AU6048499A - Pyrrolopyrimidines as protein kinase inhibitors - Google Patents

Description

WO 00/17203 PCT/US99/21560 -1 PYRROLOPYRIMIDINES AS PROTEIN KINASE INHIBITORS RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Numbers 60/100,832, filed September 18, 1998; 60/100,833, filed September 18, 1998; 60/100,834, filed September 18, 1998, and 60/100,946, filed September 18, 1998. The teachings of each of these referenced applications are expressly incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the 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 the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases. The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell. Protein Tyrosine Kinases. Protein tyrosine kinases (PTKs) are enzymes WO 00/17203 PCT/US99/21560 which catalyse the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ulrich, 1992, Neuron 9:383-391). Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas). Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). Receptor Tyrosine Kinases (RTKs). The RTKs comprise a large family of transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response.

WO 00/17203 PCT/US99/21560 (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) see Schlessinger and Ullrich, 1992, Neuron 9:1-20. Proteins with SH2 (src homology -2) or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals into cell. Both of the domains recognize phosphotyrosine. (Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol. Cell. Biol. 14:2777-2785; Songyang et al., 1993, Cell 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 that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Cell 72:767-778). The specificity of the interactions between receptors or proteins and SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors correlate with the 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 pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor as well as the timing and duration of those stimuli. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. Several receptor tyrosine kinases such as FGFR-1, PDGFR, TIE-2 and c Met, and growth factors that bind thereto, have been suggested 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 subclass of RTKs. An WO 00/17203 PCT/US99/21560 alternative designation 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) since it binds VEGF with high affinity. The murine version of FLK 1/VEGFR-2 has also been called NYK (Oelrichs et al, Oncogene 8(1):11-15, 1993). DNAs encoding mouse, rat and human FLK-1 have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews et al., Proc. Natl. Acad. Sci. USA, 88:9026-30, 1991; Terman et al., 1991, supra; 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 in Millauer et al., supra, suggest that VEGF and FLK-1/KDR/VEGFR-2 are a ligand receptor pair that play an important role in the proliferation of vascular endothelial cells, and formation and sprouting of blood vessels, termed vasculogenesis and angiogenesis, respectively. Another type III subclass RTK designated "fins-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 designation for Flt-1 is "vascular endothelial cell growth factor receptor 1" (VEGFR-1). To date, members of the FLK-1/ KDR/VEGFR-2 and Flt-l/ VEGFR-1 subfamilies have been found expressed primarily on endothelial cells. These subclass members 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 to FLK-1/KDR and is mitogenic toward 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. Flt-I expression is associated with early vascular development in mouse embryos, and with neovascularization during wound healing (Mustonen and Alitalo, supra). Expression of Flt-I in monocytes, osteoclasts, and osteoblasts, as well as in adult tissues such as kidney glomeruli suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra).

WO 00/17203 PCT/US99/21560 As previously stated, recent evidence suggests that VEGF plays a role in the stimulation of both normal and pathological 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. L. D. Goldberg and E.M. Rosen), 209-232, 1997). In addition, VEGF has been implicated in the control and enhancement of vascular permeability (Connolly, et al., J. Biol. Chem. 264: 20017 20024, 1989; Brown et al., Regulation ofAngiogenesis (ed. L.D. Goldberg and E.M. Rosen), 233-269, 1997). Different forms of VEGF arising from alternative splicing of mRNA have been reported, including the four species described by Ferrara et al. (J. Cell. Biochem. 47:211-218, 1991). Both secreted and predominantly cell associated species of VEGF have been identified by Ferrara et al. supra, and the protein is known to exist in the form of disulfide linked dimers. Several related homologs of VEGF have recently been identified. However, their roles in normal physiological and disease processes have not yet been elucidated. In addition, the members of the VEGF family are often coexpressed with VEGF in a number of tissues and are, in general, capable of forming heterodimers with VEGF. This property likely alters the receptor specificity and biological effects of the heterodimers and further complicates the elucidation of their specific functions as illustrated below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159 164, 1998 and references cited therein). Placenta growth factor (PlGF) 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, different species of PlGF arise from alternative splicing of mRNA, and the protein exists in dimeric form (Park et al., supra). PIGF-1 and P1GF-2 bind to Flt-1 with high affinity, and PlGF-2 also avidly binds to neuropilin-1 (Migdal et al, J. Biol. Chem. 273 (35): 22272-22278), but neither binds to FLK-1/KDR (Park et al., supra). PlGF has been reported to potentiate both the vascular permeability and mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (purportedly due to heterodimer formation) (Park et al., supra).

WO 00/17203 PCT/US99/21560 VEGF-B is produced as two isoforms (167 and 185 residues) that also appear to bind Flt-1/VEGFR-1. It may play a role in the regulation of extracellular matrix degradation, cell adhesion, and migration through modulation of the expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1 (Pepper et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(20): 11709-11714). 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 proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models ( Lymboussaki et al, Am. J. Pathol. (1998), 153(2): 395-403; Witzenbichler et al, Am. J. Pathol. (1998), 153(2), 381-394). The transgenic overexpression of VEGF-C causes proliferation and enlargement of only lymphatic vessels, while blood vessels are unaffected. Unlike VEGF, the expression of VEGF-C 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/Flt-4 and KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominently expressed in the mesenchymal cells of the lung and skin (Achen et al, Proc. NatL. Acad. Sci. U. S. A. (1998), 95(2), 548-553 and references therein). As for VEGF, VEGF-C and VEGF-D have been claimed to induce increases in vascular permeability in vivo in a Miles assay when injected into cutaneous tissue (PCT/US97/14696; W098/07832, Witzenbichler et al., supra). The physiological role and significance of these ligands in modulating vascular hyperpermeability and endothelial responses in tissues where they are expressed remains uncertain. There has been recently reported a vitally encoded, novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), which preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain (Meyer et al, EMBO J. (1999), 18(2), 363-374; Ogawa et al, J. Biol. Chem. (1998), 273(47), 31273-31282.). VEGF-E sequences possess 25% homology to mammalian VEGF and are encoded by the parapoxvirus Orf virus (OV). This WO 00/17203 PCTIUS99/21560 7 parapoxvirus that affects sheep and goats and occasionally, humans, to generate lesions with angiogenesis. VEGF-E is a dimer of about 20 kDa with no basic domain nor affinity for heparin, but has the characteristic cysteine knot motif present in all mammalian VEGFs, and was surprisingly found to possess potency and bioactivities similar to the heparin-binding VEGF 165 isoform of VEGF-A, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF 165, VEGF-E was found to bind with high affinity to VEGF receptor- 2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentrations, while in contrast to VEGF 165, VEGF-E did not bind to VEGF receptor-1 (Flt-1). Based upon emerging discoveries of other homologs of VEGF and VEGFRs and the precedents for ligand and receptor heterodimerization, the actions of such VEGF homologs may involve formation of VEGF ligand heterodimers, and/or heterodimerization of receptors, or binding to a yet undiscovered VEGFR (Witzenbichler et al., supra). Also, recent reports suggest 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, S.A., Vitali, A., Domagala, T., Nice, E., and Wilks, A.F., "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 a recently discovered family of endothelial cell specific receptor tyrosine kinases which is involved in critical angiogenic processes, such as vessel branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian receptor tyrosine kinase for which both agonist ligand(s) (e.g., Angiopoietinl ("Ang I"), which stimulates receptor autophosphorylation and signal transduction), and antagonist ligand(s) (e.g., Angiopoietin 2 ("Ang2")), have been identified. Knock-out and transgenic manipulation of the expression of Tie-2 and its ligands indicates tight spatial and temporal control of Tie-2 signaling is essential for the proper development of new vasculature. The current model suggests that stimulation of Tie-2 kinase by the Ang1 ligand is directly involved in the branching, WO 00/17203 PCT/US99/21560 sprouting and outgrowth of new vessels, and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and inducing quiescence. The absence of Angl stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation by Ang2, which is produced at high levels at sites of vascular regression, may cause a loss in vascular structure and matrix contacts resulting in endothelial cell death, especially in the absence of growth/survival stimuli. The situation is however more complex, since at least two additional Tie-2 ligands (Ang3 and Ang4) have recently been reported, and the capacity for heterooligomnerization of the various agonistic and antagonistic angiopoietins, thereby modifying their activity, has been demonstrated. Targeting Tie-2 ligand-receptor interactions as an antiangiogenic therapeutic approach is thus less favored and a kinase inhibitory strategy preferred. The soluble extracellular domain of Tie-2 ("ExTek") can act to disrupt the establishment of tumor vasculature in a breast tumor xenograft and lung metastasis models and in tumor-cell mediated ocular neovasculatization. By adenoviral infection, the in vivo production of mg/ml levels ExTek in rodents may be achieved for 7-10 days with no adverse side effects. These results suggest that disruption of Tie-2 signaling pathways in normal healthy animals may be well tolerated. These Tie-2 inhibitory responses to ExTek may be a consequence sequestration of ligand(s) and/or generation of a nonproductive heterodimer with full-length Tie-2. Recently, significant upregulation of Tie-2 expression has been found within the vascular synovial pannus of arthritic joints of humans, consistent with a role in the inappropriate 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 venous malformation disorders. Tie-2 inhibitors are, thereful, useful in treating such disorders, and in other situations of inappropriate neovascularization. The Non-Receptor Tyrosine Kinases. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, WO 00/17203 PCT/US99/21560 Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bohlen, 1993, Oncogene 8:2025-2031, which is incorporated herein by reference. Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyper-immune responses. Development of Compounds to Modulate the PTKs. In view of the surmised importance of PTKs to the control, regulation, and modulation of cell proliferation, the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase "inhibitors" using a variety of approaches, including the use of mutant ligands (U.S. Application No. 4,966,849), 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; U.S. Patent No. 5,330,992; Mariani, et al., 1994, Proc. Am. Assoc. Cancer Res. 35:2268). More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al; Expert Opin. Ther. Pat. (1998), 8(4): 475-478), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO WO 00/17203 PCT/US99/21560 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. Anilinocinnolines (PCT W097/34876) and quinazoline derivative compounds (PCT W097/22596; PCT W097/42187) have been described as inhibitors of angiogenesis and vascular permeability. In addition, attempts have been made to identify small molecules which act as serine/threonine kinase inhibitors. For example, bis(indolylmaleimide) compounds have been described as inhibiting particular PKC serine/threonine kinase isoforms whose signal transducing function is associated with altered vascular permeability in VEGF-related diseases (PCT W097/40830; PCT W097/4083 1). P1k-1 Kinase Inhibitors Plk-1 is a serine/threonine kinase which is an important regulator of cell cycle progression. It plays critical roles in the assembly and the dynamic function of the mitotic spindle apparatus. P1k-I and related kinases have also been shown to be closely involved in the activation and inactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of Plk-1 expression are associated with cell proliferation activities. It is often found in malignant tumors of various origins. Inhibitors of Plk-1 are expected to block cancer cell proliferation by disrupting processes involving mitotic spindles and inappropriately activated cyclin-dependent kinases. Cdc2/Cyclin B Kinase Inhibitors (Cdc2 is also known as cdki) Cdc2/cyclin B is another serine/threonine kinase enzyme which belongs to the cyclin-dependent kinase (cdks) family. These enzymes are involved in the critical transition between various phases of cell cycle progression. It is believed that uncontrolled cell proliferation, which is the hallmark of cancer is dependent upon elevated cdk activities in these cells. The inhibition of elevated cdk activities in cancer cells by cdc2/cyclin B kinase inhibitors could suppress proliferation and may restore the normal control of cell cycle progression. The regulation of CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits (Draetta, Trends WO 00/17203 PCTIUS99/21560 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)). A further level of regulation occurs through both activating and inactivating phosphorylations 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, 10:3331-3341 (1991); Solomon et al., Cell, 63:1013-1024 (1990)). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences, 18:195-197 (1993); Sherr, Cell, 73:1059 1065 (1993)). Both the critical G1-S and G 2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase (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)). Progression through S phase requires the activity of cyclin A/CDK2 (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 the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are 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, 89:2824-2828 (1992); Walker and Maller, Nature, 354:314-317 (1991); Zindy et al., Biochemical & Biophysical Research Communications, 182:1144-1154 (1992)). It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer.

WO 00/17203 PCTIUS99/21560 (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 represent novel 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), raf (Powis, Pharmacology & Therapeutics, 62:57-95 (1994)) and the 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., Proceedings of the National Academy of Science USA, 92:2258-2262 (1995)), (3) inhibition of CDK5 and GSK3 kinases in Alzheimers (Hosoi et al., Journal ofBiochemistry (Tokyo), 117:741-749 (1995); Aplin et al., Journal ofNeurochemistry, 67:699-707 (1996), (4) inhibition of c-Src kinase in osteoporosis (Tanaka et al., Nature, 383:528-531 (1996), (5) inhibition of GSK-3 kinase in type-2 diabetes (Borthwick et al., Biochemical & Biophysical Research Communications, 210:738-745 (1995), (6) inhibition of the p38 kinase in inflammation (Badger et al., The Journal of Pharmacology and Experimental Therapeutics, 279:1453-1461 (1996)), (7) inhibition of VEGF-R 1-3 and TIE-1 and 2 kinases in diseases which involve 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 hematopoetic 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)). It is additionally possible that inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not misregulated, but it nonetheless essential for maintenance of the disease state. In this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases. For example, 5 many viruses, such as human papilloma virus, disrupt the cell cycle and drive cells WO 00/17203 PCT/US99/21560 /3 into the S-phase of the cell cycle (Vousden, FASEB Journal, 7:8720879 (1993)). Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2, may disrupt the virus life cycle by preventing virus replication. This same principle may be used to protect normal 5 cells of the body from toxicity of cycle-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 CDKs 2 or 4 will prevent progression into the cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis. Furthermore, CDK2/cyclin E activity has also been 10 shown to regulate NF-kB. Inhibition of CDK2 activity stimulates NF-kB-dependent gene expression, an event mediated through interactions with the p300 coactivator (Perkins et al., Science, 275:523-527 (1997)). NF-kB regulates genes involved in inflammatory responses (such as hematopoetic growth factors, chemokines and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of 15 Immunology, 12:141-179 (1994)) and may be involved in the suppression of apoptotic signals within the 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 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-kB. This therefore suggests that 20 inhibition of CDK2 activity may also have utility in other cases where regulation of NF-kB plays a role in etiology of disease. A further example may be take from fungal infections: Aspergillosis is a common infection in immune-compromised patients (Armstrong, Clinical Infectious Diseases, 16:1-7 (1993)). Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A (Osmani et al., EMBO Journal, 25 10:2669-2679 (1991); Osmani et al., Cell, 67:283-291 (1991)) may cause arrest or death in the fungi, improving the therapeutic outcome for patients with these infections. The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of receptor 30 and non-receptor tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is WO 00/17203 PCT/US99/21560 therefore desirable. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for antiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well 5 as associated disorders would be beneficial. SUMMARY OF THE INVENTION The present invention provides compounds of Formula I, 10 NH2 A L- (CH 2 )j--

R

3 (I) N 15 R2 N N R1 and pharmaceutically acceptable salts thereof. 20 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 substituents: a substituted or unsubstituted aliphatic group, a halogen, a substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl, substituted or 25 unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR 4 R,, -C(O) 2 H, -OH, a substituted or unsubstituted alkoxycarbonyl, -C(O)2-haloalkyl, a substituted or unsubstituted alkylthio ether, a substituted or unsubstituted alkylsulfoxide, a substituted or unsubstituted alkylsulfone, a substituted or unsubstituted arylthio ether, a substituted 30 or unsubstituted arylsulfoxide, a substituted or unsubstituted arylsulfone, a substituted or unsubstituted alkyl carbonyl, -C(O)-haloalkyl, a substituted or WO 00/17203 PCT/US99/21560 unsubstituted aliphatic ether, a substituted or unsubstituted aromatic ether, carboxamido, tetrazolyl, trifluoromethylsulphonamido, trifluoromethylcarbonylamino, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkyl amido, a substituted or unsubstituted aryl amido, a substituted 5 or unsubstituted styryl and a substituted or unsubstituted aralkyl amido. L is one of the following linkers: -0-; -S-; -S(O)-; -S(0) 2 -; -N(R)-; N(C(O)OR)-; -N(C(O)R)-; -N(SO 2 R)-; -CH 2 0-; -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-; 10 C(=NOR)-; -C(O)-; -CH(OR)-;-C(O)N(R)-; -N(R)C(O)-; -N(R)S(O)-;-N(R)S(0) 2

-;

OC(O)N(R)-;-N(R)C(O)N(R)-; -NRC(0)O-;-S(0)N(R)-;-S(0) 2 N(R)-; N(C(O)R)S(O)-; N(C(O)R)S(0) 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(0)-; -S(0) 2 N(R)C(O)-; -OS(O)N(R)-; -OS(0) 2 N(R)-; -N(R)S(O)0-; -N(R)S(0) 2 0-; -N(R)S(0)C(0)-; -N(R)S(O) 2 C(O)-; -SON(C(O)R)-; 15 SO 2 N(C(0)R)-; -N(R)SON(R)-; -N(R)SO 2 N(R)-; -C(0)0-; -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')-. R and R' are each, independently, -H, an acyl group, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted 20 heteroaromatic group, or a substituted or unsubstituted cycloalkyl group. Alternatively, L is -RbN(R)S(0) 2 -, -RbN(R)P(O)-, or -RbN(R)P(0)0-. Rb is an alkylene group which when taken together with the sulphonamide, phosphinamide, or phosphonamide group to which it is bound forms a five or six membered ring fused to ring A. 25 Alternatively, L is represented by one of the following structural formulas: 30 WO 00/17203 PCT/US99/21560 N-P /N---P

R

85

-

R85-O 5 N--P-O N--P 10 R 8 5 -- O R 8 5 -O N O 15 or N R85 5 R85 R., taken together with the phosphinamide, or phophonamide is a 5-, 6-, or 7 20 membered, aromatic, heteroaromatic or heterocycloalkyl ring system. In Formula I, R, is a substituted aliphatic group, a substituted cycloalkyl, a substituted bicycloalkyl, a substituted cycloalkenyl, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, an optionally substituted heteroaralkyl, an optionally substituted heterocycloalkyl, an optionally 25 substituted heterobicycloalkyl, an optionally substituted alkylamindo, and optionally substituted arylamido, an optionally substituted -S(O) 2 -alkyl or optionally substituted -S(O) 2 -cycloalkyl, a -C(O)-alkyl or an optionally substituted -C(O) alkyl. R, can be substituted with one or more substituents. Preferably, R, is 30 substituted with a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic, a WO 00/17203 PCT/US99/21560 / '7 substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic ether, a substituted or unsubstituted aliphatic ether, a substituted or unsubstituted alkoxycarbonyl, a 5 substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aryloxycarbonyl, -OH, a substituted or unsubstituted aminocarbonyl, an oxime, a substituted or unsubstituted azabicycloalkyl, heterocycloalkyl, oxo, aldehyde, a substituted or unsubstituted alkyl sulfonamido group, a substituted or 10 unsubstituted aryl sulfonamido group, a substituted or unsubstituted bicycloalkyl, a substituted or unsubstituted heterobicycloalkyl, cyano, -NH 2 , an alkylamino, ureido, thioureido and -B-E. B is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic, a substituted or 15 unsubstituted heteroaromatic, an alkylene, an aminoalkyl, an alkylenecarbnonyl, or an aminoalkylcarbonyl. E is a substituted or unsubstituted azacycloalkyl, a substituted or unsubstituted azacycloalkylcarbonyl, a substituted or unsubstituted azacycloalkylsulfonyl, a substituted or unsubstituted azacycloalkylalkyl, a 20 substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylcarbonyl, a substituted or unsubstituted heteroarylsulfonyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl sulfonamido, a substituted or unsubstituted aryl sulfonamido, a substituted or unsubstituted bicycloalkyl, a substituted or unsubstituted ureido, a substituted or unsubstituted 25 thioureido or a substituted or unsubstituted aryl. However, when R, is an aliphatic group or cycloalkyl group, R, is not exclusively substituted with one or more substitutent selected from the group consisting of hydroxyl and lower alkyl ethers. In addition, a heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl, and an aliphatic group is not substituted exclusively with 30 one or more aliphatic groups. In Formula I, R 2 is -H, a substituted or unsubstituted aliphatic group, a WO 00/17203 PCT/US99/21560 /9E substituted or unsubstituted cycloalkyl, a halogen, -OH, cyano, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, -NR 4

R

5 , or -C(O)NR 4

R

5 . 5 In Formula I, R 3 is 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 I, R 4 , R, and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl, substituted or 10 unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic. Alternatively, R 4 and R, are each, independently, -H, azabicycloalkyl, heterocycloalkyl, a substituted or unsubstituted alkyl group or Y-Z. 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 )pO-, -(CH 2 )pNH-, -(CH 2 ),S-, -(CH 2 )pS(O)-, and 15

(CH

2

),S(O)

2

-

p is an integer from 0 to to about 6. Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group. 20 j 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 -0- and R 3 is phenyl, j is 0. The compounds of this invention are useful as inhibitors of serine/threonine 25 and tyrosine kinases. In particular, compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially in cancer and in the process of angiogenesis. For example, certain of these compounds are inhibitors of such receptor kinases as KDR, Flt-1, FGFR, PDGFR, c-Met, TIE-2 or IGF-1-R. Since certain of these compounds are anti 30 angiogenic, they are important substances for inhibiting the progression of disease states where angiogenesis is an important component. Certain compounds of the WO 00/17203 PCT/US99/21560 invention are effective as inhbitors of such serine/threonine kinases as PKCs, erk, MAP kinases, MAP kinase kinases, MAP kinase kinase kinases, cdks, Plk-I or Raf 1. These compounds are useful in the treatment of cancer, and hyperproliferative disorders. In addition, certain compounds are effective inhibitors of non-receptor 5 kinases such as those of the Src (for example, Ick, blk and lyn), Tec, Csk, Jak, Map, Nik and Syk families. These compunds are useful in the treatment of cancer, hyperproliferative disorders and immunologic diseases. Certain compounds of this invention are selective TIE-2 kinase inhibitors which may be anti-angiogenic (especially in combination with one or more VEGFR 10 inhibitors), or pro-angiogenic, when employed in the presence of, or in conjunction with, a VEGF-related stimulus. In this manner such inhibitors can be used in the promotion of therapeutic angiogenesis to treat, for example, ischemia, infarct or occlusion, or to promote wound healing. The present invention provides a method of inhibiting the kinase activity of 15 tyrosine kinases and serine/threonine kinases comprising the administration of a compound represented by formula I to said kinase in sufficient concentration to inhibit the enzyme activity of said kinase. The present invention further includes the use of these compounds in pharmaceutical compositions with a pharmaceutically effective amount of the above 20 described compounds and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions can be administered to individuals to slow or halt the process of angiogenesis in angiogenesis-aided diseases, or to treat edema, effusions, exudates or ascites and other conditions associated with vascular hyperpermeability. Certain pharmaceutical compositions can be administered to individuals to treat 25 cancer and hyperproliferative disorders by inhibiting serine/threonine kinases such as cdk, Plk-1, erk, etc. DETAILED DESCRIPTION OF THE INVENTION The values of substituents in a first preferred group of compounds of formula 30 I are given below. Preferably, L is -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -0-.

WO 00/17203 PCT/US99/21560 Preferably, R 3 is a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted benzotriazole, a substituted or unsubstituted tetrahydropyranyl, a substituted or unsubstituted tetrahydrofuranyl, a 5 substituted or unsubstituted dioxane, a substituted or unsubstituted dioxolane, a substituted or unsubstituted quinoline, a substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanyl, a substituted or unsubstituted bezofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzisoxazole, substituted or unsubstituted 10 benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted bezoxazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted bezimidazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline, substituted or unsubstituted quinoxaline, substituted or unsubstituted indole or 15 substituted or unsubstituted pyrazole. Alternatively, R 3 can 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(0) 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 a substituted or unsubstituted phenyl. 20 R 3 can be substituted by one or more substituents. Preferable substituents for

R

3 are F, Cl, Br, I, CH 3 , NO 2 , OCF 3 , OCH,, 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 25 unsubstituted tetrazolyl, styryl, -S-(substituted or unsubstituted aryl), -S-(substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -C(O)NRfRg, R , CH 2 OR. Rf, Rg and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 30 heterobicycloalkyl or a substituted or unsubstituted heteroaromatic. Alternatively, R, and Rg are each, independently, a substituted or WO 00/17203 PCT/US99/21560 o( unsubstituted aliphatic group or a substituted or unsubstuituted aromatic group. Rc is hydrogen, or substituted or unsubstituted alkyl or substituted or unsubstituted aryl; -W-(CH 2 )-NRRA, -W-(CH 2 )t-O-alkyl, , -W-(CH 2 )t-S-alkyl, or W-(CH2)-OH. 5 t is an integer from 0 to about 6. W is a bond or -0-, -S-, -S(O)-, -S(0) 2 -, or -NRk-. Rk is -H or alkyl. Rd, Re and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or 10 unsubstituted heterobicyclic group. Alternatively, Rd and R. are each, independently, -H, alkyl, alkanoyl or -K D. K is -S(O) 2 -, -C(O)-, -C(O)NH-, -C(O) 2 -, or a direct bond. D is a substituted or unsubstituted aryl, a substituted or unsubstituted 15 heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminocycloalkyl, COOR,, or substituted or unsubstituted 20 alkyl. R, 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 . 25 Preferably, ring A is a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, or a substituted or unsubstituted indole. In one embodiment, ring A is a substituted or unsubstituted phenyl. Ring A can be substituted by one or more substituents. Preferable 30 substituents for ring A are F, Cl, Br, I, CH 3 , NO, OCF 3 , OCH,, CN, CO 2

CH

3 , CF 3 , t butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted WO 00/17203 PCT/US99/21560 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 heteroaryl), substituted or 5 unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, C(O)NRR 8 , R, and CH 2 OR. Rf, R, and R, are defined as above. Ring A is more preferably substituted with F, Cl, and nitro.

R

2 is preferably hydrogen. In one embodiment, R, is of the formula 10 I(a) 15 0 m is an integer from 0 to about 3. 20 In another embodiment, R, is of the formula I(b) 25 m 30 (CH 2 )t

NR

8

R

9 35 WO 00/17203 PCT/US99/21560 m, t are defined as above. R 8 , R 9 and the nitrogen atom together form a 3-, 4-, 5-, 6 or 7-membered, substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaromatic or substituted or unsubstituted heterobicyclicalkyl group. Alternatively, R, and R 9 are each, independently, -H, azabicycloalkyl, 5 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 )q0-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, or -(CH 2 )qS(O) 2 -. q is an integer from 0 to 6. Z 2 is a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 10 In another embodiment, R, is of the formula I(c) 15 m (CJ) ( 2)t

R

77

NR

8

R

9 20 m, t , R,, and R 9 are defined as above. s is an integer from 0 to 6. q is an integer from 0 to about 6. R 7 is -OR 78 , or -NR 79 RO. R 78 is -H or a substituted or unsubstituted aliphatic group. R 79 , R 0 and the nitrogen atom together form a 3, 4, 5, 25 6 or 7-membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group. R, 9 and RO 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 r, -C(O)O-, -SO2NH-, CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)- and-(CH2)qS(O)2-. Z is 30 H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl. In another embodiment, R, is of the formula 35 WO 00/17203 PCT/US99/21560 I(d) N 5

R

10 0 v v is an integer from 1 to about 3. Ro is -H, azabicycloalkyl, heterocycloalkyl or Y 2 10 Z 2 . Y 2 and Z 2 are as defined previously. In another embodiment, R, is of the formula 15 N mnIe R10 20 m and Rio are as previously defined. RII represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, oxo, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or 25 unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, a substituted or unsubstituted aminoalkyl and a substituted or-unsubstituted aralkyl groups, provided that the carbon atoms adjacent 30 to the nitrogen atom are not substituted by a hydroxy group. In another embodiment, R, is of the formula 35 WO 00/17203 PCT/US99/21560 5 I(f) 10 N N 151 15 R10 R,, is as previously defined. In another embodiment, R, is of the formula 20 I(g) 25 r N R\ 30 r is an integer from 1 to about 6. R. and R 9 are as previously defined. In another embodiment, R, is of the formula 35 40 WO 00/17203 PCT/US99/21560 5 )w

R

12 0 CH I(h) O RN 10 R8

R

8 , R 9 and t are as previously defined. w is an integer from 0 to about 4. u is 0 or 1. 15 R 12 is hydrogen or a substituted or unsubstituted alkyl group. In another embodiment, R, is of the formula I(i) 20 w

R

1 0 0 t N 25 R12 w, t, RIO, R 1 2 are as previously defined. In another embodiment, when R, is 1(g) or I(H), R 8 , R 9 and the nitrogen atom together form a heterocycloalkyl group of the formula 30 (R20 N R 1 3 R1g u R14 R1 8R 15

R

17 x R 16 35 u is as previously defined. R 13 , R 14 , R 1 5 , R 1 6 , R 17 , R 1 8 , R 1 9 and R 2 0 are each, independently, lower alkyl or hydrogen. Alternatively, at least one pair of WO 00/17203 PCT/US99/21560 substituents R,, and R 1 4 ; Rs and R,,; R 1 7 and RI.; or R 1 , and R 2 0 together are an oxygen atom. Alternatively, at least one of R 13 and RI, is cyano, CONHR 21 ,

COOR

21 , CH 2 0R 2 1 or CH 2

NR

2 1

(R

22 ). R 21 , R 22 and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl group, 5 substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group. Alternatively, R 2 1 and R 2 2 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or Y 3

-Z

3 ; Y 3 and Z 3 are as previously defined. X is -0-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 23 )- or NR 2 3 . R23 is -H, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, -C(NH)NH 2 , 10 -C(O)R 24 , or -C(O)OR 2 4 . R 24 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl. In another embodiment, R,, R, and the nitrogen atom together form a heterocycloalkyl of the formula 15 N

R

2 5 CH2) R2 I (H2C N R22 20 R21 t, R 2 1 and R 22 are as previously defined. R 2 s and R 26 are each, independently, hydrogen or lower alkyl. Alternatively, R 2 s and R 26 together are an oxygen atom. i is an integer from 1 to about 6. In another embodiment, R,, R 9 and the nitrogen atom together form a 25 heterocycloalkyl group; of the formula N 30

CH

2 R27 i is as previously defined. R27 is CH2OH, C(0)NR24R,, or COOR24. R24 and R2, are WO 00/17203 PCT/US99/21560 -28 as previously defined. In another embodiment, R,, R, and the nitrogen atom together form a heteroaromatic group of the formula 5 N

R

29 10

R

2 9 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, carboxylic acid, cyano, C(O)OR 0 ,

CH

2 0R 3 0 , CH 2

NRIR

2 2 or C(O)NR1R- 2 . R 3 . is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted 15 or unsubstituted heterocycloalkyl or heterocycloaryl group. R 21 and R 22 are as previously defined. In another embodiment, at least one of R, and R, is of the formula Y 3 -D, wherein D is of the formula 20 N \ T 25 Y 3 is as previously defined. x is 0, 1 or 2. T is -0-, -C(O)-, -S-, -SO-, -S02r, -CH 2 -,

-CH(OR

24 )- or -N(R 2 4 )-. R 24 is as previously defined. In another embodiment, at least one of R 8 and R 9 is of the formula Y

N(R)R

32 , Y 3 is as previously defined. R 3 , and R 32 are each, independently, substituted or unsubstituted carboxyalkyl, a substituted or unsubstituted 30 alkoxycarbonylalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted cyanoalkyl. Alternatively, R 3 , and R 32 , together with the nitrogen atom, form a five- or six-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl. 35 In another embodiment, when R, is I(e), Z, is of the formula N(R 3 5

)R

6 . R 35 WO 00/17203 PCT/US99/21560 and R 36 are each, independently, hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl. In another embodiment, when R, is I(e), Z 2 is of the formula x1 x 1 5/ \ N R37 10 Each X, is, independently, CH or N. R 3 , is hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted 15 or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. 20 In another embodiment, when R, is I(e), Z2 is of the formula 25 -N T R37 30 g is an integer from 0 to about 3. T is as previously defined. R 3 7 is WO 00/17203 PCTIUS99/21560 hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or 5 unsubstituted aralkyl group. In another embodiment, when RI is I(e), Z 2 is of the formula 9 10 N N

R

37 15 g and R 3 , are as previously defined unsubstituted aralkyl group. In another embodiment, when R, is I(e), Z 2 is of the formula 20 b T R37 25 T, g and R 3 7 are as previously defined. In another embodiment, when R, is I(e), Z 2 is of the formula N N R 3 7 30

R

38 WO 00/17203 PCTIUS99/21560 3/

R

3 7 is as previously defined. R 3 8 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted 5 alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, perhaloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl. In another embodiment, R, is of the formula 10 R42 R43 R41 u R44 15

R

40 R45

R

39 N R 46 R47 u is as previously defined. R 3 9 , R 40 , R 41 , R 4 2 , R 43 , R44, R 4 , and R46 are each, independently,methyl or hydrogen. Alternatively, at least one pair of substituents 20 R 3 9 and R4O; R 3 6 and R 37 ; R38 and R 3 9 . Alternatively, R40 and R 4 , together are an oxygen atom. R47 is H, azabicycloalkyl, heterocycloalkyl or Y 2

-Z

2 . Y 2 and Z 2 are as previously defined. Alternatively, R47 is of the formula 25

R

51 R52

R

50 y R 53

R

49

R

54 30

R

48 N R 55 R56 yisOorl. R 48 , 1R49, R 50 , RM, R52, R 5 3 , Rs54 and R are each, independently, methyl or 35 hydrogen. Alternatively, at least one pair of substituents R4, and R 49 ; R,, and R51;

R

52 and R53; or R54 and R55 together are an oxygen atom. Rs5 is -H, azabicycloalkyl, heterocycloalkyl or Y 3

-Z

3 . Y, and Z 3 are defined as above.

WO 00/17203 PCTIUS99/21560 -32 In another embodiment, R, is of the formula 5 ReoRe1/ R59 u6 10 (R 58 N 6 h R 5 N R 64 /

R

7 15 e, f, h, u and y are independently 0 or 1. R 57 , R 58 , R 59 , R6, R6, R 62 , R 63 , R4, R 6 5 and RZ6 are each, independently, methyl or hydrogen. Alternatively, at least one pair of substituents R.

7 and R 58 ; R, and R.6; R61 and R 6 2 ; or R 63 and R64 together are an oxygen atom. R6 7 is H, azabicycloalkyl, heterocycloalkyl or Y-Z 2 . Y 2 and Z 2 are defined as above. Alternatively, R67 is of the formula 20

(R

7 1 R 72 70- d R73 R69 ,R74

R

68 N R 75 R76 25 d is 0 or 1. R 8 , R 69 , R 70 , R 7 1 , R 7 2 , R 7 3 , R 74 and R 75 are each, independently, lower alkyl or hydrogen. Alternatively, at least one pair of substituents R 68 and R 69 ; R 7 0 and R 71 ; R 72 and R 7 3 . R 74 and R7 5 together are an oxygen atom. R 7 6 is -H, 30 azabicycloalkyl, heterocycloalkyl or Y 3

-Z

3 . Y 3 and Z 3 are defined as above. As used herein, aromatic groups include carbocyclic ring systems (e.g. benzyl and cinnamyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1,2,3,4-tetrahydronaphthyl). Arromatic groups are also referred to as aryl groups herein. 35 Heteroaromatic groups, as used herein, include heteroaryl ring systems (e.g., WO 00/17203 -33- PCT/US99/21560 thienyl, pyridyl, pyrazole, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furans, pyrroles, imidazoles, pyrazoles, triazoles, pyrimidines, pyrazines, thiazoles, isoxazoles, isothiazoles, tetrazoles, or oxadiazoles) and heteroaryl ring systems in which a carbocyclic aromatic ring, carbocyclic non-aromatic ring or heteroaryl ring 5 is fused to one or more other heteroaryl rings (e.g., benzo(b)thienyl, benzimidazole, indole, tetrahydroindole, azaindole, indazole, quinoline, imidazopyridine, purine, pyrrolo[2,3-d]pyrimidine, pyrazolo[3,4-d]pyrimidine) and their N-oxides. An aralkyl group, as used herein, is an aromatic substituent that is linked to a compound by an aliphatic group having from one to about six carbon atoms. 10 An heteroaralkyl group, as used herein, is a heteroaromatic substituent that is linked to a compound by an aliphatic group having from one to about six carbon atoms. A heterocycloalkyl group, as used herein, is a non-aromatic ring system that has 3 to 8 atoms and includes at least one heteroatom, such as nitrogen, oxygen, or 15 sulfur. An acyl group, as used herein, is an -C(O)NRRz, -C(O)OR., -C(O)R., in which R, and R, are each, independently, -H, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. As used herein, aliphatic groups include straight chained, branched or cyclic 20 C,-C, hydrocarbons which are completely saturated or which contain one or more units of unsaturation. A "lower alkyl group" is a saturated aliphatic group having form 1-6 carbon atoms. Compounds of formula I may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include 25 hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. 30 Certain compounds of formula I which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such WO 00/17203 PCT/US99/21560 -34 salts. Example of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art. Certain compounds of formula I and their salts may exist in more than one 5 crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof. 10 Certain compounds of formula I may contain one or more chiral centres, and exist in different optically active forms. When compounds of formula I contain one chiral centre, the compounds exist in two enantioneric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers may be resolved by methods known to those skilled in 15 the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer specific reagent, for example enzymatic esterification; or gas-liquid or liquid 20 chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific 25 enantiomers may be synthesized by asymmetric synthesis using optically active reagents, 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 centre it may exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by 30 methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as WO 00/17203 PCT/US99/21560 3 Y described above. The present invention includes each diastereoisomer of 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 5 geometric isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each 10 conformational isomer of 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 compounds of formula I and mixtures thereof. A preferred group of compounds of the present invention are: 15 Cis-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex-1 -yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine Trans-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex-1-yl)-7H-pyrrolo[2,3 20 d]pyrimidin-4-ylamine Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine hydrochloride 25 Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1 -yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine Trans-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-ylamine 30 Cis-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine WO 00/17203 PCT/US99/2 1560 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrihidil-4-ylalllfe dihycirochioride 5 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo [2,3-d]pyrimidin-4-ylamnine dihydrochioride Cis-7-[4-(4-isopropylpiperazino)cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[ 2

,

3 d]pyrimidin-4-amine 10 Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-pheloxypheflyl)- 7

H

pyrrolo[2,3-d]pyrimidin-4-ammne Cis-7- {4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4-phenoxyphenyl)-7H 15 pyrrolo[2,3-djjpyrimidin-4-amine Trans-7- {4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-ammie 20 Cis-7-[-4-(4-ethylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)- 7 H-pyrolo[ 2

,

3 d]pyrimidin-4-amine trans-7-[4-(4-e-thylpiperazino)cyclohexy1]-5-(4-phenoxyphelyl)- 7 H-pyrrolo[ 2

,

3 d]pyrimidin-4-amine 25 Cis-7-[4-(4-isopropylpiperazino)cyclohexyll-5-(4-phenoxyphelyl)-7H-pyrrolo[ 2

,

3 d]pyrimidin-4-amine tris maleate Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphelyl)- 7

H

30 pyrrolo [2,3-d]pyrimidin-4-amine tris maleate WO 00/17203 PCTUS99/21 560 Cis-7- {4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine tris maleate 5 Trans-7- {4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine tris maleate Cis-7-(4- { [3-( 1H- 1 -imidazolyl)propyl] amino) cyclohexyl)-5-(4-phenoxyphenyl)-7H pyrrolo [2,3-d]pyrimidin-4-amnine trimaleate salt 10 Trans-7-(4-1{[3-( 1H- 1 -imidazolyl)propyl] amino}I cyclohexyl)-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-djjpyrimidin-4-amine dimaleate salt Cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 15 d]pyrimidin-4-amnine dimaleate salt Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine dimaleate salt 20 Trans-5-(4-phenoxyphenyl)-7-(4-tetrahydro- 1H- 1-pyrrolylcyclohexyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin 4-amine ftrimaleate salt 25 Trans-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo [2,3 d]pyrimidin-4-amine trimaleate salt 7-[3-(4-methylpiperazino)cyclopentyl]-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3 30 d]pyrimidin-4-amine tri-maleate WO 00/17203 PCT/US99/2 1560 -38 Trans- 7

-[

3 -(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)>7H-pyrrolo[2,3. d]pyrimidin-4-amine Trans-7-[3-(4-methylpiperazino)cyclohexy1]-5-(4-phenoxyphenyl>7H-pyroo[2,3. 5 d]pyrimidin-4-amine tri-maleate trans- 7 -[3-(4-methylpiperazino)cyclohexyl]--(4phenoxyphenyly7H-pyrolo[2,3 d]pyrimidin-4-amine tri-hydrochloride 10 cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7Hpyrrolo[2,3 d]pyrimidin-4-amine tri-maleate salt cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)>7H-pyrrolo[2,3 d]pyrimidin-4-amine tri-hydrochloride 15 Trn--2mty--hnxpey)7[-4mtypprzn~ylhxl-H pyrrolo[2,3-d]pyrimidin-4-amine trimaleate Cis- benzyl N-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3. 20 dljpyrimidin-5 -yl}I 2-methoxcyphenyl)carbamnate tri-maleate Trans- benzyl N-(4- f{ 4 -amiino-7-[4-(4-methylpiperazino)cyclohexyly7H pyrrolo [2,3-dlpyrimidin-5-yl} -2-methoxyphenyl)carbamate tri-maleate 25 Trans-Ni -(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]y7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-methoxyphenyl)benzamide Trans-Ni -(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]y7Hpyrrolo [2,3 d]pyrimidin-5-yl} -2-methoxyphenyl)benzamide tri-maleate 30 Cis-N 1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3- WO 00/17203 -39- PCTIUS99/21560 d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide Trans- N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[ 2

