) NH-, -C (O) ₂ - or a direct bond; D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, 244 unsubstituted aminocycloalkyl, COOR ¹ or substituted or unsubstituted alkyl; and R ¹ is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. The compound of claim 6, wherein ring A is substituted or unsubstituted phenyl. The compound of claim 1, wherein R ¹ is of the formula wherein m is an integer from 0 to 3. The compound of claim 1, wherein R ¹ is of the formula CH ₂ ) _t NR8R9 where: m is an integer from 0 to 3; t is an integer from 1 to 6; a r r 245 R ⁸ , R ⁹ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicyclic alkyl group; or R ⁸ and R ⁹ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( _CH2) "O-, - _{(CH2) q} NH-, - _{(CH2) q} S-, - _{(CH2) q} S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula wherein: m is an integer from 1 to 3; s and t are each independently an integer from 0 to 6; and R ⁸ , R ⁹ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted e * 246 a heteroaryl group or a substituted heterobicyclic alkyl group; or R ⁸ and R ⁹ are each independently -H, azabicycloalkyl, heterocycloalkyl or -Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - a - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; R ⁷⁷ is -OR ⁷⁸ or -NR ⁷⁹ R ⁸⁰ ; R ⁷⁸ is -H or a substituted or unsubstituted aliphatic group; R ⁷⁹ , R ⁸⁰ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl group, or substituted heterobicyclic alkyl group; or R ⁷⁹ and R ⁸⁰ are each independently -H, azabicycloalkyl, heterocycloalkyl or -Y ³ Z ³ ; Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( _{CH2) q} O-, - (CH _{z) q} NH-, - _{(CH2) q} S-, - _{(CH2) q} S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, rt 247 substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula R10 where: v is an integer from 1 to 3; and R ¹⁰ is -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - a - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula R10 r p 248 where: m is an integer from 0 to 3; R ¹⁰ is -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _p -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) O-, - (CH ₂ ) n NH-, - (CH ₂ ) n S, - (CH ₂ ) n S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; and R ¹¹ represents one or more substituents selected from the group consisting of hydrogen, hydroxy, oxo, substituted or unsubstituted aliphatic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl, and substituted or unsubstituted aralkyl, provided that the carbon atoms adjacent to the nitrogen atom are not substituted with a hydroxyl group. A compound according to claim 1, wherein R ¹ is of formula r 249 n R10 where: R ¹⁰ is H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO 3 NH-, -CONH-, (CH ₂₎ ) _q O-, - (CH _{2) q} NH-, - _{(CH2) q} S-, - _{(CH2) q} S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. A compound according to claim 1, wherein R ¹ is of formula (I) N R9 = R8 250 where: r is an integer from 1 to 6; and R ⁸ , R ⁹ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted heterobicyclic alkyl group; or R ⁸ and R ⁹ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - a - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula wherein: Γ ~ 251 w is an integer from 0 to 4; t is an integer from 0 to 6; u is 0 or 1; R ¹² is hydrogen or substituted or unsubstituted alkyl; R ⁸ , R ⁹ and the nitrogen atom together form a 3, 4, 5 or 6-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicycloalkyl; or R ⁸ and R ⁹ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( _{CH2) q} O-, - (CH _{z) q} NH-, - _{(CH2) q} S-, - _{(CH2) q} S (O) - and - _{(CH2) q} S (O) ₂ -; q is an integer from 0 to 6; and · Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula 252 where: w is an integer from 0 to 4; t is an integer from 0 to 6; R ¹⁰ is hydrogen or substituted or unsubstituted alkyl; R ¹² is -H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - a - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 14, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl of formula 253 where: R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently lower alkyl or hydrogen; or at least one pair of substituents R ¹³ and R ¹⁴ ; R ¹⁵ and R ¹⁶ ; R ¹⁷ and R ¹⁸ ; or R ¹⁹ and R ²⁰ together are an oxygen atom; or at least one of R ¹³ and R ¹⁵ is cyano, CONHR ²¹ , COOR ²¹ , CH ² OR ²¹ or CH ² NR ²¹ (R ²² ); R ²¹ , R ²² and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl group, or substituted heterobicyclic alkyl group; or R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; 254 X is -Ο-, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ²³ ) - or NR ²³ ; R ²³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R ²⁴ , or -C (O) OR ²⁴ ; R ²⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and u is 0 or 1. The compound of claim 14, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl of the formula wherein: R ²⁵ and R ²⁶ are each independently hydrogen or