,

3 d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide 5 cis- N1-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamfide trimaleate salt trans-Ni-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]- 7 H-pyrrolo[ 2

,

3 10 d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamide tri-maleate cis-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tri-maleate 15 trans-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tri-maleate cis-2-amino-6-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)benzonitrile tri-maleate 20 trans-2-amino-6-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)benzonitrile tri-maleate cis-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 25 d]pyrimidin-5-ylphenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tri-maleate trans-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tri-maleate 30 cis-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]- 7 H-pyrrolo[ 2

,

3 d]pyrimidin-5-ylphenoxy)-6-(2-pyridylsulfanyl)benzonitrile tri-maleate WO 00/17203 PCTIUS99/21 560 trans-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexy]-7H-pyrrolo[ 2

,

3 d]pyrimidin-5-yiphenoxy)-6-(2-pyridylsulfanyl)benzonitriie tri-maleate 5 cis-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazno)cyciohexyiF-7H pyrroio[2,3-d]pyrimidin-4-amnine tri-maleate trans-5-(2-methy1-4-phenoxypheny)-7-[4-(4-methylpiperazio)cyciohexyl]- 7

H

pyrroio[2,3-d]pyrimidin-4-amine tri-maleate 10 cis-Ni -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl-7H-pyrTolo[ 2

,

3 dlpyrimidin-5-yl} -2-fluorophenyi)-4-fluoro-l1-benzenesulfonamide tri-maleate trans-Ni -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl-7H-pyrTolo[ 2

,

3 15 d]pyrimidin-5-yl} -2-fluorophenyi)-4-fluoro-l1-benzenesulfonamide tri-maleate Ni -4-[4-amnino-7-(1 -benzyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]- 2 fluorophenyl-4-fluoro-l1-benzenesulfonamide 20 Ni -4-[4-amino-7-(l1-benzyl-4-piperidyi)-7H-pyrroio[2,3-d]pyrimiidin-5-yl]- 2 fluorophenyi-2,3-dichloro-l1-benzenesuifonamnide Ni -4-[4-amino-7-(4-piperidyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yi]-2-fluorophenyi-4 fluoro-l1-benzenesulfonamide 25 Ni -4-[4-amino-7-( 1-formyl-4-piperidyi)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl]-2 fluorophenyl-4-fluoro-l1-benzenesulfonamnide Ni -[4-(4-amino-7- 1-[(i-methyl-i H-4-imidazolyl)sulfonyl]-4-piperidyi-7H- WO 00/17203 PCT/US99/21560 pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-l1-benzenesulfonamide dimaleate Ni -[4-(4-amino-7- 1-[(1 ,2-dimnethyl-l1H-4-imidazolyl)sulfonyl]-4-piperidyl-7H 5 pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-l1-benzenesulfonamide Ni -[4-(4-amino-7- 1-[(1 ,3-dimethyl- iH-5-pyrazolyl)carbonyl]-4-piperidyl-7H pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-l1-benzenesulfonamnide 10 Ni -(4- {4-amnino-7-[l1 (2-pyridylcarbony)-4-piperidy1]-7H-pyrroloII2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-4-fluoro-l1-benzenesulfonamide NI -4-(4-amino-7- {4-[l1-(1 -methylpiperid-4-yl)piperidyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} )-2-fluorophenyl-4-fluoro-l1-benzenesulfonamide tri-maleate 15 trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexy1]-7H-pyrroloI2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-(trifluoromethoxy)-l1-benzenesulfonamiide trimaleate trans-N-i -(4- {4-amnino-7-[4-(4-rnethylpiperazino)cyclohexyl]-7H-pyrrolo[ 2

,

3 d]pyrimidin-5-yl} -2-fluorophenyl)-5-chloro-2-thiophenesulfonamide benzenesulfonamide trimaleate trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexy]-7H-pyrTolo[ 2

,

3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-fluoro-l1-benzenesulfonamide benzenesulfonamide trimaleate trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2, 3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate W 00123-42- PCT/US99/21560 cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-chloro-4-fluoro- 1 -benzenesulfonamide trimaleate cis-N- 1-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl-2-fluorophenyl)-2,5-difluoro- 1 -benzenesulfonamide trimaleate trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl }-2-fluorophenyl)-2,6-difluoro-l1-benzenesulfonamide trimaleate trans- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexylj-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2, 1,3-benzothiadiazole-4-sulfonamide trimaleate trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrixnidin-5-yl} -2-fluorophenyl)-2,3,4-trifluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-nitro-l1-benzenesulfonamnide trimaleate cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-fluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,4,6-trichloro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-d]pyrim-idin 5-yl} -2-fluorophenyl)-2,6-dichloro-l1-benzenesulfonamTide trimaleate cis-N- 1 -(4- f{4-amino-7-[4-(4-methylpiperazino)cyclohexyll-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-chloro-l1-benzenesulfonamide trimaleate WO 00/17203 PCT/US99/2 1560 -43 cis-N- 1 -(4- f{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyimilin 5-yl} -2-fluorophenyl)- 3-fluoro-l1-benzenesulfonamnide dimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-5-chloro-2-thiophenesulfonamide dimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-4-bromo-2,6-difluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyriindin 5-yl} -2-fluorophenyl)-3-chloro-4-fluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyirnidin 5 -yl} -2-fluorophenyl-2-iodo-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-(trifluoromethoxy)-l1-benzenesulfonamnide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-aniino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-chloro-6-methyl- 1 -benzenesulfonamide trimaleate cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-chloro-4-cyano-l1-benzenesulfonamnide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 -d]pyrimidin- WO 00/17203 PCTIUS99/21560 5-yl} -2-fluorophenyl)-2,3 ,4-trifluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-dilpyrimidin 5-yl} -2-fluorophenyl)-3 ,4-difluoro-l1-benzenesulfonamnide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexylj-7H-pyrrolo [2,3-dipyrimidin 5-yl} -2-fluorophenyl)-4-bromo-2-fluoro- 1 -benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-djpyrimidin 5-yl} -2-fluorophenyl)-5-bromo-2-thiophenesulfonamnide trimaleate cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,4-dichloro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-dipyrimidin 5 -yl} -2-fluorophenyl)-2,3 ,4-trichloro- 1 -benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-3-bromo-5-chloro-2-thiophenesulfonamtide trimaleate cis- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2, 1,3-bonzothiadiazole-4-sulfonamide trimaleate cis- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2, 1,3-benzoxadiazole-4-sulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,5-dichloro-l1-thiophenesulfonamide trimaleate cis- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3 d]pyrimidin-5 -yl }-2-fluorophenyl)-(7-chloro-2L, 1,3-benzoxadiazole)-4-sulfonamide WO 00/1 7203 PCT/US99/2 1560 -45 trimaleate cis- N-4-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(7-methyl-2, 1,3-benzothiadiazole)-4-sulfonamide tnimaleate cis- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyriniidin-5-yl} -2-fluorophenyl)-(5-methyl-2, 1,3-benzothiadiazole)-4-sulfonainide tnimaleate cis- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(5-chloro-2, 1,3-benzothiadiazole)-4-sulfonamnide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-3-chloro-2-methyl-l1-benzenesulfonamnide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2-bromo-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,5-dibromo-3 ,6-difluoro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3-dipyrirnidin 5-yl} -2-fluorophenyl)- (2-nitrophenyl)methanesulfonamnide trimaleate trans-N-i -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl] -7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-nitro-l1-benzenesulfonamnide trimaleate WO 00/17203 PCTIUS99/21560 -46 trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-fluoro-1-benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,4,6-trichloro-1-benzenesulfonamide trimaleate trans-N-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 trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-chloro-1-benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)- 3-fluoro-1-benzenesulfonamide dimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate trans-N-1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-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[2,3 d]pyrimidin-5-yl}-2-fluorophenyl-2-iodo-1-benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide trimaleate trans-N-1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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[2,3- WO 00/17203 .47- PCTIUS99/21560 d]pyrimidin-5-yl}-2-fluorophenyl)-2-chloro-4-cyano- 1 -benzenesulfonamide trimaleate trans-N-1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-3,4-difluoro-1-benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-4-bromo-2-fluoro- 1 -benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-5-bromo-2-thiophenesulfonamide trimaleate trans-N-1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,4-dichloro-1-benzenesulfonamide trimaleate trans-N-1-(4-{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,3,4-trichloro-1-benzenesulfonamide trimaleate trans-N-1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,1,3-benzoxadiazole-4-sulfonamide trimaleate trans-N-1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,5-dichloro-1-thiophenesulfonamide trimaleate trans- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(7-chloro-2,1,3-benzoxadiazole)-4-sulfonamide trimaleate trans- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3- WO 00/17203 PCTIUS99/21560 -48 d]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]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(5-chloro-2,1,3-benzothiadiazole)-4-sulfonamide trimaleate trans-N-1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-bromo- 1 -benzenesulfonamide trimaleate trans-N-i-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate trans-N-I -(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)- (2-nitrophenyl)methanesulfonamide trimaleate The compounds of this invention have antiangiogenic properties. These antiangiogenic properties are due at least in part to the inhibition of protein tyrosine kinases essential for angiogenic processes. For this reason, these compounds can be 5 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 injury, wound healing, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat WO 00/17203 PCT/US99/21560 -49 scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, or age-related macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, 5 hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis. 10 Further, some of these compounds can be used as active agents against bums, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, brain tumor associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, glomerulonephritis and other 15 diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. keloid, fibrosis, cirrhosis and carpal tunnel syndrome). Increased VEGF production 20 potentiates inflammatory processes such as monocyte recruitment and activation. The compounds of this invention will also be useful in treating inflammatory disorders such as inflammatory bowel disease (IBD) and Crohn's disease. VEGF's are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, 25 vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke 30 VEGF/VPF mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often WO 00/17203 -50- PCT/US99/21560 accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. Because blastocyst implantation, placental development and embryogenesis 5 are angiogenesis dependent, certain compounds of the invention areuseful as contraceptive agents and antifertility agents. It is envisaged that the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity involving the KDR/VEGFR-2 and/or the Flt-1/VEGFR-1 and/or TIE-2 tyrosine kinases. By inhibiting the activity of these 10 tyrosine kinases, the progression of the listed disorders is inhibited because the angiogenic or vascular hyperpermeability component of the disease state is severely curtailed. The action of certain compounds of this invention, by their selectivity for specific tyrosine kinases, result in a minimization of side effects that would occur if less selective tyrosine kinase inhibitors were used. Certain compounds of the 15 invention are also effective inhibitors of FGFR, PDGFR, c-Met and IGF-1-R. These receptor kinases can directly or indirectly potentiate angiogenic and hyperproliferative responses in various disorders, hence their inhibition can impede disease progression. The compounds of this invention have inhibitory activity against protein 20 kinases. That is, these compounds modulate signal transduction by protein kinases. Compounds of this invention inhibit protein kinases from serine/threonine and tyrosine kinase classes. In particular, these compounds selectively inhibit the activity of the KDR/FLK-1/VEGFR-2 tyrosine kinases. Certain compounds of this invention also inhibit the activity of additional tyrosine kinases such as Flt 25 1/VEGFR-1, Tie-2, FGFR, PDGFR, IGF-lR, c-Met, Src-subfamily kinases such as Lck, Src, fyn, yes, etc. Additionally, some compounds of this 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 this invention 30 towards a particular protein kinase can often be altered and optimized by variations in the nature, number and arrangement of the substituents (i.e., R,, R2, R 3 , A and ring WO 00/17203 PCT/US99/21560 1 1) and conformational restrictions. In addition the metabolites of certain compounds may also possess significant protein kinase inhibitory activity. The compounds of this invention, when administered to individuals in need of such compounds, inhibit vascular hyperpermeability and the formation of edema 5 in these individuals. These compounds act, it is believed, by inhibiting the activity of KDR tyrosine kinase which is involved in the process of vascular hyperpermeability and edema formation. The KDR tyrosine kinase may 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 cell growth 10 factor (VEGF) or another activating ligand (such as VEGF-C, VEGF-D, VEGF-E or HIV Tat protein) binds to a KDR tyrosine kinase receptor which lies on the surface of vascular endothelial cells. Following such KDR tyrosine kinase activation, hyperpermeability of the blood vessels occurs and fluid moves from the blood stream past the blood vessel walls into the interstitial spaces, thereby forming an 15 area of edema. Diapedesis also often accompanies this response. Similarly, excessive vascular hyperpermeability can disrupt normal molecular exchange across the endothelium in critical tissues and organs (e.g., lung and kidney), thereby causing macromolecular extravasation and deposition. Following this acute response to KDR stimulation which is believed to facilitate the subsequent 20 angiogenic process, prolonged KDR tyrosine kinase stimulation results in the proliferation and chemotaxis of vascular endothelial cells and formation of new vessels. By inhibiting KDR tyrosine kinase activity, either by blocking the production of the activating ligand, by blocking the activating ligand binding to the KDR tyrosine kinase receptor, by preventing receptor dimerization and 25 transphosphorylation, by inhibiting the enzyme activity of the KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme) or by some other mechanism that interrupts its downstream signaling (D. Mukhopedhyay et al., Cancer Res. 58:1278-1284 (1998) and references therein), hyperpermeability, as well as associated extravasation, subsequent edema formation and matrix deposition, 30 and angiogenic responses, may be inhibited and minimized. One group of preferred compounds of this invention have the property of WO 00/17203 -52- PCT/US99/21560 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-I tyrosine kinase are activated by VEGF binding to KDR tyrosine kinase receptors and to Flt-i tyrosine kinase 5 receptors, respectively. Certain preferred compounds of this invention are unique because they inhibit the activity of one VEGF-receptor tyrosine kinase (KDR) that is activated by activating ligands but do not inhibit other receptor tyrosine kinases, such as Flt-1, that are also activated by certain activating ligands. In this manner, certain preferred compounds of this invention are, therefore, selective in their 10 tyrosine kinase inhibitory activity. In one embodiment, the present invention provides a method of treating a protein kinase-mediated condition in a patient, comprising adiminstering to the patient a therapeutically or prophylactically effective amount of one or more compounds of Formula I. 15 A "protein kinase-mediated condition" is a medical condition, such as a disease or other undesirable physical condition, the genesis or progression of which depends, at least in part, on the activity of at least one protein kinase. The protein kinase can be, for example, a protein tyrosine kinase or a protein serine/threonine kinase. 20 The patient to be treated can be any animal, and is preferably a mammal, such as a domesticated animal or a livestock animal. 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 such compounds, which inhibits, totally or 25 partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a 30 therapeutically effective amount can be determined by methods known to those of skill in the art.

WO 00/17203 -53- PCTIUS99/21560 The method of the present invention is useful in the treatment of protein kinase-mediated conditions, such as any of the conditions described above. In one embodiment, the protein kinase-mediated condition is characterized by undesired angiogenesis, edema, or stromal deposition. For example, the condition can be one 5 or more more ulcers, such as ulcers caused by bacterial or fungal infections, Mooren ulcers and ulcerative colitis. The condition can also be due to a microbial infection, such as Lyme disease, sepsis, septic shock or infections by Herpes simplex, Herpes Zoster, human immunodeficincy virus, protozoa, toxoplasmosis or parapoxvirus; an angiogenic disorders, such as von Hippel Lindau disease, polycystic kidney disease, 10 pemphigoid, Paget's disease and psoriasis; a reproductive condition, such as endometriosis, ovarian hyperstimulation syndrome, preeclampsia or menometrorrhagia; a fibrotic and edemic condition, such as sarcoidosis, fibrosis, cirrhosis, thyroiditis, hyperviscosity syndrome systemic, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, and edema following bums, 15 trauma, radiation, stroke, hypoxia or ischemia; or an inflammatory/immunologic condition, such as 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 also include sickle cell anaemia, osteoporosis, osteopetrosis, 20 tumor-induced hypercalcemia and bone metastases. Additional protein kinase mediated conditions which 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, optic pits, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt's disease and 25 Eales disease, in addition to retinopathy and macular degeneration. The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease. The compounds of the present invention are also useful in the treatment of 30 cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, WO 00/17203 -54- PCT/US99/21560 hematopoietic malignancies, including leukaemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites. The compounds of the present invention are also useful in the treatment of Crow-Fukase (POEMS) syndrome and diabetic conditions such as glaucoma, 5 diabetic retinopathy and microangiopathy. The Src, Tec, Jak, Map, Csk, NFiB and Syk families of kinases play pivotal roles in the regulation of immune function. The Src family currently includes Fyn, Lek, 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 10 Itk. The Janus family of kinases is involved in the transduction of growth factor and proinflammatory cytokine signals through a number of receptors. Although BTK and ITK, members of the Tec family of kinases, 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 Csk and Chk. The 15 kinases RIP, IRAK-1, IRAK-2, NIK, p38 MAP kinases, Jnk, IKK-1 and IKK-2 are involved in the signal transduction pathways for key pro-inflammatory cytokines, such as TNF and IL-1. By virtue of their ability to inhibit one or more of these kinases, compounds of formula I may function as immunomodulatory agents useful for the maintenance of allografts, the treatment of autoimmune disorders and 20 treatment of sepsis and septic shock. Through their ability to regulate the migration or activation of T cells, B-cells, mast cells, monocytes and neutrophils, these compounds could be used to treat such autoimmune diseases and sepsis. Prevention of transplant rejection, either host versus graft for solid organs or graft versus host for bone marrow, are limited by the toxicity of currently available 25 immunosuppressive agents and would benefit from an efficacious drug with improved therapeutic index. Gene targeting experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for bone resorption. Compounds of formula I, through their ability to regulate Src, may also be useful in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor 30 induced hypercalcemia and in the treatment of bone metastases. A number of protein kinases have been demonstrated to be protooncogenes.

WO 00/17203 PCT/US99/21560 -55 Chromosome breakage (at the ltk kinase break point on chromosome 5), translocation as in the case of the Abi gene with BCR (Philadelphia chromosome), truncation in instances such as c-Kit or EGFR, or mutation (e.g., Met) result in the creation of dysregulated proteins converting them from protooncogene to oncogene 5 products. In other tumors, oncogenesis is driven by an autocrine or paracrine ligand/growth factor receptor interactions. Members of the src-family kinases are typically involved in downstream signal transduction thereby potentiating the oncogenesis and themselves may become oncogenic by over-expression or mutation. By inhibiting the protein kinase activity of these proteins the disease process may be 10 disrupted. Vascular restenosis may involve FGF and/or PDGF - promoted smooth muscle and endothelial cell proliferation. The ligand stimulation of FGFR, PDGFR, IGF1-R and c-Met in vivo is proangiogenic, and potentiates angiogenesis dependent disorders. Inhibition of FGFr, PDGFr, c-Met, or IGF1-R kinase activities individually or in combination may be an efficacious strategy for inhibiting these 15 phenomena. Thus compounds of formula I which inhibit the kinase activity of normal or aberrant c-kit, c-met, c-fins, src-family members, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, IGF1-R and other receptor or cytosolic tyrosine kinases may be of value in the treatment of benign and neoplastic proliferative diseases. In many pathological conditions (for example, solid primary tumors and 20 metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inappropriate ocular neovascularization, psoriasis and atherosclerosis) disease progression is contingent upon persistent angiogenesis. Polypeptide growth factors often produced by the disease-tissue or associated inflammatory cells, and their corresponding endothelial cell specific receptor tyrosine kinases (e.g., KDR/VEGFR-2, Flt 25 1/VEGFR-1, Tie-2/Tek and Tie) are essential for the stimulation of endothelial cell growth, migration, organization, differentiation and the establishment of the requisite new functional vasculature. As a result of the vascular permeability factor activity of VEGF in mediating vascular hyperpermeability, VEGF-stimulation of a VEGFR kinase is also believed to play an important role in the formation of tumor 30 ascites, cerebral and pulmonary edema, pleural and pericardial effusions, delayed type hypersensitivity reactions, tissue edema and organ dysfunction following WO 00/17203 PCT/US99/21560 -56 trauma, bums, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), post-cardiopulmonary bypass-related hypotension and hyperpermeability, and ocular edema leading to glaucoma or blindness due to inappropriate neovascularization. In addition to VEGF, recently identified VEGF-C 5 and VEGF-D, and virally-encoded VEGF-E or HIV-Tat protein can also cause a vascular hyperpermeability response through the stimulation of a VEGFR kinase. KDR/VEGFR-2 and/or Tie-2 are expressed also in a select population of hematopoietic stem cells. Certain members of this population are pluripotent in nature and can be stimulated with growth factors to differentiate into endothelial 10 cells and participate in vasculogenetic angiogenic processes. For this reason these have been called Endothelial Progenitor Cells (EPCs) (J. Clin. Investig. 103 : 1231 1236 (1999)). In some progenitors, Tie-2 may play a role in their recruitment, adhesion, regulation and differentiation (Blood, 4317-4326 (1997)). Certain agents according to formula I capable of blocking the kinase activity of endothelial cell 15 specific kinases could therefore inhibit disease progression involving these situations. Vascular destabilization of the antagonist ligand of Tie-2 (Ang2) is believed to induce an unstable "plastic" state in the endothelium. In the presence of high VEGF levels a robust angiogenic response may result; however, in the absence of 20 VEGF or a VEGF-related stimulus, frank vessel regression and endothelial apoptosis can occur (Genes and Devel. 13: 1055-1066 (1999)). In an analogous manner a Tie 2 kinase inhibitor can be proangiogenic or antiangiogenic in the presence or absence of a VEGF-related stimulus, respectively. Hence, Tie-2 inhibitors can be employed with appropriate proangiogenic stimuli, such as VEGF, to promote therapeutic 25 angiogenesis in situations such as wound healing, infarct and ischemia. The compounds of formula I or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system, as described above. For example, 30 such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's WO 00/17203 PCTIUS99/21560 -57 disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (eg. kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic 5 malignancies (leukemia and lymphoma), and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and 10 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 envisaged that the disorders listed above are mediated to a significant 15 extent by protein tyrosine kinase activity involving the VEGF receptors (e.g. KDR, Flt-1 and/or Tie-2). By inhibiting the activity of these receptor tyrosine kinases, the progression of the listed disorders is inhibited because the angiogenic component of the disease state is severely curtailed. The action of the compounds of this invention, by their selectivity for specific tyrosine kinases, result in a minimization 20 of side effects that would occur if less selective tyrosine kinase inhibitors were used. In another aspect the present invention provides compounds of formula I as defined initially above for use as medicaments, particularly as inhibitors of protein kinase activity for example tyrosine kinase activity, serine kinase activity and threonine kinase activity. In yet another aspect the present invention provides the 25 use of compounds of formula I as defined initially above in the manufacture of a medicament for use in the inhibition of protein kinase activity. In this invention, the following definitions are applicable: "Physiologically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by 30 reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as sulfonic acid, carboxylic WO 00/17203 PCTIUS99/21560 -58 acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like. "Alkyl" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups having 1 to 6 carbons or cyclic hydrocarbons having 3 to 5 6 carbons. "Alkoxy" refers to an "0-alkyl" group, where "alkyl" is defined as described above. Pharmaceutical Formulations 10 The compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate vascular hyperpermeability, edema and associated disorders. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated 15 pharmaceutical compositions. A therapeutically effective dose further refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of inappropriate neovascularization, progression of hyperproliferative disorders, edema, VEGF-associated hyperpermeability and/or VEGF-related hypotension. Techniques for formulation and administration of the compounds of 20 the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Routes of Administration Suitable routes of administration may, for example, include oral, eyedrop, 25 rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Alternatively, one may administer the compound in a local rather than a 30 systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.

WO 00/17203 PCT/US99/21560 -59 Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody. Composition/Formulation 5 The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions for use in accordance with the present 10 invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. 15 For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. 20 For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. 25 Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such 30 as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium WO 00/17203 PCT/US99/21560 -60 carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, 5 concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, 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 tablets or dragee coatings for identification or to characterize different combinations of active compound doses. 10 Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft 15 capsules, the active compounds may be dissolved or suspended in suitable liquids, such as 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 20 lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, 25 dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. 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. 30 The compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be WO 00/17203 PCTIUS99/21560 -61 presented in unit dosage form, e.g.in ampoules or in multi-dose containers, with an added 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. 5 Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. 10 Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. 15 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 such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. 20 In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example 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 25 acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may 30 be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol WO 00/17203 PCT/US99/21560 -62 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent 5 system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl 10 pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater 15 toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to 20 over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, 25 cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous 30 or other protonic solvents than are the corresponding free base forms.

WO 00/17203 -63- PCT/US99/21560 Effective Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount 5 means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cellular assays. For example, a dose 10 can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC 0 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity). In some cases it is appropriate to determine the IC, 0 in the presence of 3 to 5% serum albumin since such a determination approximates 15 the binding effects of plasma protein on the compound. Such information can be used to more accurately determine useful doses in humans. Further, the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma. A therapeutically effective dose refers to that amount of the compound that 20 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., for determining the maximum tolerated dose (MTD) and the ED 5 0 (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed 25 as the ratio between MTD and ED 50 . Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 0 with little or no toxicity. The dosage may vary within this range 30 depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the WO 00/17203 PCT/US99/21560 -64 individual physician in view of the patient's condition. (See e.g. Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p1). In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response. 5 Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein. 10 Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the 15 MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drugmay not be related to plasma concentration. The amount of composition administered will, of course, be dependent on the 20 subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Packaging The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. 25 The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. 30 In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained WO 00/17203 PCT/US99/21560 -65 by fluid energy milling. The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but 5 particularly any compound which is the final product of one of the preceding Examples. a) Capsules 10 In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound. 15 b) Tablets Tablets can be prepared from the following ingredients. Parts by weight Active compound 10 20 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch can be de 25 aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinyl- pyrrolidone in ethanol. The dry granulate can be blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound. 30 WO 00/17203 PCT/US99/21560 -66 c) Enteric coated tablets Tablets can be prepared by the method described in (b) above. The tablets can be enteric coated in a conventional manner using a solution of 20% cellulose 5 acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1). d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the 10 mixture formed into suppositories each containing a therapeutically effective amount of active ingredient. In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. For example, the compounds of this invention can be administered in combination 15 with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization. The compounds of the invention can be administered 20 prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate. The additional pharmaceutical agents include but are not limited to anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-1R 25 inhibitors, PKC inhibitors and P13 kinase inhibitors. The compounds of the invention and the additional pharmaceutical agents act either additively or synergistically. Thus, the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative 30 disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone. In the treatment of malignant disorders combinations with WO 00/17203 PCT/US99/21560 -67 antiproliferative or cytotoxic chemotherapies or radiation are anticipated. The present invention also comprises the use of a compound of formula I as a medicament. A further aspect of the present invention provides the use of a compound of 5 formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings. The present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or 10 disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of formula I to a mammal, particularly a human being, in need thereof. The in vitro potency of compounds in inhibiting these protein kinases may be determined by the procedures detailed below. 15 The potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a test compound relative to control. KDR Tyrosine Kinase Production Using Baculovirus System: 20 The coding sequence for the human KDR intra-cellular domain (aa789-13 5 4 ) was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL 1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the 25 BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection. 30 WO 00/17203 PCT/US99/21560 -68 Purification of KDR 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, 1mM PMSF, 10pg/ml aprotinin, 1 pg/ml leupeptin) to the cell pellet 5 from 1L of cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4'C. The cell lysate was applied to a 5 ml NiCl 2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase 10 activity. The purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM NaCl, 5 mM DTT buffer and stored at -80'C. Human Tie-2 Kinase Production and Purification The coding sequence for the human Tie-2 intra-cellular domain (aa775-1124) 15 was generated through PCR using cDNAs isolated from human placenta as a template. A poly-His 6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and 20 verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR. 25 Human Flt-1 Tyrosine Kinase Production and Purification The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-i (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was 30 generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous WO 00/17203 PCT/US99/21560 -69 to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection. EGFR Tyrosine Kinase Source 5 EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 pl) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100). Expression of ZAP70 10 The baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.) The nucleotide sequence encoding amino acids M(H)6 LVPRS was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619). The nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cDNA libraries isolated from Jurkat immortalized T-cells. The histidine 15 residues enabled affinity purification of the protein (vide infra). The LVPR 9 S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling 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 post infection. 20 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 pag/ml leupeptin, 10 pg/ml aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM HEPES, pH 25 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT. Protein kinase source 30 Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained ( e.g. from Upstate Biotechnology Inc. (Saranac Lake, N.Y) WO 00/17203 PCTIUS99/21560 -70 and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods. Enzyme Linked Immunosorbent Assay (ELISA) For PTKs 5 Enzyme linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA were conducted according to known protocols which are described in, for example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, 10 Washington, D.C. The disclosed protocol was adapted for determining activity with respect to a specific PTK. For example, preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non 15 receptor tyrosine kinases, are well within the abilities of those in the art. For purposes of determining inhibitor selectivity, a universal PTK substrate (e.g., random copolymer of poly(Glu 4 Tyr), 20,000-50,000 MW) was employed together with ATP (typically 5 yM) at concentrations approximately twice the apparent Km in the assay. 20 The following procedure was used to assay the inhibitory effect of compounds of this invention on KDR, Flt-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1 R, c-Met, Lck, Blk, Csk, Src, Lyn, Fyn and ZAP70 tyrosine kinase activity: Buffers and Solutions: 25 PGTPoly (Glu,Tyr) 4:1 Store powder at -20"C. Dissolve powder in phosphate buffered saline (PBS) for 50mg/ml solution. Store lml aliquots at -20'C. When making plates dilute to 250pg/ml in Gibco PBS. Reaction Buffer: 100mM Hepes, 20mM MgCl,, 4mM MnC1 2 , 5mM DTT, 30 0.02%BSA, 200pM NaVO 4 , pH 7.10 ATP: Store aliquots of 100mM at -20*C. Dilute to 20pM in water WO 00/17203 PCTIUS99/21560 -71 Washing Buffer: PBS with 0.1% Tween 20 Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue Substrate from Neogen 5 Stop Solution: 1M Phosphoric Acid Procedure 1. Plate Preparation: Dilute PGT stock (50mg/ml, frozen) in PBS to a 250ptg/ml. Add 125A per well of 10 Coming modified flat bottom high affinity ELISA plates (Corning #25805-96). Add 125pl PBS to blank wells. Cover with sealing tape and incubate overnight 37"C. Wash lx with 250pl washing buffer and dry for about 2hrs in 37'C dry incubator. Store coated plates in sealed bag at 4"C until used. 15 2. Tyrosine Kinase Reaction: -Prepare inhibitor solutions at a 4x concentration in 20% DMSO in water. -Prepare reaction buffer -Prepare enzyme solution so that desired units are in 5 0 1 , e.g. for KDR make to 1 ng/pl for a total of 50ng per well in the reactions. Store on ice. 20 -Make 4x ATP solution to 20pM from 100mM stock in water. Store on ice -Add 504 of the enzyme solution per well (typically 5-50 ng enzyme/well depending on the specific activity of the kinase) -Add 25pl 4x inhibitor -Add 254 4x ATP for inhibitor assay 25 -Incubate for 10 minutes at room temperature -Stop reaction by adding 50pl 0.05N HCl per well -Wash plate **Final Concentrations for Reaction: 5,pM ATP, 5% DMSO 30 3. Antibody Binding -Dilute lmg/ml aliquot of PY20-HRP (Pierce) antibody(a phosphotyrosine WO 00/17203 PCT/US99/21560 -72 antibody)to 5Ong/ml in 0.1% BSA in PBS by a 2 step dilution (100x, then 200x) -Add 100pl Ab per well. Incubate 1 hr at room temp. Incubate lhr at 4C. -Wash 4x plate 4. Color reaction 5 -Prepare TMB substrate and add 100yl per well -Monitor OD at 650nm until 0.6 is reached -Stop with 1M Phosphoric acid. Shake on plate reader. -Read OD immediately at 450nm Optimal incubation times and enzyme reaction conditions vary slightly with 10 enzyme preparations and are determined empirically for each lot. For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl 2 , 20 mM MgCl 2 , 5 mM DTT, 0.2% BSA, 200 mM NaVO 4 under the analogous assay conditions. 15 Compounds of formula I may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formula I. All compounds exemplified herein significantly inhibit either FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, Blk, Lyn or Src at concentrations of 50 micromolar or below. 20 Some compounds of this invention also significantly inhibit other tyrosine or serine/threonine kinases such as cdc2 (cdkl) at concentrations of 50 micromolar or below. Cdc2 source 25 The human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods. Cdc2 Assay 30 The protocol used was that provided with the purchased reagents with minor modifications. In brief, the reaction was carried out in a buffer consisting of 50mM WO 00/17203 PCT/US99/21560 -73 Tris pH 7.5, 100mM NaCl, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10mM MgCl 2 (commercial buffer) supplemented with fresh 300 ytM ATP (31 yCi/ml) and 30 pg/ml histone type Iss final concentrations. A reaction volume of 80p2L, containing units of enzyme, was run for 20 minutes at 25 degrees C in the 5 presence or absence of inhibitor. The reaction was terminated by the addition of 120pL of 10% acetic acid. The substrate was separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts were measured by a betacounter in the presence of liquid scintillant. 10 Certain compounds of this invention significantly inhibit cdc2 at concentrations below 50 uM. PKC kinase source 15 The catalytic subunit of PKC may be obtained commercially (Calbiochem). PKC kinase assay A radioactive kinase assay was employed following a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. 20 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 pH7.5, 10mM MgCl 2 , 2mM DTT, 1mM EGTA, 100 4M ATP, 8 yaM peptide, 5% DMSO and 3 3 P ATP (8Ci/mM). Compound and enzyme were mixed in the reaction vessel and the reaction initiated by addition of the ATP and substrate 25 mixture. Following termination of the reaction by the addition of 10 4L stop buffer (5 mM ATP in 75mM phosphoric acid), a portion of the mixture was spotted on phosphocellulose filters. The spotted samples were washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Incorporation of radiolabel was quantified by liquid scintillation counting. 30 WO 00/17203 74 PCTIUS99/21560 Erk2 enzyme source The recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods. 5 Erk2 enzyme assay In brief, the reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 2 (commercial buffer) supplemented with fresh 100 pUM ATP (31 ptCi/ml) and 30p.M 10 myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity were as described for the PKC assay (vide supra). In Vitro Models for T-cell Activation 15 Upon activation by mitogen or antigen, T-cells are induced to secrete IL-2, a growth factor that supports their subsequent proliferative phase. Therefore, one may measure either production of IL-2 from or cell proliferation of, primary T-cells or appropriate T-cell lines as a surrogate for T-cell activation. Both of these assays are well described in the literature and their parameters well documented (in Current 20 Protocols in Immunology, Vol 2, 7.10.1-7.11.2). In brief, T-cells may be activated by co-culture with allogenic stimulator cells, a process termed the one-way mixed lymphophocyte reaction. Responder and stimulator peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) per directions of the manufacturer. Stimulator cells are 25 mitotically inactivated by treatment with mitomycin C (Sigma) or gamma irradiation. Responder and stimulator cells are co-cultured at a ratio of two to one in the presence or absence of the test compound. Typically 10' responders are mixed with 5 x 104 stimulators and plated (200 pl volume) in a U bottom microtiter plate (Costar Scientific). The cells are cultured in RPMI 1640 supplemented with either 30 heat inactivated fetal bovine serum (Hyclone Laboratories) or pooled human AB serum from male donors, 5 x 10-' M 2mercaptoethanol and 0.5% DMSO, The WO 00/17203 -75- PCT/US99/21560 cultures are pulsed with 0.5 ACi of 3 H thymidine (Amersham) one day prior to harvest (typically day three). The cultures are harvested (Betaplate harvester, Wallac) and isotope uptake assessed by liquid scintillation (Betaplate, Wallac). The same culture system may be used for assessing T-cell activation by 5 measurement of IL-2 production. Eighteen to twenty-four hours after culture initiation, the supernatants are removed and the IL-2 concentration is measured by ELISA (R and D Systems) following the directions of the manufacturer. In-vivo Models of T-Cell Activation 10 The in vivo efficacy of compounds can be tested in animal models known to directly measure T-cell activation or for which T-cells have been proven the effectors. T-cells can be activated in vivo by ligation of the constant portion of the T-cell receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB/c mice are given 10ptg of anti-CD3 Ab intraperitoneally two hours prior to 15 exsanguination. Animals to receive a test drug are pre-treated with a single dose of the compound one hour prior to anti-CD3 Ab administration. Serum levels of the proinflammatory cytokines interferon-y (IFN- y) and tumor necrosis factor-a(TNF-ca), indicators of T-cell activation, are measured by ELISA. A similar model employs in vivo T-cell priming with a specific antigen such as keyhole limpet 20 hemocyanin (KLH) followed by a secondary in vitro challenge of draining lymph node cells with the same antigen. As previously, measurement of cytokine production is used to assess the activation state of the cultured cells. Briefly, C57BL/6 mice are immunized subcutaneously with 100 pg KLH emulsified in complete Freund's adjuvant (CFA) on day zero. Animals are pre-treated with the 25 compound one day prior to immunization and subsequently on days one, two and three post immunization. Draining lymph nodes are harvested on day 4 and their cells cultured at 6 x 106 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) for both twenty-four and forty-eight hours. 30 Culture supernatants are then assessed for the autocrine T-cell growth factor Interleukin-2 (IL-2) and/or IFN-y levels by ELISA.