lower alkyl; or R ²⁵ and R ²⁶ together are an oxygen atom; and R ²¹ , R ²² and the nitrogen atom together form a 3,4, 5 or 6-membered, substituted or unsubstituted heterocycloalkyl; or R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; 255 Y ³ is -H, selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, C (O) O-, -SO 3 NH-, -CONH-, ( CH ₂ ) _S O-, - (CH ₂ ) _s NH- _t - (CH ₂ ) _s S-. - (CH ₂ ) _with S (O) - and - (CH ₂ ) _with S (O) ₂ -; s is an integer from Q to 6; and Z ³ is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; i is an integer from 1 to 6; and t is an integer from 0 to 6. A compound according to claim 14, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl of formula R27 where: i is an integer from 1 to 6; and R ²⁷ is CH ₂ OH, C (O) NR ²⁴ R ²⁸ or COOR ²⁴ ; R ²⁴ and R ²⁸ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. A compound according to claim 14, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heteroaromatic group of formula c * 256 R29 where: R ²⁹ is Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, carboxylic acid, cyano, C (O) OR ^30, CH 2 OR ^30, CH 2 NR ²¹ R ²² or C (O) NR ²¹ R ^22; R ³⁰ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl or heterocycloaryl; and R ²¹ , R ²² and the nitrogen atom together form a 3, 4, 5 or 6-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicycloalkyl; or R ²¹ and R ²² are each independently H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _t -, - S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _t O-, - (CH ₂ ) _t NH-, - (CH ₂ ) _t S-, - (CH ₂ ) _t S (O) - and - (CH ₂ ) _t S (O) ₂ t is an integer from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. * · R 257 The compound of claim 14, wherein at least one of R ⁸ and R ⁹ is of the formula Y ³ -D, wherein D is of the formula wherein: Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _r , -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, (CH ₂ ) _t O-, - (CH ₂ ) _t NH-, - (CH ₂ ) _t S-, - (CH ₂ ), S (O) - and - (CH ₂ ) _t S (O) ₂ t is whole a number from 0 to 6; T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ²⁴ ) - or -N (R ²⁴ ) -; R ²⁴ is hydrogen or substituted or unsubstituted alkyl, aryl or aralkyl; and x is 0, 1 or 2. The compound of claim 14, wherein at least one of R ⁸ and R ⁹ is of the formula Y ³ -N (R ³¹ ) R ³² , wherein: Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _t -, - S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _t O-, - (CH ₂ ) _t NH-, - (CH ₂ ) _t S-, - (CH ₂ ) _t S (O) - and - (CH ₂ ) _t S (O) ₂ t is an integer from 0 to 6; R ³¹ and R ³² are each independently substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hydroxyalkyl; 258 unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted cyanoalkyl; or R ³¹ and R ³² together with the nitrogen atom form a five- or six-membered heterocycloalkyl, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl. A compound according to claim 15, wherein R ^B , R ⁹ and the nitrogen atom together form a heterocycloalkyl of the formula wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently lower alkyl or hydrogen; or at least one pair of substituents R ¹³ and R ¹⁴ ; R ¹⁵ and R ¹⁶ ; R ¹⁷ and R ¹⁸ ; or R ¹⁹ and R ²⁰ together are an oxygen atom; or at least one of R ¹³ and R ¹⁵ is cyano, CONHR ²¹ , COOR ²¹ , CH ² OR ²¹ or CH ² NR ²¹ (R ²² ); R ²¹ , R ²² and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl group, or substituted heterobicyclic alkyl group; or R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; 259 Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _with O-. - (CH ₂ ) _with NH-, - (CH ₂ ) _with S-, - (CH ₂ ) _with S (O) - and - (CH ₂ ) .S (O) ₂ -; s is an integer from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; X is -O-, -S-, -SO ₂ -, -SO ₂ -, -CH ₂ -, -CH (OR ²³ ) - or NR ²³ ; R ²³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R ²⁴ , or -C (O) OR ²⁴ ; R ²⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and y is 0 or 1. A compound according to claim 15, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl of the formula wherein rr * r 260 R ²⁵ and R ²⁶ are each independently hydrogen or lower alkyl; or R ²⁵ and R ²⁶ together are an oxygen atom; R ²¹ , R ²² and the nitrogen atom together form a 3, 4, 5 or 6-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicycloalkyl; or R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ), O-, - (CH ₃ -NH-, - (CH ₂ ) _with S-, - (CH ₂ ), S (O) - and - (CH ₂ ). S (O) ₂ -; s is an integer from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; or r is an integer from 1 to 6; and z is an integer from 0 to 6. A compound according to claim 15, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heterocycloalkyl of the formula wherein 261 i is an integer from 1 to 6; and R ²⁷ is CH ₂ OH, C (O) NR ²⁴ R ²⁸ or COOR ²⁴ ; R ²⁴ and R ²⁸ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. The compound of claim 15, wherein R ⁸ , R ⁹ and the nitrogen atom together form a heteroaromatic group of the formula wherein: R ²⁹ is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl, carboxyl, cyano, C (O) OR ^30, CH 2 OR ^30, CH 2 NR ²¹ R ²² or C (O) NR ²¹ R ^22; R ³⁰ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloaryl; R ²¹ , R ²² and the nitrogen atom together form a 3, 4, 5 or 6-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterobicycloalkyl; or R ²¹ and R ²² are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; 262 Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) O-, - (CH ₂ ) _with NH-, - (CH ₂ ) _with S-, - (CH ₂ ) _with S (O) - and - (CH ₂ ) _with S (O) ₂ -; s is an integer from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 15, wherein at least one of R ⁸ and R ⁸ is of formula Y ³ -D, wherein D is of formula x wherein: Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( _{CH2) p} O-, - (CH _{2) p} -NH-, - (CH _{2) p} S-, - (CH _{2) p} s (O) - and - (CH ₂ ) _with S (O) ₂ -; s is an integer from 0 to 6; T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ³³ ) - or -NR ³³ -; R ³³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R ³⁴ , or -C (O) R ³⁴ ; R ³⁴ is hydrogen, substituted or unsubstituted alkyl, aryl or aralkyl; and x is 0, 1 or 2. r e 263 29th 29th 30th 30th A compound according to claim 15, wherein at least one of R ⁸ and R ⁹ is of the formula Y ³ -N (R ³¹ ) R ³² , wherein: Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _S -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( _{CH2) p} O-, - (CH _{2) p} -NH-, - (CH _{2) p} S-, - (CH _{2) p} s (O) - and - (CH ₂ ) ₈ S (O) ₂ -; s is an integer from 0 to 6; R ³¹ and R ³² are each independently substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted cyanoalkyl; or R ³¹ and R ³² together with the nitrogen atom form a five- or six-membered heterocycloalkyl, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl. A compound according to claim 12 wherein Z ² is of formula N (R ³⁵ ) R ³⁶ , wherein R ³⁵ and R ³⁶ are each independently hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl. A compound according to claim 12 wherein Z ² is of the formula X1 — X1 where: each X ¹ is independently CH or N; and R37 264 R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl. The compound of claim 12, wherein Z ² is of the formula -NT at _R <_37> wherein g is an integer from 0 to 3; T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ³⁴ ) - or -N (R ³⁴ ) -; R ³⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl. A compound according to claim 12, wherein Z ² is of formula pr 265 R37 where: g is an integer from 0 to 3; and R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl. The compound of claim 12, wherein Z ² is of the formula R37 where: T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ^M ) - or -N (R ³⁴ ) -; R ³⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and g is an integer from 0 to 3; and R ³⁷ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted 266 hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl. The compound of claim 12, wherein Z ² is of the formula wherein: R ³⁷ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted thioalkoxy; R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, perhaloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl. The compound of claim 1, wherein R ¹ is of formula rr 267 where: u is 0 or 1; R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ are each independently methyl or hydrogen; or at least one pair of substituents R ³⁹ and R ⁴⁰ ; R ⁴¹ and R ⁴² ; R ⁴³ and R ⁴⁴ ; or R ⁴⁵ and R ⁴⁶ together are an oxygen atom; and R ⁴⁷ is H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - and - (CH ₂ ) _q S (O) ₂ -; q is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; or R ⁴⁷ is of the formula 268 where: y is 0 or 1; R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ and R ⁵⁵ are each independently methyl or hydrogen; or at least one pair of substituents R ⁴⁸ and R ⁴⁹ ; R ⁵⁰ and R ⁵¹ ; R ⁵² and R ⁵³ ; or R ⁵⁴ and R ⁵⁵ together are an oxygen atom; and R ⁵⁶ is -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ , Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ) _r , -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, (CH ₂ ) _t O-, - (CH ₂ ) _t NH-, - (CH ₂ ), S-, - (CH ₂ ), S (O) - and - (CH ₂ ) _t S (O) ₂ t is whole a number from 0 to 6; and Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ¹ is of the formula 269 where: e, f, h, u and y are independently 0 or 1; R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ and R ⁶⁶ are each independently methyl or hydrogen; or at least one pair of substituents R ⁵⁷ and R ⁵⁸ ; R ⁵⁹ and R ⁶⁰ ; R ⁶¹ and R ⁸² ; or R ⁶³ and R ⁶⁴ together are an oxygen atom; and R ⁸⁷ is H, azabicycloalkyl, heterocycloalkyl or Y ² -Z ² ; Y ² is selected from the group consisting of -C (O) -, - (CH ₂ ) _q -, -S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _q O-, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - a - (CH ₂ ) _q S (O) ₂ -; p is an integer from 0 to 6; and Z ² is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; or R ⁶⁷ is of formula 270 where: d is 0 or 1; R ⁶⁸ , R ⁶⁹ , R ⁷⁰ , R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ and R ⁷⁵ are each independently lower alkyl or hydrogen; or at least one pair of substituents R ⁸⁸ and R ⁶⁹ ; R ⁷⁰ and R ⁷¹ ; R ⁷² and R ⁷³ ; and R ⁷⁴ and R ⁷⁵ together are an oxygen atom; and R ⁷⁶ is -H, azabicycloalkyl, heterocycloalkyl or Y ³ -Z ³ ; Y ³ is selected from the group consisting of -C (O) -, - (CH ₂ ), -, - S (O) ₂ -, -C (O) O-, -SO ₂ NH-, -CONH-, ( CH ₂ ) _t O-, - (CH ₂ ), NH-, - (CH ₂ ) _t S-, - (CH ₂ ) _t S (O) - and - (CH ₂ ), S (O) ₂ p is an integer from 0 to 6; Z ³ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The compound of claim 1, wherein R ² is -H. The compound of claim 1, wherein L is -O-, -NHSO ₂ R-, -NC (O) O-, or NHC (O) -. rfrrrr · * ·· ^r Z / ¾; e Í 271 - · - ^r -. 39. A method of inhibiting protein kinase activity comprising administering a compound of claim 1 or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. The method of claim 39, wherein said protein kinase is selected from the group consisting of: KDR, FGFR-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, Flt-1, TIE-2, Lck , Src, Fyn, Lyn, Blk, and yes. 41. The method of claim 39, wherein the activity of said protein kinase affects hyperproliferative diseases. 42. The method of claim 39, wherein the activity of said protein kinase affects angiogenesis, vascular permeability, immune response, or inflammation. 43. A method of treating a patient suffering from a condition mediated by protein kinase activity, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I as defined in claim 1 or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. 44. The method of claim 43, wherein said protein kinase is selected from the group consisting of: KDR, Flt-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, TIE-2, Lck, Src, fyn , Lyn, Blk, and yes. 45. The method of claim 43, wherein the condition mediated by said protein kinase is a hyperproliferative disease. 46. The method of claim 43, wherein the activity of said protein kinase affects angiogenesis, vascular permeability, immune response or inflammatory response. 47. The method of claim 43, wherein the protein kinase is a serine / threonine kinase protein or a tyrosine kinase protein. 272 48. The method of claim 43, wherein the condition mediated by said protein kinase is one or more ulcers. The method of claim 48, wherein the ulcer or ulcers are caused by a bacterial or fungal infection; or the ulcer or ulcers are Mooren ulcers; or ulcer or ulcers are a symptom of ulcerative colitis. 50. The method of claim 43, wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection of Herpes simplex, Herpes Zoster, human immune deficiency virus, parapoxvirus, protozoa or toxoplasmosis. 51. The method of claim 43, wherein the condition mediated by protein kinase activity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease or polycystic kidney disease. 52. The method of claim 43, wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, chronic occlusive pulmonary disease, asthma, exudates, ascites, pleural effusions, pulmonary edema, cerebral edema or edema due to pop edema. injury, radiation, defeat, hypoxia or ischemia. 53. The method of claim 43, wherein the condition mediated by said protein kinase is ovarian overstimulation syndrome, preeclampsia, menometroragy or endometriosis. 54. The method of claim 43, wherein the condition mediated by said protein kinase is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis and osteoarthritis, multiple sclerosis or graft rejection. 55. The method of claim 43, wherein the condition mediated by said protein kinase is sickle cell anemia. r ^r 56. The method of claim 43, wherein the condition mediated by said protein kinase is an ocular condition. 57. A method according to claim 56, wherein the ocular condition is ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, papilla excision, chronic retinal detachment, post-laser complications, post-laser complications, post-laser complications disease, Eales' disease, retinopathy or macular degeneration. 58. The method of claim 43, wherein the condition mediated by said protein kinase is a cardiovascular condition. 59. The method of claim 58, wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, post-traumatic ischemia / reperfusion, vascular occlusion, venous malformation, or carotid obstruction disease. 60. The method of claim 43, wherein the condition mediated by said protein kinase is cancer. 61. The method of claim 60, wherein the cancer is solid tumor, sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignant tumors, and malignant ascites. 62. The method of claim 61, wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia. 63. The method of claim 43, wherein the condition mediated by said protein kinase is Crow-Fukase syndrome (POEMS) or diabetic condition. 