WO 00/17203 -76- PCT/US99/21560 Lead compounds can also be tested in animal models of human disease. These are exemplified by experimental auto-immune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models which mimic aspects of human multiple sclerosis have been described in both rats and mice (reviewed FASEB J. 5 5:2560-2566, 1991; murine 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 neurogenic peptide derivatives thereof, and CFA. Acute disease can be induced with the addition of bacterial toxins such as bordetella pertussis. Relapsing/remitting disease is induced by adoptive 10 transfer of T-cells from MBP/ peptide immunized animals. CIA may be induced in DBA/1 mice by immunization with type II collagen (J. Immunol:142(7):2237-2243). Mice will develop signs of arthritis as early as ten days following antigen challenge and may be scored for as long as ninety days after immunization. In both the EAE and CIA models, a compound may be administered 15 either prophylactically or at the time of disease onset. Efficacious drugs should reduce severity and/or incidence. Certain compounds of this invention which inhibit one or more angiogenic receptor PTK, and/or a protein kinase such as lck involved in mediating inflammatory responses can reduce the severity and incidence of arthritis in these 20 models. Compounds can also be tested in mouse allograft models, either skin (reviewed in Ann. Rev. Immunol., 10:333-58, 1992; Transplantation: 57(12): 1701-17D6, 1994) or heart (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 25 examined daily, beginning at day six, for evidence of rejection. In the mouse neonatal heart transplant model, neonatal hearts are ectopically transplanted from C57BL/6 mice into the ear pinnae of adult CBA/J mice. Hearts start to beat four to seven days post transplantation and rejection may be assessed visually using a dissecting microscope to look for cessation of beating. 30 WO 00/17203 PCT/US99/21560 -77 Cellular Receptor PTK Assays The following cellular assay was used to determine the level of activity and effect of the different compounds of the present invention on KDR/VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed 5 along the same lines for other tyrosine kinases using techniques well known in the art. VEGF-Induced KDR Phosphorylation in Human Umbilical Vein Endothelial Cells (HUVEC) as Measured by Western Blots: 1. HUVEC cells (from pooled donors) were purchased from Clonetics 10 (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) were used for this assay. Cells were cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complete EBM media (Clonetics). 2. For evaluating a compound's inhibitory activity, cells were 15 trypsinized and seeded at 0.5-1.0 x 10' cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA). 3. 3-4 days after seeding, plates were 90-100% confluent. Medium was removed from all the wells, cells were rinsed with 5-10ml of PBS and incubated 18 24h with 5ml of EBM base media with no supplements added (i.e., serum 20 starvation). 4. Serial dilutions of inhibitors were added in lml of EBM media (25pM, 5MM, or lyM final concentration to cells and incubated for one hour at 37 C. Human recombinant VEGF,,s ( R & D Systems) was then added to all the wells in 2 ml of EBM medium at a final concentration of 50ng/ml and incubated at 37 C 25 for 10 minutes. Control cells untreated or treated with VEGF only were used to assess background phosphorylation and phosphorylation induction by VEGF. All wells were then rinsed with 5-10ml of cold PBS containing 1mM Sodium Orthovanadate (Sigma) and cells were lysed and scraped in 2 00pl of RIPA buffer (50mM Tris-HC1) pH7, 150mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 30 1mM EDTA) containing protease inhibitors (PMSF 1mM, aprotinin lyg/ml, pepstatin lyg/ml, leupeptin lyg/ml, Na vanadate 1mM, Na fluoride 1mM) and WO 00/17203 PCT/US99/21560 -78 lgg/ml of Dnase (all chemicals from Sigma Chemical Company, St Louis, MO). The lysate was spun at 14,000 rpm for 30min, to eliminate nuclei. Equal amounts of proteins were then precipitated by addition of cold (-20 C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. Pellets 5 were reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins were resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), the proteins were probed overnight with anti-KDR 10 polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with 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 of goat anti-rabbit or goat-anti-mouse IgG the bands were visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Height, IL). 15 Certain examples of the present invention significantly inhibit cellular VEGF induced KDR tyrosine kinase phosphorylation at concentrations of less than 50 pM. In vivo Uterine Edema Model This assay measures the capacity of compounds to inhibit the acute increase 20 in uterine weight in mice which occurs in the first few hours following estrogen stimulation. This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), 133:829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the 25 uterus. These results have been confirmed by the use of neutralizing monoclonal antibody to VEGF which significantly reduced the acute increase in uterine weight following estrogen stimulation (WO 97/42187). Hence, this system can serve as a model for in vivo inhibition of VEGF signalling and the associated hyperpermeability and edema. 30 WO 00/17203 PCT/US99/21560 -79 Materials: All hormones were purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions. Vehicle components (DMSO, Cremaphor EL) were purchased from Sigma (St. 5 Louis, MO). Mice (Balb/c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines. 10 Method: Day 1: Balb/c mice were given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG). Day 3: Mice received 15 units of human chorionic gonadotropin (hCG) i.p. 15 Day 4: Mice were randomized and divided into groups of 5-10. Test compounds were administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group received vehicle only and two groups were left untreated. Thirty minutes later, experimental, vehicle and 1 of the untreated groups 20 were given an i.p. injection of 17 -estradiol (500 pg/kg). After 2-3 hours, the animals were sacrificed by CO 2 inhalation. Following a midline incision, each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts. Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight). Uteri were blotted 25 to remove fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. Uteri were weighed following blotting (blotted weight). The difference between wet and blotted weights was taken as the fluid content of the uterus. Mean fluid content of treated groups was compared to untreated or vehicle treated groups. Significance was determined by Student's test. Non-stimulated 30 control group was used to monitor estradiol response. Results demonstrate that certain compounds of the present invention inhibit WO 00/17203 PCT/US99/21560 -80 the formation of edema when administered systemically by various routes. Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization. The Matrigel neovascularization model involves the formation 5 of new blood vessels within a clear "marble" of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (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). The model preferably runs over 3-4days and 10 endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors. The model may alternatively employ bFGF or HGF as the stimulus. 15 Certain compounds of this invention which inhibit one or more oncogenic, protooncogenic, or proliferation-dependent protein kinases, or angiogenic receptor PTK also inhibit the growth of primary murine, rat or human xenograft tumors in mice, or inhibit metastasis in murine models. 20 EXAMPLES Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention. The processes are preferably carried out at atmospheric pressure. Compounds of formula I may be prepared by condensing a compound of 25 formula 30 WO 00/17203 PCT/US99/21560 -81

R

3 -- (H 2 C)--L A CN 5R2 N NH2 R1 (II) 10 in which R 1 , R 2 , R 3 , L and ring A are as previously defined 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 15 formula (III) NH2 Rx 20 R2 N N

R

1 (III) 25 wherein R, is bromo or iodo bromo or iodo with one of the following compounds:

R

3

B(OH)

2 , R 3 Sn(CH 3

)

3 or a compound represented by formula IV 30 WO 00/17203 PCTIUS99/21560 -82 R3-(H 2 C)-L A

R

3

-(H

2 C)--L A

B(OH)

2 Sn(CH 3 )a 5 or R - (H 2 C) -L A B 0 IV 10 in which R 3 is as defined above, in the presence of a catalyst for example palladium (0) compounds eg. Pd(PPh 3

)

4 . Compounds of formula I in which R, represents an alkyl group or an aralkyl group may be prepared by alkylating a compound of formula (V) 15 NH2 A L--(CH 2)7--R3 20 N R2 NN H (V) 25 in which R 2 and R 3 are as previously defined with a compound of formula RIX' in which R, represents an alkyl group or an aralkyl group and X' represents a leaving group, for example halo, mesyloxy or tosyloxy. 30 Compounds of formula I in which RI represents an optionally substituted cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl, may be prepared by WO 00/17203 PCTIUS99/21560 -83 alkylating a compound of formula VI

NH

2

R

3 N N R2 N N H (v) 10 in which R2 and R3 are as previously defined with a compound of formula R IX' in which X' is as previously defined and R, is an optionally substituted cyclic ether. Compounds of formula I in which RI represents cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl, optionally substituted by formyl may be prepared by alkylating a compound of formula VI with a compound RiX in which 15 Ri represents a cyclic ether substituted by a formyl group which has been protected, by a method known to those skilled in the art, for example by means of an acetal, (See for example Tet. Letts. 30(46):6259-6262 (1989)) followed by deprotection. Compounds in which RI represents a cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl, substituted by an (optionally substituted amino)methyl group 20 may be prepared by reductive amination of a compound in which RI represents a cyclic ether substituted by formyl. Compounds of formula I in which RI represents optionally substituted furyl, thienyl or pyrrolyl may be prepared by reacting 4 -chloro-5-iodo-7H-pyrrolo[2,3 d]pyrimidine with the appropriate heteroarylboronic acid in the presence of a copper 25 salt catalyst, for example copper (II) acetate in the presence of a solvent for the reactants, e.g. a halogenated solvent for example, dichloromethane, in the presence of a drying agent, for example 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 ambient temperature. (For conditions see Tet. Letts. (1998), 30 39:2942-2944 and references cited therein. This paper is incorporated herein by WO 00/17203 PCT/US99/21560 -84 reference.) These compounds may be formulated by methods known to those skilled in the art to give compounds in which RI represents furyl, thienyl or pyrrolyl substituted by formyl. The formyl group in these compounds may be productively aminated by methods known to those skilled in the art to give compounds in which 5 Ri represents furyl, thienyl or pyrrolyl substituted by aminomethyl groups. Alternatively intermediates in which R1 represents furyl, thienyl or pyrrolyl may be subjected to a Mannich reaction to give intermediates in which RI represents furyl, thienyl or pyrrolyl substituted by an aminomethyl group. Compounds of formula I may be prepared by reacting a compound of 10 formula VII A L- (CH2)r---R 15 R2 N N R, 20 in which R 1 , R 2 , R 3 , L and ring A are as previously defined and R, represents a leaving group, for example halo or phenoxy, with ammonia or an ammonium salt, for example ammonium acetate, at a temperature in the range of 15-250'C, preferably in a pressure vessel. 25 Compounds of formula I in which R 2 represents chloro, bromo or iodo may be prepared by reacting a compound of formula VIII 30 WO 00/17203 -85- PCT/US99/21560 A L-(CH2)F----R3

NH

2 5 N N R1 (VIMI 10 in which R,, R 3 , L and ring A are as previously defined with a halogenating agent for example an iodinating agent, e.g. N-iodosuccinimide, or a brominating agent, e.g. N bromosuccinimide, or a chlorinating agent, e.g. N-chlorosuccinimide. Compounds of formula I in which -L-R, represents -NHC(O)R may be prepared by reacting a compound of formula IX 15 y A NH2 20 NR2 N N

R

1 Ix 25 in which R 1 , R 2 and ring A are as previously defined and Y represents a protected amine, with a compound of formula R 3 COR, in which R, represents a leaving group, for example chloro. Alternatively compounds of formula IX in which Y represents halo, for example chloro, may be reacted with a compound of formula R 3 COR, and 30 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 -L-R 3 is - WO 00/17203 PCT/US99/21560 -86

NRSO

2

R

3 . Analogous methods may be used to prepare compound of formula I in which -L-R 3 is -NRCO 2

-R

3 or -NRCONR'. R and R' are as previously defined. Compounds of formula I in which -L-R is -OS02- may be prepared by reacting a compound of formula X 5 A OH

NH

2 10 N R2 N N R1 x 15 in which R, R 2 and ring A are as previously defined with a compound of formula

R

4

SO

2 R,. Compounds of formula I may then be prepared from such intermediates 20 following Scheme 2 or the alternative for Scheme 2, which is described later. Compounds of formula II may be prepared as shown in Scheme 1 in which IPA represents propan-2-ol, 25 30 WO 00/17203 PCTIUS99/21560 -87 Scheme I 0 Br 5 R 3 - (H 2 C)--L A R2 1) H 2 NR, IIPA or CH 3CN 10 2) HC/IPA 0 HC NHR1

R

3 - (H 2 C)--L A R2 15 1) NaOCH 2

CH

3

/CH

3

CH

2 OH 2) NCCH 2 CN/NaOCH 2

CH

3 ,

CH

3

CH

2 0H, 50 C 20 R3-(H2C);-- L- A C CN 25 R2 N NH 2 It will be appreciated by those skilled in the art that compounds of formula I may be converted into other compounds of formula I by known chemical reactions. 30 For example, an alkoxy group may be cleaved to give hydroxy, nitro groups may be reduced to amines, amines may be acylated or sulfonylated and N-acyl compounds WO 00/17203 PCT/US99/21560 -88 may be hydrolyzed to amines. Compounds of formula I in which -L- is S may be oxidized to give compounds of formula I in which -L- represents SO and SO 2 , respectively, by methods known to those skilled in the art. Compounds of formula III are commercially available or may be prepared by 5 methods known to those skilled in the art. Compounds of formula V in which R 2 represents hydrogen may be prepared as shown in Scheme 2. The amino group may be protected prior to 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 may be 10 prepared by analogous methods. (see J. Med. Chem. (1990), 33, 1984.) Scheme 2 CA

NH

2 1 15 N NH 3 , CHOH N N+ R 3 - (H 2 cjL A NKN ~ ur N

B(OH)

2 H H A L-(CH 2

);-R

3

NH

2 20 Pd(O) N N N H 25 Alternatively in Scheme 2, (ring A)-L-R may be coupled first, prior to amination. Alternatively a substituent R, as defined previously may be present prior to carrying out either process. Compounds of formula VII, in which Ry is a -Cl, may be prepared as shown 30 in Scheme 3.

WO 00/17203 PCT/US99/21560 Scheme 3 OH CI C1 5 R2 N R2 N-iodosuccinamide NR2 + R3---(HC 2CR B(H) Nd0 N N NR R1 10 N x 15 Compounds in which (ring A)-L-R 3 is absent may be prepared as in Scheme 4 and as described in JMed. Chem., (1988), 31:390 and references cited therein. Compounds in which (ring A)-L-R 3 is other than hydrogen may be prepared by 20 analogous methods. C1

NH

2 N

NH

3 , CH 3 0H N N N\ pressure N 25 N N R1 R1 Scheme 4 30 WO 00/17203 PCTIUS99/21560 Compounds of formula VII may be prepared by coupling a 5-iodo compound in an analogous manner to that described for the preparation of compounds of formula V. R, may be modified by the method depicted in Schemes 5 and 6. In Schemes 5 5 and 6 P represents a protecting group. Scheme 5 A L---(CH2);--R3

NH

2 10 N N N 15 0 R N R Na(OAc) 3 BH, HoAc 20

CICH

2

CH

2 CI A L- (CH2)T-R3

NH

2 25 N N N 30 0 WO 00/17203 PCT/US99/21560 9( Scheme 6 A L-(CH2)j--R3

NH

2 5N N N ( ) r N H 10 0 N p Na(OA) 3 B, HoAc 15 CIGH 2 cH 2 CI A L-(CH--R 3 NH2 20 N N N () r N 25 N p It will be appreciated by those skilled in the art that in cases where a substituent is identical with, or similar to, a functional group which has been 30 modified in one of the above processes that these substituents will require protection before the process is undertaken, followed by deprotection after the process.

WO 00/17203 PCTIUS99/21560 9; Otherwise competing sidereactions will occur. Alternatively, another of the processes described above, in which the substituent does not interfere, may be used. Examples of suitable protecting groups and methods for their addition and removal may be found in the textbook "Protective Groups in Organic Synthesis" by T.W. 5 Green, John Wiley and Sons, 1981. For example suitable protecting groups for amines are formyl or acetyl. The following synthetic examples were prepared using the general preparative procedures described above: 10 Example 1: Benzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]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) 15 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 minimum amount of dichloromethane. The combined filtrate was washed with water, 1.0 N HCl, 20 water and brine. The organic layer was dried (MgSO 4 ) and filtered. The solvent was evaporated to give tetrahydro-2H-4-pyranyl trifluoromethanesulfonate. 'H NMR (CDCl 3 ) a 1.99 (m, 2H), 2.11 (m, 2H), 3.58 (m, 2H), 3.96 (m, 2H), 5.17 (m, 1H). 25 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 ( 0.891g 22.2 mmol) in N,N dimethylformamide (40 ml) at 0 0 C. After completed the addition the ice water bath was removed and the resulting mixture was stirred for 30 minutes. 30 Tetrahydro-2H-4-pyranyl trifluoromethanesulfonate was added dropwise and the reaction mixture was stirred at ambient temperature for 24 hours. The mixture WO 00/17203 PCT/US99/21560 ?3 was poured to ice water (100ml) and the solid was collected by filtration and purified by re-crystallization to give 4-chloro-5-iodo-7-tetrahydro-2H-4-pyranyl 7H-pyrrolo[2,3-d]pyrimidine. 'H NMR (CDCl 3 ) 8 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*=364) 5 c) tert-Butyl N-(4-(4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate. tert-Butyl N-[2-methoxy-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbainate (1.66g, 4.75 mmol) in water was degassed by sonication under vacuum for 1 minute. 4 10 Chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidine (1.1g, 3.17 mmol), tetrakis(triphenylphosphine) palladium(0) (0.22g, 0.19 mmol), Sodium carbonate (0.8g, 7.60 mmol) and 1,2-dimethoxyethane (30 ml) was added to the aqueous mixture. The resulting suspension was degassed again for 2 minutes and then headed to 85"C for 24 hours. The reaction mixture was 15 cooled to ambient temperature and solvent was evaporated. The residue was dissolved in ethyl acetate. The organic layer washed and dried (MgSO4). The solid was purified by flash column chromatography on silica using heptane/ethyl acetate (7:3) as the mobile phase to give tert-butyl N-(4-(4-chloro-7-tetrahydro 2

H-

4 -pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl) carbamate. 20 'H NMR (CDCl 3 ) a 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=8 Hz, 1H), 8.64(s, 1H). LC/MS (MH*=459) d) 4

-(

4 -chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 25 methoxyaniline. A solution of ten percent trifluoroacetic acid in dichloromethane (50 ml) was added to tert-butyl N-(4-(4-chloro-7-tetrahydro 2

H-

4 -pyranyl-7H-pyrrolo[2,3-d]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 ambient temperature for 4 hours. The solvent was removed and 30 the residue taken into dichloromethane. Saturated sodium bicarbonate was added and the layers separated. The aqueous layer was extracted with WO 00/17203 PCT/US99/21560 dichloromethane. The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The solid was purified by passing though a pat of silica gel using heptane/ethyl acetate (3:2) as the mobile phase to give 4 (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 5 methoxyaniline. 'H NMR (CDC1 3 ) 8 2.09 (in, 4H), 2.51 (br. s, NH 2 ), 3.66 (m, 2H), 3.91 (s, 3H), 4.16 (in, 2H), 5.05 (in, 1H), 6.79 (d, J=8 Hz, 2H), 6.93 (d, J=8 Hz, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 8.63 (s, 1H). LC/MS (MHW=359) e) 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 10 d]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 (0.73g, 2.03 mmol) in dioxane (25 ml) in a pressure tube. The pressure tube was sealed and heated to 122'C for 2 days. The tube was cooled to ambient temperature and the solvent was evaporated. Ethyl acetate was added 15 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. 'H NMR (DMSO-d 6 ) 5 1.87 (in, 2H), 2.11 (in, 2H), 3.52 (m, 2H), 3.79 (s, 3H), 3.99 (in, 2H), 4.87 (in, 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 20 (MH*=340) f) Benzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin 5-yl)-2-methoxyphenyl)carbamate. Benzylchloroformate(16 uL, 0.110 mmol) was added dropwise to a stirring solution of 5-(4-ainino-3-methoxyphenyl)-7 25 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 the mobile phase to 30 give benzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyriiidin-5-yl)-2-methoxyphenyl) carbamate. 'H NMR (CDCl 3 ) 6 2.07 (in, WO 00/17203 PCTIUS99/21560 9< 4H), 3.65 (in, 2H), 3.9 (s, 3H), 4.13 (in, 2H), 4.97 (m, 1H), 5.23 (s, 2H), 6.96 (s, 1H), 7.03 (s, 1H), 7.08 (d, J=8 Hz, 1H), 7.42 (m, 6H), 8.20 (br. s, J=8 Hz, 1H). 8.32 (s, 1H). LC/MS (MH*=474). 5 Example 2: Neopentyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate. Neopentylchloroformate(13 uL, 0.110 mmol) was added dropwise to a stirring 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 10 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 the mobile phase to give neopentyl N-(4-(4 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 15 methoxyphenyl)carbamate. 'H NMR (CDC1 3 ) 5 1.00 (s, 3H), 2.07 (in, 4H), 3.65 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.13 (m, 2H), 4.97 (in, 1H), 5.18 (s, 2H), 6.97 (s, 1H), 7.03 (s, 1H), 7.07 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.19 (br. s, J=8 Hz, 1H). 8.33 (s, 1H). LC/MS (MH*=454). 20 Example 3: Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]carbanate 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-4-amine (100 mg, 0.294 mmol) was dissolved in dichloromethane (2 mL). Pyridine (2mL) was added followed by phenylchloroformate (44 uL, 0.353 25 mmol). After stirring for 3 hours, another 44 uL of phenylmethanesulfonyl chloride was added and the reaction mixture was 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-yl)-2-methoxyphenyl] carbamate (52 mg, 0.113 mmol). 1H NMR (CDC1 3 -d) 8 2.09 (m, 4H), 3.66 (m, 2H), 30 3.98 (s, 3H), 4.16 (in, 2H), 4.98 (in, 1H), 5.24 (s, 2H), 7.09 (m ,3H), 7.23 (in, 4H), 7.41 (in, 2H), 7.62 (s, 1H), 8.20(bd, J=7.80 Hz, 1H), 8.33 (s, 1H). LC/MS MH*=460.

WO 00/17203 PCT/US99/21560 Example 4: 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 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate 5 Tetrahydro-2H-4-pyranol (1.0 ml, 10.5 mmol) was mixed with 4 methylmorpholine (2.0 ml) in dichloromethane (20 mL). 4- Nitrochloroformate (1.98 g, 9.82 mmol) was added slowly to the reaction mixture. After stirring for 5 hours, the reaction mixture was diluted with dichloromethane. The organic layer was washed with water, 1.0 N HC, saturated sodium bicarbonate, brine, dried over 10 MgSO 4 , filtered and evaporated. The crude product was purified by flash column chromatography 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). 1H NMR (CDCl 3 -d) 8 1.87 (in, 2H), 2.06 (in, 2H), 3.58 (in, 2H), 3.98 (in, 2H), 4.97 (m,1H), 7.40(d, J=9.OHz, 2H), 8.30 (d, J=9.OHz, 2H). 15 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 20 carbonate (90 mg, 0.336 mmol) was mixed in pyridine (1 mL). After stirring for 5 hours, another 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 0 C for 2 hours. The solvent was removed and the residue was purified by preparative thin layer chromatography to give tetrahydro-2H-4 25 pyranyl N-[ 4

-(

4 -amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin 5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.064 mmol). 1H NMR (CDCl 3 -d) 8 1.78 (in, 4H), 2.08 (in, 4H), 3.60 (in, 4H), 3.94 (s, 3H), 3.97 (in, 2H), 4.15 (in, 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, IH). LC/MS MH*=468. 30 WO 00/17203 PCT/US99/21560 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- Nitrochloroformate (2.49 g, 12.3 5 mmol) in dichloromethane (20 mL) was cooled on an ice-water bath. 3 pyridylmethanol (1.0 mL, 10.3 mmol) and 4-methylmorpholine (2.0 mL, 18.5 mmol) was added slowly. After 20 minutes, the ice-water bath was removed and the reaction mixture was allowed to warm up to room temperature. 30 minues later, ethyl acetate was added and the reaction mixture was filtered. The filtrate 10 was washed with water, saturated sodium bicarbonate, brine, dried over MgSO4, filtered and evaporated to give a dark brown solid which was re-crystallized with ethyl acetate/heptane to give 4-nitrophenyl (3-pyridylmethyl) carbonate (1.52 g, 5.54 mmol).lH NMR (CDCl-d) 6 7.38 (m, 3H), 7.79 (m, 1H), 8.28 (d, J=9.09Hz, 2H), 8.65 (m, 1H), 8.72 (s,1H). 15 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 20 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-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]carbamate (12 mg, 0.025 mmol). 1H NMR (CDCl 3 -d) 8 2.08 (m, 25 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), 8.61 (s, 1H), 8.71 (s, 1H). LC/MS M*=475 30 WO 00/17203 PCTIUS99/21560 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 5 (2.OmL). 1.ON HCI in ether (1 mL) was added slowly. The precipatate was collected through 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). 1H NMR (DMSO-d 6 ) 5 1.91 (m, 2H), 2.17(m, 2H), 3.54 (m, 2H), 3.87 (s, 3H), 4.03 (m, 10 2H), 4.97(m, 1H), 5.23 (s, 2H), 7.05 (d, J=8.2Hz, 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, 1H), 8.71 (s, 1H), 8.82 (s, 1H). LC/MS MH*=475. Example 6: 2-Morpholinoethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H 15 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 20 purified by preparative reverse phase HPLC to give 2-morpholinoethyl N-[4-(4 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl] carbamate (24 mg, 0.048mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.ON HCl in ether (0.2 mL) was added slowly. The precipitate was collected through filtration under nitrogen to give 2-morpholinoethyl N-[4-(4 25 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl] carbamate hydrochloride (24 mg, 0.045 mmol). 1H NMR (DMSO d,) 5 1.88(m, 2H), 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*=497. 30 WO 00/17203 PCTIUS99/21560 9/ 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 5 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed with dimethyl formamide (2.56 mL, 34 mmol). The mixture was then heated at 75*C for 1 hours and at 100oC for 5 hours. After cooled to room temperature, the mixture was added to ice-water (500ml) and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated 10 sodium bicarbonate, dried over MgSO4, filtered and evaporated to give a brown solid which was washed with petroleum ether. Evaporation of solvent gave 2,4 dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). 1H NMR (CDCl 3 -d) 6 9.90 (S, 1H). 15 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 10 minutes later and the reaction mixture was stirred at room temperature overnight. Solvent was removed and saturated ammonium 20 chloride was added. 1.ON 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 MgSO4, filtered and evaporated. The residue was purified by flash column chromatogrphy to give (2,4-dibromo-1,3-thiazol-5-yl)methanol (0.946 g, 3.47 mmol). 1H NMR (CDCl 3 -d) 5 2.11 (bs, 1H) S 4.79 (S, 2H). 25 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 tri-hydrade (1.34 g) and palladium on carbon (10%, 0.07g) were mixed in methanol (33 mL). The resulting mixture was hydrogenated at 60 psi for 2 days. The solid was filtered off through a pat 30 of celite. The solvent was evaporated and the residue was purified by frash column chromatography to give (4-bromo-1,3-thiazol-5-yl)methanol (0.32 g, WO 00/17203 PCT/US99/21560 2.78 mmol). 1H NMR (CDC 3 -d) 5 2.29 (bs, 1H) 8 4.86 (s, 2H), 8.72 (s, 1H). 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-methoxyphenyl]carbamate. Phenyl N-[4-(4 5 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 10 thiazol-5-yl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl-d) 5 2.07(m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.13 (in, 2H), 4.98 (in, 1H), 5.35 (s, 1H), 5.40(s, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.09 (m, 1H), 7.35 (s, 1H), 8.17 (s, 1H), 8.32 (s, 1H), 8.78(s, 1H). LC/MS MH*=481. 15 Example 8: Tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H pyrrolo[2,3-d]pyriidin-5-yl)-2-methoxyphenyl]carbamate Phenyl N-[4-(4-ainino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 20 with tetrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 1 00 0 C overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7 tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl] carbamate (14 mg, 0.031mmol). 1H NMR (CDCl-d) 5 2.07(m, 6H), 3.66 (m, 2H), 25 3.96 (m, 7H), 4.13 (in, 2H), 4.98 (in, 1H), 5.26 (s, 2H), 5.40(m, 1H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2Hz, 1H), 7.26 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H). LC/MS MH*=455. 30 WO 00/17203 PCT/US99/21560 Examples 9 and 10: 1,3-Dioxan-5-yl N-[ 4

-(

4 -amino-7-tetrahydro-2H-4-pyranyl 7 H-pyrrolo[ 2 ,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate 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 5 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 glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 1 00"C overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7 10 tetrahydro- 2 H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl] carbamate (2 mg, 0.004mmol). 1H NMR (CDCl-d) 8 2.06(m, 4H), 3.66 (in, 2H), 3.92 (m, 3H), 4.07 (in, 6H), 4.79 (in, 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 (in, 2H), 7.53 (s, 1H), 8.15 (d, J=8.2Hz, 1H), 8.22 (s, 1H). LC/MS MH*=471 and 1,3-dioxolan-4-ylmethyl

N

15 (4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl) carbamate(6.Omg, 0.013 mmol). 1H NMR (CDCI-d) 8 2.06(m, 4H), 3.66 (m, 2H), 3.75 (m, 1H), 3.92 (in, 3H), 4.03 (m, 1H), 4.13 (in, 1H), 4.34 (m, 2H), 4.94 (s, 1H), 4.97 (in, 1H), 5.10(s, 1H), 5.32 (bs, 2H), 6.97 (s, 1H), 7.03 (m, 2H), 7.06 (d, J=8.2Hz, 1H), 7.38(s, 1H), 8.15 (d, J=7.9Hz, 1H), 8.31 (s, 1H). LC/MS 20 MH*=471. Example 11: 2-Pyridylnethyl 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 25 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 2 pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 1 00 0 C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylnethyl N-[4-(4-amino-7 tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl] 30 carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.ON HCl in ether (0.1 mL) was added slowly. The precipitate was collected through WO 00/17203 PCT/US99/21560 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). 1H NMR (DMSO-d 6 ) 6 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, 5 J=8.2Hz, 1H), 7.14 (s, 1H), 7.37 (m, 1H), 7. 53 (d, J=7.8Hz, 1H), 7.87 (m, 3H), 8.42(s, 1H), 8.57 (d, J=4.2Hz, 1H), 8.85 (s, 1H). LC/MS MH*=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 10 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 4 pyridylmethanol (0.05 iL) in pyridine (0.5 mL). The reaction mixture was heated at 1 00C 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 15 tetrahydro-2H-4-pyranyl-7H-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.ON HCl in ether (0.1 mL) was added slowly. The precipatate was collected through filtration under nitrogen to give 4-pyridylmethyl N-[ 4 -(4-amino-7-tetrahydro-2H-4 pyranyl- 7 H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl] carbamate 20 hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d,) 6 1.91(m, 2H), 2.16(m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (in, 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=5.6Hz, 1H), 9.05 (s, 1H). LC/MS: MH*=475. 25 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-pyr-rolo[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 30 mixture was heated at 100 0 C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (5-methyl-3- WO 00/17203 PCT/US99/21560 isoxazolyl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (18 mg, 0.038mmol). 1H NMR (CDCL-d) 8 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, 5 1H), 8.21(s, 1H). LC/MS: MH* 479. Example 14: [(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 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 preparative reverse phase LC/MS to give [(2S)-5 15 oxotetrahydro- 1 H-2-pyrrolyl]methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbanate (10 mg, 0.021mmol). 1H NMR (CDCl-d) 8 1.90 (m, 111), 2.06(m, 411), 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 20 (s, 1H). LC/MS: MH* 481. Example 15: 4-Aminobenzyl N-(4-(4-anino-7-tetrahydro-2H-4-pyranyl-7H pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate 25 a) tert-Butyl N-(4-(hydroxymethyl)phenyl)carbamate. (4-Aminophenyl)methanol (1.23 g, 10 mmol) and diisopropylethylamine ( 2.6 mL, 15 mmol) was mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with water, 1.ON HCl, saturated sodium 30 carbonate, water, brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography with Ethyl acetate/ WO 00/17203 PCT/US99/21560 heptane (2:3) to give tert-butyl N-(4-(hydroxymethyl)phenyl) carbamate (2.16g, 9.67 mmol). 1H NMR (CDCl-d) 6 1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5Hz, 2H), 7.36 (d, 8.5Hz,2H). 5 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 (51mg, 0.111 mmol) was mixed with tert-butyl N-(4 (hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The 10 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]pyrimidin-5-yl)-2-methoxyphenyl)carbamate (9 mg, 0.015mmol). 1H NMR (CDCl-d) 6 1.52(s, 1H), 2.08(m, 4H), 3.65 (m, 2H), 3.90 (s, 3H), 4.14(m, 2H), 15 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 20 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-4-amine (80mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 uL, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and 25 precipitate was formed. The solid was collected by filtration to give Ni -[4-(4 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]benzamide (64 mg, 0.144 mmol). 1H NMR (CDCl 3 -d) 6 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=8.2Hz, 1H), 7.53 (m, 3H), 7.94(d, J=7.8Hz, 1H), 8.33 (s, 1H), 8.58 30 (s, 1H), 8.63 (d, J=8.2Hz, 1H). LC/MS: M*=444 WO 00/17203 PCT/US99/21560 Example 17: N2-[4-(4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]-2-pyridinecarboxamide 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 5 d]pyrimidin-4-amine (80mg, 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 DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to 10 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). 1H NMR (CDCl 3 -d) 8 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=8.2Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70(d, J=8.2Hz, 1H), 10.62 (s, 1H). LC/MS: MH*=445. 15 Example 18: 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 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-4-amine (80mg, 0.236 mmol) was dissolved in dichloromethane (2.0 20 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 DMSO, methanol (1 mL) was added and precipitate was 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) 25 2-methoxyphenyl]--1,3-dimethyl-1H-5-pyrazolecarboxamide (30 mg, 0.065 mmol). 1H NMR (CDC1 3 -d) 6 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=8.2Hz, 1H), 8.33 (2, 2H), 8.49(d, J=8.2Hz, 1H). LC/MS: MH*=462. 30 WO 00/17203 PCTIUS99/21560 Example 19: Ni-[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-methoxypheny)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[ 2

,

3 d]pyrimidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 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 DMSO, methanol (1 mL) was added and precipitate was 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 10 methoxyphenyl]-2,2-dimethylpropanamide (27 mg, 0.064 mmol). 1H NMR (CDCl 3 d) 6 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=8.2Hz, 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49(d, J=8.2Hz, 1H). LC/MS: MH*=424. 15 Example 20: Ni-[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[2,3 d]pyrimidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 1-cyclopentanecarbonyl chloride 20 (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 DMSO, methanol (1 mL) was added and precipitate was 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-y1)-2 methoxyphenyl]-2,2-dimethylpropanamide (33 mg, 0.076mmol). 1H NMR (CDCl 3 25 d) 6 1.66 (m, 2H), 1.81 (m, 2H), 1.95 (in, 4H), 2.06 (m, 4H), 2.77 (in, 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=8.2Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H), 8.49(d, J=8.2Hz, 1H). LC/MS: MH*=437. 30 WO 00/17203 PCT/US99/21560 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[2,3 d]pyrimidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 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 DMSO, methanol (1 mL) was added and precipitate was 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 10 methoxyphenyl]-2,2-dimethylpropanamide (7 mg, 0.015mmol). 1H NMR (CDCl 3 -d) 8 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=8.2Hz, 1H). LC/MS: MH*=472. 15 Example 22: 5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine. a) Tosyl chloride (12.0 g) was added in portions to a mixture of 3 hydroxytetrahydofuran (5.0 g) in pyridine (100 ml) at 0 C under nitrogen with 20 stirring. The mixture was stirred at 0*C for 2 hours and then warmed to ambient temperature. The mixture was stirred at ambient temperature for 72 hours. The mixture was cooled to 0 0 C and 5M 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 with brine, then dried, filtered 25 and evaporated to give 3-tosyloxytetrahydrofuran 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) with stirring under nitrogen. The 30 mixture was stirred for 30 minutes and then a solution of 3-(tosyloxy) tetrahydrofuran (750 mg) in dimethyl formamide (10 ml) was added with WO 00/17203 PCT/US99/21560 stirring. The mixture was stirred and heated at 95*C for 18 hours and then evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried and evaporated to give a residual gummy solid which was triturated with ether and filtered to give 5-(4 5 phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine m.p. 196-196.5*C. Example 23: 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine. 10 In a similar manner to Example 1, 4-amino-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidine was reacted with 4-tosyloxytetrahydropyran to give after flash column chromatography 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 193-193.5*C. 15 Example 24: 4-amino-5-(4-phenoxyphenyl)-7-[4-(N-tert-butoxycarbonyl) tetrahydroisoxazolyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylanine. a) Di-tert-butyl dicarbonate (4.56 g) was added to a solution of 4 hydroxytetrahydroisoxazole (2.4 g) and triethylamine (4.2 g) in tetrahydrofuran 20 (100 ml) with stirring at 0 0 C under nitrogen. The mixture was stirred at ambient 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 part of this example. 25 b) The product from a) above (3.6 g) was stirred in pyridine (50 ml) at 0*C under nitrogen and then tosyl chloride (3.62 g) was added in portions at 0*C with stirring. The mixture was stirred at 0 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 1M solution in 30 water) were added. The organic layer was separated and washed with IM citric WO 00/17203 PCTIUS99/21560 acid solution and then brine, then dried, filtered and evaporated to give an oil which was purified by flash column chromatography using petroleum ether, b.p 40-60*C containing 20-30% of ethyl acetate as the mobile phase. Appropriate fractions were collected and combined to give N-(tert 5 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 with stirring to a suspension of sodium hydride (0.145 g, of a 60% dispersion in mineral oil) in 10 dimethylformamide (60 ml) with stirring under nitrogen at 0*C. The mixture was stirred at 0*C for 1 hour and then the product from b) (1.25 g) was added. The mixture was heated at 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 solid obtained was collected by 15 filtration to give 4-amino-5-(4-phenoxyphenyl)-7-[4-(N-tert butoxycarbonyl)tetrahydroisoxazolyl]-7H-pyrrolo[2,3-dlpyrimidin-4-ylamine, m.p. 162-163*C. Example 25: 5-(4-phenoxyphenyl)-7-(4-tetrahydroisoxazolyl)-7H-pyrrolo[2,3-d] pyrimidin-4-ylamine dihydrochloride. 20 The product from Example 3 (0.29 g) was dissolved in dichloromethane (8 ml) and then stirred at 0*C whilst trifluoroacetic acid (2.0 ml) was added. The mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 2 hours. The mixture was basified with sodium bicarbonate solution and extracted with dichloromethane to give an oil which was purified by flash 25 column chromatography using ethyl acetate and then ethyl acetate/methanol (9:1) as the mobile phase. The appropriate fractions were collected and combined, then evaporated to give a solid which was dissolved in ethyl acetate and then treated with ethereal hydrogen chloride (3.0 ml, of a 1M solution). The solid obtained was collected by filtration, washed with ether and dried under vacuum at 45*C for 2 WO 00/17203 PCT/US99/21560 hours to give 5-(4-phenoxyphenyl)-7-(4-tetrahydroisoxazoly1)-7H-pyrrolo[2,3-d] pyrimidin-4-ylamine dihydrochloride, m.p. 208*C (with decomposition). Example 26: 4-chloro-5-iodo-7-(3-tetrahydrofury1)-7H-pyrrolo(2,3-dlpyrimidine 5 a) 4-Chloro-5-iodo-7H-pyrrolo[2,3-dlpyrimidine (5.0 g) was added to a mixture of sodium hydride (0.79 g of a 60% dispersion in mineral oil) in dimethylforramide (100 ml) with stirring under nitrogen at 0*C. The mixture was stirred until hydrogen evolution ceased. 3-Tosyloxytetrahydrofuran (4.65 g) 10 was added at 0 0 C and then the mixture was warmed to 90*C. The mixture was stirred at this temperature for 2 hours and then overnight at ambient temperature. Water (100 ml) was added cautiously and the mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7-(3-tetrahydrofury1)-7H-pyrrolo(2,3 d]pyrimidine, m.p. 184-186*C. 15 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 at 120 0 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 20 mixture was extracted with ethyl acetate to give a solid which was triturated with hot hexane (500 ml). The supernatant liquid was decanted from a residual gum and cooled. The solid which precipitated was collected by filtration to give 2-(4-iodophenoxy) benzaldehyde, m.p. 84.5-86'C. 25 c) Toluene (250 ml) was deoxygenated and then nitrogenated for 30 minutes. 2-(4 Iodophenoxy)benzaldehyde (6.46 g), hexamethylditin (10.0 g) and tetrakis (triphenylphosphine) palladium (0) (1.4 g) were added to the toluene. The mixture was boiled under reflux under nitrogen with stirring for 7 hours. The mixture was cooled to ambient temperature then filtered. The filtrate was 30 evaporated and the residue was purified by flash column chromatography on WO 00/17203 PCT/US99/21560 silica using 3% ethyl acetate in petroleum ether, b.p. 40-60*C as the mobile phase to give 2-(4-trimethylstannylphenoxy)benzaldehyde as an oil. d) A mixture of the product from c) (1.80 g), the product from b) (1.76 g), 5 tris(dibenzylideneacetone)dipalladium (228 mg), triphenylarsine (383 mg) and dimethylformamide (75 ml) was heated at 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 10 ethyl acetate from 30-50% in petroleum ether, b.p. 40-60*C as the 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. 15 e) The product from d) (360 mg) was dissolved in methanol (5 ml) and sodium borohydride (65 mg) was added at 0*C with stirring. The mixture was warmed to ambient temperature and stirred at this temperature for 1 hour. The mixture was quenched with dilute sodium hydroxide solution and then evaporated under reduced pressure to give a residue which was extracted with ethyl acetate to give 20 2-[(4-(4-chloro-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-dlpyrimidin-5 ylphenoxy]benzyl alcohol. f) A mixture of the product from e) (280 mg), 1,4-dioxane (15 ml) and concentrated aqueous ammonia solution (15 ml, S.G. 0.88) was heated at 120*C 25 in a pressure vessel for 20 hours. The mixture was cooled to ambient temperature and the solvent removed under reduced pressure. The residue was taken up in ethyl acetate, washed with water, then dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate/methanol (9:1) as the mobile phase to give 2-[(4-(4-amino-7 30 (3-tetrahydrofuryl)-7H-pyrrolo[ 2

,

3 -d]pyrimidin-5-yl)phenoxy]benzyl alcohol as a glassy solid, m.p. 92-96*C.

WO 00/17203 PCT/US99/21560 Example 27: 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5 yl)phenoxy]-N,N-diethylbenzylamine 5 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 a vial (5 ml) and the vial septum sealed. The mixture was stirred at ambient temperature for 20 hours then quenched with saturated 10 aqueous sodium bicarbonate solution (5 ml). The mixture 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 from a) (280 mg), concentrated aqueous ammonia 15 solution (10 ml, S.G. 0.88) and 1,4-dioxane (10 ml) was heated in a pressure vessel for 16 hours at 120*C. The mixture was cooled and the solvent removed under reduced pressure. The residue was taken up in ethyl acetate, washed with water, then dried, filtered and evaporated to give an oil which was purified by flash column chromatography using ethyl acetate/methanol as a mobile phase to 20 give 2-[4-(4-amino-7-(3-tetrahydrofury1)-7H-pyrrolo[2,3-d]pyrimdin-5 yl)phenoxy]-N,N-diethylbenzylamine, m.p. 107-11 0*C. Example 28: 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5 yl)phenoxy]-benzonitrile 25 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 with stirring under nitrogen at 120*C for 5 hours. The mixture was allowed to stand overnight at ambient temperature and then partitioned between ethyl acetate and 30 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 WO 00/17203 PCTIUS99/21560 b.p. 40-60*C and filtered to give 2-(4-bromophenoxy)benzonitrile. b) A mixture from the product of part a) (5.57 g), hexamethylditin (10.0 g), tetrakis (triphenylphosphine) palladium (0) (1.4 g) and degassed toluene (250 ml) was 5 heated at 1 10*C with stirring under nitrogen for 4.5 hours. The mixture was allowed to stand for 18 hours at ambient temperature and then filtered through a silica pad. The pad was washed with ethyl acetate and the combined filtrate and washes evaporated to dryness. The residue was purified by flash column chromatography on silica using petroleum ether b.p. 40-60*C and diethyl ether 10 (2%) increasing to 5% as the mobile phase. Appropriate fractions were collected combined and evaporated to give 2-(4-trimethylstannylphenoxy)benzonitrile. c) A mixture 4-chloro-5-iodo-7-(3-tetrahydrofuryl)pyrrolo[2,3-d]pyrimidine (1.8 g, prepared as described in Example 5) and the product from part b) (1.23 g) were 15 reacted and then worked up in a similar manner to 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 from c) (470 mg), concentrated aqueous ammonia (33 20 ml, SG 0.880) and 1,4-dioxane (33 ml) were heated together in a pressure vessel at 120*C for 18 hours and then worked up on a similar manner to Example 5 to give 2-[4-(4-amino-7-(3-tetrahydrofury1)-7H-pyrrolo[2,3-d]pyrimidin-5 yl)phenoxy]-benzonitrile, m.p. 201-203*C. 25 Example 29: 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5 yl)phenoxy]benzaldehyde a) In a similar manner to Example 2, 3-tosyloxytetrahydrofuran (1.84 g) was reacted with 5-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (2.9 30 g) using sodium hydride (0.30 g, of a 60% dispersion in mineral oil) and dimethylformamide (40 ml) except that the mixture was heated for 4.5 hours at WO 00/17203 PCT/US99/21560 90*C 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 from part a) (6.0 g), 10% palladium on charcoal (3.0 g), 5 ammonium formate (4.9 g) and ethanol (500 ml) was heated on a steam bath with stirring under nitrogen for 2 hours. The mixture was cooled and filtered and the solvent 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 m.p. 257-259*C. 10 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 at 120*C with stirring under nitrogen for 5 hours. The mixture was cooled to ambient temperature quenched 15 with water and extracted with ethyl acetate to give 2-[4-(4-amino-7-(3 tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]benzaldehyde, m.p. 185-187 0 C. Example 30: 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo-[2,3-d]pyrimidin-7 20 yl]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) with stirring under nitrogen. The mixture was stirred for 30 minutes and then 3,6-dioxabicyclo[3.L.0]hexane (300 mg) was added and the 25 mixture was warmed to 80'C. The mixture was left for 64 hours and then evaporated under reduced pressure. The residue was triturated with water which left an oily gum. Ether was added and the mixture was stirred rapidly for 30 minutes which gave a solid which was collected by filtration and washed with methanol. The solid was discarded. The filtrate produced a second crop of solid which was 30 recrystallised from ethanol to give 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo- WO 00/17203 PCT/US99/21560 //3 [2,3-d]pyrimidin-7-yl]tetrahydrofuran-3-ol, m.p. 234.5-235.5 0 C. Example 31: 5-[4-(2-morpholinomethylphenoxy)phenyl]-7-(3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine 5 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), sodium triacetoxyborohydride (117 mg) and 1,2 dichloroethane (5 ml) was stirred at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was filtered through an EMPORE@ cartridge. The filtrate was 10 evaporated and the residue was dissolved in dichloromethane (5 ml) and then tris(2-aminoethyl)amine-polymer bound (0.3 g) and 2 drops of glacial acetic acid were added and the mixture was stirred at ambient temperature overnight. The polymer was removed by filtration and washed with dichloromethane and then with methanol. The combined organic filtrate and washings were evaporated under 15 reduced pressure to give an oil which was triturated with diethyl ether/ethyl acetate with warming to dissolve the solid and then the solution was cooled in ice and filtered to give 5-[4-(2-morpholinomethylphenoxy)phenyl]-7-(3-tetrahydrofuryl) 7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 169-171*C. 20 Example 32: 5-[4-(2-piperidinomethylphenoxy)phenyl]-7-(3-tetrahydrofiryl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine In a similar manner 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 25 tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine m.p. 76-78*C (glassy foam).

WO 00/17203 PCT/US99/21560 Example 33: 5-{4-[2-(2-methoxyethyl)aminomethylphenoxy]phenyl}-7-(3 tetrahydrofuryl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine In a similar manner 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 5 methoxyethylamine (56 mg) were reacted together to give 5-{4-[2-(2 methoxyethyl)aminomethylphenoxy]phenyl}-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3 d]-pyrimidin-4-ylamine m.p. 66-68*C (glassy foam). Example 34: 4

-[(

4 -(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]-pyrimidin-5 10 yl)phenoxy]benzyl alcohol a) In a similar manner 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)-7H-pyrrolo[2,3-d]pyrimidin-5 15 yl)phenoxy] benzaldehyde. b) The product from a) (0.35 g) was dissolved in methanol (10 ml) and to this solution was added sodium borohydride (32 mg) at 0 0 C. The mixture was warmed at ambient temperature and stirred at this temperature for 10 minutes. 20 1,2-Dichloroethane (4 ml) was added to aid solubility. The mixture was stirred to ambient temperature for 18 hours and then glacial acetic acid (1 ml) was added and the mixture evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The ethyl acetate was separated, dried, filtered and evaporated to give 25 4

-[(

4

-(

4 -amino-7-(3-tetrahydrofiryl)-7H-pyrrolo[2,3-d]-pyrimidin-5 yl)phenoxy]benzyl alcohol, m.p. 92-95'C. 30 WO 00/17203 PCT/US99/21560 Example 35: 5-[4-(4-fluorophenoxy)phenyl]-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3 d]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 (II) acetate (0.36 g), 5 triethylamine (1.01 g), dichloromethane (20 ml) and activated ground 4 molecular sieves (0.5 g) was stirred under nitrogen in a dry atmosphere for 64 hours. The reaction mixture was filtered through a small pre-flushed silica pad and eluted with dichloromethane (200 ml) then ethyl acetate (250 ml) and finally ethyl acetate/methanol 9:1 (250 ml). The dichlormethane and ethyl acetate fractions were 10 combined and purified by flash column chromatography on silica using ethyl acetate/methanol as the mobile phase to give 5-[4-(4-fluorophenoxy)phenyl]-7-(3 tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 198-199*C. Example 36: 5-[4-(4-morpholinomethylphenoxy)-phenyl]-7-(3-tetrahydrofuryl) 15 7H-pyrrolo[2,3-d]pyrimidin-4-ylamine In a similar manner to Example 10 a mixture of 4-[4-(4-amino-7-(3 tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyriniidin-5-yl)phenoxy]benzaldehyde (336 mg), and morpholine (146 mg) were reacted to give 5-[4-(4-morpholinomethylphenoxy) phenyl]-7-(3-tetrahydrofuiryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p 142 20 144 0 C. Example 37: 5-[4-(3-morpholinomethylphenoxy)phenyl]-7-(3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine 25 a) A mixture of 4

-[

4 -amino-7-(3-tetrahydrofuryl-7H-pyrrolo[2,3-d]pyrimidin-5 yl)phenol (0.297 g), was reacted with 3-formylphenylboronic acid in a similar manner to Example 14 to give 3-[4-(4-amino-7-(3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde. 30 b) The product from part a) (100 mg) and morpholine (44 mg) were reacted together using similar reagents and conditions as described in Example 10 to WO 00/17203 PCT/US99/21560 / I e give 5-[ 4 -(3-morpholinomethylphenoxy)phenyl]-7-(3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 83-85*C. Example 38: 2

-[

4

-(

4 -amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5 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) were heated at 120*C under nitrogen for 8 hours. The mixture was allowed to cool, diluted with water 10 then extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate to give solid which was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate/methanol (9:1, 8:1, 4:1) to give 2-[4-(4 amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(2-(4 pyridyl) ethylamino)-benzonitrile, m.p 212-213*C. 15 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-ylphenol (0.49 g), 2 -fluoro-6-(3-imidazol-1-yl)propylamino benzonitrile, potassium carbonate 20 (0.45 g) and dimethylformamide were reacted in a similar manner 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, m.p.11 0*C (glassy foam). Example 40: 4 -amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidine 25 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 treated with N-bromosuccinimide (178 mg) in dichloromethane (10 ml). The mixture was left stirring ambient temperature for 16 hours. The WO 00/17203 PCT/US99/21560 mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid which was collected by filtration and dried to give 4 amino- 6 -bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, m.p. 282 283 0 C. 5 b) A mixture of the product from a) (1.14 g) in dry dimethylformamide (30 ml) was stirred under nitrogen whilst sodium hydride (120 mg of a 60% dispersion in mineral oil) was added. This was followed by 3-tosyloxytetrahydrofuran (0.8 g) in dimethylformamide (10 ml). The mixture was heated at 90*C overnight. The 10 mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid which was collected by filtration and dried to give a solid which was purified by dissolving in ethanol, adding water to cloud point and filtering. The filtrate was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica to give 4 15 amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3 d]pyrimidine, m.p. 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 20 In a similar manner to Example 17, 4 -amino-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidine (0.65 g), 2-fluoro-6-(3-methoxypropylamino)benzonitrile (0.46 g), potassium carbonate (0.61 g) and dimethylformamide (40 ml) was heated under nitrogen at 120*C for 8 hours to give, after workup, 2-[4-(4-amino-7-(3 tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(3 25 methoxypropylamino) benzonitrile, m.p. 183-184*C. 30 WO 00/17203 PCTIUS99/21560 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[2,3 5 d]pyrimidin-4-ylamine (2.83 g), 10% palladium on carbon (1.41 g), ammonium formate (2.31 g) and ethanol (250 ml) was boiled under reflux under nitrogen with stirring for 1.5 hours. The mixture was cooled to ambient temperature, filtered, then the filtrate cooled and filtered. The filtrate was evaporated to give a solid 4-[4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5 10 yl]phenol. b) A warm solution of 4-[4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3 d]pyrimidin-5-yl]phenol (0.082 g) in dimethylformamide (3.4 ml) was added to a mixture of 2-fluorobenzonitrile (80 mg) and potassium carbonate (76 mg) in a 15 vial. The vial was flushed with nitrogen then sealed. The mixture was shaken at 120*C for 6 hours and then left to cool to ambient temperature over 16 hours. The mixture was diluted with water (11 ml) and then 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. 125'C (softens). 20 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-5 yl]phenol with the appropriate nitrile except that the mixtures were shaken together for periods up to 48 hours. The reactions were monitored for the disappearance of 25 starting material and heated for the appropriate 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. 30 WO 00/17203 PCT/US99/21560 Example 50: 2-(4-(4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin 5-yl)phenoxy]- 6-(2-morpholinoethoxy)benzonitrile, m.p. 1 10*C (glass), from 2 fluorobenzonitrile. 5 Example 51: 2-[4-(4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin 5-yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)benzonitrile, m.p. 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 10 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. 15 Examples 54-101 General Method Portions of the amines listed in Table 1 (9 molar equivalents with respect to the ester employed, weights ranging from 47.5 mg to 184.5 mg) were weighed into 20 separate vials and methanol (1 ml) was added to each vial. A solution of ethyl 2-[4 amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl acetate (1 molar equivalent) in a mixture of methanol and triethylamine (4 ml, ratio of methanol to triethylamine is 23.2:1 v/v. The reaction mixtures were shaken at 60-65* C for 36 hours. The methanol and triethylamine were removed under reduced pressure at 25 50"C for 3 hours and to each vial was added water (3 ml) followed by dichloromethane (3 ml). The vials were agitated for 15 seconds and then allowed to stand for 18 hours. The mixtures were poured into EMPORE@(10 mm/6 ml) extraction disk cartridges and the dichloromethane phases were collected and evaporated at 50"C for 3 hours. During work-up it was observed that solid had WO 00/17203 PCTIUS99/21560 separated out in the vials on standing for 18 hours. Consequently the aqueous layer in each cartridge was forced through with compressed air. Dichloromethane (4 ml) was added to each extraction cartridge. Each filtrate was evaporated under reduced pressure at 50'C for 3 hours. The desired products were either found in the original 5 dichloromethane extract, in which case they are indicated as being present in the liquid, or were found in the insoluble solid on reworking and are referred to as being found in the solid. Certain products were found in both phases. These phases are indicated in Table 1. Each sample was analysed by LCMS and in each case the target ion was 10 found. The retention time for each product is given in Table 1. The conditions used are given below. Column: 5 pim hypersil BDS c18 (100 x 2.1 mm). Mobile Phase: 0. 1M NH4OAc [pH 4.55] : MeCN (gradient - see below). 15 Conditions: 10-100% MeCN in 8 minutes. (Gradient) 100% MeCN for 1 minute. 100-10% MeCN in 2 minutes. (Total analysis run time 11 minutes. Flow Rate: 1 ml/minute (no split in MS). 20 Wavelength Range: 250-320 nm Injection Volume: 20 l. MS Method: APCI1 1H. lonisation APcI +ve/-ve. 25 Mass Range: 100-700 m/z. Cone voltage: 20. In a similar manner to Examples 54-101, the amines listed in Table 2 were reacted, respectively, with ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 30 d]-pyrimidin-7-yl]propionate to give the products listed in Examples 102-146 WO 00/17203 PCT/US99/21560 respectively. The work-up and the analysis conditions were identical to those used for Examples 54-101. In each case the target ion was found by LCMS. TABLE 1 Amine Name Phase RT / min Number 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 Liquid 3.78 58 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 N,N-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 Liquid 3.29 69 N2,N2-Dimethyl-1,2-propanediamine Both 3.37 70 1-Dimethylamino-2-propylamine Liquid 3.44 71 dl-2-Amino-3-methyl- 1 -butanol Solid 3.98 72 N- {2-[1 -(N-Morpholine)- 1 -oxo]ethyl} piperazine Liquid 3.56 73 2-Amino-2-methyl-1-propanol Both 3.86 74 2-Amino-2-methyl-1,3-propanediol Both 3.49 45 2-(2-Aminoethoxy)ethanol Both 3.47 76 1-(2-Aminoethyl)pyrrolidine Liquid 3.40 77 N-Methylhomopiperazine Liquid 3.32 WO 00/17203 PCT/US99/21560 Amine Name Phase RT / min Number Product 78 1-Amino-1-cyclopentane methanol Both 4.16 79 2-Aminocyclohexanol Solid 3.98 80 N,N-Diethylethylenediamine Liquid 3.44 81 N-(3-Hydroxypropyl)ethylenediamine Both 3.24 82 2-((2-Aminoethyl)thio)ethanol Both 3.69 83 2-(2-Aminoethyl)pyridine Liquid 3.89 84 3-(2-Aminoethyl)pyridine Liquid 3.79 85 N-(3-Aminopropyl)imidazole Liquid 3.37 86 1-[2-(N-Morpholine)ethyl]piperazine Liquid 3.39 87 2-(Aminomethyl)-1-ethylpyrrolidine Both 3.48 88 1-(2-Aminoethyl)piperidine Both 3.49 89 1-Pyrrolidinepropanamine Liquid 3.37 90 (R)-(+)-2-Aminomethyl- 1 -ethylpyrrolidine Both 3.48 91 4-(2-Aminoethyl)morpholine Both 3.39 92 3-Diethylaminopropylamine Both 3.43 93 N,N-Dimethylneopentanediamine Both 3.47 94 Ethyl 1-piperazinecarboxylate Liquid 4.34 95 2-(Aminomethyl)-2-ethyl-1,3-propanediol Both 3.69 96 1-(3-Aminopropyl)-2-pyrrolidinone Both 3.68 97 1-Piperidinepropylamine Liquid 3.46 98 4-(3-Aminopropyl)morpholine Liquid 3.33 99 N,N-Diisopropylethylenediamine Liquid 3.59 100 N,N-Bis(3-aminopropyl)methylamine Liquid 3.03 101 Tris(2-aminoethyl)amine Liquid 3.01 The compounds prepared are given below.

WO 00/17203 PCT/US99/21560 Example 54: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-hydroxyethyl)acetamide Example 55: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N 5 (1-hydroxyprop-2-yl)acetamide Example 56: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-hydroxypropyl)acetamide 10 Example 57: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-methoxyethyl)acetamide Example 58: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (3-hydroxypropyl)acetamide 15 Example 59: (S)-4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl N-(1-hydroxyprop-2-yl)acetamide Example 60: (R )-4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 20 yl-N-(2-hydroxypropyl)acetamide Example 61: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [2-(N,N-dimethylamino)ethyl]acetamide 25 Example 62: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo2,3-d]pyrimidin-7-yl-N (1-hydroxybut-2-yl)acetamide Example 63: 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyimidin-7-yl-N (2-hydroxybutyl)acetamide 30 WO 00/17203 PCTIUS99/21560 Example 64: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2,3-dihydroxypropyl)acetamide Example 65: (S)-4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl 5 N-(2,3-dihydroxypropyl)acetamide Example 66: (R)-4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl N-(2,3-dihydroxypropyl)acetamide 10 Example 67: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl N,N-(3-azapentamethylene)acetamide Example 68: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [3-(N,N-dimethylamino)propyl]acetamide 15 Example 69: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [1-(N,N-dimethylamino)prop-2-yl]acetamide Example 70: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N 20 [2-(N,N-dimethylamino)propyl]acetamide Example 71: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (1-hydroxy-3-methylbut-2-yl)acetamide 25 Example 72: 7-{2-[4-(2-Morpholino-2-oxoethyl)piperazin-1-yl]-2-oxo-ethyl}-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine Example 73: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (1-hydroxy-3-methylprop-2-yl)acetamide 30 WO 00/17203 PCTIUS99/21 560 Example 74: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl-N (1 ,3-dihydroxy-2-methylprop-2-yl)acetamide Example 75: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl-N 5 [2-(2-hydroxyethoxy)ethyl]acetamide Example 76: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [2-(pyrrolidin-1 -yl)ethyl]acetamide 10 Example 77: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-dlpyrimidin-7-yl N,N-(3-azahexamethylene)acetamide Example 78: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl-N [ 1 -(hydroxymethyl)cyclopentyl]acetamide 15 Example 79: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-hydroxycyclohexyl)acetamide Example 80: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl-N 20 [2-(N,N-diethylamino)ethyl]acetamide Example 81: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimnidin-7-yl-N [2-(3-hydroxypropylamino)ethyl]acetamide 25 Example 82: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[12,3-dlpyrimidin-7-yl-N [2-(2-hydroxyethylthio)ethyl]acetamide Example 83: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-djpyrimidin-7-yl-N [2-(pyrid-2-yl)ethyl]acetamide 30 WO 00/17203 PCTIUS99/2 1560 Example 84: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [2-(pyrid-3-yl)ethyl]acetamide Example 85: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N 5 [3-(imidazol- 1 -yl)propyl]acetamide Example 86: 7- {2-[4-(2-Morpholinoethyl)piperazin- 1-yl]-2-oxo-ethyl} -5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine 10 Example 87: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (N-ethylpyrrolidin-2-yl)methylacetamide Example 88: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-piperidinoethyl)acetamide 15 Example 89: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [3-(pyrrolidin- 1-yl)propyl]acetamide Example 90: (R)-4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl 20 N-(N-ethylpyrrolidin-2-yl)methylacetamnide Example 91: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (2-morpholinoethyl)acetamnide 25 Example 92: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [3-(N,N-diethylamino)propyljacetamide Example 93: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-djpyrimidin-7-yl-N [3-(N,N-dimethylamino)-2,2-dimethylpropyl]acetaxnide 30 WO 00/17203 PCTIUS99/21560 Example 94: 7-[2-(4-Ethoxycarbonylpiperazin- 1-yl)-2-oxoethyl]-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-dlpyrimidin-4-ylamine Example 95: 4-Amino-.5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N 5 [2,2-bis(hydroxymethyl)butyl]acetamide Example 96: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N [3-(2-pyrrolidinon- 1-yl)propyl]acetamide 10 Example 97: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (3-piperidinopropyl)acetamide Example 98: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl-N (3-morpholinopropyl)acetamide 15 Example 99: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N (3-hydroxy-l1-methylprop-2-yl)acetamide Example 100: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-N 20 [3-(iN-3-aminopropyl,N-methyl)axninopropyl]acetamide Example 101: 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl-N [N-bis(2-aniinoethyl)aminoethyl]acetamide 25 30 WO 00/17203 PCT/US99/21560 /3e> TABLE 2 Amine Name Phase RT / min Number Product 102 Ethanolamine Both 3.68 103 dl-2-Amino-1-propanol Both 3.78 104 1-Amino-2-propanol Both 3.81 105 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 Liquid 3.81 109 N,N-Dimethylethylenediamine Liquid 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 Liquid 3.47 116 N2,N2-Dimethyl-1,2-propanediamine Liquid 3.57 117 1-Dimethylamino-2-propylamine Liquid 3.67 118 D1-2-Amino-3-methyl-1-butanol Both 4.15 119 2-(2-Aminoethylamino)ethanol Liquid 3.40 120 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 Liquid 3.71 123 1-(2-Aminoethyl)pyrrolidine Both 3.61 124 1-Amino-1-cyclopentane methanol Both 4.48 125 2-Aminocyclohexanol Both 4.19 126 N,N-Diethylethylenediamine Both 3.68 127 N-(3-Hydroxypropyl)ethylenediamine Both 3.42 WO 00/17203 PCT/US99/21560 / 3( Amine Name Phase RT / min Number Product 128 2-((2-Aminoethyl)thio)ethanol Liquid 3.94 129 2-(2-Aminoethyl)pyridine Liquid 4.13 130 3-(2-Aminoethyl)pyridine Both 4.05 131 N-(3-Aminopropyl)imidazole Liquid 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-Pyrrolidinepropanamine Both 3.60 136 (R)-(+)-2-Aminomethyl-1-ethylpyrrolidine Both 3.70 137 4-(2-Aminoethyl)morpholine Both 3.63 138 3-Diethylaminopropylamine Both 3.64 139 N,N-Dimethylneopentanediamine Both 3.68 140 2-(Aminomethyl)-2-ethyl-1,3-propanediol Both 3.94 141 1-(3-Aminopropyl)-2-pyrrolidinone Liquid 3.91 142 1-Piperidinepropylamine Both 3.70 143 4-(3-Aminopropyl)morpholine Liquid 3.53 144 N,N-Diisopropylethylenediamine Liquid 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-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(2-hydroxyethyl)propanamide 5 Example 103: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(1 -hydroxyprop-2-yl)propanamide Example 104: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(2-hydroxypropyl)propanamide WO 00/17203 PCT/US99/21560 Example 105: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(2-methoxyethyl)propanamide Example 106: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 5 N-( 3 -hydroxypropyl)propanamide Example 107: (S)-1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]-N-(1 -hydroxyprop-2-yl)propanamide 10 Example 108: (R)-1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]-N-( 2 -hydroxypropyl)propanamide Example 109: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]

N-[

2 -(N,N-dimethylamino)ethyl]propanamide 15 Example 110: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-y] N-(1-hydroxybut-2-yl)propanamide Example 111: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 20 N-(2-hydroxybutyl)propanamide Example 112: 1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]

N-(

2 ,3-dihydroxypropyl)propanamide 25 Example 113: (S)-1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]-N-( 2

,

3 -dihydroxypropyl)propanamide Example 114: (R)-1-[ 4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]-N-(2,3-dihydroxypropyl)propanamide 30 WO 00/17203 PCT/US99/21560 /3-3 Example 115: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[3-(N,N-dimethylamino)propyl]propanamide Example 116: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 5 N-[2-(N,N-dimethylamino)propyl]propanamide Example 117: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[1-(N,N-dimethylamino)prop-2-yl]propanamide 10 Example 118: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(1-hydroxy-3-methylbut-2-yl)propanamide Example 119: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[2-(2-hydroxyethylamino)ethyl]propanamide 15 Example 120: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(1-hydroxy-2-methylprop-2-yl)propanamide Example 121: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 20 N-(1,3-dihydroxy-2-methylprop-2-yl)propanamide Example 122: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[2-(2-hydroxyethoxy)ethyl]propanamide 25 Example 123: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[2-(pyrrolidin- 1 -yl)ethyl]propanamide Example 124: 1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[ 1 -(hydroxymethyl)cyclopentyl]propanamide 30 WO 00/17203 PCTIUS99/21 560 Example 125: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl N-(2-hydroxycyclohexyl)propanamide Example 126: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 5 N-[2-(N,N-diethylamino)ethyl]propanamide Example 127: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[2-(3-hydroxypropylamino)ethyl]propananiide 10 Example 128: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] N-[2-(2-hydroxyethylthio)ethyl]propanamide Example 129: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] N-[2-(pyrid-2-yl)ethyl]propananmide 15 Example 130: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[2-(pyrid-3-yl)ethyl]propanamide Example 131: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] 20 N-[3-(imidazol- 1-yl)propyl]propanamide Example 132: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-djpyrimidin-7-yl] N-[2-(N-methylpyrrolidin-2-yl)ethyl]propanamide 25 Example 133: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] N-[(N-ethylpyrrolidin-2-yl)methyl]propanamide Example 134: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] N-(2-piperidinoethyl)propanamide 30 WO 00/17203 PCTIUS99/21 560 Example 135: 1 -[4-Am-ino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[3-(pyrrolidin- 1-yl)propyl]propanamide Example 136: (R)-l1-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 5 yl]-N-[(N-ethylpyrrolidin-2-yl)methyl]propanamide Example 137: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-(2-morpholinoethyl)propanaxnide 10 Example 138: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[3-(N,N-diethylamnino)propyl]propanamide Example 139: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] N-[3-(N,N-dimethylamino)-2,2-dimethylpropyl]propanamide 15 Example 140: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3.-d]pyrimidin-7-yl] N- [2 ,2-bis(hydroxymethyl)butyl]propanamide Example 141: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] 20 N-[3-(2-pyrrolidinon- 1-yl)propyl]propanamide Example 142: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3 -djpyrimidin-7-yl] N-(3-piperidinopropyl)propanamide 25 Example 143: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl] N-(3-morpholinopropyl)propanamide Example 144: 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3 -d]pyrimidin-7-yl] N-[2-(N,N-di-isopropylarmino)ethyl]propanamide 30 WO 00/17203 PCT/US99/21560 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-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 5 N-[N-bis(2-aminoethyl)aminoethyl]propanamide Example 147: 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]butyrolactone a) 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 g) was added 10 to a mixture of sodium hydride (0.158 g of a 60% dispersion in mineral oil) in dimethyl formamide (70 ml) with stirring under nitrogen at 0 0 C. The mixture was stirred at 0 0 C for 1 hour and then a-bromo-y-butyrolactone (0.60 g) in dimethylformamide (6 ml) was added dropwise with stirring at 0"C. The mixture was stirred at ambient temperature for 18 hours and then quenched with water 15 (100 ml). The mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give 2-[4-amino-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-7-yl]--butyrolactone as an oil which was used directly in b). 20 b) N,N-Dimethylethylenediamine (5.0 ml) was added to a mixture of the product from a) (1.2 g) and pyridin-2-one (50 mg) in toluene (100 ml). The mixture was heated to 100"C for 2 hours 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 5M hydrochloric acid (3 x 50 ml) 25 and the acidic extracts were washed with ethyl acetate then basified with 6M sodium hydroxide solution at 0"C and then back extracted with ethyl acetate and then dichloromethane. The combined organic extracts were dried, filtered and evaporated to give an oil which was crystallised from ethyl acetate/ether to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-4-hydroxy 30 N-[2-dimethylamino)ethyl]utyramide, m.p. 178-179 0

C.

WO 00/17203 PCTIUS99/21560 /3 7 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 a 5 mixture of 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 ambient temperature. A solution of ethyl 2-bromopropionate (543 mg) in dry DMF (10 ml) was added dropwise via a syringe over 10 minutes. The mixture was stirred at ambient temperature for 2 hours and then left for 18 hours. The 10 mixture was evaporated under vacuum and the residue was washed with water to give a solid which was triturated with ether and filtered to give ethyl 2-[4-amino-5 (4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate, m.p. 139-140'C. Example 149: N-(2-dimethylaminoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H 15 pyrrolo[2,3-d]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 boiled under reflux for 18 hours with the exclusion of carbon dioxide. The mixture was cooled and filtered, the filtrate was diluted with water 20 (50 ml) and stirred with ether. The mixture was left standing for 18 hours and the solid which precipitated 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. 163-164*C. 25 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 dimethylformamide (30 ml) was stirred at ambient temperature under nitrogen for 30 30 minutes. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added over 5 minutes at 0-5 0 C with stirring. The mixture was stirred for 30 minutes at ambient WO 00/17203 PCT/US99/21560 temperature and then allowed to stand for 18 hours. The mixture was evaporated under vacuum and the residue was triturated with water and ether. The solid obtained was collected by filtration, washed with water and then with ether to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate, 5 m.p. 161-161.3 0 C. Examples 151-156 General Method Ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 10 yl] acetate (194 mg) was heated at 62 0 C and stirred with 10 molar equivalents of the appropriate amine as listed below in methanol (12 ml) for 18 hours to give after work up the following compounds: Example 151 15 N-[2-hydroxyethyl-1,1-di(hydroxymethyl)]-2-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetamide, m.p. 222-223*C with decomposition, from 2-hydroxyethyl-1,1-di(hydroxymethyl)ethylamine. Example 152 20 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 25 N-(2-morpholinoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]acetamide, m.p. 164-165"C, from 2-morpholinoethylamine.

WO 00/17203 PCT/US99/21560 Example 154 N-[3-(1-imidazol)propyl]-2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]acetamide, m.p. 170-171 C, from 3-(1-imidazolyl)propylamine. 5 Example 155 N-(N-ethylpyrrolidin-2-ylmethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]-pyrimidin-7-yl]acetamide, m.p. 122-122.5"C, from 1-(N ethylpyrrolodin-2-yl)methyl-amine. 10 Example 156 N-[-2(2-hydroxyethoxy)ethyl]-2-[4-amino-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]-pyrimidin-7-yl]acetamide, m.p. 145-147*C, from 2-(2 hydroxyethoxy)ethylamine. 15 Example 157: 2-[4-amino-5-(4-phenoxyphenyl)-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 2M solution) and methanol (20 ml) was boiled under reflux for 1 hour. The 20 mixture was concentrated under reduced pressure to around 5 ml and then diluted with water (30 ml). The mixture was hot filtered and filtrate was cooled and then acidified with -dilute acetic acid until no further precipitation occurred. The mixture was heated on a hot plate until the gel which had been obtained became a finely divided solid. The solid was collected by filtration to give 2-[4-amino-5-(4 25 phenoxyphenyl)-7H-pyrrolo[2,3-d]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 30 (1.5 g) was dissolved in DMF (30 ml) and treated with sodium hydride (0.22 g of a WO 00/17203 PCT/US99/21560 / V .C>; 60% dispersion in mineral oil) and then with ethyl 4-bromobutyrate (1.08 g) in DMF (15 ml) in a similar manner to Example 95 to give ethyl 4-[4-amido-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]butyrate, m.p. 104-104.5*C. 5 Example 159: ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 7-yl]carbox-amide In a similar manner to Example 97, 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl amine (1.0 g), sodium hydride (1.032 g of a 60% dispersion in mineral oil), 2-bromoacetamide (0.55 g) and dimethylformamide (50 ml) were 10 reacted together to give after work-up a solid which was recrystallised from isopropanol to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]carbox-amide, m.p. 232-233 0 C. Example 160: 2-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrmidin-7-yl]-2 15 methylpropionamide 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) with stirring and sodium hydroxide (0.158 g) was added at ambient temperature and the mixture stirred for 15 minutes. 2-Bromo-2-methylpropanamide (0.5 g) was added 20 and the mixture was stirred vigorously for 18 hours at ambient temperature under a water-free atmosphere, then further 2-bromo-2-methylpropanamide (0.15 g) was added and stirred for a further 24 hours. Water (3 ml) was added to the reaction mixture together with dilute hydrochloric acid (5M) to adjust the pH to 0. The suspension was added to water (60 ml) and the mixture left to stand for 18 hours at 25 ambient temperature. The solid was collected by filtration, washed well with water and dried under high vacuum at 50'C. The solid was purified by preparative HPLC (reverse phase). Appropriate fractions were collected and combined and extracted with dichloromethane. Evaporation of the dichloromethane gave 2-[4-amino-5-(4 phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropionamide, m.p. 227 30 228 0

C.

WO 00/17203 PCT/US99/21560 Example 161: 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimin-7-yl] N (2-dimethylaminoethyl)butyramide A mixture of ethyl 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 5 d]pyrimin-7-yl]butyrate (100 mg) in 30 ml methanol was heated under reflux with 0.6 ml 2-dimethylaminoethylamine for 18 hours. The mixture was evaporated under reduced pressure and the residue was heated with 2-dimethylaminoethylamine (10 ml) on a steam bath for 18 hours. Excess amine was removed under reduced pressure. Water was added to the residue and the mixture filtered to give 4-[4 10 amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimin-7-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 listed. 15 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. 20 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 25 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimin-7-yl]-N-(3 morpholinopropyl)butyramide from 3-morpholinopropylamine.

WO 00/17203 PCT/US99/21560 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 5 propan-2-ol and the mixture heated at 80 0 C for 3 hours. The mixture was cooled to 0 0 C and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212 0 C. 10 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. 15 2) In a separate flask sodium (331 mg) was dissolved in ethanol (50 ml) and malononitrile (858 mg) was added. The solution was stirred at ambient temperature for 5 minutes and then to this solution was added the solution of 4'-phenoxy-2-(tert-butylamino)acetophenone obtained in part (1) in one 20 portion excluding the precipitated sodium chloride. The resultant mixture was heated at 50*C for 3 hours and then at 80"C for 2 hours. The solvent was removed under reduced pressure and the resultant 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 25 triturated with water, filtered and dried 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 at 30 180 0 C for 6 hours. The mixture was cooled to ambient temperature and water was added to precipitate a dark solid. The solid was collected by filtration, WO 00/17203 PCT/US99/21560 washed with water, then boiled up in ethanol and the insoluble material collected by hot filtration and dried. The solid was purified by preparative HPLC on a silica column using dichloromethane/propan-2-ol/ethanol, 98:1:1 as the mobile phase to give 7-tert-butyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4 5 ylamine (4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d]pyrimidine), m.p. 157-158 0 C. 1H NMR (d6 DMSO) 8 8.15 (1H,s), 7.50-7.35 (4H,m), 7.30 (1H,s), 7.15 (1H,t), 7.10 (4H,m), 6.05 (2H,brs), 1.75 (9H,s). c) A mixture of 4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d] 10 pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (55 ml of a 48% solution) was boiled under reflux for 18 hours under nitrogen. The mixture was allowed to cool and a solid was collected by filtration. This solid was washed with methanol and then with ether to give 4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidine hydrobromide, m.p. 288-292"C. 15 The hydrobromide salt was converted into the free base by warming with dilute sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filtration and washed well with water to give 5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 272"C. 20 Example 168: 7-cyclopentanesulphonyl-5-(4-phenoxyphenyl)-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) in 25 dry dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes and then cyclopentanesulphonyl 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 vacuum. The residue was triturated with water and filtered to give a solid 30 which was washed well with water, then stirred with ethyl acetate then filtered. The filtrate was purified by flash column chromatography on silica using ethyl acetate as WO 00/17203 PCT/US99/21560 the mobile phase. Appropriate fractions were collected and evaporated to give 7 cyclopentanesulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4 ylamine, m.p. 188-188.5 0 C. 5 Example 169: 5-(4-phenoxyphenyl)-7-(8-phthalimidooctyl)-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) in dry dimethylformamide (30 ml) with stirring under nitrogen. The mixture was 10 stirred for 30 minutes under nitrogen and then N-(8-bromooctyl)phthalimide (1.4 g) in dimethyl-formamide (5 ml) was added. The mixture was stirred at ambient temperature for 18 hours under nitrogen 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 15 phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 85-86*C. Example 170: 7-(8-aminooctyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 4-ylamine dihydrochloride dihydrate 20 A mixture of 5-(4-phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine (1.0 g), hydrazine hydrate (1.0 ml) and ethanol (40 ml) was boiled under reflux for 2 hours with the exclusion of carbon dioxide. The mixture was cooled for 18 hours and a solid which precipitated was collected by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue 25 was dissolved in ethyl acetate, dried and then treated with a solution of concentrated hydrochloric acid in isopropanol dropwise until no further precipitation occurred. The mixture was left to stand overnight, then supernatent liquid was decanted off and the semi-solid residue was triturated with ethyl acetate to give 7-(8-aminooctyl) 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine dihydrochloride 30 dihydrate, m.p 120*C.

WO 00/17203 PCTIUS99/21560 Example 171: N-{2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]ethyl}phthalimide In a similar manner to Example 468, but with additional heating at 90 0 C for 3 5 hours, 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine was reacted with 2-bromoethylphthalimide to give N-{2-[4-amino-5-(4-phenoxyphenyl)-7H pyrrolo [2,3-d]pyrimidin-7-yl] ethyl}phthalimide, m.p. 111-1 12C. Example 172: 7-(2-aminoethyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 10 4-ylamine hydrochloride In a similar manner to Example 469, the product from the previous example was treated with hydrazine hydrate to give 7-(2-aminoethyl)-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-ylamine hydrochloride, m.p. 284-285"C. Example 173: 7-isobutyryl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4 15 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 dimethyl formamide (200 ml) and dry pyridine (2 ml) with stirring under nitrogen at 20C. The mixture was stirred at ambient temperature for 1 hour and evaporated under 20 vacuum. The residue was partitioned between water and ethyl acetate. The ethyl acetate was separated, dried and evaporated and the residue obtained was recrystallised from toluene to give 7-isobutyryl-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 160.5-161 C. 25 Example 174: 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4,5]decan-8-yl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine Sodium hydride (0.26 g of a 60% dispersion in mineral oil) was added to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.94 g) in dimethylformamide (50 ml) at ambient temperature with stirring. The mixture was WO 00/17203 PCTIUS99/21560 stirred until the evolution of hydrogen 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]decan-8-one, (which was prepared according to J. Med. Chem. 1992, 2246)) was added. The mixture was heated at 120*C for 5 hours under nitrogen, 5 cooled to ambient temperature, quenched with water and extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate followed by ethyl acetate containing increasing amounts of methanol up to 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. 193-194*C.. 10 Example 175: 4

-[

4 -amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexanone The product from the previous example (500 mg), acetone (20 ml) and 3M hydrochloric acid (10 ml) was stirred under nitrogen at ambient temperature for 20 15 minutes. The mixture was then heated at 60"C for 1 hour and then the acetone was removed under reduced pressure. The residue was basified with aqueous 5M sodium hydroxide solution and then extracted with ethyl acetate to give a solid which was triturated with diethyl ether and filtered to give 4 -[4-amino-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone, m.p. 252-254"C. 20 Example 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 25 added to the product from 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 a further portion of morpholine (0.15 g) and sodium triacetoxyborohydride (0.21 g) were added. The mixture was stirred at ambient temperature for 20 hours then quenched with saturated aqueous bicarbonate solution. The mixture was filtered through an 30 EMPORE@ cartridge and the filtrate was extracted with 3M hydrochloric acid. The acidic extracts were basified with 5M sodium hydroxide solution and extracted with WO 00/17203 PCT/US99/21560 dichloromethane to give a residue which was purified by chromatography on silica to give 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. 5 Examples 178 and 179: cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4 phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine 10 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 of 40% pure material) and 1-ethoxycarbonyl-piperidine (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 15 and chromatography cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4 phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine. 20 Example 180: 2-[4-amino-5-(4-phenoxyphenyl)-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 reacted 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 25 ( 4 -phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-3-carbonitrile, m.p. 242-242.5"C, after workup. Example 181: 7

-[

3 -(aminomethyl)pyrid-2-yl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]-pyrimidin-4-ylamine dimaleate 30 The product from the previous example (468 mg), ethanol saturated with ammonia (200 ml) and Raney@ nickel (2 ml) was shaken under hydrogen at a WO 00/17203 PCT/US99/21560 pressure of 26 bar at 80*C for 6 hours and then left standing at ambient temperature for 68 hours. The mixture was filtered and the residue was washed well with ethanol. The filtrate was evaporated under reduced pressure and the residue was taken up in ethyl acetate and filtered. Maleic acid (135 mg) dissolved in ethyl 5 acetate (20 ml) was added in portions to the filtrate until no further precipitation occurred. The mixture was warmed and decanted from a small residual amount of gum. The gum was further heated with ethyl acetate and decanted. The combined ethyl acetate extracts were cooled and the solid which precipitated was collected by filtration to give 7-[3-(aminomethyl)pyrid-2-yl]-5-(4-phenoxyphenyl)-7H 10 pyrrolo[2,3-d]-pyrimidin-4-ylamine dimaleate, m.p. 131-134"C. Example 182: 3-[4-amino-5-(4-phenoxyphenyl)-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 15 mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (770 mg, in dimethylformamide (30 ml). 3-Mesyloxy-8-methyl-8-azabicyclo[3.2.1 ]octane (900 mg, prepared as described in J.A.C.S. 1958, 80, 4679) in dimethylformamide (10 ml) was added under nitrogen with stirring. The mixture was warmed at 75"C for 5 hours (and left standing at ambient temperature for 7 days). The solvent was 20 removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol (50:50) as the mobile phase to remove starting material and then a mixture of ethyl acetate/methanol/ triethylamine (5:5:1) as the mobile phase to elute the product. Appropriate fractions 25 were combined and evaporated to give a solid which 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, m.p. 238-250'C. Examples 183 and 184: cis-7-(N-methylhomopiperazin-1-ylcyclohexyl)-5-(4 30 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- WO 00/17203 PCT/US99/21560 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 of a 40% pure material), N-methylhomopiperazine (114 mg), sodium 5 triacetoxyborohydride (296 mg), glacial acetic acid (60 mg) and 1,2-dichloroethane (15 ml) were reacted together. After filtration, the filtrate was evaporated and the residue was purified by chromatography on silica to give 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 10 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 -ylcyclohexyl)-5-(4-phenoxy-phenyl)-7-pyrrolo[2,3-d]prymidin-4 15 ylamine In a similar manner to the previous Example, N-methylpiperazine (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) 20 5-( 4 -phenoxy-phenyl)-7-pyrrolo[2,3-d]prymidin-4-ylamine. Example 187: 3-[ 4 -amino-5-(4-phenoxyphenyl)-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 25 7-yl]-cyclopentan-1-ol (100 mg), activated manganese dioxide (500 mg) and dichloromethane (100 ml) was stirred at ambient temperature for 18 hours to give, after filtration, a solution of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-cyclopentan-1-one in dichloromethane which was used in the next Example. 30 WO 00/17203 PCT/US99/21560 Example 188: cis-7-(3-morpholinocyclopent-1-yl)-5-( 4 -phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine and trans- 7

-(

3 -morpholinocyclopent-1-yl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine Morpholine (45 mg) was added to the solution obtained in the previous 5 Example followed by sodium triacetoxyborohydride (151 mg) and glacial acetic acid (47 mg). The mixture was stirred at ambient temperature under nitrogen for 18 hours during which time the dichloromethane evaporated. Tetrahydrofuran (100 ml) was added and the mixture was stirred for a further 8 hours. The mixture was worked up to give cis-7-(3-morpholinocyclopent-1-yl)-5-( 4 -phenoxyphenyl)-7H 10 pyrrolo[2,3-d]pyrimidin-4-ylamine and trans- 7

-(

3 -morpholinocyclopent-1-yl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine. Example 189: 3

-(

4 -amino-5-( 4 -phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl)cyclopentyl N-( 2 -morpholinoethyl)-carbamate hydrochloride 15 a) To a solution of 3

-(

4 -Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 7 -yl)cyclopentanol (20 mg) in dichloromethane (1 ml) at 0"C was added N methylmorpholine (7 ml) and the mixture stirred for 20 minutes. The cooling bath was removed and 4-nitrophenylchloroformate (12.5 mg) was added and the 20 resulting mixture stirred overnight at ambient temperature. The mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulphate and evaporated to give crude product. b) The crude product from a) in dichloromethane (2 ml) was added to 2 25 morpholinoethylamine (0.2 ml) and the mixture stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried, filtered and evaporated to give a crude product which was purified by preparative HPLC to give 3-(4-amino-5-(4 phenoxyphenyl)-7H- pyrrolo[ 2 ,3-d]pyrimidin-7-yl)cyclopentyl N-(2 30 morpholinoethyl)carbamate.

WO 00/17203 PCT/US99/21560 c) The product from b) was dissolved in ethyl acetate (2 ml) and hydrogen chloride gas was bubbled through the solution for 2 minutes. A precipitate formed and stirring was continued for a further 10 minutes. The solvent was evaporated and water added to dissolve the solid. Lyophilisation gave 3-(4-amino-5-(4 5 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl N-(2 morpholinoethyl)-carbamate hydrochloride as a solid. Example 190: 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentyl 2-aminoacetate hydrochloride 10 a) 3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentanol (50 mg, 0.129 mmol) and N-tert-butoxycarbonyl glycine (34 mg, 0.194 mmol) was mixed in N,N-dimethylformamide (1 ml). 1-(3 Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) 15 and 4-dimethylamino pyridine (16 mg, 0.129 mmol) was added. The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The solid was purified by flash column chromatography on silica 20 using ethyl acetate as the mobile phase to give 3-[4-amino-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-[(tert butoxycarbonyl)amino]acetate. The structure was confirmed by 'H NMR. b) 3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 25 2-[(tert-butoxycarbonyl)amino]acetate (39 mg, 0.072 mmol) was disolved in ethyl ecetate (2.5 ml). Hydrogen chloride gas was passed through for 1 minute. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The solid was collected by filtration to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 30 yl]cyclopentyl 2-aminoacetate hydrochloride. The structure was confirmed by 'H WO 00/17203 PCT/US99/21560 NMR and LC/MS (MH = 444). Example 191: 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentyl (2S)-2-amino-3-methylbutanoate hydrochloride 5 a) (2S)-1-[(tert-Butoxycarbonyl)amino]-2-methylbutanoic 2,5-dioxo-2,5-dihydro 1H-1-pyrrolecarboxylic anhydride ( 114 mg, 0.362 mmol) was added to a solution of 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 10 mixture was stirred under nitrogen at ambient 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)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (2S)-2-[(tert 15 butoxycarbonyl)amino]-3-methylbutanoate. The structure was confirmed by '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-methylbutanoate (35 mg, 0.060 mmol) 20 was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed through for 5 minutes. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The 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-methylbutanoate 25 hydrochloride. The structure was confirmed by 'H NMR and LC/MS (MHE= 486). 30 WO 00/17203 PCT/US99/21560 Example 192: 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl)cyclopentyl N-(2-morpholinoethyl)carbamate hydrochloride a) N-Methylmorpholine (0.007 ml, 0.062 mmol) was added dropwise to solution of 5 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 up 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 10 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-d]pyrimidin-7-yl]cyclopentyl (4-nitrophenyl) carbonate. The structure was confirmed by 'H NMR. 15 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 2-morpholinoethylamine (0.2 ml). The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was diluted 20 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 'H NMR and LC/MS (MH = 543). 25 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 gas was passed through for 2 minutes, and a precipitate formed. The flask was capped and the solution stirred for additional 30 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- WO 00/17203 PCTIUS99/21560 morpholinoethyl)carbamate hydrochloride. The structure was confirmed by 'H NMR and LC/MS (MH*= 543). Preparation of Starting Materials 5 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 heated at 80'C for 3 hours. The mixture was cooled 10 to 0 0 C and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212 0 C. 15 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 0 C for 30 minutes under nitrogen. 20 (2) In a separate flask sodium (331 mg) was dissolved in ethanol (50 ml) and malononitrile (858 mg) was added. The solution was stirred at ambient temperature for 5 minutes and then to this solution was added the solution of 4'-phenoxy-2-(tert-butylamino)acetophenone obtained in part (1) in one portion excluding the precipitated sodium chloride. The resultant mixture 25 was heated at 50 0 C for 3 hours and then at 80'C for 2 hours. The solvent was removed under reduced pressure and the resultant 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, filtered and dried to give 2-amino-3-cyano-4-(4 30 phenoxyphenyl)- 1 -(tert-butyl)pyrrole.

WO 00/17203 PCT/US99/21560 / SY3 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 heated at 180 0 C for 6 hours. The mixture was cooled to ambient temperature and water was added to precipitate a dark solid. The solid was collected by filtration, 5 washed with water, then boiled up in ethanol and the insoluble material collected by hot filtration and dried. The solid was purified by preparative HPLC on a silica column using dichloromethane/propan-2-ol/ 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), 10 m.p. 157-158'C. 1H NMR (d6 DMSO) 6 8.15 (1H,s), 7.50-7.35 (4H,m), 7.30 (1H,s), 7.15 (1H,t), 7.10 (4H,m), 6.05 (2H,brs), 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 a 15 48% solution) was boiled under reflux for 18 hours under nitrogen. The mixture was allowed to cool and a solid was collected by filtration. This solid was washed with methanol and then with ether to give 4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidine hydrobromide, m.p. 288-292"C. The hydrobromide salt was converted into the free base by warming with dilute 20 sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filtration and washed well with water to give 5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. 25 e) A mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (600 mg) and tetrakis(triphenylphosphine) palladium (40 ml) and dry dimethyl sulphoxide (30 ml) was stirred under nitrogen in an ice/water bath and then a solution of cyclopentadiene monoepoxide (200 mg) in tetrahydrofuran (10 ml) was added via syringe under nitrogen at 0"C. The mixture was stirred at ambient 30 temperature (with exclusion of light) for 66 hours and then the tetrahydrofuran was removed under reduced pressure and water was added to the residue. The WO 00/17203 PCT/US99/21560 mixture was allowed to stand for 18 hours and then extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopent-2 5 enol, as an oil. The structure was confirmed by 1 lHnmr 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 atmospheric pressure using 10% palladium on charcoal (50 mg) as the catalyst. 10 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 1H nmr and mass spectra. Example 193: Cis-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex-1-yl)-7H 15 pyrrolo[2,3-d]pyrimidin-4-ylamine Trans-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex-1-yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine To a stirred suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidinyl-7-yl]cyclohexanone (2.34 g, 5.9 mmol) in 1,2 dichloroethane (250 20 mL) was added, under an atmosphere of nitrogen, pyrrolidine (1.25 g, 17.6 mmol) and glacial acetic acid ( 1.00 mL, 17.6 mmol), and the resultant mixture stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion, and the resultant mixture stirred for 70 hours. The mixture was extracted with 2M aqueous hydrochloric acid (2 x 200 mL). The combined 25 extracts were washed with dichloromethane (300 mL), made basic with 12.5M aqueous sodium hydroxide solution, and extracted with dichloromethane (3 x 200 mL). The combined extracts were dried over sodium sulphate, and purified by chromatography with a Biotage 40S column using ethyl acetate / triethylamine (95:5) and ethyl acetate / triethylamine / methanol (85:10:5) as a mobile phase to 30 yield 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), melting point 101 - WO 00/17203 PCT/US99/21560 104 deg.C., LC/MS Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.): MH' 454 t,= 3.56 minutes 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), melting 5 point 183 - 185 deg.C, LC/MS (Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.): MHI 454 , t, = 3.68 minutes Example 194: Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H 10 pyrrolo[2,3-d]pyrimidin-4-ylamine hydrochloride Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine To a stirred suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimin-7-yl]cyclohexanone (2.34 g, 5.9 mmol) in 1,2 dichloroethane (250 mL) 15 was added, under an atmosphere of nitrogen, piperidine (1.50 g, 17.6 mmol) and glacial acetic acid ( 1.00 mL, 17.6 mmol), and the resultant mixture stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion, and the resultant mixture stirred for 70 hours. The mixture was extracted with 2M aqueous hydrochloric acid (2 x 200 mL). The combined extracts 20 were washed with dichloromethane (300 mL), made basic with 12.5M aqueous sodium hydroxide solution, and extracted with dichloromethane (3 x 200 mL). The combined extracts were dried over sodium sulphate, and purified by chromatography with a Biotage 40S column using ethyl acetate / triethylamine (95:5) as a mobile phase to yield Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H 25 pyrrolo[2,3-d]pyrimidin-4-ylamine (0.23 g) as a clear oil., LC/MS :ypersil BDS c1 8 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.) MH* 468 t, = 3.67 minutes and Trans-5-(4-phenoxyphenyl)-7-(4 piperidinocyclohex-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as an off-white solid (193 mg, 0.4 mmol), melting point 192 - 195 deg.C, LC/MS: Hypersil BDS 30 c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.)MH* 468 t,= 3.71 minutes WO 00/17203 PCT/US99/21560 Example 195: Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine was dissolved in ethyl acetate (50 mL), diluted with diethyl ether (50 mL) and treated with a 1M solution of hydrogen chloride in 5 diethyl ether until no further precipitation occurred. The resultant solid was collected and re-crystallised from absolute ethanol to give Cis-5-(4-phenoxyphenyl)-7-(4 piperidinocyclohex-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine hydrochloride as a colourless solid (75 mg, 0.2 mmol) melting point 185 - 189 deg.C. 10 Example 196: Trans-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-ylamine Cis-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine To a stirred solution of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 15 d]pyrimin-7-yl]cyclohexanone (3.24 g, 8.1 mmol) in dichloromethane (1000 mL) was added, under an atmosphere of nitrogen, N-methylpiperazine (1.20 g, 12.0 mmol) and glacial acetic acid ( 0.69 mL, 12.0 mmol), and the resultant solution stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (1.70 g, 8.0 mmol) was added in one portion, and the resultant solution stirred for 6 hours. 20 The additions were repeated on the same scale and the resultant solution stirred for 70 hours. The solution was. extracted with 2M aqueous hydrochloric acid (2 x 300 mL). The combined extracts were washed with dichloromethane (300 mL), made basic with .880 aqueous ammonia solution, and extracted with ethyl acetate (3 x 250 mL). The combined extracts were washed with saturated aqueous sodium chloride 25 solution, dried over sodium sulphate, and purified by chromatography with a Biotage 40M column using ethyl acetate / methanol / triethylamine (8:1:1) as a mobile phase to yield 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.) melting point 180 - 182 deg.C, LC/MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1M 30 ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.)MH* 428 t,= 3.43 minutes The column was flushed with ethyl acetate / methanol / triethylamine (4:1:1, WO 00/17203 PCT/US99/21560 500 mL), and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (200 mL)and purified by chromatography with a Biotage 40M column using dichloromethane/methanol (9:1 to 7:3) to yield Trans-7 (4-dimethylamino-cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4 5 ylamine as an off-white solid (320 mg, 0.75 mmol) melting point 207.5 - 210 deg. C, LC/MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.)MH*428 t, = 3.48 minutes R - (+) -4 -[4-amino-5-(4-phenoxyphenyl)-7- (3-tetrahydrofuryl)-7H pyrrolo[2,3-d]pyrimidine. 10 Example 197: 4 -{(S) - tetrahydrofuran-3-yl}toluenesulphonate To a solution of (S)-3-hydroxytetrahydrofuran (2.0 g, 23 mmol) injpyridine (40 ml) at 0*C was added tosylchloride portionwise (4.8 g, 25 mmol). The solution was stirred at 0*C for 1 hr and then at room temperature overnight. The pyridine was 15 evaporated in vacuo and the residue was partioned between EtOAc and saturated aquoeus citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2 x 200 ml) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave an oil (4.5 g, 85%). '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 (2H, m). 20 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), under an atmosphere of nitrogen, was added 60% sodium hydride in mineral oil (0.75 g, 19 mmol), and the mixture stirred at room temperature for 30 minutes. The resultant dark solution was treated with a solution of 4 -{(S) - tetrahydrofuran-3 25 yl}toluenesulphonate (4.20 g, 18 mmol) in N,N-dimethylformamide (20 mL) in 2 mL aliquots. The resultant solution was stirred at room temperature for 30 minutes, then at 95 deg.C. for 18 hours. The solution was allowed to cool to ambient temperature, then poured onto ice/water (200 mL). The aqueous was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water 30 (4 x 150 mL), dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was warmed with dichloromethane (1000 mL) until a WO 00/17203 PCT/US99/21560 solution was obtained, cooled to ambient temperature, and purified by chromatography with a Biotage 40M column using ethyl acetate/ triethylamine (95:5), then ethyl acetate / triethylamine / methanol (90:5:5) as a mobile phase, to yield R - (+) - 4 -[4-amino-5-(4-phenoxyphenyl)-7- (3-tetrahydrofuryl)-7H 5 pyrrolo[2,3-d]pyrimidine as an off-white solid (4.35 g, 12 mmol) melting point 165 166 deg. C, LC/MS : Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.) 4H* 373 t,= 4.44 minutes. []D + 20.5 ± 0.6 (dichloromethane, 22.6 deg.C.) 10 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 0 C was added sodium borohydride (1.9 g, 50 mmol) 15 portionwise. Stir at 0"C for 1 hr and then at room temperature for 20 hr. Quench with 2N NaOH (20 ml), evaporate solvent and partition residue between ethylacetate and water (100 ml each). Extract the aqueous layer with ethylacetate (3 x 100ml) and wash the combined organic layers with brine and water (1 x 100 ml each). Dry (NaS0 4 ), filter and concentrate to leave N-tert-butoxycarbonylpiperidinol as a 20 colourless oil (10.5 g, 100%). Rf in 20% EtOAc / hexane = 0.05 (KMnO 4 dip). IR (thin film) : 3428, 2939, 1693 cm' 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 25 pyridine (150 ml) at 0 0 C under nitrogen was added tosylchloride (9.94 g, 0.052 mol) portionwise. Stir at 0"C for 2 hr. Warm to room temperature and stir at room temperature overnight. Evaporate the solvent and partition between citric acid solution (IM, 100 ml) and ethylacetate (200 ml). Extract acidic layer with ethylacetate (1 x 100 ml) and wash combined organics with citric acid solution (1M, 30 2 x 100 ml), brine (100 ml) and water (100 ml). Dry (Na 2

SO

4 ), filter and evaporate to leave an oil which was purifed by flash column chromatography using 10% WO 00/17203 PCT/US99/21560 EtOAc / cyclohexane then 15% EtOAc / cyclohexane to give in F 30-68 tert-butyl 4 [(4-methylphenyl)sulfonyl]oxy-1-piperidinecarboxylate as a white solid (11.0 g, 60%) Rf in 20% EtOAc / cyclohexane = 0.17 'H NMR (CDCl 3 , 250 MHz) : 8 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 5 1.83 (4H, m), 1.43 (9H, s) Example 200: tert-butyl 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-piperidinecarboxylate To a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine 10 (2.0 g, 6.6 mmol) in dry DMF (100 ml) under nitrogen at OoC was added NaH (0.264 g, 60% dispersion, 6.6 mmol) and the reaction mixture warmed to room temperature and stirred for lhr. Tert-butyl 4-[(4-methylphenyl)sulfonyl]oxy-1 piperidinecarboxylate (2.34 g, 6.6 mmol) was added and the resulting solution heated at 95*C for 72 hr. The reaction was quenched by careful addition of water 15 (150 ml). Extract with EtOAc (3 x 100 ml) and wash with water (4 x 100 ml) and brine (2 x 100 ml). The organic solution was dried (Na 2

SO

4 ), filtered and evaporated to leave a solid which was adsorbed onto silica and purified by flash silica gel column chromatography using EtOAc then 5% MeOH/EtOAc as eluent to give in F 13-22 tert-butyl4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] 20 1-piperidinecarboxylate (1.0 g, 31%) as a white solid, m.pt. 168.5-169.5oC. Rf in 10% EtOAc/MeOH = 0.4. 'H NMR (d 6 DMSO, 250 MHz) : 8 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). Mass spec. C 2 sH 31 0 3

N

5 (485.2430).IR (KBr disc) : 3059, 1695, 1588, 1235 cm-' 25 Example 201: 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4 ylamine 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) 30 at 0*C was added TFA (5 ml). The solution was stirred at room temperature for 20 WO 00/17203 PCT/US99/21560 hr and the solvent evaporated. NaOH solution (5N, 10 ml) was added and the resulting slurry was extracted with EtOAc (3 x 50 ml). Wash with brine (1 x 50 ml). Dry, filter and concentrate to leave a solid which was triturated with diethylether and filtered to leave 5-(4-phenoxyphenyl)-7-(4-piperidy)-7H-pyrrolo[2,3 5 d]pyrimidin-4-ylamine (433258) as a white solid (500 mg, 91%). M.pt 209-21 1C. Rfin 1:1 EtOAc : MeOH = 0.1. . 'H NMR (dDMSO, 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, m), 3.10 (2H, m), 2.80 (1H, bs), 2.67 (2H, m), 1.94 (4H, m). Mass spec. C 23

H

2 3 0N. (385.1902). IR (KBr disc) : 3278, 1620, 1585, 1490, 1245 cm-' 10 Example 202: 5-( 4 -phenoxyphenyl)-7-(4-piperidyl)-7H-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) was added ether.HCl 15 solution (1.0 M, 3 ml). The resulting white precipitate was filtered under a stream of nitrogen and dried in vacuo for 6 hr to leave 5-(4-phenoxyphenyl)-7-(4-piperidyl) 7 H-pyrrolo[2,3-d]pyrimidin-4-ylamine dihydrochloride (1.4 hydrate) as a white solid (120 mg), m.pt. 304 0 C (dec.). 'H NMR (D 2 0, 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), 20 2.49 (4H, m). ). IR (KBr disc) : 3937, 1657. 1231 cm-' Example 203: tert-butyl 3

-[

4 -amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate N-tert-butoxycarbonylpyrrolidin-3-ol 25 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 butyldicarbonate (28.8 g, 0.13 mol) at 0 0 C. Warm to room temperature and stir at room temperature overnight. Quench with saturated aqueous citric acid (150 ml) amd wash the organic layer with water, brine and water again (1 x 100 ml each). The 30 organic layer was dried (sodium sulphate), filtered and evaporated to leave N-tert- WO 00/17203 PCT/US99/21560 butoxycarbonylpyrrolidin-3-ol (20.0g, 93% crude) as a golden oil. Example 204: tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate To a solution of N-tert-butoxycarbonylpyrrolidin-3-o1 (19.8 g, 0.106 mol) in 5 pyridine (200 ml) at 0*C under nitrogen was added tosyl chloride (22.3 g, 0.117 mol) portionwise. Stir at 0*C for 2 hr, warm to room temperature and stir at room temperature overnight. The pyridine was evaporated in vacuo and the residue was partioned between EtOAc and saturated aquoeus citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2 x 200 ml) and the combined organics 10 were dried (sodium sulphate), filtered and evaporated to leave an oil which was purified by flash silica gel column chromatography using 10% EtOAc/cyclohexane as eluent to give in F40-85 an oil. The oil was dissolved in a small volume of cyclohexane/ diethylether (5:1, 50 ml), cooled and scratched with a spatula to induce crystallisation. The resulting solid was filtered to give tert-butyl 3-[(4 15 methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate (10.5 g, 29%) as a white solid. Rf in EtOAc/cyclohexane = 0.13. '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)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.6 mmol) in dry DMF (120 ml) under nitrogen at 0*C was added NaH 20 (0.264 g, 60% dispeersion, 6.6 mmol) and then reaction mixture warmed to room temperature and stirred for lhr. tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1 pyrrolidinecarboxylate (2.25 g, 6.6 mmol) was added portionwise and the mixture heated at 95C -for 72 hr. Quench with water and extract with EtOAc (4 x 100 ml). Wash the combined organic solutions with water (4 x 100 ml) and brine (2 x 100 25 ml). The organics were dried (sodium sulphate), filtered and evaporated to leave a solid which was dissolved in EtOAc/MeOH and adsorbed onto silica. Purification using flash silica gel column chromatography with 5% MeOH/ EtOAc as eluent gave in F17-25 tert-butyl 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate (1.0 g, 32%) as a white solid m.pt. 168 30 170 0 C. Rf in 9:1 EtOAc: MeOH = 0.46. 'H NMR (d 6 DMSO, 250 MHz): 8.17 (1H, WO 00/17203 PCT/US99/21560 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 spec. 471.2250 (C 7

H

2

,

9 0 3 N) IR (KBr disc): 3130, 1683, 1585, 1404, 1245 cm-' Example 205: 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo[2,3-d]pyrimidin 5 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 warmed to room temperature and stirred at room temperature for 20 hr. The solvent 10 was evaporated and dilute NaOH added (5N, 10 ml). The resulting residue solution was extracted with EtOAc (3 x 50 ml) and the combined organics were washed with brine (1 x 75 ml). The organic solution was dried (sodium sulphate), filtered and evaporated in vacuo to leave 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H pyrrolo[2,3-d]pyrimidin-4-ylamine as a white solid (0.5 g, 79%) m.pt. 182-184"C. Rf 15 in 1:1 EtOAc : MeOH = 0.15. 'H NMR (d, 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 0N). IR (KBr disc): 3106, 1585, 1489, 1232 cm-' 20 Example 206: 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-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 ether.HCl (1.0 M, 3 ml) and the resulting precipitate was filtered under nitrogen to give 5-(4 25 phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo[2,3-d]pyrimidin-4-ylamine dihydrochloride (0.4 hydrate) as a white solid (190 mg) m.pt. 298'C (dec.). IR (KBr disc): 2909, 1658, 1249 cn' WO 00/17203 PCT/US99/21560 Example 207: 7-perhydro-1-pyrrolizinyl-5-(4-phenoxyphenyl)-7H-pyrrolo[ 2

,

3 ,d] pyrimidin-4-amine dihydrochloride salt a) perhydro-1-pyrrolizinol 5 Prepared as described by Schnekenburger J, Briet E, Arch. 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, 10 5.91 mmol) in dichloromethane (10 ml) was stirred at 0*C under an atmosphere of nitrogen. Methanesulfonyl chloride (0.68 g, 5.91 mmol) was added, then the mixture was allowed to warm to ambient temperature and stirred for 8 hours. Saturated aqueous ammonium chloride (10 ml), dichloromethane (25 ml) and saturated aqueous sodium bicarboante (10 ml) were added. The organic layer was dried over 15 magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (1:3) as an eluent yielded perhydro-1-pyrrolizinyl methanesulfonate (0.54 g): 'H NMR (DMSO-d 6 , 400MHz) 8 4.96 (m, 1H), 3.61 (m, 1H), 2.9-3.3 (m, 6H), 2.35 (m, 1H), 1.55-2.25 (m, 6H). 20 c) 7-perhydro-1-pyrrolizinyl-5-(4-phenoxyphenyl)- 7 H-pyrrolo[ 2

,

3 ,d]pyrimidin-4 amine dihydrochloride salt A mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.49g, 1.62 mmol) and 60% sodium hydride in oil (100 mg, 2.43 mmol) in DMF 25 was stirred at ambient temperature for 15 minutes under an atmosphere of nitrogen. The mixture was heated at 1 00"C for 18 hours then cooled to ambient temperature. Additional 60% sodium hydride in oil (100 mg, 2.43 mmol) was added and heating WO 00/17203 PCT/US99/21560 continued for another 2 hours. The mixture was cooled to ambient temperature and the solvents removed under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (30 ml). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed from the filtrate under 5 reduced pressure. The resulting residue was purified by preparative C-18 RP HPLC to give 150 mg of white solid which was dissolved in ethyl acetate (10 ml) and treated with 1 N hydrogen chloride in diethyl ether to give 7-perhydro-1 pyrrolizinyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3,d] pyrimidin-4-amine dihydrochloride salt as a white solid: 'H NMR (DMSO-d 6 , 400MIHz) 8 8.52 (s, 1H), 10 7.95 (s, 1H), 7.02-7.58 (m, 1H), 5.38 (in, 1HO, 4.40 (in, 1H), 1.9-3.9 (in, 10H); (Hypersil HS C18, 5 pm, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min ) t,=7.62 min; MS: MH* 412. Example 208: 7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-5-(4-phenoxyphenyl) 15 7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride salt a) 2-methylperhydrocyclopenta[c]pyrrol-5-ol Prepared as described by Bohme H, Setiz G, Arch. Pharm. (Wienheim) 301, 341 (1968). 20 b) 4-chloro-5-iodo-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3 d]pyrimidine A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (0.38 g, 1.36 mmol), 25 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 treated with diethylazodicarboxylate (0.474 g, 2.72 mmol) and stirred for 2 hours at ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (10 ml). The organic layer 30 was washed with saturated aqueous sodium chloride (10 ml) then dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica using WO 00/17203 PCTIUS99/21560 dichloromethane/ methanol (8:2) as mobile phase to yield 4-chloro-5-iodo-7-(2 methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.25 g): 'H NMR (DMSO-d,, 400MHz) 5 8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 5.36 (in, 1H), 2.88 (in, 2H), 2.68 (in, 2H), 2.43 (in, 2H), 2.36 (s, 3H), 2.06-2.02 (in, 4H); TLC 5 (dichloromethane/methanol 8:2) Rf = 0.29; RP-HPLC (Hypersil HS C18, 5 pm, 100A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, Iml/min) t,=6.50 min; MS: MH* 403. c) 7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-5-(4-phenoxyphenyl)-7H 10 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-phenoxyphenyl boronic acid (0.16 g, 0.746 mmol), tetrakis(triphenylphosphine)palladium (0.043 g, 0.037 mmol) and sodium carbonate (0.172 g, 1.62 mmol) was heated in a mixture of ethylene glycol 15 dimethyl ether (8 mL) and water (4 mL) at 900 C for 18 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and 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 concentrated to a 20 residue under reduced pressure (0.354 g). The material was dissolved in 1,4-dioxane (10 ml) and concentrated (28%) ammonium hydroxide (10 ml). The mixture was heated in a sealed tube at 120'C for 20 hours then cooled to ambient temperature. The solvents were evaporated under reduced pressure then purified by flash column chromatography on silica using dichloromethane/methanol 7:3) as an eluent to give 25 7-(2-methylperhydrocyclopenta [c]pyrrol-5-yl)-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine (0.05 g): 'H NMR (DMSO-d 6 , 400MHz) shows two sets of peaks due to the cis and trans isomers of the desired compound 8 10.6 10.8 (bs, 1H), 8.49 (s, 1H), 6.99-7.98 (m, 1iH), 5.39 and 5.48 (in, 1H), 2-3.8 (in, 10H); PH 454098: RP-HPLC (Hypersil HS C18, 5 ptm, 100A, 250 x 4.6 mm; 25 30 100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min) t,=7.53 min; MS: MH* 426. The dihydrochloride salt of 7-(2-methylperhydrocyclopenta[c]pyrrol-5- WO 00/17203 PCTIUS99/21560 yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was prepared by dissolving the free base in 10 ml 1 N hydrochloric acid and lyophilizing. Example 209: Cis and trans-7-[4-(N-tert-butoxycarbonyl-lS, 4S-2,5-diaza[2.2.1] 5 heptanyl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-l-cyclohexanone (0.67 g, 1.68 mmol) in dichloroethane (40 ml) was treated with tert-Butyl (IS, 4S)-(-) 2,5-diazabicyclo[2.2. 1 ]heptane-2-carboxylate (1.0 g, 5.04 mmol) and glacial acetic acid (0.30 g, 5.04 mmol) at room temperature 10 for 1 h. Subsequently, Na(OAc) 3 BH (0.46 g, 2.17 mmol) was added and stirred for 8 days at 80'C. To the cooled reaction solution, a solution of NaHCO 3 (0.377 g, 10.08 mmol) in water (15 ml) was added and stirred for 15 min. 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 combined , dried 15 (MgS04), filtered and concentrated. The solid was purified by flash silica gel column chromatography, (2 L, 6% MeOH in CH2Cl2, then 2 L 10% MeOH / 5%

NH

4 0H in CH 2 Cl 2 ) to give: Example 210: Cis-7-[4-(N-tert-butoxycarbonyl-1S, 4S-2,5-diaza[2.2.1]heptanyl) 20 cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (605 mg, 64%) 'H NMR (d 6 DMSO, 400 MHz): 8 8.13 (1H, s), 7.39-7.49 (4H, in), 7.32 (1H, m), 7.07-7.17 (5H,m), 6.09 (2H, bs), 4.63 (1H, in), 4.15 (1H, in), 3.30-3.70 (2H, in), 3.03-3.08 (2H, in), 2.80-2.90 (1H, in), 2.70-2.75 (1H, in), 2.29-2.35, (1H, 25 in), 2.09-2.21 (1H, in), 1.81-1.93 (4H, in), 1.60-1.80 (4H, m), 1.39 (9H, m). HPLC/MS: Perkin Elmer Pecosphere C18, 3p.M, 33 x 4.6, 3.5 ml/min 100 - 100% 50 mM ammonium acetate to acetonitrile in 4.5 minutes, C 3 6 H44N 6 0 3 (581.2), 95%. 30 WO 00/17203 PCT/US99/21560 Example 211: Trans-7-[4-(N-tert-butoxycarbonyl- iS, 4S-2,5-diaza[2.2. 1 ]heptanyl) cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (183 mg, 20%) 'H NMR (d 6 DMSO, 400 MHz): 8 8.13 (1H, s), 7.39-7.47 (5H, m), 7.15 5 7.17 (1H, m), 7.07-7.11 (4H,m), 6.10 (2H, bs), 4.62 (1H, m), 4.1-4.2 (1H, 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 (9H, s). HPLC/MS Perkin Elmer Pecosphere C18, 3jiM, 33 x 4.6, 3.5 ml/min 100 100% 50 mM ammonium acetate to acetonitrile in 4.5 minutes, C 30

H

36

N

6 0 (581.2), 99%. 10 Example 212: Cis-N1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl] cyclohexyl}-Ni,N2,N2-trimethyl-1,2-ethanaediamine trimaleate salt Trans-N1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 15 yl]cyclohexyl}-Ni,N2,N2-trimethyl-1,2-ethanaediamine trimaleate salt A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine 7-yl]-1-cyclohexanone (1.0 g, 2.51 mmol), N,N,N'-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 an atmosphere of nitrogen for 30 minutes. 20 Sodium triacetoxyborohydride (0.69 g, 3.26 mmol) was added and the mixture stirred at ambient temperature for 18 hours. Water (20 ml) and sodium bicarbonate (1.26 g, 15.1 mmol) were added, the mixture was stirred for one hour, filtered through a pad of celite and the pad was washed with dichloromethane (75 ml). The filtrate was transferred to a separatory funnel and the layers were separated. The 25 organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using dichloromethane/methanol (7:3) as an eluent to give cis-N1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}-Ni,N2,N2-trimethyl-1,2-ethanaediamine (0.442 g) and trans-Ni-{4 30 [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl} N1,N2,N2-trimethyl-1,2-ethanaediamine (0.336 g). The cis-N1-{4-[4-amino-5-(4- WO 00/17203 PCT/US99/21560 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl} -N1,N2,N2-trimethyl 1,2-ethanaediamine (0.44 g, 0.909 mmol) was dissolved in warm ethyl acetate (100 ml) then 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 sides of the flask. The 5 supernatant was poured off and the residue was dissolved in water and lyophilized to give cis-N1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}-Ni,N2,N2-trimethyl-1,2-ethanaediamine trimaleate salt (0.55 g):'H NMR (DMSO-d 6 , 400MHz) 5 8.22 (s, IH), 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), 10 2.79 (s, 6H), 2.50 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.78 (m, 4H); RP-HPLC (Hypersil CPS, 5 im, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 1Omin, 1ml/min) t,=9.27 min; MS: MH* 485. trans-Ni - {4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-7 15 yl]cyclohexyl}-Ni,N2,N2-trimethyl-1,2-ethanaediamine trimaleate salt was prepared from the free base in the same manner: 'H NMR (DMSO-d 6 , 400MHz) 8 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, IH), 2.9-3.3 (m, 5H), 2.74 (s, 6H), 2.56 (s, 3H), 1.9-2.2 (m, 6H), 1.73 (m, 2H); RP-HPLC (Hypersil CPS, 5 pm, 100A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M 20 ammonium acetate over 10min, 1ml/min) t,=8.17 min; MS: MH* 485. The following compounds were made in a similar manner to cis-N1-{4-[4 amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl} Ni,N2,N2-trimethyl-1,2-ethanaediamine 25 Example 214: Cis-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyriinidin-4-amine: 'H NMR (d 6 DMSO, 400 MHz): 5 8.13 (iH, 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 (5H, m), 1.70-1.72 (2H, m), 1.53-1.59 (2H, m), 0.97 30 (d, J = 6.5 Hz, 6H). Mass spec. C 3

,H

3 ,NO (511.2). HPLC: (Hypersil HS C18, WO 00/17203 PCT/US99/21560 /7 ( 5pm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t,=7.817 min., 99% TLC: Rf in 90% CH 2 Cl 2 /MeOH = 0.30 (UV visible). 5 Example 215: Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine: 'H NMR (d 6 DMSO, 400 MHz): 8 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 spec. C 3

,H

38

N

6 0 (511.2). HPLC: (Hypersil HS C18, 5pim, 254 rim, 250 10 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 mil/min) t,=7.367 min., 91% TLC: Rf in 90% CH 2 Cl 2 /MeOH = 0.21 (UV visible). Example 216: Cis-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine: 'H NMR (d 6 DMSO, 400 15 MHz): 8 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 spec. C 3

,H

38

N

6 0 2 (527.2). HPLC: (Hypersil HS C18, 5im, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t=7.317 min, 95% TLC: Rf in 90% 20 CH 2 Cl 2 /MeOH = 0.22 (UV-visible). Example 217: Trans-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine: 'H NMR (d 6 DMSO, 400 MHz): 8 8.13 (1H, s), 7.39-7.47 (5H, m), 7.07-7.16 (5H, m), 6.09 (2H, bs), 4.55 25 (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 spec. C 3

,H

3 8

N

6 0 2 (527.2). HPLC: (Hypersil HS C18, 5pim, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t,=7.200 min, 99% TLC: Rf in 90% CH 2 Cl 2 /MeOH = 0.31 (UV visible).

WO 00/17203 PCT/US99/21560 / '793 Example 218: Cis-7-[-4-(4-ethylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine 'H NMR (d 6 DMSO, 400 MHz) : 8 8.23 (1H, s), 7.41-7.49 (4H, m), 7.07 5 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 30min, 1ml/min ) tr=1 3 .851, 100%. trans-7-[4-(4-ethylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 10 d]pyrimidin-4-amine 'H NMR (d 6 DMSO, 400 MHz) : 8 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 (3H, t). HPLC (Waters delta pack C18, 150 x 3.9 mm; 5 - 95% acetonitrile-0.1 M 15 ammonium acetate over 30min, 1ml/min ) tr=1 3

.

7 01, 96%. The following compounds were prepared as salts in a similar manner to that of trans-N1 - {4-[4-ainino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}--N1,N2,N2-trimethyl-1,2-ethanaediamine trimaleate salt: 20 Example 219: Cis-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate: 'H NMR (d 6 DMSO, 400 MHz): 6 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 25 Hz, 6H). Mass spec. C 3

H

38

N

6 0 (511.1). HPLC: (HypersilHS C18, 5pm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t,=7.967 min, 99% WO 00/17203 PCT/US99/21560 /t)3 Example 220: Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate: 'H NMR (d 6 DMSO, 400 MHz): 8 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= 5 6.5 Hz, 6H). Mass spec. C 3 jH 3 8

N

6 0 (511.2). HPLC: (Hypersil HS C18, 5pm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t,=7.733 min, 90% Example 221: Cis-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4 10 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate: 'H NMR (d 6 DMSO, 400 MHz): 8 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 spec. C 3

,H

3 8

N

6 0 2 (527.2). HPLC: (Hypersil HS C18, 5Lm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N 15 ammonium acetate over 10 min, 1 ml/min) t,=7.750 min, 99% Example 222: Trans-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate: 'H NMR (d 6 DMSO, 400 MHz): 8 8.21 (1H, s), 7.41-7.48 (5H, m), 7.08-7.17 (5H, m), 6.53 (2H, 20 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 spec. C 3

,H

3 8

N

6 0 2 (527.2). HPLC: (Hypersil HS C18, 5pm, 254 nm, 250 x 4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) t,=7.383 min, 99% 25 Example 223: Cis-N1-{ 4 -[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]cyclohexyl}-N2,N2-dimethyl-1,2-ethanaediamine trimaleate salt Trans-N1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}-N2,N2-dimethyl-1,2-ethanaediamine monomaleate salt cis-NI-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 30 yl]cyclohexyl}-N2,N2-dimethyl-1,2-ethanaediamine trimaleate salt:'H NMR WO 00/17203 PCT/US99/21560 (DMSO-d,, 400MHz) 8 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), 1.8-2.25 (m, 8H); RP-HPLC (Hypersil CPS, 5 pm, 1OA, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min) t,=8.90 min; MS: MH* 471. 5 Example 224: trans-Ni-{ 4 -[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]cyclohexyl} -N2,N2-dimethyl- 1,2-ethanaediamine mononaleate salt:'H NMR (DMSO-d 6 , 400MiHz) 8 9.5 (bs, 1H), 8.26 (s, 1H), 7.41-7.55 (m, 5H), 7.08-7.19 (m, 5H), 6.7 (bs, 2H), 6.16 (s, 2H), 4.63 (m, 1H), 3.12-3.55 (m, 5H), 2.85 10 (s, 3H), 2.27 (m, 2H), 1.99-2.05 (m, 4H), 1.67-1.75 (m, 2H); RP-HPLC (Hypersil CPS, 5 pm, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min ) tr=8.6 min; MS: MH*{ 471. Example 225: Cis-7-(4- { [3-(1H- 1 -imidazolyl)propyl]amino} cyclohexyl)-5-(4 15 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt Trans-7-(4-f{[3-(1H-1-imidazolyl)propyl]amino}cyclohexyl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt Example 227: cis-7-(4-{[3 -(1 H-1 -imidazolyl)propyl]amino} cyclohexyl)-5-(4 20 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt:'H NMR (DMSO-d 6 , 400MHz) 6 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, 10 H); RP-HPLC (Hypersil CPS, 5 im, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 25 1ml/min) t;=9.07 min; MS: MH* 508. Example 228: trans-7-(4- { [3-(1 H-i -imidazolyl)propyl]amino } cyclohexyl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt:'H NMR (DMSO-d 6 , 400MHz) 6 8.76 (bs, 1H), 8.51 (bs, 2H), 8.18 (s, 1H), 7.66 (s, 1H), 7.55 30 (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); WO 00/17203 PCT/US99/21560 RP-HPLC (Hypersil CPS, 5 pim, 1OA, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min) t,=8.72 min; MS: MH*i 508. Example 229: Cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 5 pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt 'H NMR (DMSO-d 6 , 400MHz) 8 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 C-18, 5 pim, 1OA, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 10 lml/min) t,=7.38 min; MS: MH* 428. Example 230: Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt 'H NMR (DMSO-d 6 , 400MHz) 8 8.92 (bs, 1H), 8.18 (s, 1H), 7.4-7.5 (m, 15 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, 5 im, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min ) t,-=7.98 min; MS: MHI 468. Trans-5-(4-phenoxyphenyl)-7-(4-tetrahydro-1H-1 pyrrolylcyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt 20 'H NMR (DMSO-d 6 , 400MHz) 8 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 C 18, 5 pim, 100A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 10min, 1ml/min ) t,=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-amine dihydrochloride salt Trans-7-[4-(4-methyl-1,4-diazepan-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H 30 pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride salt WO 00/17203 PCT/US99/21560 cis-7-[4-(4-methyl- 1,4-diazepan- 1 -yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride salt: 'H NMR (DMSO-d., 400MHz) 8 11.7 (d, 1H), 11.38 (d, 1H), 8.57 (s, 1H), 8.34 (d, 1H), 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), 5 1.86-2.57 (10 H); RP-HPLC (Hypersil HS C-18, 5 pim, 100A, 250 x 4.6 mm; 25 100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min ) t,=: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: 'H NMR (DMSO-d 6 , 10 400MIHz) 8 11.94 (d, 1H), 11.52 (d, 1H), 8.56 (s, 1H), 7.8 (s, 1H), 7.42-7.51 (m, 4H), 7.10-7.20 (m, 5H), 4.76 (1H, m)< 3.2-4.0 (m, 9H), 2.80 (s, 3H), 1.78-2.4 (m, 1OH); RP-HPLC (Hypersil HS C-18, 5 pim, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min) t,=7.42 min; MS: MH' 497. 15 Example 232: Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt Trans-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine trimaleate salt 20 a) cis and trans-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate Example 233: cis-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 25 d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate: 'H NMR (DMSO-d 6 , 400MiHz) 6 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); RP-HPLC (Hypersil HS C-18, 5 Lm, 1OA, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min ) t,=13.60 min. 30 WO 00/17203 PCTIUS99/21560 trans-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}-1-piperazinecarboxylate: 'H NMR (DMSO-d 6 , 400MHz) 5 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); RP-HPLC 5 (Hypersil HS C-18, 5 pim, 100A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, Iml/min) t,=10.40 min. b) Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine trimaleate salt 10 The cis-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate (1.85 g, 3.27 mmol) was treated with a 20% trifluoroacetic acid/dichloromethane solution (60 ml) and stirred for 30 minutes at ambient temperature. The solvents were removed under reduced pressure then the residue was partitioned between dichloromethane (200 ml) and 15 aqueous saturated sodium bicarbonate solution (30 ml). The organic solution was dried over magnesium sulfate, filtered and the filtrate 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) then treated with maleic acid (0.75 g, 0.44 mmol) in warm ethyl acetate (75 ml). The mixture was cooled to ambient temperature then the solid was 20 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: 'H NMR (DMSO-d 6 , 400MHz) 8 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 pm, 1OA, 250 x 4.6 mm; 25-100% 25 acetonitrile-0.1 M ammonium acetate over 10min, 1ml/min) t,=8.63 min; MS: MH* 469. c) trans-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine trimaleate salt 30 'H NMR (DMSO-d 6 , 400MHz) 6 8.22 (s, 1H), 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, 17 H); RP-HPLC WO 00/17203 PCT/US99/21560 (Hypersil HS C-18, 5 pm, 1O0A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10min, lml/min) tr=8.08 min; MS: M* 469. Example 234: 7-[3-(4-methylpiperazino)cyclopentyl]-5-(4-phenoxyphenyl) 5 7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentan-1-ol (2.14 g, 0.0055 mol) in 11 dichloromethane was stirred with 12 g active manganese dioxide for 5 hours, filtered and fresh manganese dioxide (8 g) added to the filtrate. After stirring for a further 17 hours, the mixture was filtered 10 and used directly. 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, 4.38 minutes. The dichloromethane solution was stirred with 1.0 g N-methylpiperazine (0.01 mol) and acetic acid (0.6 g, 0.01 mol) for 15 minutes then sodium triacetoxyborohydride (0.89 g, 0.0042 mol) was added. After 2 hours 1.0 g N 15 methylpiperazine, 0.6 g acetic acid and 0.89 g sodium triacetoxyborohydride was added and the mixture stirred for 17 hours. Further addition of 2.0 g N methylpiperazine, 1.2 g acetic acid and 1.2 g sodium triacetoxyborohydride and stirring for 3 days gave a mixture which was evaporated under reduced pressure. The residue was treated with water (200 ml) and 6M - hydrochloric acid (50 ml) then 20 washed with ethyl acetate (discarded) and basified with excess aqueous ammonia. The mixture was extracted with ethyl acetate and the extract dried (sodium sulphate) then purified by flash chromatography in 9:1 ethyl acetate : ethanol to remove impurities followed by 8:1:1 ethyl acetate : ethanol : triethylamine to elute the product. Solvent was removed under reduced pressure, the residue dissolved in ethyl 25 acetate and treated with a solution of maleic acid in ethyl acetate giving 7-[3-(4 methylpiperazino) cyclopentyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 4-amine tri-maleate (444395) as a 1.4 solvate with ethyl acetate after drying at 80* C under reduced pressure (0.95 g, 0.001 mol) m.pt. 168-170" C (decomposes). 30 WO 00/17203 PCT/US99/21560 /'7 9 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) 5 followed by the addition of Amberlyst- 15 H*. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 15 min, filtered through a celite pad and the solvent removed under reduced pressure. The residue was purified by preparative RP-HPLC (Rainin, Hypersil C18, 8 pm, 1O0A, 25 cm; 5%-85% acetonitrile - 0.1% ammonium acetate over 20 min, 21 mL/min) to yield [4-(4 10 amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl](phenyl)methanol (0.005 g, 0.000013 mol): 'H NMR ( DMSO-d 6 400MHz) 5 8.12 (s, 1H), 7.31 (m, 1OH), 6.01 ( br, 2H), 5.91 (d, 1H), 5.75 (d, 1H), 5.06 (m, 1H), 2.10(br, 2H), 1.88 (br, 4 H), 1.67 (br, 2H) RP-HPLC( Delta Pak C18, 5pm, 300A, 15 cm; 5%-85% acetonitrile - 0.1M 15 ammonium acetate over 20 min, 1mL / min) R, 16.74 min. NM 385 Example 236: Trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 20 pyrrolo[2,3-d]pyrimidin-4-amine (1.30 g, 0.0027 mol) in 300 ml warm ethyl acetate was treated with a solution of maleic acid (0.94 g, 0.0081 mol) in 100 ml ethyl acetate and allowed to cool. The colourless solid was collected, washed with ethyl acetate and dried to constant weight at 900 C / 3 mbar giving 1.85 g (0.0022 mol) of trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 25 d]pyrimidin-4-amine tri-maleate solvated with 0.18 mol ethyl acetate m.p. 189* C (decomposes). Example 237: trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-hydrochloride 30 trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine (0.36 g, 0.00075 mol) in 25 ml warm isopropanol WO 00/17203 PCT/US99/21560 was treated with a solution of 0.225 ml 12M hydrochloric acid (0.0027 mol) in 2 ml isopropanol and the suspension heated briefly to boiling then volatile material was removed under reduced pressure. The resulting colourless solid was dried to constant weight at 84* C / 5 mbar giving the trans- 7

-[

3

-(

4 -methylpiperazino)cyclohexyl]-5 5 ( 4 -phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-hydrochloride (444626) solvated with 1 mol water and 0.25 mol isopropanol (0.25 g, 0.0004 mol) m.p. 304 306* C(dec). Example 238: cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 10 pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate salt cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine (1.45 g, 0.0030 mol) in ethyl acetate with 1.05 g (0.0091 mol) maleic acid giving colourless solid after drying to constant weight at 90* C / 3 mbar. 2.15 g cis-7 -[3-(4-methylpiperazino)cyclohexyl]-5-(4 15 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate salt solvated with 0.14 mol ethyl acetate and 0.5 mol water (0.0025 mol) obtained m.p. 186 (dec). Example 239: cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine tri-hydrochloride 20 cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine 0.80 g (0.0017 mol) in isopropanol was treated with 0.5 ml 12M hydrochloric acid (0.006 mol). The resulting solid was filtered to give cis-7 -[ 3

-(

4 -methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine tri-hydrochloride as a hygroscopic solid until 25 dried at 800 C / 3 mbar to constant weight. (0.75 g, 0.0011 mol) m.p. 224.5-226.5 (dec). Example 240: Trans-5-(2-methyl-4-phenoxypheny)-7-[4-(4 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate 30 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 an WO 00/17203 PCT/US99/21560 atmosphere of nitrogen. The solvent was removed under reduced pressure. Carbon tetrachloride was added to the residue and the resulting solid was removed by filtration. The filtrate was concentrated to yield 4-bromo-3-methylphenyl phenyl ether as yellow oil (3.5 g, 0.0 133 mol): 5 'H NMR (Chloroform-d, 400 MHz) 6 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 pm, 250 x 4.6 mm; 25% - 100% over 23 min with 0.1 M ammonium acetate, lmL/min) R, 14.72 min. A mixture of 4-bromo-3-methylphenyl phenyl ether (1.7 g, 0.00646 mol), 10 diboron pinacol ester (2.0 g, 0.00775 mol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) 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 an atmosphere of nitrogen for 22 hours. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced 15 pressure. Dichloromethane was added to the residue and the resulting solid was removed by filtration through a pad of celite. The filtrate was concentrated into black mixture, which was purified by flash chromatography on silica using ethyl acetate/n-heptane (3:97) as mobile phase to yield 3-methyl-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)phenyl phenyl ether (1.05 g, 0.00338 mol): 20 'H NMR (Chloroform-d, 400 MHz) 8 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) R, 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 25 tetrahydrofuran (120 mL) and acetone (600 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 17 hours. The solvent was removed under reduced pressure and 6NHCl(aq) (20 mL), tetrahydrofuran (60 mL), and acetone (300 mL) were added to the mixture. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 4.5 hour. The solvent was removed 30 under reduced pressure and the yellow colored residue was washed with water to WO 00/17203 PCT/US99/21560 yield 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclohexanone (12.3 g, 32.7 mmol). RP-HPLC (Hypersil C18, 5pm, 250 x 4.6 mm; 25% - 100% over 15 min with 0.05 M ammonium acetate, ImL/min) R, 10.20 min. A mixture of 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1 5 cyclohexanone (5.6 g, 14.9 mmol), N-methylpiperazine (3.3 mL, 29.8 mmol), acetic acid (2.6 mL, 44.7 mmol), and trimethylorthoformate (9.9 mL, 89.4 mmol) in dichloroethane (100 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 1 hr. Sodium triacetoxyborohydride (14.2 g, 67.05 mmol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen 10 for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water 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 15 using triethylamine/ dichloromethane (2:98) followed by methanol/triethylamine/dichloromethane (2:3:95) as mobile phase to yield trans-4 chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 3.7 mmol). '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, 5km, 20 250 x 4.6 mm; 25% - 100% over 15 min with 0.05 M ammonium acetate, 1mL/min) R, 6.17 min. Trans-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 at 120 'C in a pressure vessel for 18 hours. 25 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 solution and ethyl acetate. The water 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 30 pressure to yield trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3- WO 00/17203 PCTIUS99/21560 d]pyrimidin-4-amine (0.35 g, 0.8 mmol). RP-HPLC (Hypersil C18, 5pm, 250 x 4.6 mm; 25% - 100% over 15 min with 0.1 M ammonium acetate, lmL/min) R, 4.01 min. MS: NM' 441 A mixture of trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H 5 pyrrolo[2,3-d]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(triphenyl-phosphine)palladium(0) (0.054 g, 0.000047 mmol), and sodium carbonate (0.209 g, 0.00197 mol) in N,N-dimethylformamide (15 mL) and water (10 mL) was heated at 80 0 C under an atmosphere of nitrogen for 16 hours. The mixture 10 was allowed to cool to ambient temperature and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water 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 15 chromatography on silica gel using triethylamine/dichloromethane (5:95) followed by methanol! triethylamine/ dichloromethane (3:5:92) as mobile phase to yield 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). Trans-5-(2-methyl-4 phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3 20 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 collected by filtration, washed with cool ethanol and dried to give trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino) 25 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), 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, 5pm, 250 x 4.6 mm; 25% - 100% over 23 min with 0.1 M ammonium acetate, 30 1mL/min) R, 7.30 min. MS: MH 497 WO 00/17203 PCT/US99/21560 Example 241: 3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentyl 2-aminoacetate hydrochloride A mixture of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 5 7-yl]-1-cyclopentanol (50 mg, 0.129 mmol), 2-[(tert-butoxycarbonyl)amino]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 pour onto ice-water. The aqueous layer was extracted with ethyl acetate three times. 10 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 mobile phase to give 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). HPLC: tr=1 9

.

2 2 min. (Delta-Pack, C-18, 5um, 300A, 3.9x150 mm; 5-85% 15 acetonitrile-0.1 M ammonium acetate over 20 min, lml/min ) 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). Hydrochloride gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred for additional 30 minutes. 20 Ether was added and the precipatate was collected through filtration under nitrogen to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclopentyl 2-aminoacetate hydrochloride (39 mg) as white solid. 1H NMR (DMSO-d 6 ) 6 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), 8.40 (s, 1H). 25 LC/MS: MH*=444, tr= 2 .25 min. (Pecospher, 3C-18, 3um, 4.6x33 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-7 yl]cyclopentyl N-(2-morpholinoethyl)carbamate hydrochloride 30 4- Nitrochloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 mL) was cooled on an ice-water bath. 4-Methylmorpholine (7 uL, 0.062 mmol) was WO 00/17203 PCT/US99/21560 added slowly. After 20 minutes, the ice-water bath was removed and the reaction mixture was allowed to warm up to room temperature. 3-(4-Amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclopentanol (20 mg, 0.052 mmol) was added and the reaction mixture was stirred for 4days. The reaction 5 mixture was diluted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate, brine, dried over MgSO4, filtered and evaporated to give a yellow solid. A solution of the yellow solid 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 10 organic layer was washed with water (3 times), brine, dried over MgSO4, filtered and evaporated. The crude product was purified by HPLC to give 3-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl N-(2 morpholinoethyl)carbamate (17 mg, 0.031 mmol). 1H NMR (CDC1 3 -d) 5 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, 15 6H), 7.40 (m, 4H), 8.30 (s, 1H). LC/MS: M*=543, tr= 2 .1 3 min. (Pecospher, 3C 18, 3um, 4.6x33 mm; 0-100% acetonitrile-0.1 M ammonium acetate over 5 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 20 dissolved in ethyl acetate (2.5 mL). Hydrochloride gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred for additional 10 minutes. The precipitate was collected through 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. 1H NMR (DMSO-d 6 ) 8 25 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, tr= 2 .1 6 min. (Pecospher, 3C 18, 3um, 4.6x33 mm; 0-100% acetonitrile-0.1 M ammonium acetate over 5 min, 3.5 ml/min). 30 WO 00/17203 PCT/US99/21560 Example 243: 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexanol Sodium borohydride (500mg, 13 mmol) was added in one portion to a stirred solution of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimin-7 5 yl]cyclohexan-l-one (780mg, 2.0 mmol) in methanol (500 mL), and the mixture stirred under an atmosphere of nitrogen for 1 hour, then left to stand overnight. The solvent was removed under reduced pressure, and the residue partitioned between 2M aqueous sodium hydroxide solution (100 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer further extracted with 10 dichloromethane (2 x 100 mL). The combined organic extracts were washed with water (150 mL), dried over potassium carbonate, and purified by chromatography with a Biotage 40S column using ethyl acetate / triethylamine (98:2 to 95:5) and ethyl acetate / ethanol (95:5) as a mobile phase to yield 4-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanol as a white solid 15 (750mg, 1.9 mmol), melting point: 199-200 deg. C.LC/MS: Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.)MW 401 , t,= 4.12 minutes. Example 244 20 Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl) 2-methoxyphenyl]carbamate -(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-4-amine (100 mg, 0.294 mmol) was dissolved in dichloromethane (2 mL). Pyridine (2mL) was added followed by phenylchlorofornate (44 uL, 0.353 25 mmol). After stirring for 3 hours, another 44 uL of phenylmethanesulfonyl chloride was added and the reaction mixture was 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-yl)-2 methoxyphenyl]carbamate (52 mg, 0.113 mmol). 1H NMR (CDCl 3 -d) 8 2.09 (m, 30 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, 1H), 8.33 (s, WO 00/17203 PCT/US99/21560 1H). LC/MS MH*=460. Example 245 Tetrahydro-2H-4-pyranyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 5 d]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). 4- Nitrochloroformate (1.98 g, 9.82 mmol) was added slowly to the reaction mixture. After stirring for 5 10 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 MgS04, filtered and evaporated. The crude product was purified by flash column chromatography 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). 15 1H NMR (CDCl 3 -d) 6 1.87 (in, 2H), 2.06 (in, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m,1H), 7.40(d, J=9.OHz, 2H), 8.30 (d, J=9.OHz, 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 20 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, another 90 mg of 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate was added and the reaction mixture was stirred for 2 days. The reaction 25 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[2,3-d]pyrimidin-5 yl)-2-methoxyphenyl]carbamate (30 mg, 0.064 mmol). 1H NMR (CDCl 3 -d) 6 1.78 (in, 4H), 2.08 (m, 4H), 3.60 (in, 4H), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (in, 2H), 4.98 30 (in, 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, IH). LC/MS NMH=468.

WO 00/17203 PCT/US99/21560 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 5 a) 4-Nitrophenyl (3-pyridylmethyl) carbonate 4- Nitrochloroformate (2.49 g, 12.3 mmol) in dichloromethane (20 mL) was cooled on an ice-water bath. 3-pyridylmethanol (1.0 mL, 10.3 mmol) and 4 methylmorpholine (2.0 mL, 18.5 mmol) was added slowly. After 20 minutes, the 10 ice-water bath was removed and the reaction mixture was allowed to warm up to room temperature. 30 minues later, ethyl acetate was added and the reaction mixture was filtered. The filtrate was washed with water, saturated sodium bicarbonate, brine, dried over MgSO4, filtered and evaporated to give a dark brown solid which was re-crystallized with ethyl acetate/heptane to give 4-nitrophenyl (3 15 pyridylmethyl) carbonate (1.52 g, 5.54 mmol).1H NMR (CDCl-d) 6 7.38 (m, 3H), 7.79 (m, 1H), 8.28 (d, J=9.09Hz, 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 20 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-pyridylnethyl 25 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). 1H NMR (CDC1 3 -d) 5 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, IH), 7.35 (m, 2H), 7.79 (d, J=7.8Hz, 1H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (s, 1H), 8.71 (s, 1H). LC/MS 30 MH'=475 WO 00/17203 PCT/US99/21560 b) 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 5 in ethyl acetate (2.OmL). 1.ON HCl in ether (1 mL) was added slowly. The precipatate was collected through 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). 1H NMR (DMSO-d 6 ) 6 1.91 (m, 2H), 2.17(m, 2H), 3.54 (m, 2H), 3.87 (s, 3H), 4.03 (m, 2H), 4.97(m, 1H), 10 5.23 (s, 2H), 7.05 (d, J=8.2Hz, 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, 1H), 8.71 (s, 1H), 8.82 (s, 11). LC/MS MH*=475. Example 247 15 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 20 was heated at 1 00C overnight. The solvent was removed and the residue was purified by preparative reverse phase HPLC to give 2-morpholinoethyl N-[4-(4 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]carbamate (24 mg, 0.048mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.ON HCl in ether (0.2 mL) was added slowly. The precipitate 25 was collected through 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). 1H NMR (DMSO d 6 ) 6 1.88(m, 2H), 2.16(m, 2H), 3.55 (m, 8H), 3.90 (s, 3H), 4.03 (m, 4H), 4.49(m, 2H), 4.92 (m, 111), 7.07 (m, 1H), 7.15 (s, 1H), 7.65 (bs, 2H), 7. 84 (s, 1H), 8.45 (s, 30 1H), 8.75(s, 1H) 10.95 (bs, 1H). LC/MS MH*=497.

WO 00/17203 PCT/US99/21560 Example 248 (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 5 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 dimethyl formamide (2.56 mL, 34 mmol). The mixture was then heated at 75'C for 1 hours and at 1OOoC for 5 hours. After cooled to room temperature, the mixture was added to ice-water (500ml) and the aqueous layer was 10 extracted with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate, dried over MgSO4, filtered and evaporated to give a brown solid which was washed with petroleum ether. Evaporation of solvent gave 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). 1H NMR (CDCl 3 -d) 6 9.90 (S, 1H). 15 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 10 minutes later and the reaction 20 mixture was stirred at room temperature overnight. Solvent was removed and saturated ammonium chloride was added. 1.ON 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 MgS04, filtered and evaporated. The residue was purified by flash column chromatogrphy to give (2,4-dibromo-1,3-thiazol-5 25 yl)methanol (0.946 g, 3.47 mmol). 1H NMR (CDCl 3 -d) 8 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), sodium carbonate tri 30 hydrade (1.34 g) and palladium on carbon (10%, 0.07g) were mixed in methanol (33 mL). The resulting mixture was hydrogenated at 60 psi for 2 days. The solid was WO 00/17203 PCT/US99/21560 /? ( filtered off through a pat of celite. The solvent was evaporated and the residue was purified by frash column chromatography to give (4-bromo-1,3-thiazol-5 yl)methanol (0.32 g, 2.78 mmol). 1H NMR (CDC 3 -d) 6 2.29 (bs, 1H), 4.86 (s, 2H), 8.72 (s, 1H). 5 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-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 10 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)-2-methoxyphenyl]carbamate. 1H NMR (CDCl-d) 6 2.07(m, 4H), 3.65 (in, 2H), 15 3.92 (s, 3H), 4.13 (in, 2H), 4.98 (in, 1H), 5.35 (s, 1H), 5.40(s, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.09 (in, 1H), 7.35 (s, 1H), 8.17 (s, 1H), 8.32 (s, 1H), 8.78(s, 1H). LC/MS MH*=481. Example 249 20 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 25 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 preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4 pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (14 mg, 0.03 1mmol). 1H NMR (CDC1-d) 6 2.07(m, 6H), 3.66 (in, 2H), 3.96 (in, 7H), 4.13 30 (in, 2H), 4.98 (in, 1H), 5.26 (s, 2H), 5.40(m, 1H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2Hz, 1H), 7.26 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H). LC/MS M*=455.

WO 00/17203 PCT/US99/21560 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 5 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 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 glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 10 100"C overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7 tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]carbamate (2 mg, 0.004mmol). 1H NMR (CDCl-d) 6 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 15 (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=8.2Hz, 1H), 8.22 (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.Omg, 0.013 mmol). 1H NMR (CDCl-d) 8 2.06(m, 4H), 3.66 (m, 2H), 3.75 (m, 1H), 3.92 (m, 3H), 4.03 (m, 1H), 4.13 (m, 20 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=8.2Hz, 1H), 7.38(s, 1H), 8.15 (d, J=7.9Hz, 1H), 8.31 (s, 1H). LC/MS MH*=471. Example 251 25 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 nmol) was mixed 2-pyridylmethanol 30 (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 WO 00/17203 PCT/US99/21560 reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4 pyranyl-7H-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.ON HCl in ether (0.1 mL) was added slowly. The precipitate was collected through filtration under 5 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). 1H NMR (DMSO-d) 8 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=8.2Hz, 1H), 7.14 (s, 1H), 7.37 (m, 1H), 7. 53 (d, J=7.8Hz, lH), 7.87 (m, 3H), 8.42(s, 1H), 8.57 (d, 10 J=4.2Hz, 1H), 8.85 (s, 1H). LC/MS MIH*=475. Example 252 4-Pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate Hydrochloride 15 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 4 pyridylinethanol (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 20 tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 2 methoxyphenyl]carbamate (11 Img, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.ON HCl in ether (0.1 mL) was added slowly. The precipatate was collected through 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 25 methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO d 6 ) 6 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, lH), 8.46(s, 1H), 8.76 (d, J=5.6Hz, 1H), 9.05 (s, 1H). LC/MS: NH*=475. 30 WO 00/17203 PCT/US99/21560 Example 253 (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 5 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 10 d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (18 mg, 0.038mmol). 1H NMR (CDCl-d) 5 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: M 479. 15 Example 254 [(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 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 20 with (5S)-5-(hydroxymethyl)tetrahydro-1H-2-pyrrolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 1 00C 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, 0.021mmol). 25 1H NMR (CDC1-d) 6 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: NM 481. 30 WO 00/17203 PCT/US99/21560 Example 255 4-Aminobenzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate 5 a) tert-Butyl N-(4-(hydroxymethyl)phenyl)carbamate (4-Aminophenyl)methanol (1.23 g, 10 mmol) and diisopropylethylamine ( 2.6 mL, 15 mmol) was mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with water, 1.0N HCl, 10 saturated sodium carbonate, water, brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography with Ethyl acetate/heptane (2:3) to give tert-butyl N-(4 (hydroxymethyl)phenyl)carbamate (2.16g, 9.67 mmol). 1H NMR (CDCl-d) 5 1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5Hz, 2H), 7.36 (d, 8.5Hz,2H). 15 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 (51mg, 0.111 mmol) was mixed with tert-butyl N-(4 20 (hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 1 00"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]pyrimidin-5-yl)-2 methoxyphenyl)carbamate 25 (9 mg, 0.015mmol). 1H NMR (CDCl-d) 5 1.52(s, 1H), 2.08(m, 4H), 3.65 (in, 2H), 3.90 (s, 3H), 4.14(m, 2H), 4.97 (in, 1H), 5.17 (s, 2H), 5.37(bs, 1H), 6.55 (s, 1H), 6.95 (s, 1H), 7.03 (s, 1H), 7.06 (in, 1H), 7.31(s, 1H), 7.38 (m, 3H), 8.16 (bs, 1H), 8.30 (s, 1H). LC/MS: MH* 589.

WO 00/17203 PCTIUS99/21560 Example 256 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[2,3 5 d]pyrimidin-4-amine (80mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 uL, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4 10 amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]benzamide (64 mg, 0.144 mmol). 1H NMR (CDCl 3 -d) 8 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=8.2Hz, 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*=444 15 Example 257 N2-[4-(4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]-2-pyridinecarboxamide 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 20 d]pyrimidin-4-ainine (80mg, 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 DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to 25 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). 1H NMR (CDCl 3 -d) 6 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=8.2Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70(d, J=8.2Hz, 1H), 10.62 (s, 1H). LC/MS: M'=445. 30 WO 00/17203 PCT/US99/21560 Example 258 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 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 5 d]pyrimidin-4-amine (80mg, 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 DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to 10 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). 1H NMR (CDCl 3 -d) 5 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=8.2Hz, 1H), 8.33 (2, 2H), 8.49(d, J=8.2Hz, 1H). LC/MS: 15 MiH*=462. Example 259 N1-[4-(4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]-2,2-dimethylpropanamide 20 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]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 DMSO, methanol (1 mL) was added 25 and precipitate was 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). 1H NMR (CDCI 3 d) 6 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=8.2Hz, 1H), 8.15 (s, 1H), 30 8.29 (s, 1H), 8.49(d, J=8.2Hz, 1H). LC/MS: MH*=424.

WO 00/17203 PCT/US99/21560 Example 260 N1-[4-(4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]-1-cyclopentanecarboxamide 5 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-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 DMSO, methanol (1 mL) was 10 added and precipitate was formed. The solid was collected by filtration to give Ni

[

4

-(

4 -amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 methoxyphenyl]-2,2-dimethylpropanamide (33 mg, 0.076mmol). 1H NMR (CDC13 d) 6 1.66 (m, 2H), 1.81 (in, 2H), 1.95 (in, 4H), 2.06 (in, 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, 15 1H), 7.07 (d, J=8.2Hz, IH), 7.84 (s, 1H), 8.30 (s, 1H), 8.49(d, J=8.2Hz, 1H). LC/MS: MH*=437. Example 261 N1-[ 4

-(

4 -Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 20 methoxyphenyl]-3-phenylpropanamide 5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3 d]pyrimidin-4-amine (50mg, 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 25 removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was 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 (7 mg, 0.015mmol). 1H NMR (CDCl 3 -d) 5 2.07 (in, 4H), 2.75 (m, 2H), 3.09 (m,2H), 3.65 (m, 2H), 3.88 (s, 3H), 4.13(m, 2H), 30 4.96 (m, 1H), 5.97(bs, 2H), 6.93 (s, 1H), 7.05 (m, 2H), 7.26 (in, 5H), 7.70 (s, 1H), WO 00/17203 PCT/US99/21560 129 8.24 (s, 1H), 8.46(d, J=8.2Hz, 1H). LC/MS: MH*=472. Examples 262-267 were synthesized using the following procedure: a) 5 A mixture of cis-5-(4-amino-3-methoxyphenyl0- 7

-[

4

-(

4 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin- 4 -amine (0.25 g, 0.575 mmol), pyridine (2.5 ml) and dichloromethane (2.5 ml) was treated with the appropriate acid chloride (0.862 mmol) and then stirred at ambient temperature under an atmosphere of nitrogen for 1 hour. The solvents were removed under 10 reduced pressure and the residue was purified by preparative reverse phase chromatography. The compound (280 mg, 0.460 mmol) was dissolved in hot ethyl acetate (25 ml) then treated with maleic acid (160 mg, 1.38 mmol) dissolved in ethyl acetate (10 ml) the mixture was allowed to cool to ambient temperature then stirred for 1 hour. The solid was collected by filtration and dried to give the compound as 15 the trimaleate salt. (370 mg). Analytical RP-HPLC RT listed in the table were obtained on a Hypersil HS C 18 column ((5 um, 100A) 250 x 4.6 mm) using a linear gradient of 25-100% acetonitrile/0.1 M ammonium acetate over 10 min at Iml/min. Retention time is 20 indicated by "RT" Mass spectrum molecular weights are indicated by "MH+". 0 H~ NHI - F N N. 0\ 0 0 Example 262 RT 6.62 MH+ 576.3 Gradient a WO 00/17203 PCT/US99/21560 0 000 NH,+ N HO- o N H 0 O0 N'O 0~ N Example 263 RT 7.7 MH+ 608.2 Gradient a 5 N + N N HOC 0~ N Example 264 RT 14.23 10 MH+ 588.3 Gradient b 15 WO 00/17203 PCT/US99/21560 0( -0 NN+ N H4-0 o N N NM-0 O O N' Example 265 RT 6.85 MH+540.2 5 Gradient a O0 NHt+ CI N N HO O H0 0 N'. O-r -O N' 10 Example 266 RT 8.15 MH+ -608.2 Gradient a 15 WO 00/17203 PCT/US99/21560 -o NH CF N N HO O~ 0 HOr 0 0 0 Example 267 RT 8.15 5 MH+ 642.3 General salt formation procedure: 10 Trans- benzyl N-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)carbamate was dissolved in ethylacetate and treated with maleic acid (280 mg) in ethylacetate. The resulting solid was filtered under a stream of nitrogen and dried in vacuo for 4 hr to give Cis benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 15 d]pyrimidin-5-yl}-2-methoxyphenyl)carbamate tri-maleate salt (580 mg) as a cream solid. M.pt. 158*C (dec.) 'H NMR (d, DMSO, 400 MiHz):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 to 95% CH 3 CN in 0.1 N aqueous ammonium 20 acetate over 20 min.) t, = 13.30 min, 94%. In a similar manner were prepared the following salts. The LCMS conditions are described below.

WO 00/17203 PCT/US99/21560 LSMS data: Perkin Elmer Pecosphere C18, 3mM, 33 x 4.6, 3.5 mI/min 100 100% 50 mM ammonium acetate to acetonitrile in 4.5 minutes Ret. Structure .e* MH+ Time 2.92 497.1 N 0 3.02 497.2 6 '* 2.64 481.2 2.7 481.2 Example 268: Cis and trans-N1-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl] 5 7H-pyrrolo[2;3-d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamide To 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin 7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine/dichloromethane (1:2.5, 45 ml) was added hydrocinnamylchloride (0.57 g, 3.4 mmol) in dichloromethane (2 ml) at 0"C under a flow of nitrogen. The solution was stirred at 0"C for 2 hr. The solution 10 was quenched with saturated aquoeus citric acid solution ( 50 ml) and the organic layer was washed with saturated aquoeus citric acid solution ( 2 x 50 ml). Dry, filter and concentrate to leave a brown foam (1.0 g). This was dissolved in dichloroethane (100 ml) and N-methylpiperazine (0.63 g, 6.3 mmol) and acetic acid (0.38 g, 6.3 WO 00/17203 PCT/US99/21560 mmol) was added. Sodium triacetoxyborohydride (0.67 g, 3.15 mmol) was added portionwise under nitrogen and the mixture stirred overnight at room temperature. Quench with saturated aq. NaHCO3 solution (50 ml) and extract with dichloromethane (3 x 100 ml). The combined organics were dried (sodium sulphate), 5 filtered and evaporated to leave a sludge which was purified by flash silica gel column chromatography using dichloromethane / methanol (100/0 to 50/50 in 5%increments). The fractions corresponding to the faster running material were combined to give cis- N1-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamide (0.26 g) as a 10 glass. This was dissolved in ethylacetate (5 ml) and maleic acid (160 mg) in ethylacetate (2 ml) added. The resulting solid was filtered to give cis- N1 -(4-4 amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl-2 methoxyphenyl)-3-phenylpropanamide trimaleate salt (260 mg) as a white solid. Analytical LC/MS conditions: Column: Pecosphere, C18, 3 um, 33x4.6 mm. Eluent: 15 0% B/A to 100% B/A in 4.5 min.( B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5) , 3.5 mL/min. (r, = 2.86 mins, 568.4). The fractions corresponding to the slower running material were combined to give trans-N1-(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 glass. This 20 was dissolved in ethylacetate (5 ml) and treated with a solution of maleic acid (68 mg) in ethylacetate (2 ml). The resulting solid was filtered to give trans-N1-(4-4 amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl-2 methoxyphenyl)-3-phenylpropanamide tri-maleate (94 mg) as a white solid. Analytical LC/MS conditions: Column: Pecosphere, C18, 3 um, 33x4.6 mm. Eluent: 25 0% B/A to 100% B/A in 4.5 min.( B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5) , 3.5 mL/min. (rt = 2.68mins, 568.2).

WO 00/17203 PCT/US99/21560 oR 0 0

NH

2 N (._ N 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7 5 yl]-1-cyclohexanone (2.25 g, 6.5 nmol), 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 portionwise and the mixture stirred at room temperature overnight. Saturated sodium bicarbonate solution (150 ml) was added and the aqueous layer extracted with dichloromethane 10 (3 x 100 ml). The combined organics were washed with water, dried (sodium sulphate), filtered and evaporated to leave a semi-solid whaich was purified by flash silica gel column chromatography using CH 2

C

2 / methanol (0% MeOH to 50% MeOH in 5% increments). The fractions corresponding to the faster running material were combined and evaporated to give cis- 5-(4-amino-3-methoxyphenyl)-7-[4-(4 15 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2 g, 43%) as a cream solid. 'H NM R(d 6 -DMSO): 8 8.1 (1H, s), 7.11 (1H, 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, s), 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%). 20 The fractions corresponding to the slower running material were combined and evaporated to give trans- 5-(4-amino-3-methoxyphenyl)-7-[4-(4 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.4 g, 14%) as a white solid. 'H NMR (d 6 -DMSO): 8 8.10 (1H, s), 7.26 (1H, s), 6.87 (1H, s), 6.77 (1H, d), 6.71 (1H, d), 6.05 (2H, bs), 4.79 (2H, s), 4.52 (1H, m), 3.81 (3H, s), 3.35 WO 00/17203 PCT/US99/21560 (1H, m), 2.50 (5H, m), 2.31 (5H, m), 2.14 (1H, m), 1.97 (6H, m), 1.45 (2H, m). HPLC (r,= 10.13 min, 97.9%). To a solution of cis- 5-(4-amino-3-methoxyphenyl)-7-[4-(4 5 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 capped and shaken overnight on an orbital shaker. Another two equivalent of acid chlorides (0.138 mmol) was added in two portions (1 equivalent each) and the resulting mixtures were shaken overnight again. LCMS 10 (Micromass- Column: Pecosphere, C18, 3 um, 33x4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.( B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.) of the resulting mixtures showed presence of product in all cases. The solutions were evaporated to dryness and the resulting residues were re- dissolved in a small volume of DMF and purified by reverse phase prep. HPLC. The structures 15 are detailed below alongwith the appropriate LCMS data. Examples 269 to 293 were made by methods analogous to Example 268. 20 25 WO 00/17203 PCT/US99/21560 pH F N cH, Example 269 RT 2.61 5 MH+ 576.3 CH, NH I _ , Example 270 10 RT 3.02 MH+ 570.3 s, MH 60. 20N OC' NH N~ 15 Example 271 RT 2.61 NM+ 600.3 20 WO 00/17203 PCT/US99/21560 c20 CH, NH, N N 5 Example 272 RT 3.26 MH+ 608.3 NH, c1% 10 Example 273 RT 2.74 MH+ 570.3 15 H N N CH, Example 274 RT 2.78 MH+ 558.4 20 WO 00/17203 PCTIUS99/21560 Q o o NH2 HNL Example 275 5 RT 3.00 MH+ 574.3 10 -CH, N N CH, 15 Example 276 RT 2.76 570.3 20 WO 00/17203 PCT/US99/21560 FF 0 0 N Example 277 RT 3.26 5 MH+ 608.3 10 15 p CH Example 278 RT 2.94 20 MH+ 570.3 WO 00/17203 PCT/US99/21560 6l

CH

3 Example 279 RT 3.13 5 MfH+ 604.3 10 Example 280 15 - RT 3.16 580.3 20 25 WO 00/1 7203 PCT/US99/21560 WO~ 00170 Example 281 RT 2.68 5 MH+ 565.3 10 15 20 Example 282 RT 2.90 MH+ 585.3 25 WO 00/17203 PCTIUS99/21560

NC

4 d 0 NHt Example 283 RT 2.84 5 MH+ 585.3 10 15 F o a NN CHN 20 Example 284 RT 2.90 MH+ 576.3 25 WO 00/17203 PCTIUS99/21560 21 Y e0 NH2 N c1 Example 285 RT 2.90 5 MH+ 584.4 10 CN 0 0 CH, 15 Example 286 RT 2.74 MH+ 565.6 20 25 WO 00/17203 PCTIUS99/21560 F Example 287 RT 3.06 5 MIH+ 576.3 10 15 PH, 0 0 NH N N0 cH3 20 Example 288 RT 2.53 MH+ 575.3 25 WO 00/17203 PCT/US99/21560 egL t t ~Io F CH 2 NN NN Example 289 RT 3.32 5 MH+ 624.3 F CH 3 F 0 0

NH

2 N CH, Example 290 RT 2.85 10 MIH+ 594.4 F o 0

NH

2 N Q CH, 15 Example 291 RT 2.76 MH+ 592.3 WO 00/17203 PCT/US99/21560 H N-CH 0 0 N O c Ha Example 292 RT 2.86 5 MH+ 583.3 I-c 10 Example 293 RT 2.29 MH+ 508.3 15 20 WO 00/17203 PCT/US99/21560 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 5 (7.60 mmol) in 50 mL of dichloroethane was stirred at room temperature for 1.5 hours. 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 concentrated to 10 afford a brown oil. Purification by flash chromatography on silica gel afforded the cis and trans-7-[(4-piperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amines. Method B 15 A mixture of the appropriate pyrrolidine (7.53 mmol), 4-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin- 7 -yl]-1-cyclohexanone (2.51 mmol), and glacial acetic acid (7.35 mmol) in 45 mL of 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 20 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 concentrated to afford a brown oil. Purification by flash chromatography on silica gel afforded the cis- and trans-7-(4-pyrrolidino)cyclohexyl] 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amines. 25 Salt Formation To a warm solution of pyrrolopyrimidine (2.48 mmol; from methods A or B, above) in ethanol was added a solution of maleic acid (7.28 mmol) in ethanol. A white precipitate formed as the solution was cooled to ambient temperature. The resulting solid was 30 isolated by filtration and dried under vacuum to yield the desired tris maleate salt. Analytical RP-HPLC RT listed in the table were obtained on a Hypersil HyPurity Elite WO 00/17203 PCT/US99/21560 C18 column ((5uM, 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. N N \O NN ON xO Example 294 5 RT 7.967 MH+ 511.1 Gradient a o O N .--- O N N N 0 Example 295 10 RT 7.383 MH+ 527.2 Gradient a WO 00/17203 PCT/US99/21560 4N N NO N O Example 296 RT 13.941 MH+ 497.1 5 Gradient b N N0 N N( O N O O Example 297 RT 7.733 MH+-' 511.2 Gradient a 10 WO 00/17203 PCTIUS99/21560 0 N N0 N O N N NO 0 Example 298 RT 14.067 MH+ 497.1 Gradient b 0r'o N N 0 N0 0 NO O -N 5 Example 299 RT 13.891 MH+ 497.1 Gradient b 10 WO 00/17203 PCT/US99/21560 N N N 0 P 0 Example 300 RT 14.076 MH+ 497.1 5 Gradient b _N N N0 0 N 0 Example 301 10 RT 7.750 MH+ 527.2 Gradient a 15 WO 00/17203 PCTIUS99/21560 Example 302: Cis and trans 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide A solution of diisopropylamine (0.649 g, 0.0050 mol) in tetrahydrofuran (10 mL) 5 was cooled to 00 C. A solution of 1.6 M n-butyl lithium ( 3.14 mL, 0.0050 mol) in hexanes was added dropwise, keeping the temperature less than 50 C. After the addition was complete, the mixture was stirred for 20 minutes at 0* C. The mixture was cooled to -78* C, and dry acetonitrile (0.175 g, 0.0043 mol) was added, keeping the temperature less than -70 C. After the addition was complete, the mixture was stirred 10 for 20 minutes at -78* C, and a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-cyclohexanone (1.000 g, 0.0025 mmol) in tetrahydrofuran (10 mL) and hexamethylphosphoramide (10 mL) was added, keeping the temperature less than -70* C. After the addition was complete, the mixture was stirred for 30 15 minutes at -78* C, then stirred at ambient temperature for 18 hours. The mixture was partitioned between dichloromethane and saturated ammonium chloride (aq). The organic phase was washed with water and saturated sodium bicarbonate (aq), and dried over magnesium sulfate. The solvent was removed in vacuo and the cis and trans isomers were separated by flash column chromatography on silica using 20 dichloromethane/methanol (95:5) as an eluent to give less polar 4-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0. 120g, 0.00027 mol) and more polar 4-[4-amino-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0.170g, 0.00038 mol): 25 Less polar: 'H NMR (DMSO-d 400MHz) . 8.13 (s, 1H), 7.48 (d, 2H), 7.41 (t, 2H), 7.37 (s, 1H), 7.15 (t, 1H), 7.093 (d, 2H), 7.088 (d, 2H), 6.11 (b, 2H) 5.05 (s, 1H), 4.53-4.61 (m, 1H), 2.66 (s, 2H), 2.18 (q, 2H), 1.80 (t, 4H) 1.66 (t, 2H); RP-HPLC (Delta Pak 30 C18, 5pm, 300A, 15 cm; 5%-85% acetonitrile - 0.1M ammonium acetate over 20 min, I mL/min)1R, 15.90. NM* 440.

WO 00/17203 PCT/US99/21560 More polar: (Probably trans, aryl-axial, OH-axial) 'H NMR (DMSO-d 6 ,400MHz) 3 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 (in, 5 1H), 2.98 (s, 2H), 1.82-1.99 (in, 6H), 1.65-1.73 (in, 2H); RP-HPLC (Delta Pak C18, 5pim, 300A, 15 cm; 5%-85% acetonitrile - 0.1M ammonium acetate over 20 min, 1mL/min) R 15.88. MH* 440. 10 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 Sodium bis(trimethylsilyl)amide solution (1.OM soln. in THF, 2.05 equiv., 270 mL, 15 270 mmol) was added dropwise to a solution of 4-bromo-2-fluoroaniline (24.78 g, 130.4 mmol) in THF (250 niL) over 15 min. under nitrogen. After a further 15 min., di-tert-butyl dicarbonate (1.2 equiv., 34.12 g, 156.3 mmol) was added portionwise (note: a slight exotherm was observed). The reaction became very viscous and after 4 h. reached completion (t.l.c. analysis using 1:9 EtOAc:heptane as the eluent). The 20 reaction was concentrated in vacuo and the residue was partitioned between EtOAc (300 mL) and saturated aq. NaHCO 3 (150 mL). The aqueous layer was further extracted EtOAc (2 x 200 mL) and the combined organic layers were dried (Na 2

SO

4 ) and concentrated under reduced pressure. Purification by column chromatography using a 10% to 15% EtOAc : heptane gradient afforded tert-butyl N-(4-bromo-2 25 fluorophenyl)carbamate a light yellow waxy solid (30.0 g, 79%), 'H NMR (400 MHz, CDC1 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 30 A solution of the tert-butyl N-(4-bromo-2-fluorophenyl)carbamate (54.0 g, 0.186 mmol), bis-pinacolatodiborane (1.2 equiv, 56.8 g, 223.3 mmol), potassium WO 00/17203 PCTIUS99/21560 acetate (3.0 equiv, 54.7 g, 558 mmol) and PdCl 2 (dppf) (0.03 equiv, 4.65 g, 5.58 mmol) in degassed DMF (11) was heated at 80"C under nitrogen for 16 h. The DMF was removed under reduced pressure and the resulting dark solid residue was dissolved in CH 2 C1 2 (500 mL). The inorganic residues were removed by filtration 5 through a silica gel pad and the filtrate was purified by column chromatography using a 10% to 15% EtOAc : heptane gradient to afford the product as a yellow viscous oil which crystallized on standing to give tert-butyl N-[2-fluoro-4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (56.5 g, 92 %), 'H NMR (400 MiHz, CDCl 3 ) 1.33 (12 H, s), 1.53 (9 H, s), 6.82 (1H, br s), 7.46 (1H, d, J 11 10 Hz), 7.55 (1 H, br d), and 8.12 (1 H, br t), m/z 337.2, and RP-HPLC (5 to 100 %

CH

3 CN in 0.1 N aqueous ammonium acetate over 15 min at 1 mL/min using a Hypersil HyPurity Elite C18, 5m, 200 A, 250 x 4.6 mm column) t,= 10.16 min, 90%. c) tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3 15 d]pyrimidin-5-yl]-2-fluorophenylcarbamate A suspension of the 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 equiv, 37.6 g, 111.6 mmol), sodium carbonate (2.5 equiv, 19.72 g, 186 mmol) and Pd(PPh 3

)

4 (4 mol%, 20 3.44 g, 2.98 mmol)in DME (1.2 1) and degassed H 2 0 (230 mL) was heated at 80*C under nitrogen for 17 h. Additional Pd catalyst (1 mol%, .86 g, 0.74 mmol) was added and the reaction was continued heating at 80 0 C for a further 24 h. at which point the reaction had proceeded to completion (t.l.c. analysis using 3:7 EtOAc:heptane as the eluent, Rf=0.7). The solvent was removed under reduced 25 pressure and the residue dissolved in EtOAc (500 mL) and the inorganics were removed by filtration through a celite pad. The filtrate was washed with 10% aq. Na 2

CO

3 (200 mL) and brine (200 mL), dried (MgSO 4 ) and concentrated in vacuo. Column chromatography purification over silica gel using 1:2 EtOAc:heptane afforded tert-butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3 30 d]pyrimidin-5-yl]-2-fluorophenylcarbamate as an off-white solid (21.0 g, 56%), 'H NMR (400 MHz, CDC1 3 ) 1.55 (9 H, s), 1.89 (4 H, m), 2.07 (4 H, m), 4.01 (4 H, s), WO 00/17203 PCTIUS99/21560 4.89 (1 H, m), 6.75 (1 H, br s), 7.23 (1 H, br s), 7.25 (1 H, br s), 7.34 (1 H, br s), 8.14 (1 H, br t), and 8.64 (1 H, s) and RP-HPLC (5 to 100 % CH 3 CN in 0.1 N aqueous ammonium acetate over 15 min at 1 mL/min using a Hypersil HyPurity Elite C18, 5gm, 200A, 250 x 4.6 mm column) t,= 10.48 min., 100%. 5 d) 5-(4-Amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine A cloudy mixture of 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 ( 10.5 g, 20.92 10 mmol), aq. ammonium hydroxide (28 - 30 %, 100 mL) and dioxane (100 mL) was placed in a sealed vessel at ambient temperature then heated to 120*C with stirring for 24 h. (t.l.c. analysis using 9:1 EtOAc:heptane as the eluent). The reaction was concentrated in vacuo, diluted with EtOAc (300 mL), washed with brine (2x 150 mL), dried (Na 2

SO

4 ) and concentrated under reduced pressure and scrupulously 15 dried to afford 5-(4-Amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H pyrrolo[2,3-dpyrimidin-4-amine as a yellow solid (7.93 g, 99 %), 'H NMR (400 MHz, d 6 -DMSO) 1.74 (4 H, m), 1.90 (2 H, m), 2.06 (2 H, m), 3.90 (4 H, m), 4.64 (1 H, m), 5.18 (2 H, br s), 6.02 (2 H, br s), 6.84 (1 H, t), 6.97 (1 H, d), 7.08 (1 H, d), 7.26 (1 H, s) and 8.10 (1 H, s) and m/z 384.2 (MH*). 20 e) 4

-[

4 -amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1 cyclohexanone 5M HCl (300 mL) was added slowly 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 25 (18.49 g, 48.28 mmol) in acetone (800 mL) at 0"C the resulting dark orange-brown solution was heated at 60"C for 4 h. (t.l.c. analysis using 10% MeOH in CH 2 Cl 2 ). The acetone was removed under reduced pressure and the acidic layer was basified to approx. pH 8 using sat. aq. Na 2

CO

3 . The resulting precipitate was collect by filtration and scrupulously dried to afford 4

-[

4 -amino-5-(4-amino-3-fluorophenyl) 30 7 H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a light brown solid (12.67 g, 77%). A second crop was also obtained from the mother liquor on standing (2.01 g, 12%), 'H NMR (400 MHz, d 6 -DMSO) 2.27 (2 H, m), 2.30 (4 H, br d), 2.73 (2 H, in), WO 00/17203 PCT/US99/21560 5.14 (1 H, m), 5.20 (2 H, br s), 6.05 (2 H, br s), 6.85 (1 H, t), 6.97 (1 H, dd), 7.06 (1 H, dd), 7.35 (1 H, s) and 8.12 (1 H, s) and m/z 340.1 (Mf). cis- and trans- 5-(4-Amino-3-fluorophenyl)-7-[4-(4-methylpiperazino)cyclohexyl] 5 7H-pyrrolo[2,3-d]pyrimidin-4 Example 304: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrinidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide tri maleate 10 To a solution of 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-cyclohexanone (1.0 g, 2.95 mmol), N-methylpiperazine (3 equiv, 0.885 g, 8.85 mmol, 0.98 mL) and glacial acetic acid (3 equiv., 0.51 mL, 8.85 mmol) in dichloroethane (50 mL) under nitrogen was added sodium triacetoxyborohydride (1.3 equiv., 0.81 g, 3.84 mmol). The solution was stirred for 15 18 hr then additional sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added and the reaction continued for a further 48 hr. The reaction was concentrated in vacuo, partitioned between dichloromethane (100 nL) and sat. aq. 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 20 to dryness to give a yellow foam (0.95 g). Purification by column chromatography over silica gel using a dichloromethane:methanol (9:1 to 5:1) gradient afforded cis 5-(4-amino-3-fluorophenyl)- 7-[4-(4-methylpiperazino)cyclohexyl]- 7H-pyrrolo[2,3 djpyrimidin-4-amine,the higher running component, as a cream solid (400 mg, 32 %) 1H NMR (d 6 DMSO, 400 IHz) 1.56 (3H, br t), 1.68 (2H, br d), 1.99 (5H, m), 25 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, 250 x 4.6 mm column) tr= 8.619 min., 96% 30 A mixed fraction was obtained which contained both cis- and trans-isomers (440 mg, 50:50 mixture), and in addition the lower running fraction contained trans-5-(4- WO 00/17203 PCT/US99/21560 amino-3-fluorophenyl)- 7-[4-(4-methylpiperazino)cyclohexyl]- 7H-pyrrolo[2,3 d]pyrimidin-4-amine, as a yellow solid (110 mg, 9%), 'H NMR (d 6 DMSO, 400 MHz) 1.94 (6H, 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 5 (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, 250 x 4.6 mm column) t,= 7.595 min, 97% 10 Example 305: trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide tri maleate 4-Fluorobenzenesulfonyl chloride (45.9 mg, 0.236 mmol) was added to a solution of trans-5-(4-amino-3-fluorophenyl)-7-[4-(4 15 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.236 mmol) in pyridine (2 mL) at 40oC. After 27 hr at 40*C the reaction had reached completion and was concentrated in vacuo. Purification by column chromatography over silica gel using 10% to 50% MeOH in dichloromethane as the gradient afforded as a colurless oil (0.78 mmol). The product was dissolved in ethanol and maleic 20 acid (3 equiv., 27 mg, 0.233 mmol) 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 crystallised on cooling as a fawn solid (37 mg, 17 %), RP-HPLC (10 to 40 % CH 3 CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL/min using a 25 Waters Symmetry C18, 250 x 4.6 mm column) t,= 14.528 min., 96% and m/z 582.0 (MH). Example 306: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide 30 cis-NJ-(4(-4-amino-7-[4-(4-methylpiperazino)cvclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide was prepared WO 00/17203 PCT/US99/21560 using the same procedure as detailed for the free base of trans-N1-(4{-4-amino-7-[4 (4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-dJpyrimidin-5-yl}-2-fluorophenyl) 4-fluoro-1-benzenesulfonamide except on a 3.36 mmol scale. (400 mg, 32%), RP-HPLC (10 to 40 % CH 3 CN in 0.1 N aqueous ammonium acetate 5 over 12 min at 2 mL/min using a Waters Symmetry C18, 250 x 4.6 mm column) t,= 15.232, 94% min. and m/z = 582.1 (MHW). Example 307: 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3 10 d]pyrimidin-4-amine a) 7-(1-benzyl-4-piperidyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine Diethyl diazodicarboxylate (2.0 equiv., 18.19 g, 41.2 mL, 104.8 mmol) was added dropwise over approx. 1 h to a solution of 4-chloro-3-iodopyrrolo[2,3 15 d]pyrimidine (14.55 g, 52.4 mmol), 1-benzyl-4-hydroxypiperidine (3.0 equiv., 30.06 g, 157.16 mmol) and triphenylphosphine (2.0 equiv., 27.51 g, 104.8 mmol) in THF (730 mL) at room temperature under nitrogen. The reaction reached completion after 72 h (t.l.c. analysis using 1:1 EtOAc:heptane as the eluent, Rf= 0.2). The reaction was concentrated in vacuo and 1:4 ethyl acetate : heptane was added until a 20 precipitate in a clear solution was observed. The precipitate was collected by filtration (Ph3PO) and the filtrate was concentrated, dissolved in ethyl acetate (500 mL) and extracted with aq. HCI (IM, 3 x 200 mL). The combined acidic layers were basified with aq NaOH (4 N) to pH 12 then extracted into ethyl acetate(3 x 300 mL), dried (MgSO4) and concentrated in vacuo. Purification by column 25 chromatography using 5:4 light petroleum (30-60 "C):ethyl acetate over silica gel gave 2 main fractions of which the first fraction contained the product as a pale yellow crystalline solid which was recrystallised from ethyl acetate to give 7-(1 benzyl-4-piperidyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a cream crystalline solid (5.7 g, 24 %); 'H NMR (400 MHz, CDCl 3 ) 2.02 (4H, m), 2.24 (2H, 30 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 (MH*).

WO 00/17203 PCT/US99/21560 b) tert-butyl N-4-[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 5 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 equiv, 3.34 g, 31.5 mmol) and Pd(PPh 3

)

4 (4 mol%, 0.58 g, 0.5 mmol) in DME (210 mL) and degassed water (37 mL) was heated at 80*C under nitrogen for 17 h (t.l.c. analysis using 1:1 EtOAc:heptane as the eluent). The reaction mixture 10 was concentrated in vacuo, dissolved in ethyl acetate (400 mL) and washed with 10 % aq. Na 2

CO

3 (3 x 200 mL). The organic layer was dried (MgSO 4 ), concentrated and purified by column chromatography using 1:1 ethyl acetate:heptane as the eluent to afford 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 15 mmol, 77%), 1 H NMR (400 MHz, CDCl 3 ) 1.55 (9 H, 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, m), 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 20 d]pyrimidin-4-amine A mixture of the tert-butyl N-4-[7-(1-benzyl-4-piperidyl)-4-chloro-7H pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate (5.2 g, 9.7 mmol), aq. ammonium hydroxide (28 - 30 %, 100 mL) and 1,4-dioxane (100 mL) was placed in a sealed vessel at ambient temperature then heated to 120 "C with stirring for 16 h. 25 (t.l.c. analysis using EtOAc as the eluent). The reaction was concentrated in vacuo, diluted with EtOAc (300 mL), washed with brine (2x 200 mL), dried (Na 2

SO

4 ) and concentrated under reduced pressure to afford a brown solid which was triurated with ether (approx. 50 mL) to give 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4 piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a cream solid (3.0 g, 74 %), 'H 30 NMR (400 MHz, CDCl 3 ) 2.06 (4 H, m), 2.27 (2 H, m), 3.06 (2 H, m), 3.59 (2H, br s), 3.70 (2 H, br s), 4.73 (1H, m), 5.12 (2 H, s), 6.85 (1 H, t), 7.01(1 H, s), 7.06 (1 H, dd), 7.10 (1 H, dd), 7.28 (2 H, m), 7.34 (3H, m) and 8.31 (1 H, s) and m.p. 141-142 WO 00/17203 PCTIUS99/21560 *C. Example 308: Ni-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3 d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide 5 Ni-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 detailed for trans-N1-(4-{4-amino-7-[4-(4 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl} -2-fluorophenyl)-4 fluoro-1-benzenesulfonamide tri-maleate except on a 6.96 mmol scale. N1-4-[4 10 amino-7-(1 -benzyl-4-piperidyl)-7H-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 m.p. 265-6 *C. Example 309: NI-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3 15 d]pyrimidin-5-yl]-2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl] 2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide was prepared in the same manner as detailed above on a 5.04 mmol scale. The resulting N1-4-[4-amino-7-(1 benzyl-4-piperidyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1 20 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 mL/min using a Waters Delta pack 5m C18, 300A, 150 x 3.9 mm column) t,= 14.963 min., 95%. 25 Example 310: Ni-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2 fluorophenyl-4-fluoro-1-benzenesulfonamide A mixture containing Ni -4-[4-amino-7-(1 -benzyl-4-piperidyl)-7H pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide (2.40 g, 4.18 mmol), ammonium formate (10 equiv., 41.8 mmol, 2.62 g), palladium on 30 carbon (10%, 1.2g) and ethanol (100 mL) was heated at reflux with vigorous stirring for 6h., filtered and concentrated in vacuo. The solid was partitioned between dichloromethane (50 mL) and water (50 mL). The brown solid which formed at the WO 00/17203 PCT/US99/21560 phase boundary was collected and analysed for N1-4-[4-amino-7-(4-piperidyl)-7H pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide (0.33 g), m/z 485 (MH*) and m.p. 23 8-9 *C (dec.). 5 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 detailed for the preparation ofN1-4-[4-amino-7-(4-piperidyl) 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide was performed on a smaller scale (0.35 mmol) where the combined organic layers 10 from the work up were isolated, dried (Na 2

SO

4 ) and the solvent removed under reduced pressure to afford a white oil which was purified by preparative HPLC (100% pH 4.5 50mM ammonium acetate to 100% CH 3 CN in 8.5 minutes with a 1.5 minute hold at 25 mL/min using a Hypersil 5m BDS C18, 100x 21.2mm column) to yield N1-4-[4-amino-7-(1-formyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2 15 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 at 1 mL/min using a Waters Delta pack 5m C18, 300A, 150 x 3.9 mm column) t,= 13.091 min., 95%. 20 Example 312: 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 dimaleate 1-Methylimidazol-4-yl sulphonyl chloride (1.1 equiv., 0.068 mmol, 12.3 mg) was added to a suspension of 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl) 25 7H-pyrrolo[2,3-d]pyrimidin-4-amine (30 mg, 0.062 mmol) and triethylamine (3 equiv., 0.186 mmol, 26 1) in dichloromethane (1 mL) and stirred at ambient temperature for 24 h. The reaction was concentrated in vacuo, 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 30 dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography over silica gel using 10 % methanol in dichloromethane yielded a waxy white solid (10 mg). Maleic acid (2 equiv., 4 mg) was added to the product in WO 00/17203 PCT/US99/21560 hot ethanol and Ni-[4-(4-amino-7-1-[(1-methyl-JH-4-imidazolyl)sulfonyl]-4 piperidyl- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1 benzenesulfonamide dimaleatesalt crystallized on 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 using a 5 Waters Delta pack 5m C18, 300A, 150 x 3.9mm column) t,= 14.186, 100% min. and m/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]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1 10 benzenesulfonamide Using the procedure detailed for the synthesis of the free base of N1-[4-(4 amino-7-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-piperidyl-7H-pyrrolo[2,3 d]pyriniidin-5-yl)-2-fluorophenyl]-4-fluoro-1-benzenesulfonamide dimaleate, N1-[4 (4-amino-7-1-[(1,2-dimethyl-JH-4-imidazolyl)sulfonyl]-4-piperidyl-7H-pyrrolo[2,3 15 d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-benzenesulfonamide was prepared as a cream solid (9 mg), m.p. 217-8 "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 20 benzenesulfonamide 1,3-Dimethylpyrazole-5-carbonyl chloride (1.5 equiv., 14.8 mg, 0.093 mmol) was added-to a stirred 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 potassium carbonate (2 equiv., 17.1 mg, 0.124 mmol) in N-methylpyrrolidinone (2 mL) and the 25 resulting mixture was stirred at ambient temperature under nitrogen for 16 h. The solvent was removed in vacuo and the mixture purified by column chromatography over silica gel using 5 % methanol in dichloromethane as the eluent to give N1-[4 (4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl)carbonvl]-4-piperidyl- 7H-pyrrolo[2,3 d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-benzenesulfonamide as a colourless 30 glass (10 mg), RP-HPLC HPLC (100% pH 4.5 50mM ammonium acetate to 100%

CH

3 CN in 4.5 minutes with a 0.5 minute hold at 3.5 mL/min using a Perkin Elmer WO 00/17203 PCT/US99/21560 Pecosphere 3m C18 (33 x 4.6mm) column) t,= 2.98 min., 96% and m/z = 629 (MH*). Example 315: Ni-(4-{4-amino-7-[1-(2-pyridylcarbonyl)-4-piperidyl]-7H 5 pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide Ni-(4-{4-amino-7-[1-(2-pyridylcarbonyl)-4-piperidyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide was prepared using the same procedure as detailed for 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] 10 4-fluoro-1-benzenesulfonamide, (12 mg), RP-HPLC HPLC (100% pH 4.5 50mM ammonium acetate to 100% CH 3 CN in 4.5 minutes with a 0.5 minute hold at 3.5 mL/min using a Perkin Elmer Pecosphere 3m C18 (33 x 4.6mm) column) t,= 2.73 min., 98% and m/z = 590.2 (MH*). 15 Example 316: N1-4-(4-amino-7-{4-[1-(1-methylpiperid-4-yl)piperidyl]-7H pyrrolo[2,3-d]pyrinidin-5-yl})-2-fluorophenyl-4-fluoro-1-benzenesulfonamide tri maleate Sodium triacetoxyborohydride (28.1 mg, 0.134 mmol) was added to a solution of Ni-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2 20 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 was stirred for 20 h at room temperature then additional sodium triacetoxyborohydride (1.3 equiv.) was added. After a further 24 h the reaction had proceeded to completion and was 25 concentrated in vacuo, partitioned between dichloromethane (100 mL) and sat. aq. 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 over silica gel using dichloromethane:methanol:ammonium hydroxide (78:19:3) as the eluent to 30 afford a brown solid. The tri maleate salt was then formed by standard methods to give Ni-4-(4-amino-7-{4-[]-(1-methylpiperid-4-yl)piperidyl]-7H-pyrrolo[2,3- WO 00/17203 PCT/US99/21560 d]pyrimidin-5-yl})-2-fluorophenyl-4-fluoro-1-benzenesulfonamide tri-maleate as a brown solid (45 mg, 75%), m/z 582 (MH*) and RP-HPLC (5 to 85 % CH 3 CN in 0.1 N aqueous ammonium acetate over 20 min at 1 mL/min using a Waters Delta pack 5m C18, 300A, 150 x 3.9 mm column) t,= 10.658 min., 95%. 5 Example 317: Ni-4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5 yl]-2-methoxyphenylbenzamide a) To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-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, 10 0.178 mol) in THF (1.2 L) was added diethylazodicarboxylate (30.9 g, 0.178 mol) under nitrogen. The solution was stirred for 20 hr and the majority of solvent was then evaporated (250 mL remaining). EtOAc (450 mL) was then added and the resulting solid was filtered, washed with EtOAc (2 x 50 mL) and dried in vacuo to give 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 15 (22.5 g, 60%) as a cream solid. '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). Rf in 1:4 EtOAc : heptane = 0.12. b) A solution of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2 20 dioxaborolan-2-yl)phenyl]carbamate (8.2 g, 23.5 mmol), 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), tetrakistriphenylphosphinepalladium (1.1 g, 0.93 mmol), sodium carbonate (4.16 g, 39.2 mmol) in-dimethoxyethane (200 mL) and water (100 mL) was heated at 80*C for 20 hr under nitrogen. The resulting solution was cooled to room temperature and 25 partitioned between EtOAc (300 mL) and water (100 iL). The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organics were washed with water (1 x 150 mL). The organics were dried (sodium sulphate), filtered and evaporated to leave a solid. On attempting to dissolve in EtOAc/heptane (1:4), a cream solid (2.5 g) crashed out. The filtrate was adsorbed onto silica and purified by 30 flash silica gel column chromatography using 10:1 heptane:EtOAc , 4:1 heptane : EtOAc , 1:1 heptane:EtOAc and 4:1 EtOAc:heptane. The appropriate fractions were WO 00/17203 PCT/US99/21560 combined to give a white solid 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 as a solid (3.2 g), combined yield is 71%. 5 'H NMR (d 6 DMSO, 400 MHz): 8.66 (1H, s), 7.93 (2H, m), 7.74 (1H, in), 7.19 (1H, s), 7.07 (1H, d), 4.81 (1H, in), 3.93 (4H, m), 3.91 (3H, s), 2.18 (2H, in), 1.99 (2H, m), 1.79 (4H, m), 1. 48 (9H, s). HPLC (conditions: 5 to 95% CH 3 CN in 0.1 N aqueous ammonium acetate over 20 min.) t,= 21.24 min, 100%. 10 c) 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 (5.7 g, 0.011 mol), conc. ammonia solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at 120"C. The solvent was evaporated and the residue reconstituted in EtOAc/water (250 mL/100 mL). The organic layer was separated, dried (sodium sulphate), 15 filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95%

CH

3 CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1 mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2, 3 d]pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)- 7 (1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was 20 dissolved in acetone (200 mL) and HCl (5N, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred at room temperature overnight and the solvent was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling) and extracted with EtOAc (3 x 150 mL). The combined organics were washed with water (2 x 100 mL). During the extraction process a solid precipitated. This solid 25 was filtered and triturated in hot EtOAc/MeOH. The insolubles were filtered, the filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulphate), filtered and evaporated. The resulting solid was triturated with diethyl ether/ethyl acetate (5:1) and filtered to give 4-[4-amino-5-(4-amino- 3 30 methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a yellow solid. (2.3 g, combined yield = 78%). 'H NMR (d 6 DMSO, 400 MHz): 8.17 (1H, s), WO 00/17203 PCT/US99/21560 /3'7 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 a 5 mixture of 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 ambient temperature. A solution of ethyl 2-bromopropionate (543 mg) in dry DMF (10 ml) was added dropwise via a syringe over 10 minutes. The mixture was stirred at ambient temperature for 2 hours and then left for 18 hours. The 10 mixture was evaporated under vacuum and the residue was washed with water to give a solid which was triturated with ether and filtered to give ethyl 2-[4-amino-5 (4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate, m.p. 139-140 0 C. Example 149: N-(2-dimethylaminoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H 15 pyrrolo[2,3-d]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 boiled under reflux for 18 hours with the exclusion of carbon dioxide. The mixture was cooled and filtered, the filtrate was diluted with water 20 (50 ml) and stirred with ether. The mixture was left standing for 18 hours and the solid which precipitated 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. 163-164*C. 25 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 dimethylformamide (30 ml) was stirred at ambient temperature under nitrogen for 30 30 minutes. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added over 5 minutes at 0-5"C with stirring. The mixture was stirred for 30 minutes at ambient WO 00/17203 PCT/US99/21560 / $0 temperature and then allowed to stand for 18 hours. The mixture was evaporated under vacuum and the residue was triturated with water and ether. The solid obtained was collected by filtration, washed with water and then with ether to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate, 5 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 10 yl]acetate (194 mg) was heated at 62 0 C and stirred with 10 molar equivalents of the appropriate amine as listed below in methanol (12 ml) for 18 hours to give after work up the following compounds: Example 151 15 N-[2-hydroxyethyl-1,1-di(hydroxymethyl)]-2-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetamide, m.p. 222-223*C with decomposition, from 2-hydroxyethyl-1,1-di(hydroxymethyl)ethylamine. Example 152 20 N-[2-(piperazin-1-yl)ethyl]-2-[4-amino-5-[4-phenoxyphenyl)-7H pyrrolo[2,3-d]-pyrimidin-7-yl]acetanide, m.p.138-140 0 C, from 2-(piperazin-1 yl)ethylamine. Example 153 25 N-(2-morpholinoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]acetamide, m.p. 164-165 0 C, from 2-morpholinoethylamine.

WO 00/17203 PCT/US99/21560 4.74 (1H, in), 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 to 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 in ethyl acetate (10 5 mL) and treated with maleic acid (114 mg) in ethyl acetate (3 mL). The resulting solid was filtered under nitrogen and dried in vacuo for 4 hr to give trans- benzyl N (4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5 yl}-2-methoxyphenyl)carbamate tri-maleate salt (250 mg) as a cream solid. M.pt 146-148 0 C. HPLC: ( 5 to 95% CH 3 CN in 0.1 N aqueous ammonium acetate over 20 10 min.) t = 13.54 min, 94.6%. '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, in), 3.86 (3H, s), 2.70-3.10 (11H, m), 2.50 (3H, s), 1.97 (6H, m), 1.56 (2H, m). 15 Exxample 320: Trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)benzamide To a solution of N1-4-[4-amino-7-(4-oxocyclohexyl)-7H-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 20 dichloroethane (150 mL) under nitrogen was added sodium triacetoxyborohydride (0.85 g, 3.99 mmol) portionwise. The solution was stirred at room temperature overnight and then quenched by the addition of sodium hydroxide (2 N, 20 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave a solid which 25 was purified by flash silica gel column chromatography using dichloromethane then 5% MeOH/dichloronethane to 20% MeOH/ 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 treated with a solution of maleic acid ( ) in EtOAc (5 mL). The resulting fine solid was filtered under a stream of nitrogen to give trans 30 NI -(4- { 4 -anino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin 5-yl} -2-methoxyphenyl)benzamide (0.108 g) as a cream solid. 'H NMR (d 6

DMSO,

WO 00/17203 PCTIUS99/21560 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 C1 8 3 micron, conditions = 100% 100mM ammonium acetate to 100% acetonitrile over 5 min), t,= 5 1.83 min, MiH* = 540.8 Example 321: Cis-N1-(4-{ 4 -amino- 7

-[

4

-(

4 -methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide and 10 Trans- N1-(4-{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3- d]pyrimidin-5-yl} -2-methoxyphenyl)-3-phenylpropanamide a) To a solution of 4

-[

4 -amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0*C was added hydrocinnamoylchloride (0.57 g, 3.4 15 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0*C for 2 hr, warmed to room temperature and quenched by addition of saturated aqueous citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2 x 50 mL), dried (sodium sulphate), filtered and evaporated to leave NI - { 4 -[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3 20 d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 92% crude) as a brown foam.'H NMR (d, 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 to 95% CH 3 CN in 0.1 N aqueous ammonium acetate over 20 min.) t, = 14.48 min, 92.2%. 25 c) To a solution of 92% pure Ni-{ 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 sodium triacetoxyborohydride (0.67 g, 3.15 30 mmol) portionwise under nitrogen. The solution was stirred for 20 hr and then quenched by the addition of saturated aqueous sodium bicarbonate solution (50 WO 00/17203 PCT/US99/21560 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL), dried (sodium sulphate), filtered and evaporated to leave a sludge which was purified by flash silica gel column chromatography using dichloromethane to 50% MeOH/dichloromethane in 10% increments. F84-96 were combined and 5 evaporated to leave cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl] 7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.26 g) as a cream foamy glass. HPLC: (5 to 95% CH 3 CN in 0.1 N aqueous ammonium acetate over 20 min.) t, = 12.65 min, 95.2%.'H NMR (d 6 DMSO, 400 MHz): 9.17 (1H, s), 8.14 (1H, s), 8.05 (1H, d), 7.28 (5H, m), 7.18 (1H, m), 10 7.10 (1H, s), 6.99 (1H, d), 6.11 (2H, bs), 4.67 (1H, m), 3.88 (3H, s), 2.90 (2H, m), 2.73 (2H, m), 2.50 (7H, m), 2.28 (3H, s), 2.06 (3H, m), 1.71 (211, m), 1.55 (2H, m). F121-138 were combined and evaporated to leave trans- N1-(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 to 15 95% CH 3 CN in 0.1 N aqueous ammonium acetate over 20 min.) t, = 12.61 min, 96.2%. '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). 20 General Procedure for Substituted Pyrrolopyrimidine Aryl sulfonamides are as follows: A 0.19 M solution of 5-(4-amino-3-fluorophenyl)-7-[4-(4 25 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in pyridine was added one equivalent of substituted aryl sulfonyl chloride. The mixture was heated to 45o C while being shaken in an Incubator Shaker for 24h. The reaction mixture was purified by using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5u, 100x21.2mm; 100-100% ammonium acetate (0.05 M, pH 30 4.5)-acetonitrile over 12.5 min, 25 mL/min).

WO 00/17203 PCT/US99/21560 Compounds synthesized by the above procedure include: Name HPLC rt m/z mn Example 322: Trans-N-1-(4-{4-amino-7-[4-(4- 3.18 648.39 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2 (trifluoromethoxy)- 1 -benzenesulfonamide trimaleate Example 323: Trans-N-1-(4-{4-amino-7-[4-(4- 3.14 604.03 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-5-chloro-2 thiophenesulfonamide benzenesulfonamide trimaleate Example 324: Trans-N-1-(4-{4-amino-7-[4-(4- 3.07 616.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-chloro-4-fluoro 1 -benzenesulfonamide benzenesulfonamide trimaleate Example 325: Trans-N-1-(4-{4-amino-7-[4-(4- 3.39 632.12 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3-dichloro-1 benzenesulfonamide trimaleate Example 326: cis-N-1-(4-{4-amino-7-[4-(4- 2.82 616.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-fluoro 1-benzenesulfonamide trimaleate WO 00/17203 PCT/US99/21560 Example 327: cis-N-1-(4-4-amino-7-[4-( 4 - 2.66 600.3 methylpiperazino)cyclohexyl]-7H-pyrrolo[ 2

,

3 d]pyrimidin-5-yl-2-fluorophenyl)-2,6-difluoro-1 benzenesulfonamide trimaleate Example 328: Trans-N-1-(4-{4-amino-7-[4-(4- 2.53 600.3 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- 2.63 622.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[ 2

,

3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,1,3 benzothiadiazole-4-sulfonamide trimaleate Example 330: Trans-N-1-(4-{4-amino-7-[4-(4- 2.87 618.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,3,4-trifluoro-1 benzenesulfonamide trimaleate Example 331: Cis-N-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-N-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-N-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-N-1-(4-{4-amino-7-[4-(4- 3.04 632.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,6-dichloro-1 benzenesulfonamide trimaleate Example 335: Cis-N-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 WO 00/17203 PCT/US99/21560 Example 336: Cis-N-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 dimaleate Example 337: cis-N-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 dimaleate Example 338: Cis-N-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 Example 339: Cis-N-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-N-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-N-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-N-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-N-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-i -benzenesulfonamide trimaleate Example 344: Cis-N-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-N-1-(4-{4-amino-7-[4-(4- 3.08 618.3 WO 00/17203 PCT/US99/21 560 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3,4-trifluoro- 1 benzenesulfonamide trimaleate Example 346: Cis-N-l1-(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 Example 347: Cis-N-l1-(4- {4-amino-7-[4-(4- 3.13 660.2 methylpiperazino)cyclohexyl]-711-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-4-bromo-2 fluoro- 1 -benzenesulfonamide trimaleate Example 348: Cis-N-l1-(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-N-l1-(4- {4-aniino-7-[4-(4- 3.09 632.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyfimidin-5-yl} -2-fluorophenyl)-2,4-dichloro- 1 benzenesulfonamide trimaleate Example 350: Cis-N-l1-(4- {4-amino-7-[4-(4- 3.41 668.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 dljpyrimidin-5-yl} -2-fluorophenyl)-2,3,4-trichloro- 1 benzenesulfonamide trimaleate Example 351: Cis-N-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- N-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- N-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-N-l1-(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- WO 00/17203 PCTIUS99/21560 thiophenesulfonamide trimaleate Example 355: cis- N-4-(4-{4-amino-7-[4-(4- 2.84 640.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(7-chloro-2,1,3 benzoxadiazole)-4-sulfonamide trimaleate Example 356: Cis- N-4-(4-{4-amino-7-[4-(4- 2.89 636.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-(7-methyl-2,1,3 benzothiadiazole)-4-sulfonamide trimaleate Example 357: Cis- N-4-(4-{4-amino-7-[4-(4- 2.82 636.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-(5-methyl-2,1,3 benzothiadiazole)-4-sulfonamide trimaleate Example 358: Cis- N-4-(4-{4-amino-7-[4-(4- 2.82 656.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(5-chloro-2,1,3 benzothiadiazole)-4-sulfonamide trimaleate Example 359: Cis-N-1-(4-{4-amino-7-[4-(4- 3.01 612 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-3-chloro-2 methyl-1-benzenesulfonamide trimaleate Example 360: Cis-N-1-(4-{4-amino-7-[4-(4- 2.81 644.2 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-bromo-1 benzenesulfonamide trimaleate Example 361: Cis-N-1-(4-{4-amino-7-[4-(4- 3.29 758.1 methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,5-dibromo-3,6 difluoro- 1 -benzenesulfonamide trimaleate Example 362: Cis-N-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-N-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 WO 00/17203 PCT/US99/21560 General Synthesis 5 Method (a) A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl] 1-cyclohexanone (1.0 g, 2.51 mmol), the appropriate 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 an atmosphere of nitrogen for 30 minutes. Sodium 10 triacetoxyborohydride (0.69 g, 3.26 mmol) was added and the mixture 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 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 15 sulfate, filtered and evaporated to dryness under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using a methanol:dichloromethane gradient. Method (b) 20 Where appropriate the salts were made as follows. The above amine (0.909 mmol) was dissolved in warm ethyl acetate (100 mL) then 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 sides of the flask. The supernatant was poured off and the residue was dissolved in water and lyophilized to give the 25 salt Method (c) Guanidines were made as follows. The amine (0.536 mmol) was dissolved in DMF (5 mL) and cooled to -5"C and then 1-H pyrazole-1-carbonamide (95 mg, 0.644 30 mmol) followed by diisopropylethylamine (208 mg, 1.6 mmol) were added. The WO 00/17203 PCT/US99/21560 reaction mixture was allowed to warm to rt over 16h and then concentrated in vacuo. The reaction was partititoned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was lyophilized and purified by RP-HPLC. HPLC protocols: 5 1. RP-HPLC - Hypersil HyPurity Elite C18, 5 mm, 200A, 250 x 4.6 mm; 25-100% acetonitrile-0. 1 M ammonium acetate over 15 min, 1 ml/min. 2. RP-HPLC - Hypersil HyPurity Elite C18, 5 mm, 200A, 250 x 4.6 mm; 5-100% acetonitrile-0.1 M ammonium acetate over 15 min, Iml/min. It should be appreciated that protecting group chemistry is used where approriate. 10 The following examples were prepared using the methods described above: Name Synthetic HPLC-RT m/z Additional method (Min) (MH*) chemistry (Protocol) Example 364: Cis-4-{4-[4- c 14.56 511.7 amino-5-(4-phenoxyphenyl)- (2) 7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl}-1 piperazinecarboximidamide Example 365: Trans-4-{4-[4- c 14.25 511.7 amino-5-(4-phenoxyphenyl)- (2) 7H-pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl} -1 piperazinecarboximidamide Example 366: Trans-7-(4- a, b 8.55 519.6 {methyl[2-(2- (2) pyridyl)ethyl]amino} cyclohexy 1)-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4 amine trimaleate Example 367: Cis-3-({4-[4- a 10.21 472.6 Made by amino-5-(4-phenoxyphenyl)- (2) hydrolysis 7H-pyrrolo[2,3-d]pyrimidin-7- of the ester yl]cyclohexyl} amino)propanoi c acid WO 00/17203 PCT/US99/21560 Example 368: 3-({4-[4-amino- a 6.33 472.6 Made by 5-(4-phenoxyphenyl)-7H- (1) hydrolysis pyrrolo[2,3-d]pyrimidin-7- of the ester yl]cyclohexyl} amino)propanoi c acid Example 369: Ethyl cis-3-({4- a, b 10.42 500.6 [4-amino-5-(4- (1) phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-7 yl]cyclohexyl} amino)propanoa te dimaleate General Synthesis 5 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 resultant mixture was stirred at this temperature for 20 min and then at ambient temperature for 10 min. The reaction mixture was cooled to 0 0 C and 4-[4-amino-5-(4-phenoxyphenyl)-7H 10 pyrrolo[2,3-d]pyrimin-7-yl]cyclohexanone (200 mg, 0.503 mmol) added in THF (10 mL) and the resultant mixture allowed to warm to ambient temperature and stirred for 16h. The solvents were removed in vacuo and the residue 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 organics were washed with water (3 15 x 5 mL), dried (MgSO 4 ) and concentrated in vacuo. Purification by flash column chromatography on silica gel (for intermediates) or RP-HPLC (for final compounds) gave the desired compound. Method (e) 20 Hydrogenations were carried out as follows. A mixture of the alkene, (0.068 mmol) and 10% Pd/C (12 mg) in ethanol (18 mL) was stirred under hydrogen (4 atm) for WO 00/17203 PCTIUS99/21560 14h. The solids were removed by filtration and the filtrate concentrated in vacuo. Purification by RP-HPLC gave the final compound. Method (f) 5 Lithium aluminum hydride reuctions were carried out 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 16h. Fieser work up followed by purification by RP-HPLC gave the desired compound. HPLC conditions: RP-HPLC Pecosphere3 C18, 33 x 4.6 mm, 3m column; 0-100% 10 acetonitrile-0. 1 M ammonium acetate over 5 min, flow 4ml/min. It should be appreciated that protecting group chemistry is used where approriate. Name Synthetic HPLC- m/z Additional Method RT (MH*) Chemistry (Min) Example 370: {4-[4-Amino-5-(4- d 3.1 422.5 phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7-yl]cyclohexyliden} methyl cyanide Example 371: tert-Butyl 2- d 3.97 497.1 [4-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7 yl]cyclohexyliden} acetate Example 372: Ethyl 2- d 3.56 469.0 [4-[4-amino-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-7 yl]cyclohexyliden} acetate Example 373: 2-[4-[4-Amino-5- d 2.69 441.5 Made by (4-phenoxyphenyl)-7H- hydrolysis pyrrolo[2,3-d]pyrimidin-7- of the ethyl yl] cyclohexyliden} acetate ester WO 00/17203 PCT/US99/21560 Example 374: 7-[4-(2- f 2.11 428.5 Made by aminoethyl)cyclohexyl]-5-(4- lithium phenoxyphenyl)-7H-pyrrolo[2,3- aluminum d]pyrimidin-4-amine hydride reduction of the unsaturated cyanide Example 375: 2-{4-[4-amino-5- e 2.64 443.5 Made by (4-phenoxyphenyl)-7H- hydrogenatio pyrrolo[2,3-d]pyrimidin-7- n yl]cyclohexyl} acetic acid of the unsaturated acid 5 10 15 20 25 30

Claims (61)

1. 2. The compound of Claim 1, wherein R 3 is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, a substituted or 10 unsubstituted thienyl, a substituted or unsubstituted benzotriazole, a substituted or unsubstituted tetrahydropyranyl, a substituted or unsubstituted tetrahydrofuranyl, a substituted or unsubstituted dioxane, a substituted or unsubstituted dioxolane, a substituted or unsubstituted quinoline, a substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, 15 substituted or unsubstituted cyclopentanyl, a substituted or unsubstituted bezofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzisoxazole, substituted or unsubstituted benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted bezoxazole, substituted or unsubstituted benzoxazole, substituted or 20 unsubstituted bezimidazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline, substituted or unsubstituted quinoxaline, substituted or unsubstituted indole and substituted or unsubstituted pyrazole. 25 3. The compound of Claim 2 wherein R 3 is substituted with one or more substituent 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 30 unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, -S-(substituted or unsubstituted aryl), -S-(substituted or unsubstituted heteroaryl), substituted or WO 00/17203 PCT/US99/21560 unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, NRfRg, alkynyl, -C(O)NRRg, R, and CH 2 OR; R 1 , Rg and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl, substituted or 5 unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic; or Rf and Rg are each, independently, -H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aromatic group; and R, is hydrogen, or substituted or unsubstituted alkyl or substituted or 10 unsubstituted aryl, -W-(CH 2 )t-NRdRe, -W-(CH 2 )t-O-alkyl, , -W-(CH2)t-S alkyl, -W-(CH2)t-OH; or -W-(CH 2 )t-OIR; t is an integer from 0 to 6; W is a bond or -0-, -S-, -S(O)-, -S(0) 2 -, or -NRr; Rk is -H or alkyl; and 15 Rd, R. and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicyclic group; or Rd and R. are each, independently, -H, alkyl, alkanoyl or -K-D; K is -S(0) 2 -, -C(O)-, -C(O)NH-, -C(0) 2 -, or a direct bond; 20 D is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted amino, a 25 substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminocycloalkyl, COORi, or substituted or unsubstituted alkyl; and R, is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. 30 4. The compound of claim 3, wherein R 3 is a substituted or unsubstituted phenyl. WO 00/17203 PCT/US99/21560
2. 5. The compound of Claim 1, wherein ring A is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, and a 5 substituted or unsubstituted indole.
3. 6. The compound of Claim 5 wherein ring A is substituted with one or more substituent 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 10 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 heteroaryl), substituted or 15 unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, NRfRg, alkynyl, -C(O)NRRg, R. and CH 2 OR; Rf, Rg and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted 20 heteroaromatic; or Rf and Rg are each, independently, -H, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group; and R. is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, -W-(CH2)cNRRe, -W-(CH2)cO-alkyl, , -W-(CH2)-S 25 alkyl, -W-(CH2)tOH; or -W-(CH 2 )t-ORf; t is an integer from 0 to 6; W is a bond or -0-, -S-, -S(O)-, -S(0)2-, or -NRk-; Rk is -H or alkyl; and Rd, Re and the nitrogen atom to which they are attached together form 30 a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or WO 00/17203 PCT/US99/21560 unsubstituted heteroaromatic; or Rd and R, are each, independently, -H, alkyl, alkanoyl or -K-D; K is -S(O) 2 -, -C(O)-, -C(O)NH-, -C(O) 2 -, or a direct bond; D is a substituted or unsubstituted aryl, a substituted or unsubstituted 5 heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted 10 aminocycloalkyl, COORI, or a substituted or unsubstituted alkyl; and R, is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
4. 7. The compound of Claim 6, wherein ring A is a substituted or unsubstituted 15 phenyl.
5. 8. The compound of Claim 1 wherein R, is of the formula 20 0 25 wherein m is an integer from 0 to 3.
6. 9. The compound of Claim I wherein R, is of the formula 30 WO 00/17203 PCT/US99/21 56 0 In 5 (CH 2 )t NR 8 R 9 10 wherein: m is an integer from 0 to 3; t 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, a substituted or 15 unsubstituted heteroaromatic or substituted or unsubstituted heterobicyclicalkyl group; or R. and R 9 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or YrZ2; Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )q,-S(O) 2 20 C(0)0-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and -(CH2)qS(O) 2 ; q is an integer from 0 to 6; and Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or 25 unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group.
7. 10. The compound of Claim 1 wherein R, is of the formula 30 2m (C 2)s ( 2)t 35 R 77 NR 8 R9 WO 00/17203 PCTIUS99/215 6 0 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 5 membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group; or R 8 and R, are each, independently, -H, azabicycloalkyl, heterocycloalkyl or-Y2-22; 10 Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )qs-S(O)2- C(0)O-, -SO 2 NH-, -CONH-, (CH 2 )q0-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O) and-(CH 2 )qS(0)2 q is an integer from 0 to 6; Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or 15 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; R,, is -OR 7 8 , or -NR 79 R 80 ; R 7 , 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 20 membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group; or R,, and Ro are each, independently, -H, azabicycloalkyl, heterocycloalkyl or -Y 3 -Z 3 ; 25Y is selected from the group consisting of -C(O)-, -(CH2)q-,-S(O)2-, C(O)-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O) and-(CH2)qS(O)2 q is an integer from 0 to 6; Z 3 is -H, a substituted or unsubstituted alkyl, a substituted or 30 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl.
8. 11. The compound of Claim 1 wherein R, is of the formula WO 00/17203 PCT/US99/21560 N 5 R10 0 v wherein: v is an integer from 1 to 3; and RIO is -H, azabicycloalkyl, heterocycloalkyl or Y 2 -Z 2 ; 10 Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )q-,-S(O) 2 -, C(O)0-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and -(CH 2 )qS(0) 2 -; q is an integer from 0 to 6; and Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or 15 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl.
9. 12. The compound of Claim 1 wherein R, is of the formula 20 R 11 N I R10 25 wherein: m is an integer from 0 to 3; RIO is -H, azabicycloalkyl, heterocycloalkyl or Y2-Z2; 30 Y2 is selected from the group consisting of -C(O)-, -(CH2)p-,-S(O) 2 -, C(O)0-, -SO 2 NH-, -CONH-, -(CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, (CH 2 )qS(O)-, and -(CH 2 )qS(O) 2 -; q is an integer from 0 to 6; and Z, is -H, a substituted or unsubstituted alkyl, a substituted or WO 00/17203 PCT/US99/21560 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; and R 1 represents one or more substituents independently selected from 5 the group consisting of hydrogen, hydroxy, oxo, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted 10 alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or - unsubstituted heteroarylcarbonyl, a substituted or unsubstituted aminoalkyl and a substituted or unsubstituted aralkyl groups, provided that the carbon atoms adjacent to the nitrogen atom are not substituted by a hydroxy group. 15
10. 13. The compound of Claim 1 wherein R, is of the formula 20 N 25 RIO 30 wherein: R 0 is H, azabicycloalkyl, heterocycloalkyl or Y 2 -Z2; Y 2 is selected from the group consisting of -C(O)-, -(CH2)q-,-S(0)2-, C(O)0-, -SO 2 NH-, -CONH-, (CH 2 )q0-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, 35 and -(CH 2 )qS(O) 2 -; WO 00/17203 PCT/US99/21560 q is an integer from 0 to 6; and Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl. 5
11. 14. The compound of Claim 1 wherein R, is of the formula 10 r 15 / \ R8 wherein: r is an integer from 1 to 6; and 20 R 8 , R 9 and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group; or R. and R 9 are each, independently, -H, azabicycloalkyl, 25 heterocycloalkyl orY2-Z2; Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )q-,-S(O) 2 -, C(O)0-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and-(CH 2 )qS(O) 2 -; q is an integer from 0 to 6; and 30 Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 35 15. The compound of Claim 1 wherein R, is of the formula WO 00/17203 PCT/US99/21560 5 )w R 12 0 CH t 10 O /R9 u N R8 15 wherein: w is an integer from 0 to 4; t is an integer from 0 to 6; u is 0 or 1; 20 R 12 is hydrogen or a substituted or unsubstituted alkyl group; R 8 , R 9 and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaromatic, or a substituted or unsubstituted heterobicycloalkyl; or R, and R 9 are each, independently, -H, azabicycloalkyl, 25 heterocycloalkyl or Y 2 -Z 2 ; Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )q-,-S(0) 2 -, C(O)0-, S0 2 NH-1, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )S-, -(CH 2 )qS(O)-, and -(CH 2 )qS(O) 2 -; q is an integer from 0 to 6; and 30 Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl.
12. 16. The compound of Claim 1 wherein R, is of the formula 35 WO 00/17203 PCT/US99/21560 w R 10 0 t N 5 R12 wherein: - w is an integer from 0 to 4; t is an integer from 0 to 6; 10 Rio is hydrogen or a substituted or unsubstituted alkyl group; R 12 is -H, azabicycloalkyl, heteocycloalkyl or Y 2 -Z 2 ; Y 2 is selected from the group consisting of -C(O)-, -(CH 2 )q-,-S(0) 2 -, C(O)0-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and -(CH 2 )qS(0) 2 -; 15 q is an integer from 0 to 6; and Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl. 20 17. The compound of Claim 14 wherein R 8 , R 9 and the nitrogen atom together form a heterocycloalkyl group; of the formula R2o N R 13 R19 u R14 25 R 1 - T R 15 R 1 7 X R 1 6 wherein: R 13 , R 14 , R 15 , R 16 , R 7 ,, Rjg, R,, and R 20 are each, independently, lower alkyl or hydrogen; or 30 at least one pair of substituents R 13 and R,4; R, 5 and R, 6 ; R, 7 and R 1 8 ; or R 1 , and R 20 together are an oxygen atom; or WO 00/17203 PCT/US99/21560 at least one of RiD and R 15 is cyano, CONHR 21 , COOR 2 1 , CH2OR2 1 or CH 2 NR 2 1 (R 2 2 ); R 21 , R 22 and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl group, substituted 5 or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group; or R 2 1 and R 2 2 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 -, 10 C(O)0-, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O) and -(CH 2 )qS(O) 2 -; q is an integer from 0 to 6; and Z3 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or 15 unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; X is -0-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 2 3 )- or NR3; R 2 3 is -H, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, -C(NH)NH 2 , C(0)R 24 , or -C(O)OR 2 4 ; 20 R 2 4 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl; and u is 0 or 1.
13. 18. The compound of Claim 14 wherein R 8 , R, and the nitrogen atom together 25 form a heterocycloalkyl of the formula N R 25 CH2 30 R 26 H wherein: R21 R 2 s and R 26 are each, independently, hydrogen or lower alkyl; or R 2 5 and R 26 together are an oxygen atom; and WO 00/17203 PCT/US99/21560 R 2 1 , R 22 and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocycloalkyl group; or R 2 1 and R 22 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or Y 3 -Z 3 ; 5 Y 3 is -H, 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 ),NH-, -(CH 2 )sS-, (CH 2 )sS(O)-, and -(CH 2 ),S(O) 2 -; s is an integer from 0 to 6; and Z 3 is a substituted or unsubstituted alkyl, a substituted or 10 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; i is an integer from 1 to 6; and t is an integer from 0 to 6. 15 19. The compound of Claim 14 wherein R., R 9 and the nitrogen atom together form a heterocycloalkyl group; of the formula N 20 j ICH2) R27 wherein: 25 i is an integer from 1 to 6; and R 2 , is CH 2 OH, C(O)NR 2 4 R 2 8 or COOR 24 ; R 2 4 and R 2 8 are each, independently, hydrogen or a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group. 30
14. 20. The compound of Claim 14 wherein R., R, and the nitrogen atom together form a heteroaromatic group of the formula WO 00/17203 PCT/US99/21560 N N R29 5 wherein: R 2 9 is a -Cl, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, carboxylic acid, cyano, C(O)OR 30 , CH 2 0R 3 , CH 2 NRR 2 2 or C(O)NR 21 R 22 ; 10 R 3 , is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycloalkyl or heterocycloaryl group; and R 21 , R 22 and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocycloalkyl group, a substituted or 15 unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl; or R 2 , 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 -, 20 -C(O)O-, -SO 2 NH-, -CONH-, (CH 2 )tO-, -(CH 2 ),NH-, -(CH 2 ),S-, -(CH 2 ),S(O) and -(CH 2 )tS(O) 2 -; t is an integer from 0 to 6; and Z 3 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or 25 unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl.
15. 21. The compound of Claim 14 wherein at least one of R, and R 9 is of the formula Y 3 -D, wherein D is of the formula 30 -N T 35 WO 00/17203 PCT/US99/21560 wherein: Y 3 is selected from the group consisting of -C(O)-, -(CH 2 ),-,-S(O) 2 -, -C(O)O-, -SO2NH-, -CONH-, (CH2)tO-, -(CH2)tNH-, -(CH2),S-, -(CH2)tS(O) and -(CH 2 )tS(O) 2 -; 5 t is an integer from 0 to 6; T is -0-, -C(O)-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 2 4 )- or -N(R 24 )-; R 2 4 is hydrogen or a substituted or unsubstituted alkyl, aryl or aralkyl group; and x is 0, 1 or 2. 10
16. 22. The compound of Claim 14 wherein at least one of R 8 and R, is of the formula Y 3 -N(R,)R 32 , wherein: Y 3 is selected from the group consisting of -C(O)-, -(CH 2 )t-,-S(0) 2 -, -C(O)O-, -SO2NH-, -CONH-, (CH2)tO-, -(CH2)tNH-, -(CH2)tS-, -(CH2)tS(O) 15 , and -(CH 2 ),S(O) 2 -; t is an interger from 0 to 6; R 3 , and R 3 2 are each, independently, substituted or unsubstituted carboxyalkyl, a substituted or unsubstituted alkoxycarbonylalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted 20 alkylsulfonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted cyanoalkyl; or R 3 , and R 32 , together with the nitrogen atom, form a five- or six membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl. 25
17. 23. The compound of Claim 15 wherein R 8 , R, and the nitrogen atom together form a heterocycloalkyl of the formula (R 2 o N R13 R19 Y R14 30 R 18 R 15 R 1 7 X R 16 wherein WO 00/17203 PCT/US99/21560 R 13 , R 1 4 , R 1 5 , RI, R 1 7 , R 1 8 , R, and R 2 0 are each, independently, lower alkyl or hydrogen; or at least one pair of substituents R, 3 and R, 4 ; R,, and R, 6 ; R, 7 and R,8; or R,, and R 2 0 together are an oxygen atom; or 5 at least one of R 13 and R 5 is cyano, CONHR 2 1 , COOR 2 1 , CH 2 0R 2 1 or CH 2 NR 2 1 (R 2 2 ); R 21 , R 2 2 and the nitrogen atom together form a 3, 4, 5, 6 or 7 membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group; 10 or R 2 1 and R 22 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or Y3-Z3; Y 3 is selected from the group consisting of -C(O)-, -(CH 2 )s-,-S(O) 2 -, C(O)O-, -SO2NH-, -CONH-, (CH2)sO-, -(CH2)sNH-, -(CH2)sS-, -(CH2),S(O) 15 and -(CH 2 ),S(O) 2 -; s is an integer from 0 to 6; and Z3 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; 20 X is -0-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 2 3 )- or NR 23 ; R 2 3 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, -C(NH)NH 2 , C(O)R24, or -C(O)OR, 4 ; R 2 4 is hydrogen, substituted or unsubstituted alkyl, a substituted or 25 unsubstituted aryl or a substituted or unsubstituted aralkyl; and y is 0 or 1.
18. 24. The compound of Claim 15 wherein Rs, R, and the nitrogen atom together form a heterocycloalkyl of the formula 30 WO 00/17203 PCT/US99/21560 N R25 'CH2)r 5 R H 2 C N' R22 z % R 21 10 wherein R 2 5 and R 2 6 are each, independently, hydrogen or lower alkyl; or R 2 s and R 26 together are an oxygen atom; R 21 , R2 2 and the nitrogen atom together form a 3, 4, 5 or 6-membered, 15 substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl; or R 21 and R 22 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or Y 3 -Z 3 ; 20 Y 3 is selected from the group consisting of -C(O)-, -(CH 2 ),-,-S(O) 2 -, C(O)O-, -SO2NH-, -CONH-, (CH2)sO-, -(CH2)sNH-, -(CH2)sS-, -(CH2),S(O)-, and -(CH 2 ),S(0) 2 -; s is an integer from 0 to 6; and Z 3 is -H, a substituted or unsubstituted alkyl, a substituted or 25 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; or r is an integer from 1 to 6; and z is an integer from 0 to 6. 30
19. 25. The compound of Claim 15 wherein R 8 , R, and the nitrogen atom together form a heterocycloalkyl group of the formula WO 00/17203 PCT/US99/21560 N OH 2 . R 27 wherein 10 i is an integer from 1 to 6; and R,, is CH 2 OH C(O)NR,R 2 , or COOR 24 ; R 24 and R 2 s are each, independently, hydrogen or a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group. 15
20. 26. The compound of Claim 15 wherein R 8 , R 9 and the nitrogen atom together form a heteroaromatic group of the formula N 20 N R29 wherein: 25 R 29 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, carboxyl, cyano, C(O)OR 30 , CH 2 0R 30 , CH 2 NR 21 R 22 or C(O)NR 21 R 22 ; R 30 is a -H, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or 30 unsubstituted heterocycloalkyl or a substituted or unsubstituted heterocycloaryl group; R-,, R 2 2 and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted 35 heterobicycloalkyl; or WO 00/17203 PCT/US99/21560 R 2 , 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(O) 2 -, C(O)O-, -SO 2 NH-, -CONH-, (CH 2 ),O-, -(CH 2 ) 8 NH-, -(CH 2 ),S-, -(CH 2 ),S(O)-, 5 and -(CH 2 )sS(O) 2 -; s is an integer from 0 to 6; and Z 3 is -H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 10 heterocycloalkyl group.
21. 27. The compound of Claim 15 wherein at least one of R 8 and R 9 is of the formula Y 3 -D, wherein D is of the formula 15 20 wherein: Y 3 is selected from the group consisting of -C(O)-, -(CH,)s-,-S(O) 2 -, 25 C(O)O-, -SO 2 NH-, -CONH-, (CH 2 ),O-, -(CH 2 ),NH-, -(CH 2 )sS-, -(CH 2 )sS(O)-, and -(CH 2 ),S(O) 2 -; s is an integer from 0 to 6; T is -0-, -C(O)-, -S-, -SO-, -SO 2 -, -CH 2 -, -CH(OR 33 )- or -NR13-; R 3 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or 30 unsubstituted aryl, a substituted or unsubstituted aralkyl, -C(NH)NH 2 , C(O)R34, or -C(O)OR 3 4 ; R 3 4 is hydrogen, substituted or unsubstituted alkyl, aryl or aralkyl,; and x is 0, 1 or 2. 35
22. 28. The compound of Claim 15 wherein at least one of R, and R, is of the formula Y 3 -N(R 3 1 )R 32 , wherein: WO 00/17203 PCT/US99/21560 Y, is selected from the group consisting of -C(O)-, -(CH 2 )s-,-S(O) 2 -, C(O)O-, -SO2NH-, -CONH-, (CH2)sO-, -(CH2)sNH-, -(CH2)sS-, -(CH2),S(O)-, and -(CH 2 ),S(O) 2 -; s is an integer from 0 to 6; 5 R 3 , and R 3 2 are each, independently, substituted or unsubstituted carboxyalkyl, a substituted or unsubstituted alkoxycarbonylalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted cyanoalkyl; or 10 R 3 , and R 32 , together with the nitrogen atom, form a five- or six membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl.
23. 29. The compound of Claim 12 wherein Z 2 is of the formula N(R 35 )R 36 , wherein 15 R 35 and R 3 , are each, independently, hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl.
24. 30. The compound of Claim 12 wherein Z 2 is of the formula 20 N X1 R37 25 wherein: each X, is, independently, CH or N; and R 37 is hydrogen, cyano or a substituted or unsubstituted alkyl, a 30 substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. WO 00/17203 PCTIUS99/21560
25. 31. The compound of Claim 12 wherein Z 2 is of the formula 5 - N T R37 10 wherein g is an integer from 0 to 3; T is -0-, -C(O)-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 3 4 )- or -N(R34)-; R 3 4 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl; and 15 R 3 7 is hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. 20
26. 32. The compound of Claim 12 wherein Z 2 is of the formula 9 N 11-x R37 25 30 wherein: g is an integer from 0 to 3; and R 3 7 is hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted WO 00/17203 PCT/US99/21560 alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. 5 33. The compound of Claim 12 wherein Z 2 is of the formula 10 T R37 wherein: 15 T is -0-, -C(O)-, -S-, -SO-, -S02-, -CH 2 -, -CH(OR 34 )- or -N(R34) R 3 4 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl; and g is an integer from 0 to 3; and R 3 , is hydrogen, cyano or a substituted or unsubstituted alkyl, a 20 substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl. 25
27. 34. The compound of Claim 12 wherein Z 2 is of the formula N R 3 7 30 N R 38 35 wherein: WO 00/17203 PCTIUS99/21560 R 3 7 is hydrogen, cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl , a 5 substituted or unsubstituted thioalkoxy or a substituted or unsubstituted aralkyl; and R 3 , is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, perhaloalkyl, a substituted or 10 unsubstituted alkenyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl.
28. 35. The compound of Claim 1 wherein R, is of the formula 15 (42 R43 20 41 u R4 R 39 N 46 R47 wherein: 25 uis0orl; R 39 , R 40 , R 41 , R 42 , R 43 , R4, R 45 and R 4 , are each, independently, methyl or hydrogen; or at least one pair of substituents R 3 9 and R 4 ,; R41 and R42; R43 and R4; or R 45 and R 4 , together are an oxygen atom; and 30 R 4 7 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)0-, S0 2 NH-1, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and -(CH 2 )qS(O) 2 -; q is an integer from 0 to 6; and 35 Z 2 is -H, a substituted or unsubstituted alkyl, a substituted or WO 00/17203 PCT/US99/21560 unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; or R 4 7 is of the formula 5 R 5 1 R2 10 (R50 y R 53 R 49 R54 R 48 N R 55 R 56 15 wherein: y is 0 or 1; R 48 , R 49 , P5, R, R 52 , R 53 , R 4 and R, are each, independently, methyl 20 or hydrogen; or at least one pair of substituents R 4 , and R4,; R.5 and RS1; Rs2 and R 53 ; or R 5 4 and R., together are an oxygen atom; and R 56 is -H, azabicycloalkyl, heterocycloalkyl or Y3-Z3, Y 3 is selected from the group consisting of -C(O)-, -(CH 2 )t-,-S(O) 2 -, 25 C(O)O-, -SO 2 NH-, -CONH-, (CH 2 )tO-, -(CH2)tNH-, -(CH 2 ),S-, -(CH 2 )tS(O)-; and -(CH 2 )tS(0) 2 -; t is an integer from 0 to 6; and Z 3 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or 30 unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl.
29. 36. The compound of Claim 1 wherein R, is of the formula 35 40 WO 00/17203 PCT/US99/21560 60 RQ1 ( R9u 5 R 65 - R66 (R 58 R R 6 3 tRN'R64 Ray N 6 7 10 wherein: e, f, h, u and y are independently 0 or 1; R 57 , R 58 , , 59 , 60 , R, 62 , R63, R4, R6, and R 66 are each, 15 independently, methyl or hydrogen; or at least one pair of substituents R, 7 and R 58 ; R. 9 and R60; R6, and R 6 2 ; or R,, and R4 together are an oxygen atom; and R 67 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 -, 20 C(O)0, -SO 2 NH-, -CONH-, (CH 2 )qO-, -(CH 2 )qNH-, -(CH 2 )qS-, -(CH 2 )qS(O)-, and -(CH 2 )qS(0) 2 -; p is an integer from 0 to 6; and Z2 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or 25 unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; or R1 7 is of the formula R. 1 R72 7od R73 R 6 9 R74 R N R75 30 R76 wherein: 35 disOor l; WO 00/17203 PCT/US99/21560 R 68 , R 69 , R 70 , R 1 , R 7 2 , R 7 3 , R, 4 and R,, are each, independently, lower alkyl or hydrogen; or at least one pair of substituents R68 and R 69 , R 7 , and R 7 1 ; R 7 2 and R 73 ; and R 74 and R 7 , together are an oxygen atom; and 5 R 76 is -H, azabicycloalkyl, heterocycloalkyl or Y 3 -Z 3 ; Y, is selected from the group consisting of -C(O)-, -(CH 2 )t-,-S(0) 2 -, C(O)O-, -SO2NH-, -CONH-, (CH2)t0-, -(CH2),NH-, -(CH2)tS-, -(CH2)tS(0)-, and -(CH 2 )tS(O) 2 -; p is an integer from 0 to 6; 10 Z 3 is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 15 37. The compound of ClaimI, wherein R 2 is -H.
30. 38. The compound of Claim 1, wherein L is -0-, -NHSO 2 R-, -NC(O)0-, or NHC(O)-. 20
31. 39. A method of inhibiting protein kinase activity comprising administering a compound of Claim 1 or a physiologically acceptable salt, prodrug or biologically active metabolites thereof. 25 40. The method of Claim 39 wherein said protein kinase is selected from the group -consisting of KDR, FGFR-1, PDGFRp, PDGFRa, IGF-1R, c-Met, Flt 1, TIE-2, Lck, Src, fyn, Lyn, Blk, and yes.
32. 41. The method of Claim 39 wherein the activity of said protein kinase affects 30 hyperproliferative disorders.
33. 42. The method of Claim 39 wherein the activity of said protein kinase affects angiogenesis, vascular permeability, immune response or inflammation. WO 00/17203 PCT/US99/21560
34. 43. A method of treating a patient having a condition which is mediated by protein kinase activity, said method 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 5 biologically active metabolite thereof.
35. 44. The method of Claim 43 wherein said protein kinase is selected from the group consisting of KDR, Flt-1, PDGFRp, PDGFRa, IGF-1R, c-Met, TIE-2, Lck, Src, fyn, Lyn, Blk, and yes. 10
36. 45. The method of Claim 43 wherein the condition mediated by protein kinase activity is a hyperproliferative disorder.
37. 46. The method of Claim 43 wherein the activity of said protein kinase affects 15 angiogenesis, vascular permeability, an immulogic response or an imflammatory response.
38. 47. The method of Claim 43 wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase. 20
39. 48. The method of Claim 43 wherein the condition mediated by protein kinase activity is one or more ulcers.
40. 49. The method of Claim 48 wherein the ulcer or ulcers are caused by a bacterial 25 or fungal infection; or the ulcer or ulcers are Mooren ulcers; or the ulcer or ulcers are a symptom of ulcerative colitis.
41. 50. The method of Claim 43 wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes 30 Zoster, human immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis. WO 00/17203 PCT/US99/21560
42. 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. 5
43. 52. The method of Claim 43 wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, 10 cerebral edema or edema following bums, trauma, radiation, stroke, hypoxia or ischemia.
44. 53. The method of Claim 43 wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclampsia, 15 menometrorrhagia, or endometriosis.
45. 54. The method of Claim 43 wherein the condition mediated by protein kinase activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, glomerulonephritis, 20 rheumatoid arthritis and osteoarthritis, multiple sclerosis or graft rejection.
46. 55. The method of Claim 43 wherein the condition mediated by protein kinase activity is sickle cell anaemia. 25 56. The method of Claim 43 wherein the condition mediated by protein kinase activity is an ocular condition.
47. 57. The method of Claim 56 wherein the ocular condition is ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, 30 vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt's disease, Eales disease, retinopathy WO 00/17203 PCT/US99/21560 or macular degeneration.
48. 58. The method of Claim 43 wherein the condition mediated by protein kinase activity is a cardiovascular condition. 5
49. 59. The method of Claim 58 wherein the condition mediated by protein kinase acitivity is atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, venous malformation or carotid obstructive disease. 10 60. The method of Claim 43 wherein the condition mediated by protein kinase activity is cancer.
50. 61. The method of Claim 60 wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, 15 glioblastoma, neuroblastoma, teratocarcinoma, an hematopoietic malignancy and malignant ascites.
51. 62. The method of Claim 61 wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma or leukemia. 20
52. 63. The method of Claim 43 wherein the condition mediated by protein kinase actitivity is Crow-Fukase (POEMS) syndrome or a diabetic condition.
53. 64. The method of Claim 63 wherein the diabetic condition is insulin-dependent 25 diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy.
54. 65. A method of decreasing fertility in a patient, said method 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 30 or biologically active metabolite thereof. WO 00/17203 PCT/US99/21560
55. 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. 5
56. 67. The method of Claim 66 wherein the protein kinase is Tie-2.
57. 68. The method of Claim 66 wherein the compound of Formula I, or physiologically acceptable salt, prodrug or biologically active metabolite 10 thereof, is administered in combination with a pro-angiogenic growth factor.
58. 69. The method of Claim 68 wherein the pro-angiogenic growth factor is selected from the group consisiting of VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF-2, derivatives thereof and antiiodotypic 15 antibodies.
59. 70. The method of Claim 66 wherein the protein kinase-mediated condition is anemia, ischemia, infarct, transplant rejection, a wound, gangrene or necrosis. 20
60. 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, the potentiation of an inflammatory response or a combination thereof. 25
61. 72. A compound selected from the group consisting of: Cis-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex-1 -yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine, 30 Trans-5-(4-phenoxyphenyl)-7-(4-pyrrolidinocyclohex- 1 -yl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine , Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex-1-yl)-7H-pyrrolo[2,3- WO 00/17203 PCT/US99/21560 d]pyrimidin-4-ylamine hydrochloride, Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohex- 1 -yl)-7H-pyrrolo[2,3-d ]pyrimidin-4-ylamine, Trans-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo 5 [2,3-d]pyrimidin-4-ylamine, Cis-7-(4-dimethylaminocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine, 5-( 4 -phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine dihydrochlorid, 10 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo[2,3-d]pyrimidin-4 ylamine dihydrochloride, Cis- 7 -[ 4 -( 4 -isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine, Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 15 pyrrolo[2,3-d]pyrimidin-4-amine, Cis-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine, Trans-7- {4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 20 Cis- 7 -[- 4 -(4-ethylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine, trans-7-[4-(4-ethylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine, Cis- 7 -[ 4 -(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 25 pyrrolo[2,3-d]pyrimidin-4-amine tris maleate, Trans-7-[4-(4-isopropylpiperazino)cyclohexyl]-5-(4-phenoxyphenyt)-7H pyrrolo[2,3-d]pyrimidin-4-amine tris maleate, Cis-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl} -5-(4-phenoxyphenyl) 7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate, 30 Trans-7-{4-[4-(2-methoxyethyl)piperazino]cyclohexyl}-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine tris maleate, WO 00/17203 PCT/US99/21560 Cis-7-(4-{[3-(1H-1-imidazolyl)propyl]amino}cyclohexyl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aniine trimaleate salt, Trans-7-(4- {[3-(1H- 1 -imidazolyl)propyl]amino} cyclohexyl)-5-(4 phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt, 5 Cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine dimaleate salt, Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine dimaleate salt, Trans-5-(4-phenoxyphenyl)-7-(4-tetrahydro-1H-1-pyrrolylcyclohexyl)-7H 10 pyrrolo[2,3-d]pyrimidin-4-amine dimaleate salt, Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine trimaleate salt, Trans-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine trimaleate salt, 15 7 -[3-(4-methylpiperazino)cyclopentyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3 d]pyrimidin-4-amine tri-maleate, Trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-aniine, Trans-7-[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H 20 pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate, 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)-7H pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate salt, 25 cis-7 -[3-(4-methylpiperazino)cyclohexyl]-5-(4-phenoxyphenyl)-7H pyrrolo[2,3-d]pyrimidin-4-amine tri-hydrochloride, Trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl] 7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate, Cis- benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H 30 pyrrolo[2,3-d]pyrimidin-5-yl}2-methoxyphenyl)carbamate tri-maleate, Trans- benzyl N-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H- WO 00/17203 PCT/US99/21560 pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)carbamate tri-maleate, Trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl} -2-methoxyphenyl)benzamide, Trans-Ni -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H 5 pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)benzamide tri-maleate, Cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide, Trans- N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide, 10 cis- N1-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamide trimaleate salt, trans-Ni -(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl-2-methoxyphenyl)-3-phenylpropanamide tri-maleate, cis-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 15 d]pyrimidin-5-ylphenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tri maleate, trans-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tri maleate, 20 is-2-amino-6-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-ylphenoxy)benzonitrile tri-maleate, trans-2-amino-6-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-ylphenoxy)benzonitrile tri-maleate, cis-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 25 d]pyrimidin-5-ylphenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tri maleate, trans-2-(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tri maleate, 30 cis- 2 -( 4 -4-amino-7-[4-(4-methylpiperazino)cvclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-ylphenoxy)-6-(2-pyridylsulfanyl)benzonitrile tri-maleate, WO 00/17203 PCTIUS99/21560 trans- 2 -(4-4-amino-7-[4-(4-methylpiperazino)cyclohexyl]7H.pyrolo[2,3. d]pyrimidin-5-ylphenoxy)-6-(2-pyridylsulfanyl)benzonitrile tri-maleate, cis-5-( 2 -methyl-4-phenoxypheny1)-7-[4-(4-methylpiperazino)cycohexy]. 7H-pyrrolo[2,3-d]pyrimidin-4-amine tri-maleate, 5 trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperaino)cycohexyl]. 7H-pyrrolo[2,3-d]pyrimidin-4-amnine tni-maleate, cis-NI -(4- { 4 -amino-7-[ 4 -(4-methylpiperazino)cyclohexyl].7H-pyrrolo[2,3. d]pyrimidin-5-yl} -2-fluorophenyl)-4-fluoro-l1-benzenesulfonamide tri maleate, 10 trans-Ni -(4- {4-amino-7-14-(4-methylpiperazino)cyclohexyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl} -2-fluorophenyl)-4-fluoro- 1 benzenesulfonamide tri-maleate, Ni -4-[4-amino-7-( 1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-djpyrinidin-5-yl]y 2-fluorophenyl-4-fluoro-l1-benzenesulfonamide, 15 Ni -4-[4-amino-7-(l1-benzy1-4-piperidy)-7H-pyrrolo[2,3-d]pyrimdin5yl]. 2-fluorophenyl-2,3-dichloro-l1-benzenesulfonaniide, NI - 4 -[ 4 -amino-7-(4-piperidy)-7H-pyrolo[2,3d]pyrimidin5yl]y2 fluorophenyl-4-fluoro- 1 -benzenesulfonamide, NI -4-[4-amnino-7-(1 -formy1-4-piperidyl)-7H-pyrroo[2,3dpyriridin5yl]y 20 2-fluorophenyl-4-fluoro-l1-benzenesulfonamide, NI -[4-(4-amnino-7- 1 -[(1 -methyl- iH-4-imidazolyl)sulfonyl]-4-piperidyl-7H pyrrolo [2,3-d]pyrimidin-5-y1)-2-fluorophenyl]-4-fluoro- 1 benzenesulfonamide dimaleate, Ni -[4-(4-amino-7- 1-[(1 ,2-dimethyl- lH-4-imidazolyl)sulfonyl]-4-piperidyl 25 7 H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl].4fluoro-. 1 benzenesulfonaniide, Ni -[4-(4-amino-7- 1-[(1 ,3-dimethyl- 1H-5-pyrazolyl)carbonyl]-4-piperidyl 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyly4-fluoro benzenesulfonamide, 30 Ni -(4- {4-amnino-7-[ 1-( 2 -pyridylcarbonyl)-4-piperidyl]-7H-pyrrolo [2,3- WO 00/17203 PCTIUS99/21 560 d]pyrimidin-5-yl} -2-fluorophenyl)-4-fluoro- 1 -benzenesulfonaniide, Ni -4-(4-amino-7- {4-[l1-(1 -methylpiperid-4-yl)piperidyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} )-2-fluorophenyl-4-fluoro-l1-benzenesulfonamide tri maleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-(trifluoromethoxy)-l1-benzenesulfonamide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-5-chiloro-2-thiophenesulfonamide benzenesulfonamnide trimaleate, trans-N-i -(4- {4-aniino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-fluoro-l1-benzenesulfonamide benzenesulfonamide trimaleate, trans-N-i -(4- {4-amiino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate, cis-N- 1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-fluoro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4-4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3 d]pyrimidin-5-yl-2-fluorophenyl)-2,5-difluoro-l1-benzenesulfonamnide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,6-difluoro- 1 -benzenesulfonamide trimaleate, WO 00/17203 PCT/US99/21 560 trans- N-4-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2, 1,3-benzothiadiazole-4-sulfonamTide trimaleate, trans-N-i -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl }-2-fluorophenyl)-2,3 ,4-trifluoro-l1-benzenesulfonamnide trimaleate, cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-nitro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-fluoro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,4,6-trichloro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 djpyrimidin-5-yl} -2-fluorophenyl)-2,6-dichloro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)- 3 -fluoro-l1-benzenesulfonamide dimaleate, cis-N- 1-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5 -yl} -2-fluorophenyl)-5-chloro-2-thiophenesulfonamide dimaleate, WO 00/17203 PCTIUS99/21560 cis-N- 1 -(4- f{ 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-4-bromo-2,6-difluoro- 1 -benzenesulfonamnide trimaleate, cis-N- 1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3-chloro-4-fluoro- 1 -benzenesulfonamide trimaleate, cis-N- 1 -(4- f{ 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]y7Hpyrrolo[2,3 d]pyrimidin-5-yl }-2-fluorophenyl-2-iodo-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-(trifluoromethoxy)-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]y7Hpyrrolo[2,3. d]pyrimidin-5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]y7Hpyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-6-methyl-l1-benzenesulfonamide trimaleate, cis-N- 1-(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-cyano- 1 -benzenesulfonamide trimaleate, cis-N- 1 -(4- f{4-amino-7- 1 4 -(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3 ,4-trifluoro- 1 -benzenesulfonamide trimaleate, WO 00/17203 PCTIUS99/21560 cis-N- 1-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3 ,4-difluoro-l1-benzenesulfonamnide trimaleate, cis-N- 1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-4-bromo-2-fluoro- 1 -benzenesulfonamide trimaleate, cis-N- 1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-5-bromo-2-thiophenesulfonamide trimaleate, cis-N- 1 -(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,4-dichloro- 1 -benzenesulfonamide trimaleate, cis-N- 1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3. d]pyrimidin-5-yl} -2-fluorophenyl)-2,3 ,4-trichloro- 1 -benzenesulfonamide trimaleate, cis-N- 1 -(4- f{4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3-bromo-5-chloro-2-thiophenesulfonamide trimaleate, cis- N-4-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2, 1,3-benzothiadiazole-4-sulfonamnide trimaleate, cis- N-4-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyly-7Hpyrrolo[2,3 d]pyrimidin-5-yl }-2-fluorophenyl)-2, 1,3-benzoxadiazole-4-sulfonamide trimaleate, cis-N- 1-(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]y7Hpyrrolo[2,3. WO 00/17203 PCT/US99/21560 d]pyrimidin-5-yl} -2-fluorophenyl)-2,5-dichloro- 1 -thiophenesulfonamide trimaleate, cis- N-4-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(7-chloro-2,1,3-benzoxadiazole)-4 sulfonamide trimaleate, cis- N-4-(4-{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-(7-methyl-2,1,3-benzothiadiazole)-4 sulfonamide trimaleate, cis- N-4-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-(5-methyl-2,1,3-benzothiadiazole)-4 sulfonamide trimaleate, cis- N-4-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-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[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3-chloro-2-methyl-1 -benzenesulfonamide trimaleate, cis-N- 1 -(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-bromo-1-benzenesulfonamide trimaleate, cis-N-1-(4-{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide trimaleate, WO 00/1 7203 PCT/US99/21 560 cis-N- 1 -(4- f{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)- (2-nitrophenyl)methanesulfonamnide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-nitro-l1-benzenesulfonamide trimaleate, trans-N-i -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo [2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-fluoro- 1 -benzenesulfonamide trimaleate, trans-N-i -(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,4,6-trichloro- 1 -benzenesulfonamide trimaleate, trans-N-i -(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrroio[2,3 d]pyrimidin-5-yl}I -2-fluorophenyl)-2,6-dichloro- 1 -benzenesulfonamide trimaleate, trans-N-i1 -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-l1-benzenesulfonamide trimaleate, trans-N-i1 -(4- f{ 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl }-2-fluorophenyl)- 3 -fluoro-l1-benzenesulfonamide dimaleate, trans-N-i -(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyciohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-4-bromo-2,5-difluoro-l1-benzenesulfonamide trimaleate, trans-N-i -(4- { 4 -amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3- WO 00/1 7203 PCT/US99/21 560 d]pyrimidin-5-yi} -2-fluorophenyl)-3 -chloro-4-fluoro- 1 -benzenesulfonamide trimaleate, trans-N-i1 -(4- f{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl-2-iodo-l1-benzenesulfonamide trimaleate, trans-N-i1 -(4- f{4-amino-7-[4-(4-methylpiperazino)cyclohexyi]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3-dichloro-l1-benzenesulfonamide trimaleate, trans-N-i1 -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-6-methyl- 1 -benzenesulfonamide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methyipiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2-chloro-4-cyano- 1 -benzenesuifonamnide trimaleate, trans-N-i1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrroio[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3,4-difluoro-l1-benzenesuifonamnide trimaleate, trans-N-i -(4- {4-amnino-7-[4-(4-methylpiperazino)cyciohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5 -yl} -2-fluorophenyl)-4-bromo-2-fluoro-l1-benzenesulfonamide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-5-bromo-2-thiophenesulfonamide trimaleate, trans-N-i -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,4-dichloro-l1-benzenesulfonamnide trimaleate, trans-N-i -(4- {4-amnino-7-[4-(4-methylpiperazino)cyclohexyi]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,3 ,4-trichloro-l1-benzenesulfonamide WO 00/17203 PCT/US99/21560 trimaleate, trans-N-i -(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,1,3-benzoxadiazole-4-sulfonamide trimaleate, trans-N-1 -(4- { 4 -amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-2,5-dichloro- 1 -thiophenesulfonamide trimaleate, trans- N-4-(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(7-chloro-2,1,3-benzoxadiazole)-4 sulfonamide trimaleate, trans- N-4-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-(5-chloro-2,1,3-benzothiadiazole)-4 sulfonamide trimaleate, trans-N-1 -(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl} -2-fluorophenyl)-3-chloro-2-methyl-1-benzenesulfonamide trimaleate, WO 00/17203 PCT/US99/21560 trans-N-1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)-2-bromo-1-benzenesulfonamide trimaleate, trans-N-i -(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3 d]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[2,3 d]pyrimidin-5-yl}-2-fluorophenyl)- (2-nitrophenyl)methanesulfonamide trimaleate. 5 10 15