64. The method of claim 63, wherein the diabetic condition is insulin-dependent diabetes mellitus, glaucoma, diabetic retinopathy or microangiopathy. 274 65. A method of reducing fertility in a patient, comprising the step of administering to the patient an effective amount of a compound of formula I as defined in claim 1, or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. 66. The method of claim 43, wherein the compound of Formula I, or a physiologically acceptable salt, prodrug, or biologically active metabolite thereof, is administered in an amount effective to promote angiogenesis or vasculogenesis. 67. The method of claim 66, wherein the protein kinase is Tie-2. 68. The method of claim 66, wherein the compound of Formula I, or a physiologically acceptable salt, prodrug, or biologically active metabolite thereof, is administered in combination with a proangiogenic growth factor. 69. The method of claim 68 wherein the proangiogenic growth factor is selected from the group consisting of VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF-2, and derivatives and anti-idiotypic antibodies. 70. The method of claim 66, wherein the protein kinase-mediated condition is anemia, ischemia, heart attack, transplant rejection, wound, gangrene, or necrosis. 71. The method of claim 43, wherein the protein kinase activity is involved in T cell activation, B cell activation, mast cell degranulation, monocyte activation, potentiation of an inflammatory response, or a combination thereof. 72. A compound selected from the group consisting of the following: Cis-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine; 275/7-trans-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3d] pyrimidin-4-ylamine, Cis-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine hydrochloride, 7R / 7S-5- (4-phenoxyphenyl) -7- (4-piperidinocyklohex-1-yl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine, 7rans-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-ylamine, C / s-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3-d] pyrimidine 4-ylamine, 5- (4-Phenoxyphenyl) -7- (4-piperidyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-ylamine dihydrochloride, 5- (4-Phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-c] pyrimidin-4-ylamine dihydrochloride, C / 's-7- [4- (4-isopropyl) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3dJpyrimidin-4-amine, 7rans-7- [4- (4-Isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine, C / 's-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7 / - / pyrrolo [2,3-cfipyrimidin-4-amine, 7irans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrinnidin-4-amine, C / s-7 - [- 4- (4-ethyl-piperazin) cyclohexyl] -5- (4-phenoxy-phenyl) -7a / pyrrolo [2,3dJpyrimidin-4-amine, 276 trans-7- [4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine, Cis-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trismaleate, 7rans-7- [4- (4-Isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trismaleate, Cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trismalate, 7-trans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trismalate, Cis-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt . 7rans-7- (4 - {[3- (1 / - / - 1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxy-phenyl) 7H-pyrrolo [2,3-d | pyrimidin-4-amine Dimaleate salt Cis-7- [4- (dimethylamino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine dimalate salt, 7rans-5- (4-Phenoxyphenyl) -7- (4-piperidinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dimalate salt, 77´ans-5- (4-phenoxyphenyl) -7- (4-tetrahydro-1H-1-pyrrolylcyclohexyl) -7 H -pyrrolo [2,3- d] pyrimidin-4-amine dimalate salt, Cis-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-dlpyrimidin-4amine trimaleate salt, 7rans-5- (4-Phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7 H -pyrrolo [2,3- c] pyrimidin-4-amine trimaleate salt, 277 7- [3- (4-methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-c] pyrimidin-4-amine trimaleate, 7rans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine, 7-trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine trimaleate, trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7 H -pyrrolo [2,3- b] pyrimidin-4-amine trihydrochloride, cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- ( 4-Phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine trimaleate salt, cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H- p-pyrrolo [2,3d] pyrimidin-4-amine trihydrochloride, 5- (2-Methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate, N-benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} 2-methoxyphenyl) carbamate trimaleate . 77'ans-benzyl-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate . 7rans-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) benzamide, 7-trans-N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-methoxyphenyl) benzamide trimaleate, C / s-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide . 278 7R / 7S-N 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide cis- N - (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c] pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate salt trans-N- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate, c / s-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3-c /] pyrimidin-5-yl-phenoxy) -6 - [(3-methoxypropyl) amino] benzonitrile trimalate, trans / 7S-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-ylphenoxy) -6- [(3-methoxypropyl) amino] benzonitrile trimaleate, cis -2-amino-6- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3] | trans-2-amino-6- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c] pyrimidin-5-ylphenoxy) benzonitrile pyrimidin-5-ylphenoxy) benzonitrile trimaleate, cis -2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-c] py rimidin-5-ylphenoxy) -6 - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate trans-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrido [2,3d] pyrimidin-5-ylphenoxy) -6 - [(4-methylphenyl) silphanyl] benzonitrile trimaleate, cis -2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl]] -7H-pyrrolo [2,3d] pyrimidin-5-yl-phenoxy) -6- (2-pyridylsulfanyl) -benzonitrile trimaleate trans-2- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3-b] pyrimidin-5-yl-phenoxy) -6- (2-pyridylsulfanyl) -benzonitrile trimaleate, cis -5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) ) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate, Trans - 5- (2-methyl-4-phenoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-4-amine trimaleate, cis / sec -N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro- 1-Benzenesulfonamide trimaleate, N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide, N1-4- [4-amino-7- (1-benzyl-4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide, N1-4- [4-amino-7- (4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-phenyl-4-fluoro-1-benzenesulfonamide, N1-4- [4-amino-7- (1-formyl-4-piperidinyl) -7 H -pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1-benzenesulfonamide, N1 - [4- (4-amino-7-1 - [(1-methyl-1H-4-imidazolyl) sulfonyl] -4-piperidyl-7-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimalate, N1- [4- (4-amino-7-1 - [(1,2-dimethyl-1H-4-imidazolyl) sulfonyl] -4-piperidinyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) - 2-fluoro-phenyl] -4-fluoro-1-benzenesulfonamide, N1- [4- (4-amino-7-1 - [(1,3-dimethyl-1H-5-pyrazolyl) carbonyl] -4-piperidinyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) - 2-fluoro-phenyl] -4-fluoro-1-benzenesulfonamide, N 1- (4- {4-amino-7- [1- (2-pyridylcarbonyl) -4-piperidinyl] -7 H -pyrrolo [2,3-d] pyrimidine 5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide, N1-4- (4-amino-7- {4- [1- (1-methylpiperidin-4-yl) piperidyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl}) - 2-phenyl-4 -fluoro-1-benzenesulfonamide trimaleate, Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2- trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} (trifluoromethoxy) -1-benzenesulfonamide trimaleate -2-fluorophenyl) -5-chloro-2-thiophenesulfonamide benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) (cyclohexyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate, cis-N-1- (4- {4-amino- 7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate, cis / - 1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl-2-fluorophenyl) -2,5-difluoro-1-benzenesulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) (cyclohexyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide trimaleate trans-N-4- (4- {4-amino-7) - [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate, trans-N-1 - (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,3,4-trifluoro- 1-Benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2 Trifluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine- 5-yl} -2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate, 281 cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2, 4,6-Trichloro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2, 4-methyl-piperazino]) 3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimalate, cis-1- (4- {4-amino-7- [4- (4 -methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -5-chloro-2-thiophenesulfonamide dimalate, cis-1- (4- {4-amino-7) - [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-bromo-2,6-difluoro-1-benzenesulfonamide trimaleate, c / sN 1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -3-Chloè r-4-Fluoro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine-5- yl} -2-fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl]] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4 - (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate, cis / N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-cyano-1 -benzenesulfonamide trimaleate, 282 cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2, 3,4-Trifluoro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine-5- yl} -2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ 2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4 -methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -5-bromo-2-thiophenesulfonamide trimaleate, cis-1- (4- {4-amino-7) - [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,4-dichloro-1-benzenesulfonamide trimaleate, cis-N-1- ( 4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluoro-phenyl) -2,30,4-trichloro-1 benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) 3-Bromo-5-chloro-2-thiophenesulfonamide trimaleate, cis-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine -5-yl} -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate, cis-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl]] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dichloro-1-thiophenesulfonamide trimaleate, cis-N-4- (4 - {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) - (7-chloro-2,1,3 benzoxadiazole) -4-sulfonamide trimaleate, m.p. 283 cis-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (7 -methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate, cis-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2, 5-methyl-2,3-benzothiadiazole] -4-sulfonamide); 3d] pyrimidin-5-yl} -2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-ifonamide trimaleate, cis-N-4- (4- { 4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate, cis-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2 -fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2, 3-chloro-2-methyl-1-benzenesulfonamide]) 3d] pyrimidin-5-yl} -2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] - 7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino) 7- [4- (4-methylpiperazino) cyclohexyl xyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate, cis-1- (4- {4-amino-7- [4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate, trans-N-1- (4- {4 amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate, trans-N-1 - (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate . Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2, Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ _2,1- d] pyrimidin-5- 4,6-trichloro-1-benzenesulfonamide trimaleate) yl} -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ 2,3d] Pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl) 7-H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimalate trans-N-1- (4- {4-amino-7- [4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate, trans-N-1- ( 4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -3-chloro-4-fluoro-1- Benzenesulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolidin-5-yl} -2-fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4- methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate, trans-N-1- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate, trans- N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -3,4-difluoro Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-benzenesulfonamide trimaleate fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate, 285 trans - N - 1- (444-amino-7- [4- (4-methylpiperazirio) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -5-bromo-2 -thiophenesulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,4-Dichloro-1-benzenesulfonamide trimaleate, trans / 7S-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidine -5-yl} -2-fluorophenyl) -2,30,4-trichloro-1-benzenesulfonamide trimaleate trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl]] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide trimaleate, trans-N-4- (4- {4-amino-7- [4- (4-Methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dichloro-1-thiophenesulfonamide trans-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-y) trimaleate 1- (2-Fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate trans-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) (cyclohexyl) -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate, trans-N-4- ( 4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7 H -pyrrolo [2,3- d] pyrimidin-5-yl} -2-fluorophenyl) - (5-methyl-2,1,3 trans-N-4- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -benzothiadiazole) -4-sulfonamide -2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate, Trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) -3- chloro-2-methyl-1-benzenesulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5- yl} -2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate, trans-N-1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2, 3-fluoro-phenyl] -2-fluoro-phenyl) -2-bromo-1-benzenesulfonamide 3d] pyrimidin-5-yl} -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate, or trans-N-1- (4- {4-amino-7- [4]) - (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3d] pyrimidin-5-yl} -2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate.