Pyrrolopyrimidines as protein kinase inhibitors

专利摘要:
(I) The compounds of formula (I), their pharmacologically acceptable salts and metabolites, are inhibitors of cerin / threonine and tyrosine kinase activity. Various kinases whose activity is inhibited by such compounds are associated with immune, hyperproliferative, or angiogenic processes. In this way, such compounds can improve the disease state where angiogenesis or endothelial cell hyperplasia is a factor. Such compounds can be used to treat cancer, hyperproliferative disorders, rheumatoid arthritis, immune system disorders, transplant rejection and inflammatory disorders.
公开号:KR20010085824A
申请号:KR1020017003532
申请日:1999-09-17
公开日:2001-09-07
发明作者:가빈 씨. 허스트；데이비드 칼더우드；라이너 뮌스샤우어；폴 라퍼티；리 디. 아놀드；데이비드 엔. 존스톤
申请人:스타르크, 카르크；바스프 악티엔게젤샤프트；
IPC主号:

专利说明:

[0001] PYRROLOPYRIMIDINES AS PROTEIN KINASE INHIBITORS AS PROTEIN KINASE INHIBITORS [0002]
[1] At least 400 enzymes have been identified as protein kinases. These enzymes catalyze the phosphorylation of the target protein substrate. Phosphorylation is typically the transfer of a phosphato group from ATP to a protein substrate. The specific structure of the target substrate to which the phosphite is delivered is a tyrosine, serine, or threonine residue. Because the amino acid residues are the target structure for phosphate transfer, the protein kinase enzymes are generally referred to as tyrosine kinases or serine / threonine kinases.
[2] Phosphorylation reactions at tyrosine, serine, and threonine residues and counteracting phosphatase responses are mediated by responses to various intracellular signals (typically mediated through cell receptors), regulation of cellular function, and activation and inactivation of cellular action It is associated with a number of underlying cellular effects. The chain reaction of protein kinases often participates in intercellular signaling, which is necessary for the realization of the cellular action. Owing to their omnipresence in this action, protein kinases can be found as essential parts of the plasma membrane or as cytoplasmic enzymes or can often be located in the nucleus as a component of the enzyme complex. In many instances, the protein kinase is an essential component of enzymes and structural protein complexes that determine when and where cellular action occurs within a protein complex that determines when and where cellular action occurs within the cell.
[3] Protein tyrosine kinase . Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. The post-translational modification of the substrate protein, often the enzyme itself, serves as a molecular switch to control cell proliferation, activation or differentiation (Schlessinger and Ulrich, 1992, Neuron 9: 383-391). Abnormal or excessive PTK activity has been observed in many disease states, including benign and malignant proliferative disorders as well as diseases that result in inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft versus host disease . In addition, epithelial cell-specific receptor PTKs, such as KDR and Tie-2, mediate angiogenesis and are therefore useful in the treatment of cancer and other inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age- Psoriasis, arthritis, retinopathy of prematurity, infantile hemangioma).
[4] The tyrosine kinase may be a receptor-type (with extracellular, transmembrane and intracellular domains) or a non-receptor type (present within cells as a whole).
[5] Receptor tyrosine kinase (RTK) . RTKs include a large family of transmembrane receptors with diverse biological activities. Currently, at least 19 different RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors important for growth and differentiation of various cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57: 433-478, 1988; Ullrich and Schlessinger, Cell 61: 243-254, 1990). The intrinsic function of the RTK is that it is activated upon ligand binding, which results in phosphorylation of the receptor and the extracellular matrix, followed by a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61: 203-212). Thus, receptor tyrosine kinase mediated signal transduction is typically initiated by extracellular interactions with specific growth factors (ligands), following receptor dimerization, stimulation of native protein tyrosine kinase activity, and phosphorylation. Thereby forming a complex with a variety of cytoplasmic signaling molecules that promote binding sites for intercellular signaling molecules and promote appropriate cell responses (eg, cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) (Schlessinger and Ullrich, 1992, Neuron 9: 1-20).
[6] Proteins with SH2 (src homology-2) or phosphotyrosine binding (PTB) domains bind to highly-activated activated tyrosine kinases and their substrates that propagate signals into cells. Both 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. Bio . (1997), 7 (6), 835-838). Several intracellular substrate proteins that bind receptor tyrosine kinase (RTK) have been identified. These can be divided into two major groups: (1) substrates with a catalytic domain; And (2) a substrate lacking the domain but acting as an adapter and binding to a catalytically active molecule (Songyang et al ., 1993, Cell 72: 767-778). The specificity of the interaction between the receptor or protein and the SH2 or PTB domains of their substrate is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in binding affinities between SH2 domains and amino acid sequences surrounding phosphotyrosine residues on a particular receptor are correlated with differences observed in their substrate phosphorylation profile (Songyang et al ., 1993, Cell 72: 767-778). Observations suggest that the function of each receptor tyrosine kinase was determined not only by its expression pattern and ligand availability, but also by the arrangement of the downstream signaling pathway, which is activated by the timing and duration of the particular receptors as well as by the stimuli. Thus, phosphorylation provides an important regulatory step in determining the selectivity of the signaling pathway supplemented by the specific growth factor receptor as well as the differentiation factor receptor.
[7] Several receptor tyrosine kinases such as FGFR-1, PDGFR, TIE-2, and c-Met and growth factors that bind to them have been suggested to play a role in angiogenesis, although some may indirectly promote angiogenesis (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 RTK. Another notation for human FLK-1 is the " kinase insert domain-containing receptor " (KDR) (Terman et al ., Oncogene 6: 1677-83, 1991). Another alternative notation for FLK-1 / KDR is " Vascular Endothelial Growth Factor Receptor 2 " (VEGFR-2) because it binds with high affinity VEGF. The murine version of FLK-1 / VEGFR-2 is also referred to as NYK (Oelrichs et al , Oncogene 8 (1): 11-15, 1993). DNA encoding the mouse, rat and human FLK-1 has been isolated and this nucleotide and encoded amino acid sequence has been reported (Matthews et al ., Proc. Natl. Acad. Sci . USA, 88: 9026-30, 1991; Terman et al, 1991, supra; Terman et al, B iochem Biophys Res Comm 187:...... 1579-86, 1992; Sarzani et al, supra; and Millauer et al, Cell 72:.. 835 -846, 1993). A number of studies, such as those reported in Millauer et al., Have shown that VEGF and FLK-1 / KDR / VEGFR-2 are important for the proliferation of vascular endothelial cells and the formation and production of blood vessels, respectively called angiogenesis and angiogenesis, Lt; / RTI > is a ligand-acceptor pair that acts as a ligand.
[8] Another type III subclass RTK, designated "fms-like tyrosine kinase-1" (Flt-1), is associated with FLK-1 / KDR (DeVries et al. Science 255; 989-991, 1992; Shibuya et al., Oncogene 5: 519-524, 1990). Another notation for Flt-1 is " Vascular Endothelial Growth Factor Receptor 1 " (VEGFR-1). To date, members of the FLK-1 / KDR / VEGFR-2 and Flt-1 / VEGER-1 subfamilies have been found to be mainly expressed on endothelial cells. These subclass members are characteristically stimulated by members of the vascular endothelial growth factor (VEGF) family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-270, 1996). Vascular endothelial growth factor (VEGF) binds to Flt-1 with a higher affinity for FLK-1 / KDR and is fragmentogenic to vascular endothelial cells (Terman et al., 1992, supra ; Mustonen et al supra ; DeVries et al., supra ). Flt-1 is thought to be essential for endothelial cell organization during angiogenesis. Flt-1 expression is associated with angiogenesis during early angiogenesis and wound healing in mouse embryos (Mustonen and Alitalo, supra ). Expression of Flt-1 in adult tissues such as mononuclear cells, osteoclasts and osteoblasts as well as renal glomeruli suggests additional functions on the receptor that are not associated with cell growth (Mustonen and Alitalo, supra ).
[9] As described above, recent evidence suggests that VEGF plays a role in stimulating both normal angiogenesis 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. LD Goldberg and EM Rosen), 209-232, 1997]. In addition, VEGF has been associated with the control and enhancement of vascular permeability (Connolly, et al ., J. Biol. Chem . 264: 20017-20024, 1989; Brown et al ., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 233-269, 1997]. Other forms of VEGF due to another splicing of mRNA have been reported, including 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 has been found to be present in the form of a disulfide linked dimer.
[10] Several related isomorphs of VEGF have recently been identified. However, their role in normal physiological and pathological function has not yet been elucidated. In addition, members of the VEGF family are often co-expressed with VEGF in a number of tissues, and can generally form heterodimers with VEGF. These properties seem to alter receptor specificity and the biological effects of heterodimers and make it difficult to explain their specific function as further illustrated below (see Korpelainen and Alitalo, Curr. Opin. Cell Biol , 159-164, 1998, and references cited within the document).
[11] Placental growth factor (PlGF) has an amino acid sequence that exhibits significant homology with the VEGF sequence (Park et al., J. Biol. Chem . 269: 25646-54, 1994; Maglione et al. -31, 1993). Like VEGF, another species of PlGF results from another splicing of mRNA, and the protein is present in dimeric form (Park et al., Supra ). PlGF-1 and PlGF-2 bind to Flt-1 with high affinity and also PlGF-2 binds well to neurofilin-1 (Migdal et al., J. Biol. Chem . 273 (35): 22272 -22278), but not FLK-1 / KDR (Park et al., Supra ). PlGF has been reported to affect both vascular permeability and mitogenic effects on endothelial cells when VEGF is present at low concentrations (intentionally due to heterodimer formation) (Park et al., Supra ).
[12] VEGF-B is produced as two homologues (167 and 185 residues), such as binding to Flt-1 / VEGFR-1. This can serve to regulate extracellular matrix degradation, cell adhesion and migration through regulation of the expression and activity of the urokinase-type plasminogen activator and plasminogen activator inhibitor 1 (Pepper et al, Proc. Natl. Acad. Sci. USA (1998), 95 (20): 11709-11714].
[13] VEGF-C was originally cloned as a ligand for VEGFR-3 / Flt-4, which is predominantly expressed by lymphatic endothelial cells. In its fully processed form, VEGF-C may bind to KDR / VEGFR-2 and stimulate endothelial cell proliferation and migration in vitro and angiogenesis 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). Transgenic overexpression of VEGF-C results in proliferation and expansion of the lymphatic vessel only, without affecting the blood vessels. Unlike VEGF, expression of VEGF-C is not induced by hypoxia (Ristimaki et al, J. Biol. Chem . (1998), 273 (14), 8413-8418).
[14] The most recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D has been reported to bind and activate at least two VEGFRs, VEGFR-3 / Flt-4 and KDR / VEGFR-2. It is originally cloned as c-fos capable of inducing mitotic material for fibroblasts and is predominantly expressed in mesoderm cells of lung and skin (Achen et al, Proc. Natl. Acad. Sci. U.S.A. (1998), 95 (2), 548-553 and references in the document).
[15] Similar to the case of VEGF, it has been suggested that VEGF-C and VEGF-D, when injected into the skin tissue, induce an increase in vascular permeability in vivo in the Miles assay (see PCT / US97 / 14696; WO98 / 07832, Witzenbichler et al. , Supra). The physiological role and importance of the ligand in controlling the blood vessel, permeability and endothelial cell response in the tissues in which the ligand is expressed are unclear.
[16] Recently, VEGF-E (NZ-7 VEGF), a novel type of vascular endothelial growth factor encoded by the virus, has been reported, which differentially utilizes the KDR / Flk-1 receptor and produces potent mitosis (Meyer et al., EMBO J. (1999), 18 (2), 363-374; Ogawa et al, J. Biol. Chem. (1998), 273 (47), 31273-31282]. The VEGF-E sequence is 25% homologous to mammalian VEGF and is encoded by the parvovirus Orf virus (OV). The parapoxvirus affects humans, both sheep and chlorine, and sometimes, causing damage to angiogenesis. VEGF-E has a characteristic cysteine knot motif present in all mammalian VEGF, although it is an approximately 20 kDa dimer with no affinity for heparin as well as a basic domain, and surprisingly VEGF-A, Have similar potency and viability to heparin-binding VEGF165 isoforms of both factors that stimulate the release of TF, proliferation, chemotaxis, and the development of vascular endothelial cells cultured in vitro and angiogenesis in vivo It turned out. Similar to VEGF165, VEGF-E binds to VEGF receptor-2 (KDR) with high affinity leading to receptor autophosphorylation and increased intracellular free Ca2 ⁺ concentration, whereas VEGF-E, in contrast to VEGF16, Lt; RTI ID = 0.0 > Flt-1. ≪ / RTI >
[17] VEGF and VEGFR Based on the novel discovery of the animal and the precedent for ligand and receptor heterodimerization, the action of the VEGF-phase animal is to determine the hemodynamics of the VEGF ligand heterodimer and / or the heterodimerization of the receptor, 0.0 > VEGFR < / RTI > (Witzenbichler et al., Supra). Recent reports also suggest that receptors other than neurotrophilin-1 (see Migdal et al, supra ) or VEGFR-3 / Flt-4 (Witzenbichler et al., Supra) or KDR / VEGFR- Suggest that it may be related to the induction of atherosclerosis (Stacker, SA, Vitali, A., Domagala, T., Nice, E., and Wilks, AF, "Angiogenesis and Cancer" Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40: S118-120 (1997)].
[18] Tie-2 (TEK) is a member of a recently discovered family of endothelial cell-specific receptor tyrosine kinases involved in vascular branching, development, remodeling, maturation and stability. (E. G., Angiopoietin 2 (" Ang1 "), which stimulates receptor autophosphorylation and signal transduction) and antagonist ligand (s) Ang2 ")) are both the first mammalian receptor tyrosine kinases to be identified. The knock-out and transgenic manipulations of the expression of Tie-2 and its ligand have shown that strict spatial and temporal control of Tie-2 signaling is essential for proper generation of the new vascular system. Current models have shown that the stimulation of Tie-2 kinase by the Ang1 ligand is directly related to the supplementation and interaction of peripheral endothelial support cells, which are important for maintaining branching, development and growth of blood vessels, and maintaining vascular integrity and inducing inactivity . Inhibition of Tie-2 autophosphorylation by either Ang1 stimulation of Tie-2 or by Ang2 (which is produced at high levels at the site of vascular degradation) is associated with vascular structures that result in endothelial cell death, particularly in the absence of growth / Resulting in loss of the matrix contact area. This situation, however, is more complicated because at least two additional Tie-2 ligands (Ang3 and Ang4) have been reported recently and demonstrate the ability to hetero- oligomerize the various agonists and antagonists angiopoietin, thus modifying their activity . It is therefore less desirable to target Tie-2 ligand-receptor interactions as an antiangiogenic therapeutic approach, and a kinase inhibition strategy is desirable.
[19] The extracellular soluble domain of Tie-2 (" ExTek ") may function to disrupt the establishment of tumor vasculature in mammary tumor xenograft and lung metastasis models, and tumor-cell mediated ocular angiogenesis. By adenovirus infection, the in vivo production of ExTek at mg / ml level in rodents can be achieved for 7-10 days without adverse side effects. These results suggest that the collapse of the Tie-2 signaling pathway in normally healthy animals may be suitably allowed. The Tie-2 inhibition response to ExTek may be conclusive isolation of the ligand (s) and / or the production of non-productive heterodimers with full length Tie-2.
[20] Recently, a significant non-regulation of Tie-2 expression has been found in vascular synovial fluid of human joints, consistent with its role in inappropriate angiogenesis. This finding suggests that Tie-2 plays a role in the progression of rheumatoid arthritis. Point mutations that generate constitutively activated forms of Tie-2 have been identified in relation to human venous malformation disorders. Tie-2 inhibitors are useful for treating the above disorders and other conditions of inappropriate angiogenesis.
[21] Nonreceptor tyrosine kinase . Non-receptor tyrosine kinases represent a collection of extracellular and membrane-bound cellular enzymes. At present, more than 24 individual non-receptor tyrosine kinases have been identified, including 11 deficiencies (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK). Presently, the Src deficiency of non-receptor tyrosine kinases consists of the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. Src deficiency of enzymes is associated with tumor formation and immune response. A more detailed description of non-receptor tyrosine kinases is provided in Bohlen, 1993, Oncogene 8: 2025-2031, which is incorporated herein by reference.
[22] Various tyrosine kinases, which are RTK or non-receptor tyrosine kinases, psoriasis; ≪ / RTI > and other hyperproliferative conditions or hyperinflammatory responses.
[23] Development of compounds that modulate PTKs. In view of the presumed importance of PTKs to the control and regulation of cell proliferation, diseases and disorders associated with abnormal cell proliferation, mutant ligands (US Patent No. 4,966,849), soluble receptors and antibodies (WO94 / 10202; 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al., Biochemistry 33: 10450-56; 1992, J. Cellular Phys., 152: 272-402, 1992. Exp. Cell Res. 199: 56-62; Wright et al., 1993, Mol. Bio. Cell 4: 358A; Kinsella, et al. 448-57) and tyrosine kinase inhibitors (WO 94/03427, WO 91/15495, WO 94/14808, US Patent No. 5,330,922; Mariani, et al., 1994, Proc. Am. Assoc. Cancer Res. 35: 2268), there have been many attempts to identify receptor and non-receptor tyrosine kinases.
[24] More recently, attempts have been made to identify small molecules that act as tyrosine kinase inhibitors. For example, bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) are generally disclosed as tyrosine kinase inhibitors. (US Patent Application No. 5,302,606), some quinazoline derivatives (EP Patent Application No. 0 566 266 A1; Expert Opin. Ther. Paat. (1998), 8 (4): 475-478) (PCT WO 94/03427), tricyclic polyhydroxy compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) are used as tyrosine kinase inhibitors for use in the treatment of cancer. ≪ / RTI > Anilinocinoline (PCT WO97 / 34876) and quinazoline derivative compounds (PCT WO 97/22596; PCT WO 97/42187) are disclosed as inhibitors of angiogenesis and vascular permeability.
[25] Attempts have also been made to identify small molecules that act as serine / threonine kinase inhibitors. For example, bis (mono maleimide) compounds have been disclosed to inhibit specific PKC serine / threonine kinase isoforms associated with altered vascular permiability in signal transduction functions in VEGF-related diseases have.
[26] Plk-1 kinase inhibitor
[27] Plk-1 is an important regulator of cell cycle progression, serine / threonine kinase, which plays an important role in the dynamic function and assembly of the mitotic spindle apparatus. Plk-1 and related kinases also show a close association with the activity and inactivation of other cell cycle regulators such as cyclin-dependent kinases. High expression of Plk-1 is associated with cell proliferation activity. Often, it is found in malignant tumors of various origins. Inhibitors of Plk-1 are predicted to block cancer cell proliferation by disrupting processes associated with mitotic spindles and improperly activated cyclin dependent kinases.
[28] Cdc2 / Cyclin B kinase inhibitors (Cdc is also known as cdk1)
[29] Cdc2 / Cyclin B is another serine / threonine kinase enzyme belonging to the cyclin-dependent kinase (cdks) family. These enzymes are involved in important transitions between the various phases of cell cycle progression. Uncontrolled cell proliferation, a characteristic of cancer, is believed to be dependent on enhanced cdk activity in such cells. Inhibition of enhanced cdk activity by cdc2 / cyclin B kinase inhibitors in cancer cells can suppress proliferation and restore normal control of cell cycle progression.
[30] Control of CDK activity is complex, but requires CDKs to be associated with members of the Cyclin family of regulatory subunits (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)). Additional control levels occur through both active and inactive phosphorylation of the CDK subunit (Draetta, Trends in Cell Biology, 3: 287-289 (1993)); Murray and Kirschner, Nature, 339: 275-280 (1989); Solomon et al., Molecular Biology of the Cell, 3: 13-27 (1992); Ducommun et al., EMBO Journal, 10: 3311-3319 (1991); Gautier et al., Nature 339: 626-629 (1989); Gould and Nurse, Nature, 342: 39-45 (1989); Krek and Nigg, EMBO Journal, 10: 3331-3341 (~ 991); Solomon et al., Cell, 63: 1013-1024 (1990)). Coordination activity and inactivation of different cyclin / CDK complexes are essential for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences, 18: 195-197 (1993); Sherr, Cell, 73: 1059-1065 ). Both important G1-S and G2-M transitions are controlled by the action of different cyclin / CDK activities. In G1, Cyclin D / CDK4 and Cyclin E / CDK2 are thought to mediate S-phase initiation (Matsushima et al., Molecular & Cellular Biology, 14: 2066-2076 (1994); Ohtsubo and Roberts, Science , Genes & Development, 7: 1559-1571 (1993); Resnitzky et al., Molecular & Cellular Biology, 14: 1669-1679 (1994)). Progression through the 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) ; Walker and Maller, Nature, 354: 314-317 (1991); Zindy et al., Biochemical & Biophysical Research Co- munications, 182: 1144-1154 (1992)), the activity of cyclin A / cdc2 (CDK1) and cyclin B / cdc2 is required for mid-phase initiation (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). Thus, it is not surprising that CDK regulatory control loss is frequent in hyperproliferative diseases and cancer (Pines, Current Opinion in Cell Biology, 4: 144-148 (1992); Lees, Current Opinion in Cell Biology, 7: 733-780 1995); Hunter and Pines, Cell, 79: 573-582 (1994)).
[31] Inhibitors of kinases associated with modulating or maintaining disease states represent novel therapies for such disorders. Examples of such kinases include (1) cSrc in cancer (Brickell, Critical Reviews in Oncogenesis, 3: 401-406 (1992); Courtneidge, Seminars in Cancer Biology, 5: 236-246 And Therapeutics, 62: 57-95 (1994)) and cyclin dependent kinases (CDKs) 1,2 and 4 (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 recurrent stenosis (Buchdunger et al., Proceedings of the National Academy of Science, 92: 2258-2262 (1995)); (3) inhibition of CDK5 and GSK3 kinase in Alzheimer's (Hosoi et al., Journal of Biochemistry (Tokyo), 117: 741-749 (1995); Aplin et al., Journal of Neurochemistry, 67: 699-707 Inhibition of c-Src kinase in osteoporosis (Tanaka et al., Nature, 383: 528-531 (1996); (5) inhibition of GSK-3 in type 2 diabetes (Borthwick et al., Biochemical (7) inhibition of 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 in diseases associated with angiogenesis (Shawver et al., Drug Discovery Today, 2: 50-63 (1997) Inhibition of CSF-1R kinase in bone and hematopoietic diseases (Myers et al., Bioorganic & Medicinal Chemistry Letters, 7: 421-424 (1997); and (10) Lck key in autoimmune diseases and transplant rejection Inhibition of kinase (Myers et al, Bioorganic & Medicinal Chemistry Letters, 7:. 417-420 (1997)) containing the one not limited to this.
[32] Some inhibitors of kinases may not be used to control kinases, but may be used to treat diseases where kinases are essential for maintaining disease states. In this case, inhibition of kinase activity acts as a remedy or remedy for such diseases. For example, various viruses, such as viruses during human induction, disrupt the cell cycle and lead to the S-phase of the cell cycle (Vousden, FASEB Journal, 7: 8720879 (1993)). By inhibiting viral replication by preventing cells from entering DNA synthesis after viral infection by inhibiting the essential S-phase initiation activity, such as CDK2, the virus life cycle can be destroyed. The same principle as this can be used to protect the normal cells of the body from the toxicity of certain 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 would inhibit the progression from normal cells to the cycle and would limit the toxicity of cytotoxic agents acting in S-phase, G2 or mitosis. In addition, CDK2 / Cyclin E activity was shown to regulate NF-kB. Inhibition of CDK2 activity stimulated NF-kB-dependent gene expression and events were mediated through interaction with p-300 coactivators (Perkins et al., Science, 275: 523-527 (1997)). NF-kB regulates genes involved in inflammatory responses (eg, hematopoietic growth factors, chemical movements, and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology, 12: 141-179 (Beg and Baltimore, Science, 274: 782-784) (1996); Wang et al., Science, 274: 784-787 (1996); Van Antwerp et al., Science, 274: 787-789 (1996)). Thus, inhibition of CDK2 can inhibit apoptosis induced by a cytotoxic agent by a mechanism associated with NF-kB. Therefore, it is suggested that inhibition of CDK2 activity might be useful in other cases where control of NF-kB is important in the pathogenesis of the disease. Additional examples can be taken from bacterial infection. In other words, aspergillosis is a common infection in immunocompromised patients (Armstrong, Clinical Infectious Diseases, 16: 1-7 (1993)). Inhibition of aspergillosis kinase Cdc2 / CDC28 or Nim A (Osmani et al., EMBO Journal, 10: 2669-2679 (1991); Osmani et al., Cell, 67: 283-291 Termination or death of the patient, and the treatment outcome can be improved for patients with such infection.
[33] Therefore, in order to control and regulate abnormal or inappropriate cell proliferation, differentiation or metabolism, it is necessary to identify the effective small compounds that specifically inhibit signal transduction and cell proliferation by modulating the activity of receptor and non-receptor tyrosine and serine / threonine kinases desirable. In particular, anti-angiogenic methods; It is beneficial to identify methods and compounds that specifically inhibit the function of tyrosine kinases essential for the formation of edema, ascites, exudates, exudates, and macroprolactin drainage and matrix deposition as well as associated disorders causing vascular hyperpermeability .
[34] SUMMARY OF THE INVENTION
[35] The present invention provides compounds of formula (I) < EMI ID = 2.1 > and pharmaceutically acceptable salts thereof:
[36]
[37] In formula (I), Ring A is a 6 membered aromatic ring; Or a 5 or 6 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, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted cycloalkyl, a substituted Substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR ₄ R ₅ , -C (O) ₂ H, -OH, substituted or unsubstituted heteroaryl, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxycarbonyl, -C (O) ₂ -haloalkyl, substituted or unsubstituted alkylthioether, substituted or unsubstituted alkylsulfoxide, substituted or unsubstituted alkylsulfone, , Substituted or unsubstituted aryl sulfoxide, substituted or unsubstituted aryl sulfone, substituted or unsubstituted alkylcarbonyl, Substituted or unsubstituted heteroaryl, -C (O) -haloalkyl, substituted or unsubstituted aliphatic ether, substituted or unsubstituted aromatic ether, carboxamido, tetrazolyl, trifluoromethylsulfonamido, trifluoromethylcarbonylamino, substituted Substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamido, substituted or unsubstituted arylamido, substituted or unsubstituted styryl, and substituted or unsubstituted aralkylamido.
[38] L is one of the following linking groups: -O-; -S-; -S (O) -; -S (O ₂₎ -; -N (R) -; -N (C (O) OR) -; -N (C (O) R) -; -N (SO ₂ R) -; -CH ₂ O-; CH ₂ S-; -CH ₂ N (R) -; -CH (NR) -; _{-CH 2 N (C (O)} R)) -; _{-CH 2 N (C (O)} OR) -; _{-CH 2 N (SO 2 R)} -; -CH (NHR) -; -CH (NHC (O) R) -; -CH (NHSO ₂ R) -; -CH (NHC (O) OR) -; -CH (OC (O) R) -; -CH (OC (O) NHR) -; -CH = CH-; -C (= NOR) -; -C (O) -; -CH (OR) -; -C (O) N (R); -N (R) C (O) -; -N (R) S (O) -; -N (R) S (O) _2- ; -OC (O) N (R) -; -N (R) C (O) N (R) -; -NRC (O) O-; -S (O) N (R) -; _{-S (O) 2 N (R} ) -; N (C (O) R) S (O) -; N (C (O) R) S (O) 2 -; -N (R) S (O) N (R) -; -N (R) S (O) 2 N (R) -; -C (O) N (R) C (O) -; -S (O) N (R) C (O) -; _{-S (O) 2 N (R} ) C (O) -; -OS (O) N (R) -; -OS (O) ₂ N (R) -; -N (R) S (O) O-; -N (R) S (O) ₂ O-; -N (R) S (O) C (O) -; -N (R) S (O) ₂ C (O) -; -SON (C (O) R) -; _{-SO 2 N (C (O)} R) -; -N (R) SON (R) -; _{-N (R) SO 2 N (} R) -; -C (O) O-; -N (R) P (OR ')O-; -N (R) P (OR ')-; -N (R) P (O) (OR ')O-; -N (R) P (O) (OR ')-; -N (C (O) R) P (OR ')O-; -N (C (O) R) P (OR ')-; -N (C (O) R) P (O) (OR ') O- or N (C (O) R) P (OR') -. 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 heteroaromatic group, or a substituted or unsubstituted cycloalkyl group.
[39] Alternatively, L is _{-R b N (R) S (} O) 2 -, -R b N (R) P (O) -, or _{-R b N (R) P (} O) is O-. R _b is an alkylene group that forms a 5 or 6 membered ring fused to ring A when it is bound with a sulfonamide, phosphinamide, or phosphonamide group.
[40] Alternatively, L is represented by one of the following formulas:
[41]
[42] R ₈₅ forms a 5, 6 or 7 membered aromatic, heteroaromatic or heterocycloalkyl ring system when bonded together with a phosphinamide or phosphonamide.
[43] In Formula (I), R ₁ is selected from the group consisting of 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 , Optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylamine, and optionally substituted arylamido, optionally substituted -S (O) ₂ -alkyl or optionally substituted -S ) ₂ -cycloalkyl, -C (O) -alkyl or optionally substituted -C (O) -alkyl.
[44] R ₁ may be substituted with one or more substituents. Preferably, R ₁ is selected from the group consisting of a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ether, aliphatic ether, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, arylcarbonyl, heteroarylcarbamoyl, Substituted or unsubstituted aminocarbonyl, oxime, azabicycloalkyl, heterocycloalkyl, oxo, aldehyde, substituted or unsubstituted alkylsulfonamido group, substituted or unsubstituted aryl A sulfonamido group, a substituted or unsubstituted bicycle Alkyl, optionally substituted heteroaryl-bicyclo-alkyl, cyano, -NH _2, alkylamino, ureido, thioureido, and is also -BE.
[45] B is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, alkylene, aminoalkyl, alkylenecarbonyl or aminoalkylcarbonyl .
[46] E is selected from substituted or unsubstituted azacycloalkyl, substituted or unsubstituted azacycloalkylcarbonyl, substituted or unsubstituted azacycloalkylsulfonyl, substituted or unsubstituted azacycloalkylalkyl, substituted or unsubstituted heteroaryl , Substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, Substituted or unsubstituted bicycloalkyl, substituted or unsubstituted ureido, substituted or unsubstituted thioureido or substituted or unsubstituted aryl.
[47] However, when R < _{1 >} is an aliphatic group or a cycloalkyl group, R < _{1 >} is exceptionally not substituted by one or more substituents selected from the group consisting of hydroxyl and lower alkyl ethers. Also, heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl and the aliphatic group is exceptionally unsubstituted by one or more aliphatic groups.
[48] In formula (I), R ₂ is selected from the group consisting of -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl, a halogen, -OH, a cyano, a substituted or unsubstituted aromatic group, Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, -NR ₄ R ₅ or -C (O) NR ₄ R ₅ .
[49] In formula (I), R ₃ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group or substituted or unsubstituted heterocycloalkyl.
[50] In formula (I), R ₄ , R ₅ and the nitrogen atom are taken together to form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycycloalkyl, Form an unsubstituted heteroaromatic.
[51] Alternatively, R ₄ and R ₅ are each independently -H, azabicycloalkyl, heterocycloalkyl, substituted or unsubstituted alkyl or YZ.
[52] Y is -C (O) -, - ( CH 2) p -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) p O- , - (CH ₂ ) _p NH-, - (CH ₂ ) _p S-, - (CH ₂ ) _p S (O) - and - (CH ₂ ) _p S (O) ₂ -.
[53] p is an integer from 0 to about 6;
[54] Z is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[55] j is an integer of 0 to 6;
[56] However, when L is -CH ₂ NR-, -C (O) NR- or -NRC (O) - and R ₃ is azacyclic alkyl or azaheteroaryl, then j is zero. Further, when L is -O- and R ₃ is phenyl, j is 0.
[57] The compounds of the present invention are useful as inhibitors of serine / threonine and tyrosine kinases. In particular, the compounds of the present invention are useful as inhibitors of tyrosine kinases important for hyperproliferative diseases, particularly cancer and angiogenic processes. For example, certain of these compounds are inhibitors of receptor kinases such as KDR, Flt-1, FGFR, PDGFR, c-Met, TIE-2 or IGF-1-R. Since certain of these compounds have anti-angiogenic properties, they are important for inhibiting the progression of disease states, where angiogenesis is an important factor. Certain compounds of the invention are effective as inhibitors of serine / threonine kinases such as PKCs, erk, MAP kinase, MAP kinase kinase, MAP kinase kinase kinase, cdks, Plk-1 or Raf-1. These compounds are useful for treating cancer and hyperproliferative disorders. In addition, certain compounds are effective inhibitors of non-receptor kinases such as those of the Src family (e.g., Ick, blk and lyn), Tec, Csk, Jak, Map, Nik and Syk. These compounds are useful in the treatment of cancer, hyperproliferative disorders and immunological diseases.
[58] Certain compounds of the present invention may be used in combination with selective TIE-2, which may be anti-angiogenesis (especially in combination with one or more VEGFR inhibitors) or pro-angiogenesis, in the presence or in conjunction with VEGF- Kinase inhibitor. In this manner, the inhibitor may be used to enhance therapeutic angiogenesis, for example, to treat ischemia, infarction or ataxia or to promote wound healing.
[59] The present invention provides a method of inhibiting the kinase activity of said tyrosine kinase and serine / threonine kinase, comprising administering a compound of formula (I) to said kinase in an amount sufficient to inhibit the enzymatic activity of tyrosine kinase and serine / threonine kinase . ≪ / RTI >
[60] The invention further encompasses the use of these compounds in pharmaceutical compositions comprising a pharmaceutically effective amount of the above-mentioned compounds and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions can be administered to an individual to slow or stop the angiogenic process in an angiogenesis-promoted disease or to treat other conditions associated with edema, effusion, exudate or ascites, and hypervascularity . Certain pharmaceutical compositions can be administered to individuals to treat cancer and hyperproliferative disorders by inhibiting serine / threonine kinases such as cdk, Plk-1, erk, and the like.
[61] The definitions of the substituents in the first preferred group of compounds of formula (I) are as follows.
[62] Preferably, L is -N (R) S (O) 2 -, -S (O) 2 N (R) -, N (R) C (O) -, -C (O) N (R) - Or -O-.
[63] Preferably, R ₃ is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazole, Unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxane, substituted or unsubstituted dioxolane, substituted or unsubstituted quinoline, substituted or unsubstituted thiazole, substituted or unsubstituted Substituted or unsubstituted isoxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanyl, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzisoxazole, substituted or unsubstituted benzisothiazole, Substituted or unsubstituted benzothiazole, substituted or unsubstituted Benzoxazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline, Substituted or unsubstituted quinoxaline, substituted or unsubstituted indole, or substituted or unsubstituted pyrazole. Alternatively, L is -SN (R) -, -S ( O) N (R) -, -S (O) 2 N (R) -, -N (R) S-, -N (R) S ( (O) -, -N (R) S (O) ₂ -, -N (R) (O) ₂ N (R ') -, R ₃ is a substituted or unsubstituted aliphatic group or substituted or unsubstituted alkenyl.
[64] In one aspect, R ₃ is optionally substituted phenyl.
[65] R ₃ may be substituted by one or more substituents. Preferred substituents for R ₃ are F, Cl, Br, I, CH _3, NO _2, OCF _3, OCH _3, CN, CO ₂ CH _3, CF _3, t- butyl, pyridyl, substituted or unsubstituted oxazolyl , 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, -S- (substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -C (O) NR _f R _g , R _c , CH ₂ OR _c .
[66] R _f , R _g and the nitrogen atom are taken together to form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycycloalkyl or a substituted or unsubstituted Gt; heteroaromatic < / RTI >
[67] Alternatively, R _f and R _g are each independently a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
[68] R _c is hydrogen, or substituted or unsubstituted alkyl or substituted or unsubstituted aryl; _{-W- (CH 2) t -NR d} R e, -W- (CH 2) t -O- alkyl, -W- (CH _{2) t} -S- alkyl, or -W- (CH _{2) t} -OH to be.
[69] t is an integer from 0 to about 6;
[70] W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR _k -.
[71] R _k is -H or alkyl.
[72] R _d and R _e together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicyclic group.
[73] Alternatively, R _d and R _e are each independently -H, alkyl, alkanoyl, or -KD.
[74] K is -S (O) _2- , -C (O) -, -C (O) NH-, -C (O) _2- or a direct bond.
[75] D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aminocycloalkyl, COOR _i, or substituted or unsubstituted alkyl.
[76] R _i is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
[77] More preferred substituents for R ₃ are F, Cl, Br, I, cyano, nitro, OCF ₃ , CH ₃ and CF ₃ .
[78] Preferably, ring A is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted indole. In one embodiment, Ring A is substituted or unsubstituted phenyl.
[79] Ring A may be substituted by one or more substituents. Preferred substituents for ring A are F, Cl, Br, I, CH _3, NO _2, OCF _3, OCH _3, CN, CO ₂ CH _3, CF _3, t- butyl, pyridyl, substituted or unsubstituted oxazolyl , Substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, -S- (substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -C (O) NR _f R _g , R _c , CH ₂ OR _c . R _f , R _g and R _c are as defined above.
[80] Ring A is more preferably substituted by F, Cl and nitro.
[81] R ₂ is preferably hydrogen.
[82] In one embodiment, R < ₁ > is of the formula (I)
[83]
[84] In this formula,
[85] m is an integer from 0 to about 3;
[86] In another embodiment, R < ₁ > is of the formula I (b)
[87]
[88] In this formula,
[89] m and t are as defined above and R ₈ , R ₉ and the nitrogen atom are taken together to form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, Form a heteroaromatic or substituted or unsubstituted heteroicycloalkyl group. Alternatively, R ₈ and R ₉ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ . Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O -, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - or - (CH ₂ ) _q S (O) ₂ -. q is an integer of 0 to 6; Z ₂ is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[90] In another embodiment, R < ₁ > is of the formula (I)
[91]
[92] In this formula,
[93] m, t, R < ₈ > and R < ₉ > are as defined above. s is an integer of 0 to 6; and q is an integer from 0 to about 6. R ₇₇ is -OR ₇₈ or -NR ₇₉ R ₈₀ . R ₇₈ is -H or an optionally substituted aliphatic group. R ₇₉ , R ₈₀ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted To form a heterobicyclic alkyl group. R ₇₉ and R ₈₀ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ . Y ₃ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O -, - (CH ₂ ) _q NH-, - (CH ₂ ) _q S-, - (CH ₂ ) _q S (O) - and - (CH ₂ ) _q S (O) ₂ -. Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[94] In another embodiment, R < ₁ > is of the formula (I)
[95]
[96] In this formula,
[97] v is an integer from 1 to about 3; R ₁₀ is -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ . Y ₂ and Z ₂ are as defined above.
[98] In another embodiment, R < ₁ > is of the formula (I)
[99]
[100] In this formula,
[101] m and R < ₁₀ > are as defined above. R ₁₁ is 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 unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxy Alkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl, and substituted or substituted , And the carbon atom adjacent to the nitrogen atom is not substituted by a hydroxy group.
[102] In another embodiment, R < ₁ > is of the formula (f)
[103]
[104] In this formula,
[105] R ₁₀ is as defined above.
[106] In another embodiment, R < ₁ > is of the formula (g)
[107]
[108] In this formula,
[109] r is an integer from 1 to about 6; R ₈ and R ₉ are as defined above.
[110] In another embodiment, R < ₁ > is of the formula (I)
[111]
[112] In this formula,
[113] R ₈ , R ₉ and t are as defined above. w is an integer from 0 to about 4; u is 0 or 1; R ₁₂ is hydrogen or an optionally substituted alkyl group.
[114] In another embodiment, R < ₁ > is of the formula (I)
[115]
[116] In this formula,
[117] w, t, R ₁₀ and R ₁₂ are as defined above.
[118] In another embodiment, when R ₁ is Formula I (g) or I (h), R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl group of the formula:
[119]
[120] In this formula,
[121] u is as defined above. _{R 13, R 14, R 15} , R 16, R 17, R 18, R 19 and R ₂₀ are each independently, lower alkyl or hydrogen. Alternatively, the substituents R < ₁₃ > and R < ₁₄ > R ₁₅ and R ₁₆ ; R ₁₇ and R ₁₈ ; Or at least one pair of R < ₁₉ > and R < ₂₀ > together are an oxygen atom. Alternatively, at least one of R ₁₃ and R ₁₅ is cyano, CONHR ₂₁ , COOR ₂₁ , CH ₂ OR ₂₁ or CH ₂ NR ₂₁ (R ₂₂ ). R ₂₁ , R ₂₂ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted To form a heterobicyclic alkyl group. Alternatively, R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ . Y ₃ and Z ₃ are as defined above. X is _{-O-, -S-, -SO-, -SO 2} - or a _{NR 23 -, -CH 2 -,} -CH (OR 23). R ₂₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R ₂₄ or -C ₂₄ . R ₂₄ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
[122] In another embodiment, R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl of the formula:
[123]
[124] In this formula,
[125] t, R < ₂₁ > and R < ₂₂ > are as defined above. R ₂₅ and R ₂₆ are each independently hydrogen or lower alkyl. Alternatively, R ₂₅ and R ₂₆ together are an oxygen atom. and i is an integer of 1 to about 6. [
[126] In another embodiment, R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl group of the formula:
[127]
[128] In this formula,
[129] i is as defined above. R ₂₇ is CH ₂ OH, C (O) NR ₂₄ R _28, or COOR ₂₄ . R ₂₄ and R ₂₈ are as defined above.
[130] In another embodiment, R ₈ , R ₉ and the nitrogen atom together form a heteroaromatic group of the formula:
[131]
[132] In this formula,
[133] R ₂₉ is an aralkyl group, a carboxylic acid, cyano, C (O) OR ₃₀ that is substituted or unsubstituted alkyl, optionally substituted aryl, optionally _{substituted, CH 2 OR 30, CH 2} NR 21 R 22 , Or C (O) NR < ₂₁ > R < _{22 &} gt ;. R ₃₀ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl or heterocycloaryl group. R ₂₁ and R ₂₂ are as defined above.
[134] In another embodiment, R ₈ and R ₉ is one or more of those of the formula Y ₃ -D, D is is the food:
[135]
[136] Y < ₃ > is as defined above. x is 0, 1 or 2; T is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -CH 2 -, -CH (OR 24) - or -N (R ₂₄₎ - a. R ₂₄ is as defined above.
[137] In another embodiment, R ₈ and R ₉ at least one of the will of the formula _{Y 3 -N (R 31) R} 32, Y 3 is as defined above. R ₃₁ and R ₃₂ are each independently selected from the group consisting of substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, Lt; / RTI > alkylcarbonyl or unsubstituted or substituted or unsubstituted cyanoalkyl. Alternatively, R ₃₁ and R ₃₂ together with the nitrogen atom form a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or an optionally substituted heterocycycloalkyl.
[138] In another embodiment, when R ₁ is of the formula I (e), Z ₂ is of the formula N (R ₃₅₎ R _36. R ₃₅ and R ₃₆ are each independently hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl.
[139] In another embodiment, when R < ₁ > is formula I (e), Z < _{2 &}
[140]
[141] In this formula,
[142] X ₁ is each independently CH or N. R ₃₇ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, Substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl group.
[143] In another embodiment, when R < ₁ > is formula I (e), Z < _{2 &}
[144]
[145] In this formula,
[146] g is an integer from 0 to about 3; T is as defined above. R ₃₇ is selected from the group consisting of hydrogen, cyano, or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl , Substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted aralkyl group.
[147] In another embodiment, when R < ₁ > is formula I (e), Z < _{2 &}
[148]
[149] In this formula,
[150] g and R < ₃₇ > are unsubstituted aralkyl groups as defined above.
[151] In another embodiment, when R < ₁ > is formula I (e), Z < _{2 &}
[152]
[153] In this formula,
[154] T, g and R < ₃₇ > are as defined above.
[155] In another embodiment, when R < ₁ > is formula I (e), Z < _{2 &}
[156]
[157] In this formula,
[158] R ₃₇ is as defined above. R ₃₈ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, perhaloalkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl.
[159] In another embodiment, R ₁ is of the formula:
[160]
[161] In this formula,
[162] u is as defined above. R ₃₉ , R ₄₀ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ and R ₄₆ are each independently methyl or hydrogen. Alternatively, substituents R ₃₉ and R ₄₀ ; R ₃₆ and R ₃₇ ; R ₃₈ and R ₃₉ ; Or at least one of R ₄₀ and R ₄₁ is an oxygen atom. R ₄₇ is H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ . Y ₂ and Z ₂ are as defined above. Alternatively, R ₄₇ is of the following formula:
[163]
[164] In this formula,
[165] y is 0 or 1; R ₄₈ , R ₄₉ , R ₅₀ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently methyl or hydrogen. Alternatively, substituents R ₄₈ and R ₄₉ ; R ₅₀ and R ₅₁ ; R ₅₂ and R ₅₃ ; Or at least one of R < ₅₄ > and R < ₅₅ > R ₅₆ is -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ . Y ₃ and Z ₃ are as defined above.
[166] In another embodiment, R ₁ is of the formula:
[167]
[168] In this formula,
[169] e, f, h, u and y are independently 0 or 1. R ₅₇ , R ₅₈ , R ₅₉ , R ₆₀ , R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ , R ₆₅ and R ₆₆ are each independently methyl or hydrogen. Alternatively, substituents R ₅₇ and R ₅₈ ; R ₅₉ and R ₆₀ ; R ₆₁ and R ₆₂ ; Or at least a pair of R ₆₃ and R ₆₄ together are an oxygen atom. R ₆₇ is H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ . Y ₂ and Z ₂ are as defined above. Alternatively, R ₆₇ is of the formula:
[170]
[171] In this formula,
[172] d is 0 or 1; R ₆₈ , R ₆₉ , R ₇₀ , R ₇₁ , R ₇₂ , R ₇₃ , R ₇₄ and R ₇₅ are each independently lower alkyl or hydrogen. Alternatively, substituents R ₆₈ and R ₆₉ ; R ₇₀ and R ₇₁ ; R ₇₂ and R ₇₃ ; Or at least a pair of R ₇₄ and R ₇₅ together are an oxygen atom. R ₇₆ is -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ . Y ₃ and Z ₃ are as defined above.
[173] As aromatic groups as used herein are meant aromatic cyclic ring systems (such as benzyl and cinnamyl) and fused polycyclic aromatic ring systems (such as naphthyl and 1,2,3,4-tetrahydronaphthyl) . An aromatic group is also referred to herein as an aryl group.
[174] Heteroaromatic groups as used herein include heteroaryl ring systems such as thienyl, pyridyl, pyrazole, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furan, pyrrole, imidazole, pyrazole , Triazole, pyrimidine, pyrazine, thiazole, isoxazole, isothiazole, tetrazole, or oxadiazole); And heteroaryl ring systems (e.g., benzo (b) thienyl, benzimidazole, indole, tetrahydroindole, and the like) in which the carbocyclic aromatic ring, the carbocyclic non-aromatic ring or the heteroaryl ring is fused with one or more other heteroaryl rings, 2,3-d] pyrimidines, pyrazolo [3,4-d] pyrimidines), and N-oxides thereof. The term " anthraquinone "
[175] Aralkyl groups as used herein are aromatic substituents that are linked to a particular compound by an aliphatic group having from 1 to about 6 carbon atoms.
[176] Heteroaralkyl groups as used herein are heteroaromatic substituents that are linked to a particular compound by an aliphatic group having from 1 to about 6 carbon atoms.
[177] A heterocycloalkyl group as used herein is a non-aromatic ring system having 3 to 8 atoms and containing at least one heteroatom such as nitrogen, oxygen or sulfur.
[178] As used herein, an acyl group is selected from the group consisting of -C (O) NR _x R _z , -C (O) OR _x , -C (O) R _x wherein R _x and R _z are each independently -H, Or an unsubstituted or substituted aliphatic group or an unsubstituted or substituted aromatic group.
[179] Aliphatic groups as used herein include straight chain, branched or cyclic C ₁ -C ₈ hydrocarbons which are completely saturated or contain one or more units of unsaturation. The "lower alkyl group" is a saturated aliphatic group having 1 to 6 carbon atoms.
[180] The compound of formula (I) may exist as a salt with a pharmaceutically acceptable acid. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromic acid, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates such as (+) - tartrate, (-) - Mixtures thereof including mixtures thereof], succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.
[181] Certain compounds of formula (I) having an acidic substituent may be present as a salt with a pharmaceutically acceptable base. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts can be prepared by methods known to those skilled in the art.
[182] Certain compounds of formula (I) and salts thereof may exist in one or more crystalline forms and the present invention includes respective crystalline forms and mixtures thereof.
[183] Certain compounds of formula (I) and salts thereof may also be present in the form of a solvate, e.g., a hydrate, and the present invention includes each solvate and mixtures thereof.
[184] Certain compounds of formula (I) may contain one or more chiral centers and may exist in different optically active forms. When the compound of formula (I) contains a single chiral center, the compound is in two enantiomeric forms and the present invention includes a mixture of such enantiomers and enantiomers, such as a racemic mixture . The enantiomers can be prepared by methods known to those skilled in the art, for example, by forming crystallization or the like, which can be separated into diastereomeric salts; Forming a diastereomeric derivative or complex which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; Optionally reacting one enantiomer with an enantiomer-specific agent (e. G., Enzymatic esterification); Or in a chiral environment, for example, by gas-liquid or liquid chromatography on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. It should be appreciated that if the desired enantiomer is converted to another chemical by one of the separation processes mentioned above, then an additional step is required to separate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by converting one enantiomer to another by asymmetric transformation.
[185] Where the compound of formula (I) contains one or more chiral centers, it may exist in diastereomeric form. Such diastereomeric pairs can be separated by methods known to those skilled in the art, for example, by chromatography or crystallization, and individual enantiomers within each pair can be separated as mentioned above. The present invention includes each diastereomer of a compound of formula (I) and mixtures thereof.
[186] Certain compounds of formula (I) may exist in different tautomeric forms or different geometric isomers, and the invention includes each tautomer and / or geometric isomer of a compound of formula (I), and mixtures thereof.
[187] Certain compounds of formula (I) may exist in different stable conformational forms, which may be separated. For example, due to steric hindrance or ring deformation, torsional asymmetry due to limited rotation around an asymmetric single bond may enable separation of different isomeric isomers. The present invention includes each stereoisomer of a compound of formula (I) and mixtures thereof.
[188] Certain compounds of formula (I) may exist in the form of zwitterions, and the invention includes respective zwitterionic forms of the compounds of formula (I) and mixtures thereof.
[189] Preferred groups of compounds of the present invention are:
[190] Cis-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[191] Trans-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[192] Cis-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine hydrochloride;
[193] Trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[194] Trans-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[195] Cis-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[196] 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride;
[197] 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride;
[198] Cis-7- [4- (4-isopropylpiperazine) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
[199] Trans-7- [4- (4-isopropylpiperazine) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
[200] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine;
[201] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine;
[202] Cis-7- [4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
[203] Trans-7- [4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
[204] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tris maleate ;
[205] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tris maleate ;
[206] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine tris maleate;
[207] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine tris maleate;
[208] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylmethyl) ≪ / RTI > 4-amine trimaleate salt;
[209] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 4-amine dimaleate salt;
[210] Cis-7- [4- (dimethylamino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dimaleate salt;
[211] Trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine dimaleate salt;
[212] Pyrrolo [2,3-d] pyrimidin-4-amine dimaleate (2-pyrrolidinyl) salt;
[213] Cis-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt;
[214] Trans-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt;
[215] 7- [3- (4-methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tinctureate;
[216] Trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
[217] Trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate;
[218] 7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trihydrochloride;
[219] Pyrrolo [2,3-d] pyrimidin-4-amine tincaleate salt (4-methylpiperazino) cyclohexyl] -5- ;
[220] Cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trihydrochloride;
[221] Pyrrolo [2,3-d] pyrimidin-4-amine (4-methylpiperazino) cyclohexyl] Trimaleate;
[222] Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (1 H) -quinolin- -Methoxyphenyl) carbamate < / RTI >trimaleate;
[223] Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (1 H-pyrrolo [2,3- d] pyrimidin- -Methoxyphenyl) carbamate < / RTI >trimaleate;
[224] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) benzamide;
[225] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) benzamide trimaleate;
[226] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] Methoxyphenyl) -3-phenylpropanamide;
[227] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) -3-phenylpropanamide;
[228] Pyrrolo [2,3-d] pyrimidin-5-yl-2-methoxyphenyl) -7- Phenyl) -3-phenylpropanamide trimaleate salt;
[229] Pyrrolo [2,3-d] pyrimidin-5-yl-2-methoxyphenyl) -7- Phenyl) -3-phenylpropanamide < / RTI >trimaleate;
[230] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - [(3-methoxypropyl) amino] benzonitrile trimaleate;
[231] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - [(3-methoxypropyl) amino] benzonitrile trimaleate;
[232] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -7H-pyrrolo [2,3- Yl) benzonitrile trimaleate;
[233] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -7H-pyrrolo [2,3- Yl) benzonitrile trimaleate;
[234] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate;
[235] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate;
[236] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - (2-pyridylsulfanyl) benzonitrile trimaleate;
[237] Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - (2-pyridylsulfanyl) benzonitrile trimaleate;
[238] (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine Trimaleate;
[239] Pyrrolo [2,3-d] pyrimidin-4-amine (4-methylpiperazino) cyclohexyl] Trimaleate;
[240] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] Fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate;
[241] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate;
[242] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4- Fluoro-1-benzenesulfonamide;
[243] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl) -2,2-dimethyl- , 3-dichloro-1-benzenesulfonamide;
[244] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-l- - benzenesulfonamide;
[245] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl] - 4-fluoro-1-benzenesulfonamide;
[246] 7H-pyrrolo [2,3-d] pyrimidin-4-yl] -N- [4- (4-amino- 5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate;
[247] Pyrrolo [2,3-d] pyrimidin-7-ylmethyl) -1H-pyrrolo [2,3-d] ] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide;
[248] Pyrrolo [2,3-d] pyrimidin-7-one [0194] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide;
[249] Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (2-pyridyl) -Fluorophenyl] -4-fluoro-1-benzenesulfonamide;
[250] Pyrrolo [2,3-d] pyrimidin-5-yl) - lH-pyrrolo [2,3-d] pyrimidin- }) - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide trimaleate;
[251] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate;
[252] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-chloro-2-thiophenesulfonamide benzenesulfonamide trimaleate;
[253] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
[254] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
[255] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
[256] Pyrrolo [2,3-d] pyrimidin-5-yl-2- (4-methoxyphenyl) cyclohexyl] Fluorophenyl) -2,5-difluoro-1-benzenesulfonamide trimaleate;
[257] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide trimaleate;
[258] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate;
[259] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimaleate;
[260] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate;
[261] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate;
[262] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimaleate;
[263] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate;
[264] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate;
[265] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate;
[266] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-chloro-2-thiophenesulfonamide dimaleate;
[267] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2,6-difluoro-1-benzenesulfonamide trimaleate;
[268] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
[269] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-iodo-1-benzenesulfonamide trimaleate;
[270] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate;
[271] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
[272] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate;
[273] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate;
[274] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimaleate;
[275] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate;
[276] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate;
[277] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-bromo-2-thiopensulfonamide trimaleate;
[278] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2, 4-dichloro-1-benzenesulfonamide trimaleate;
[279] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide trimaleate;
[280] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-bromo-5-chloro-2-thiopensulfonamide trimaleate;
[281] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate;
[282] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate;
[283] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dichloro-1-thiopensulfonamide trimaleate;
[284] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate;
[285] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[286] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[287] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[288] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate;
[289] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate;
[290] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate;
[291] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
[292] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate;
[293] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate;
[294] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate;
[295] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimaleate;
[296] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate;
[297] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate;
[298] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate;
[299] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate;
[300] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
[301] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-iodo-1-benzenesulfonamide trimaleate;
[302] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
[303] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate;
[304] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate;
[305] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate;
[306] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate;
[307] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-bromo-2-thiopensulfonamide trimaleate;
[308] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2, 4-dichloro-1-benzenesulfonamide trimaleate;
[309] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide trimaleate;
[310] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-bromo-5-chloro-2-thiopensulfonamide trimaleate;
[311] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate;
[312] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dichloro-1-thiopensulfonamide trimaleate;
[313] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate;
[314] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[315] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[316] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
[317] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate;
[318] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate;
[319] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate;
[320] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate.
[321] The compounds of the present invention have anti-angiogenic properties. These anti-angiogenic properties are partly or wholly due to inhibition of protein tyrosine kinases essential for the angiogenic process. For these reasons, these compounds are useful in the treatment of arthritis, atherosclerosis, restenosis, psoriasis, hemangioma, myocardial vascularization, coronary and cerebral flank, ischemic blood vessel formation, ischemia / reperfusion injury, wound healing, peptic ulcer, Helicobacter- Related diseases such as angiogenesis disorders, fractures, Crow-Fukase syndrome (POEMS), preeclampsia, functional uterine bleeding, seedling fever, skin flushing, neovascular glaucoma, and diabetic retinopathy, retinopathy of prematurity or aging-related Can be used as an activator for disease states such as retinopathy such as those associated with degenerative spots. In addition, some of these compounds have been implicated in the pathogenesis of solid tumor, malignant ascites, von Hippel Lindau disease, hematopoietic cancer, and thyroid hyperplasia (especially Graves' disease) and cysts Syndrome (Stein-Leventhal syndrome) and ovarian epilepsy, which is characterized by renal disease of the polycystic kidney disease, which may be used as an active agent for hyperproliferative disorders such as those for the growth and / Because of the need for proliferation.
[322] In addition, some of these compounds have been shown to be useful in the treatment of burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed binge burns, ovarian hyperstimulation syndrome, brain tumor-associated brain edema, Can be used as an active agent for brain edema or pulmonary edema, eye and spot edema, swollen gut glomerulonephritis, and other diseases that are manifestations of hypervascularity, effusion, effusion, protein mononucleosis or edema. Such compounds would also be useful for treating disorders in which the protein monocyte promotes epileptogenesis and induces deposition of fibrin and extracellular matrix (e.g., aphrodisiac, fibrosis, cirrhosis and bony tunnel syndrome). Due to increased VEGF production, it enhances inflammatory processes such as mononuclear supplementation and activation. The compounds of the present invention will also be useful for the treatment of inflammatory disorders such as inflammatory bowel disease (IBD) and Crohn's disease.
[323] VEGF is unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and edema formation. Indeed, it is believed that vascular hyperpermeability and edema associated with the expression or administration of numerous other growth factors are mediated through VEGF production. Inflammatory cytokines stimulate VEGF production. Due to hypoxia, VEGF is significantly upregulated in numerous tissues, and conditions associated with infarct, occlusion, ischemia, anemia or circulatory damage typically result in a VEGF / VPF mediated response. Hypervascularity, associated edema, altered transendothelial exchange and macromolecular hemolysis, often accompanied by leukemic bleeding, can lead to excessive matrix deposition, malformed epilepsy, fibrotic hyperplasia, and the like. Thus, VEGF-mediated hyperpermeability can provide a significant cause for disorders with these pathologic features.
[324] Because blastocysts, placenta development and embryogenesis are angiogenesis dependent, certain compounds of the present invention are useful as pregnancy-control and contraceptive agents.
[325] It is expected that the listed disorders will be mediated to a significant extent by protein tyrosine kinase activity associated with KDR / VEGFR-2 and / or Flt-1 / VEGFR-1 and / or TIE-2 tyrosine kinases. By inhibiting the activity of these tyrosine kinases, the progression of the listed disorders is inhibited because the angiogenic or vascular permeability components of these disease states are significantly reduced. The selective action of certain compounds of the invention on specific tyrosine kinases can minimize side effects that may occur when using less selective tyrosine kinase inhibitors. Certain compounds of the invention are also effective inhibitors of FGFR, PDGFR, c-Met and IGF-1-R. Since these receptor kinases can directly or indirectly augment angiogenesis and hyperproliferative responses in various disorders, their inhibition may interfere with disease progression.
[326] The compounds of the present invention have inhibitory activity against protein kinases. That is, these compounds regulate signal transduction by protein kinases. The compounds of the present invention inhibit protein kinases from serine / threonine and tyrosine kinase classes. In particular, these compounds arbitrarily inhibit the activity of KDR / FLK-1 / VEGFR-2 tyrosine kinase. Certain compounds of the present invention may also be used in combination with other compounds such as Flt-1 / VEGFR-1, Tie-2, FGFR, PDGFR, IGF-1R, c-Met, Src-subtype kinases such as Lak, Src, fyn, Thereby inhibiting the activity of additional tyrosine kinases. Additionally, some compounds of the invention significantly inhibit PKC, MAP kinase, erk, CDKs, Plk-1 or Raf-1, which play an essential role in cell proliferation and cell-cycle progression. The efficacy and specificity of the entire compound of the invention for a particular protein kinase can often be modified and optimized by varying the type, number and arrangement of substituents (i.e., R, R, R, A and ring 1) have. In addition, metabolites of certain compounds may also have significant protein kinase inhibitory activity.
[327] The compounds of the present invention, when administered to individuals in need thereof, inhibit hypervascular permeability and edema formation in these individuals. These compounds are believed to act by inhibiting the activity of KDR tyrosine kinase, which is involved in the hypervascularity and edema process. Such KDR tyrosine kinases may also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase or VEGFR-2 tyrosine kinase. KDR tyrosine kinase is a KDR tyrosine kinase that has a vascular endothelial growth factor (VEGF) or another activating ligand (such as VEGF-C, VEGF-D, VEGF-E or HIV Tat protein) Lt; RTI ID = 0.0 > receptor. ≪ / RTI > After activation of this KDR tyrosine kinase, hyperpermeability of the blood vessels occurs and the blood flows from the bloodstream, passes through the blood vessel wall, and flows into the interstitial space, thereby forming an edema area. These reactions are often accompanied by leaky bleeding. Similarly, excessive vascular hyperpermeability can disrupt normal molecular exchange across the endothelium in intracerebral tissues and organs (e.g., lungs and kidneys), which can lead to macromolecular hemolysis and deposition. Following this acute response to KDR stimulation, which is believed to promote a subsequent angiogenic process, prolonged KDR tyrosine kinase stimulation results in proliferation of vascular endothelial cells and the formation of new blood vessels and predominance. By inhibiting KDR tyrosine kinase activity, it is possible to block the production of the activated ligand, block activation ligand binding to the KDR tyrosine kinase receptor, prevent receptor dimerization and phosphorylation, or inhibit the enzyme activity of KDR tyrosine kinase Inhibiting the phosphorylation function of such enzymes), or some other mechanism that interferes with its lower signaling (D.Mukhopedhyay et al., Cancer Res. 58: 1278-1284 (1998) and references therein], over-permeability as well as its associated hemolysis, subsequent edema formation and matrix deposition, and angiogenic response can be suppressed and minimized.
[328] One group of preferred compounds of the present invention has the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt-1 tyrosine kinase activity. (Flt-1 tyrosine kinase is also referred to as VEGFR-1 tyrosine kinase.) Both KDR tyrosine kinase and Flt-1 tyrosine kinase are activated by VEGF binding to the KDR tyrosine kinase receptor and the Flt-1 tyrosine kinase receptor, respectively. Certain preferred compounds of the present invention are unique because they are single VEGF-receptor tyrosine kinases that do not inhibit other receptor tyrosine kinases (e.g., Flt-1) that are activated by activation of the ligand, but which may also be activated by specific activation ligands (KDR). ≪ / RTI > Thus, in this manner, certain preferred compounds of the invention are selective in their tyrosine kinase inhibitory activity.
[329] In one aspect, the invention provides a method of treating a protein kinase-mediated disease in a patient, comprising administering to the particular patient a therapeutically or prophylactically effective amount of one or more compounds of formula (I).
[330] &Quot; Protein kinase-mediated disease " is a medical disorder, such as certain diseases or other undesirable physical disorders, wherein the onset or progression is dependent, in part or in whole, on the activity of one or more protein kinases. Such a protein kinase may be, for example, a protein tyrosine kinase or a protein serine / threonine kinase.
[331] The patient to be treated may be any animal, preferably a mammal such as a domesticated animal or livestock. More preferably, the patient is a human.
[332] A " therapeutically effective amount " is the amount of a compound of formula (I) or a combination of two or more such compounds that completely or partially inhibits the progression of the disease, or alleviates one or more symptoms of the disease in part or in whole. The therapeutically effective amount may also be a prophylactically effective amount. The therapeutically effective amount will depend on the size and sex of the patient, the disease to be treated, the severity of the disease and the desired outcome. For any given patient, the therapeutically effective amount may be determined by methods known to those skilled in the art.
[333] The method of the present invention is useful for the treatment of protein kinase-mediated diseases such as the diseases mentioned above. In one embodiment, such protein kinase-mediated diseases are characterized by undesirable angiogenesis, edema, or epileptic deposition. For example, the disease may be one or more ulcers, such as ulcers caused by bacterial or fungal infections, Mooren ulcers, and ulcerative colitis. Such diseases also include microbial infections such as Lyme disease, sepsis, septic shock, or herpes simplex, herpes zoster, human immunodeficiency virus, protozoa, toxoplasmosis or infection by parapoxvirus; Von Hippel Linda ' s disease, polycystic kidney disease, pemphigus, Paget ' s disease and psoriasis; Reproductive diseases such as endometriosis, ovarian hyperstimulation syndrome, preeclampsia or functional uterine bleeding; Osler-Weber-Rendu disease, chronic obstructive pulmonary artery disease, asthma, and burns, injuries, radiation, stroke, hypoxia or ischemia, ischemia, Fibrosing and edema diseases such as post edema; Inflammatory and / or immunological diseases such as systemic lupus erythematosus, chronic inflammation, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis and transplant rejection. Suitable protein kinase-mediated diseases also include sickle cell anemia, osteoporosis, osteoporosis, tumor-induced hypercalcemia and bone metastasis. Additional protein kinases-mediated diseases that can be treated by the methods of the invention include, but are not limited to, retinopathy and degenerative spots, eye and spot swelling, neovascular diseases of the eye, scleritis, radiopacity, uveitis, , Asthma, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt's disease, and Eales disease.
[334] The compounds of the present invention are also useful for the treatment of cardiovascular diseases such as atherosclerosis, restenosis, vascular occlusion and carotid artery occlusive disease.
[335] The compounds of the present invention may also be used for the treatment and / or prophylaxis of cancer, including solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic malignancies including leukemia and lymphoma, Are useful in the treatment of cancer-related indications such as exudates and malignant ascites.
[336] The compounds of the present invention are also useful for the treatment of diabetic diseases such as glaucoma, diabetic retinopathy and tubulointerstitials, and the crow-fuchsia (POEMS) syndrome.
[337] Kinases such as Src, Tec, Jak, Map, Csk, NFkB and Syk play an important role in immune function regulation. The Src sequence typically includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yrk, Fyk, Yes, Hck and Blk. The Syk sequence is generally understood to include only Zap and Syk. The TEC series include Tec, Btk, Rlk, and Itk. Zanus family kinases are involved in the transduction of growth factors and proinflammatory cytokine signals through numerous receptors. Although BTK and ITK, members of the Tec family of kinases, play less well-recognized roles in immunobiology, it can be demonstrated that modulating them by certain inhibitors is therapeutically beneficial. The Csk sequence is typically understood to include Csk and Chk. Kinase RIP, IRAK-1, IRAK-2, NIK, p38 MAP kinase, Jnk, IKK-1 and IKK-2 are involved in the signal transduction pathway to major pro-inflammatory cytokines such as TNF and IL-1. Due to their ability to inhibit one or more of these kinases, the compounds of formula (I) can function as immunomodulators useful in the maintenance of a biphasic transplant, treatment of autoimmune disorders, and treatment of sepsis and septic shock. Through their ability to regulate the migration and activation of T cells, B-cells, mast cells, monocytes and neutrophils, these compounds can be used to treat such autoimmune diseases and sepsis. Prevention of graft versus host graft rejection for host versus graft or bone marrow for solid organs will be limited by the toxicity of currently available immunosuppressants and will be beneficial from the efficacious drug with an improved therapeutic index. Gene targeting experiments have demonstrated an important role for Src in the biology of osteoclasts, cells responsible for bone resorption. The compounds of formula (I) may be useful in the treatment of osteoporosis, osteoporosis, Paget's disease, tumor-induced hypercalcemia and bone metastasis through its Src modulating ability.
[338] Numerous protein kinases have been demonstrated to be protooncogenes.
[339] Due to chromosomal cleavage (at the Itk kinase cleavage site on chromosome 5), dislocation such as in the case of the Abl gene with BCR (Philadelphia chromosome), cleavage in cases such as c-Kit or EGFR, or mutations such as Met , The anomalously regulated protein is converted into the cochine product from proto-oncogene to produce the protein. In other tumors, carcinogenesis is driven by autocrine or paracrine ligand / growth factor receptor interactions. Members of Src-family kinases typically enhance carcinogenesis because they are associated with lower-signal transduction, which itself can become over-expressed by overexpression or mutation. By inhibiting protein kinase activity of these proteins, the disease process can be interrupted. Vascular recurrent stenosis may be associated with FGF and / or PDGF-enhanced smooth muscle and endothelial cell proliferation. Ligand stimulation of FGFR, PDGFR, IGF1-R and c-Met in vivo is pro-angiogenic and increases angiogenesis-dependent disorders. Inhibition of FGFr, PDGFr, c-Met or IGF1-R kinase activity individually or in combination may be an effective strategy for inhibiting these phenomena. Thus, the kinase activity of normal or abnormal c-kit, c-met, c-fms, src-family members, EGFr, erbB2, erbB4, BCR- Abl, PDGFr, FGFr, IGF1- (I) < / RTI > that inhibit the proliferative response may be useful in treating benign and neoplastic proliferative disorders.
[340] In many pathological conditions (for example, solid primary tumors and metastasis, Kaposi sarcoma, rheumatoid arthritis, blindness due to irreversible renal vascularization, psoriasis and atherosclerosis), the progression of the disease is secondary . Polypeptide growth factors often produced by diseased tissue or related inflammatory cells and their corresponding endothelial cell specific receptor tyrosine kinases such as KDR / VEGFR-1, Flt-1 / VEGFR-1, Tie-2 / Tek and Tie) are important for endothelial cell growth, migration, organization, stimulation of differentiation and establishment of vital new functional vasculature. As a result of the vascular permeability factor activity of VEGF in mediating hypervascularity, VEGF-stimulation of VEGFR kinase has also been shown to be associated with tumorigenesis, neuroendocrine and pulmonary edema, pleural and pericardial effusion, delayed bass response, Trauma, burns, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), hypothermia associated with cardiopulmonary bypass, and hypertrophic organ dysfunction; And blindness due to inappropriate neovascularization and the formation of eye edema that causes glaucoma play an important role. In addition to VEGF, recently identified VEGF-C and VEGF-D, and viral encoded VEGF-E or HIV-Tat proteins can also induce a vascular hyperpermeability response through stimulation of VEGFR kinase. KDR / VEGFR-2 and / or Tie-2 are also expressed in selected populations of hematopoietic liver cells. Certain members of this population are inherently pluripotent, able to differentiate into endothelial cells and stimulate growth factors to participate in the angiogenic process of angiogenesis. For these reasons, they have been named endothelial progenitor cells (EPCs) (J. Clin. Investig. 103: 1231-1236 (1999)). In some progenitors, Tie-2 can play a role in their complement, adhesion, regulation and differentiation (Blood, 4317-4326 (1997)]. Thus, certain agents according to formula (I) that can block the kinase activity of endothelial cell-specific kinases can inhibit the progression of the disease associated with these conditions.
[341] It is believed that vascular destabilization of the antagonist ligand (Ang2) of Tie-2 induces an endothelial unstable " plastic " state. In the presence of high levels of VEGF, a strong angiogenic response can occur, but in the absence of VEGF or VEGF-related stimuli, obvious tube degeneration and endothelial apoptosis can occur (Gene and Devel. 13: 1055-1066 (1999)). In a similar manner, the Tie-2 kinase inhibitor may be pro-angiogenic or anti-angiogenic, respectively, with or without VEGF-related stimulation, respectively. Thus, Tie-2 inhibitors can be used in conjunction with appropriate pro-angiogenic stimuli such as VEGF to enhance therapeutic angiogenesis in conditions such as wound healing, infarction and ischemia.
[342] A pharmaceutical composition comprising a compound of formula (I) or a salt thereof, or a therapeutically effective amount thereof, is useful for the treatment of protein kinase-mediated diseases, such as benign and neoplastic proliferative diseases and immune system disorders as mentioned above . For example, such diseases include autoimmune diseases such as rheumatoid arthritis, thyroiditis, Type I diabetes, multiple sclerosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis, and systemic lupus erythematosus; (Eg, lung, breast, stomach, bladder, colon, pancreas, ovary, prostate, and rectum), including but not limited to psoriasis, organ transplant rejection (eg, renal transplant rejection, graft versus host disease), benign and neoplastic proliferative diseases ), Hematopoietic malignancies (leukemia and lymphoma); And diseases involving inadequate vascularization, such as diabetic retinopathy, retinopathy of prematurity, chorioamnion angiogenesis due to aging-related degenerative spots and infantile hemangiomas in humans. In addition, the inhibitors may be useful for the treatment of disorders associated with VEGF mediated edema, ascites, effusion, and exudates, including, for example, spot edema, cerebral edema, acute brain injury and adult respiratory distress syndrome (ARDS).
[343] The compounds of the present invention may also be useful for the prevention of the above diseases.
[344] It is expected that the listed disorders will be mediated to a significant extent by protein tyrosine kinase activity associated with 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 components of these disease states are significantly reduced. Due to the selective action of the compounds of the present invention against specific tyrosine kinases, the side effects that may occur when using less selective tyrosine kinase inhibitors can be minimized.
[345] In another aspect, the invention provides a compound of formula (I) as defined earlier, for use as an inhibitor of a drug, particularly a protein kinase activity, such as tyrosine kinase activity, serine kinase activity and threonine kinase activity, to provide. In yet another aspect, the invention provides the use of a compound of formula (I) as defined earlier in the manufacture of a medicament for use in inhibiting protein kinase activity.
[346] In the present invention, the following definition can be applied:
[347] A " physiologically acceptable salt " has the biological effectiveness and properties of the free base and includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, , p-toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid, and the like.
[348] &Quot; Alkyl " refers to a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms, including straight chain and side chain groups, or a cyclic hydrocarbon having 3 to 6 carbon atoms.
[349] &Quot; Alkoxy " refers to an " O-alkyl " group, wherein " alkyl " is as defined above.
[350] Pharmaceutical composition
[351] The compounds of the present invention are administered to a human patient by itself as a dosage for treating hypervascular hyperpermeability, edema and related disorders, or as a pharmaceutical composition in admixture with a suitable carrier or excipient (s). Mixtures of these compounds may also be administered to the patient as a simple mixture or as a suitably formulated pharmaceutical composition. The therapeutically effective dose additionally refers to the amount of compound (s) sufficient to result in inappropriate neovascularization, progression of hyperproliferative disorders, edema, VEGF-related hyperpermeability and / or prevention or attenuation of VEGF-related hypotension . A description of the formulation and administration of the compounds of the present invention can be found in the following references ("Remington's Pharmaceutical Sciences", Mack Publishing Col, Easton, PA, latest edition).
[352] Route of administration
[353] Suitable routes of administration include, for example, oral, ophthalmic, rectal, transmucosal, topical, or intestinal administration; Intramuscular, subcutaneous, intravenous, as well as parenteral, including intravenous, direct intravenous, intravenous, intraperitoneal, intramuscular or intravenous infusion.
[354] Alternatively, the compound can be administered, for example, topically, rather than systemically, by direct injection of the compound to a site where swelling has often occurred in a depot or sustained release formulation.
[355] Moreover, the drug can be administered as a liposome coated with a targeting drug delivery system, for example, an endothelium-specific antibody.
[356] Composition / Formulation
[357] The pharmaceutical composition of the present invention can be prepared by a known method, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing methods.
[358] Thus, the pharmaceutical compositions for use in accordance with the present invention may be formulated with one or more physiologically acceptable carriers, including excipients and excipients, which facilitate the processing of the active compound into preparations which can be used pharmaceutically, . ≪ / RTI > The appropriate formulation depends on the chosen route of administration.
[359] For injectable use, the formulation of the invention may be formulated in a physiologically compatible buffer such as an aqueous solution, preferably a kk solution, a Ringer's solution or a physiological saline buffer. For transmucosal administration, a suitable penetrator is used in the formulation for the barrier to be permeated. Such penetrants are generally known in the art.
[360] In the case of oral administration, the compound can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like for oral ingestion by the patient to be treated. Oral pharmaceutical preparations can be prepared by combining the active compound with a solid excipient, optionally grinding the resultant mixture, and then, if appropriate, adding a suitable adjuvant followed by processing into a granular mixture to obtain a tablet or dragee core. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP) . Optionally, disintegrants such as crosslinked polyvinylpyrrolidone, agar, alginic acid or its salts (such as sodium alginate) may be added.
[361] To provide a covering material suitable for dragee cores. To this end, concentrated sugar solutions, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carpol gel, polyethylene glycol and / or titanium dioxide, a locker solution, and a suitable organic solvent or solvent mixture . Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.
[362] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Such push-fit capsule preparations may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsule formulations, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be present in a sugar-coated form suitable for such administration.
[363] For ball administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[364] In the case of inhalation administration, the compounds for use according to the present invention may be formulated for administration by pressurized packs using a suitable container, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, Pack or sprayer in the form of an aerosol spray display. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to carry the measured amount. For example, gelatin capsules and cartridges for use in an inhaler or an air inhaler containing a powder mixture of the compound and a suitable powder base such as lactose or starch may be formulated.
[365] The compound can be formulated for parenteral administration by injection, e. G., Bolus injection or continuous infusion. The injectable formulations may be presented in unit dosage form, e.g., an ampoule or a multi-dose container, supplemented with a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.
[366] Pharmaceutical formulations for parenteral administration include aqueous solvents of the active compound 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, synthetic fatty acid esters such as ethyl oleate or triglyceride, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspensions, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, such suspending agents may contain suitable stabilizers, or agents that provide a highly concentrated solution formulation by increasing the solubility of the compound.
[367] On the other hand, the active ingredient may be in powder form for constitution with a suitable vehicle (e. G., Pyrogen-free sterile water) prior to use.
[368] The compounds may also be formulated in rectal compositions such as suppositories or oil enema suppositories containing conventional suppository bases such as, for example, cocoa butter or other glycerides.
[369] 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 (e. G., Subcutaneous or intramuscular transplantation or intramuscular injection). Thus, for example, the compound may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or with an ion exchange resin, or as a substantially insoluble derivative (e.g., a substantially insoluble salt) .
[370] Examples of pharmaceutical carriers for the hydrophobic compounds of the present invention are a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. This VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 with 5% dextran in aqueous solution. These co-solvent systems dissolve hydrophobic compounds well, and themselves exhibit low toxicity when administered systemically. In essence, the proportion of the co-solvent system can vary considerably without compromising its solubility and toxicity characteristics. Moreover, the identity of the cosolvent component may vary, for example, other low-toxic nonpolar surfactants may be used in place of polysorbate 80; The fraction size of polyethylene glycol may vary; Other biologically suitable polymers may be used instead of polyethylene glycol, for example polyvinylpyrrolidone; Dextran can be replaced by other sugars or polysaccharides.
[371] On the other hand, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethylsulfoxide, may also be used, although at the expense of typically high toxicity. Additionally, the compound can be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent. A variety of cerium-emitting materials have been established and are well known to those skilled in the art. The sustained release dosage forms release the compound for several weeks to more than 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for stabilizing the protein may be used.
[372] The pharmaceutical compositions may also comprise suitable solid or gel carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
[373] Many of the compounds of the present invention may be provided as salts with pharmaceutically suitable counterions. Pharmaceutically acceptable salts may be formed with a number of acids including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protonic solvents than in the corresponding free base form.
[374] Effective dose
[375] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredient is contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount refers to an amount effective to prevent the occurrence of symptoms that appear in the subject being treated or alleviate the symptoms. Determination of the effective amount is well within the capability of those skilled in the art.
[376] For all compounds used in the methods of the invention, a therapeutically effective amount can be initially assessed from cellular assays. For example, to achieve a circulating concentration range comprising IC ₅₀ (i.e., the concentration of a test compound to inhibit a given protein kinase activity) as determined in cellular assays, an effective amount in cellular and animal models Can be standardized. In some cases it is appropriate to determine the IC ₅₀ in the presence of 3 to 5% serum albumin because these crystals are close to the binding effect of the plasma protein on the compound. This information can be used to more accurately determine the capacity available to a person. In addition, the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in native cells to a level that can be safely achieved in plasma.
[377] A therapeutically effective amount refers to that amount of a compound that results in symptomatic relief in a patient. Toxicity and therapeutic efficacy of such compounds is determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animals to determine the maximum tolerated dose (MTD) and the ED ₅₀ (the amount effective for the 50% maximal response) . The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio between MTD and ED ₅₀ . Compounds that exhibit a high therapeutic index are preferred. These cell culture assays and data obtained from animal studies can be used to standardize the dosage range for use in humans. The dosage of such compounds is preferably within the range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the mode of administration utilized. The exact formulation, route of administration and dosage can be chosen by the clinician depending on the condition of the patient (Fingl et al., 1975, " The Pharmacological Basis of Therapeutics ", Ch. 1 p1]. In seizure therapy, administration of an acute infant or infusion approaching the MTD may be required to obtain a rapid response.
[378] The dosage and administration interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain a kinase modulating effect or minimum effective concentration (MEC). The MEC will vary for each compound, but can be assessed from in vitro data, e.g., the concentrations needed to achieve 50-90% inhibition of protein kinase using assays described herein. The dosage required to achieve the MEC will depend on the characteristics of the individual and the route of administration. However, plasma concentrations can be determined using HPLC assays or bioassays.
[379] The dosing interval can also be determined using the MEC value. The compound should be administered using a regimen that maintains a plasma level 10 to 90%, preferably 30 to 90%, most preferably 50 to 90% higher than the MEC until the desired symptom relief is achieved. In case of topical administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration.
[380] The amount of the administered composition will, of course, depend on the subject being treated, the weight of the subject, the severity of the subject, the manner of administration and the judgment of the person in charge.
[381] Packaging
[382] The composition may optionally be presented as a pack or disposable device, which may contain one or more unit dosage forms containing the active ingredient. Such packs may include metal or plastic foils, such as, for example, blister packs. The pack or disposable device has instructions for administration. A composition comprising a compound of the invention formulated in a suitable pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for the indicated disease treatment.
[383] In some formulations, it may be advantageous to use the compounds of this invention in the form of finely divided microparticles, for example as obtained by fluid energy milling.
[384] The use of the compounds of the invention in the preparation of pharmaceutical compositions is illustrated below. In the following description, the term " active compound " means all compounds of the present invention, especially all compounds which are the final products of one of the foregoing examples.
[385] (a) Capsules
[386] In the preparation of the capsule preparation, 10 parts by weight of the active compound and 240 parts by weight of lactose can be deagglomerated and then blended. The mixture may be filled into a hard gelatin capsule and each capsule contains a unit dose of the active compound or a portion of the unit dose.
[387] (b) Purification
[388] Tablets may be prepared from the following ingredients:
[389] Weight portion
[390] The active compound 10
[391] Rock Toes 190
[392] Corn starch 22
[393] Polyvinylpyrrolidone 10
[394] Magnesium stearate 3
[395] The active compound, lactose and some starches may be deagglomerated and blended, and the resulting mixture may then be granulated with a solution of polyvinylpyrrolidone in ethanol. The anhydrous microparticles can be blended with magnesium stearate and the remaining starch. The mixture is then compressed in a tabletting machine to obtain tablets each containing a unit dose of the active compound or a portion of the unit dose.
[396] (c) sheet-coated tablets
[397] Tablets can be prepared by the method described in (b) above. The tablets can be over-coated in a conventional manner using 20% cellulose acetate phthalate and 3% diethyl phthalate solution in ethanol: dichloromethane (1: 1).
[398] (d) Suppositories
[399] In the preparation of suppositories, 100 parts by weight of the active compound are incorporated into 1300 parts by weight of the substrate for triglyceride suppositories, and the mixture is each molded into a suppository containing a therapeutically effective amount of the active ingredient.
[400] In the compositions of the present invention, the active compound may optionally be associated with other pharmacologically active ingredients. For example, the compounds of the present invention may be used to inhibit or prevent the production of VEGF or angiopoietin, to weaken the intracellular response to VEGF or angiopoietin, to block intracellular signal transduction, May be administered with one or more additional pharmaceutical agents that inhibit hyperpermeability, reduce inflammation, or inhibit or prevent edema formation or neovascularization. The compounds of the present invention may be administered prior to, after, or simultaneously with the administration of the additional pharmaceutical agent, if the administration is appropriate. Additional pharmaceutical preparations include, but are not limited to, anti-edema steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL-1 agents, antihistamines, PAF-antagonists, COX- Akt / PTB inhibitors, IGF-1R inhibitors, PKC inhibitors and PI3 kinase inhibitors. The compounds of the present invention and additional pharmaceutical agents act additionally or synergistically. Accordingly, it has been found that administration of a combination of substances that inhibit angiogenesis, vascular hyperpermeability, and / or edema formation inhibits hyperproliferative disorder, angiogenesis, hypervascularity or edema Can be significantly reduced. In the treatment of malignant diseases, it may be administered in combination with antiproliferative or cytotoxic chemotherapy or radiation.
[401] The invention also encompasses the use of a compound of formula (I) as a medicament.
[402] A further aspect of the present invention relates to the use of a compound of formula (I) or a salt thereof, for the manufacture of a medicament for the treatment of hypervascular, angiogenesis-dependent, proliferative and / or immune system disorders in a mammal, Lt; / RTI >
[403] The present invention also relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of vascular hyperpermeability, inappropriate neovascularization, proliferative disease and / or immune system disorders, including the administration of a therapeutically effective amount of a compound of formula Provides a method of treatment.
[404] The in vitro potency of the compounds in inhibiting these protein kinases can be determined by the procedures detailed below.
[405] The efficacy of the compounds can be determined by the amount of phosphorylation inhibition of the exogenous substrate by the test compound (e.g., synthetic peptides (Z. Songyang et al., Nature, 373: 536-539) compared to the control.
[406] Generation of KDR tyrosine kinase using Baculovirus system:
[407] Through PCR using cDNA isolated from HUVEC cells, the coding sequence for human KDR intracellular domain (aa 789-1354) is generated. The poly-His6 sequence is also introduced at the N-terminus of the protein. This fragment is cloned into the transfection vector pVL1393 at the Xba1 and Not1 sites. Recombinant baculovirus (BV) is produced through co-transfection with baculo gold transfection reagent (PharMingen). Recombinant BV is plaque purified and confirmed by Western analysis. For protein production, SF-9 cells are grown at 2 x 106 / ml in SF-900-II medium and infected with 0.5 plaque forming units (MOI) per cell. Cells are harvested 48 hours after infection.
[408] Purification of KDR
[409] (20mM Tris, pH 8.0, 137mM NaCl, 10% glycerol, 1% Triton X-100, 1mM PMSF, pH 7.4) expressing (His) ₆ KDR (aa 789-1354) 10 μg / ml aprotinin, 1 μg / ml leupeptin) is added to cell pellets from 1 L of cell culture. The lysate is centrifuged at 19,000 rpm in a Sorval SS-34 rotator at 4 ° C for 30 minutes. The cell lysate is applied to a 5 ml NiCl ₂ chelating sepharose column and equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. The same buffer containing 0.25 M imidazole is used to elute the KDR. ELISA assays measuring kinase activity (below) and SDS-PAGE are used to analyze the column fractions. Purified KDR is exchanged with 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at -80 ° C.
[410] Generation and purification of human Tie-2 kinase
[411] Through PCR using cDNA isolated from the human placenta as a template, the coding sequence for the region within human Tie-2 cells (aa 775-1124) is generated. The poly-His ₆ sequence is introduced at the N-terminus and this construct is cloned into the transfection vector pVL 1939 at the Xba1 and Not1 sites. Recombinant BV is produced through co-transfection with baculo gold transfection reagent (PharMingen). Recombinant BV is plaque purified and confirmed by Western analysis. For protein production, SF-9 insect cells are grown at 2 x 106 / ml in SF-900-II medium and infected at MOI of 0.5. Purification of the His-tagged kinase used for screening is similar to that described for KDR.
[412] Production and purification of human Flt-1 tyrosine kinase
[413] The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles, CA) is used. The nucleotide sequence encoding poly-His6 is placed at the 5 'position to the nucleotide region encoding the complete intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding this kinase region is generated by PCR using a cDNA library isolated from HUVEC cells. The histidine residue allowed the affinity purification of the protein in a manner similar to that for KDR and ZAP70. SF-9 insect cells are infected with 0.5 duplicates and collected 48 hours after infection.
[414] EGFR tyrosine kinase source
[415] EGFR was purchased from Sigma (Cat # E-3641; 500 units / 50 μl) and the EGF ligand was obtained from Oncogene Research Rroducts / Calbiochem (Cat # PF011-100).
[416] Expression of ZAP70
[417] The baculoviral expression vector used is pVL1393 (Phar Mingen, Los Angeles, CA). The nucleotide encoding the amino acid M (H) 6 LVPR ₉ S is placed at the 5 'position to the region encoding the complete sequence of ZAP70 (amino acids 1-619). Through PCR using a cDNA library isolated from Jurkat immortalized T-cells, a nucleotide sequence encoding the ZAP70 coding region is generated. Histidine residues allowed the affinity purification of the protein (see below). The LVPR ₉ S bridge constitutes the recognition sequence for proteolytic cleavage by thrombin, which can remove the affinity tag from the enzyme. SF-9 insect cells are infected with an infected duplicate of 0.5 and collected 48 hours after infection.
[418] Extraction and purification of ZAP70
[419] SF-9 cells were cultured in RPMI-1640 containing 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg / ml leupeptin, 10 μg / ml aprotinin and 1 mM sodium orthovanadate Dissolve in buffer. This soluble lysate is applied to a chelating Sepharose HiTrap column (Pharmacia) and equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. The fusion protein is eluted with 250 mM imidazole. The enzyme is stored in a buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.
[420] Protein kinase source
[421] Lck, Fyn, Src, Blk, Csk and Lyn, and their truncated forms are commercially available or commercially available from Upstate Biotechnology (Saranac Lake, NY) and Santa Cruz Biotechnology Inc. Lt; RTI ID = 0.0 > recombinant < / RTI >
[422] Enzyme Linked Immunosorbent Assay for PTK (ELISA)
[423] An enzyme-linked immunosorbent assay (ELISA) is used to detect and measure the presence of tyrosine kinase activity. See, for example, Voller et al., 1980, Enzyme-Linked Immunosorbent Assay, In: Manual of Clinical Immunology, 2d ed., By Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.).
[424] The protocol described is adapted to determine activity against a specific PTK. For example, a preferred protocol for performing ELISA experiments is provided below. It is well within the capability of those skilled in the art to adapt these protocols to determine the activity of the compounds on non-receptor tyrosine kinases as well as other members of the receptor PTK family. To determine inhibitor selectivity, a universal PTK substrate (eg, a random copolymer of poly (Glu ₄ Tyr), 20,000-50,000 MW) was incubated with ATP (typically 5 μM) at approximately double the Km in the assay, .
[425] For the activity of KDR, Flt-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, Blk, Csk, Src, Lyn, Fyn and ZAP70 tyrosine kinase activity The inhibitory effect of the compounds of the invention is assayed:
[426] Buffer and solution:
[427] PGT poly (Glu, Tyr) 4: 1
[428] The powder is stored at -20 < 0 > C. The powder is dissolved in phosphate buffered saline (PBS) for 50 mg / ml solution. Store 1 ml aliquots at -20 캜. When making the plate, dilute to 250 μg / ml in Gibco PBS.
[429] Reaction buffer: 100 mM Hepes, 20 mM MgCl ₂ , 4 mM MnCl ₂ , 5 mM DTT, 0.02% BSA, 200 μM NaVO ₄ , pH 7.10
[430] ATP: 100 mM aliquots are stored at -20 < 0 > C. Dilute to 20 uM in water.
[431] Washing buffer: PBS containing 0.1% Tween 20.
[432] Antibody Dilution Buffer: 0.1% bovine serum albumin (BSA) in PBS.
[433] TMB substrate: Mix TMB substrate and peroxide solution immediately before use (9: 1) or use K-Blue substrate (Neogen).
[434] Stop solution: 1M phosphoric acid.
[435] process
[436] 1. Plate manufacturing:
[437] PGT stock in PBS (50 mg / ml, frozen) is diluted to 250 μg / ml. 125 [mu] l of a high affinity ELISA plate (Corning # 25805-96) with a Corning deformed flat bottom per well is added. 125 [mu] l PBS is added to the blank wells. Cover with a sealing tape and incubate overnight at 37 ° C. Washed once with 250 세척 wash buffer, and dried in a 37 캜 drying oven for about 2 hours. Store the applied plate in a closed bag at 4 ° C until use.
[438] 2. Tyrosine kinase reaction:
[439] - Prepare the inhibitor solution at 4x concentration in 20% DMSO in water.
[440] - Reaction buffer is prepared.
[441] - prepare an enzyme solution such that the desired unit is within 50 μl, for example, for KDR, 1 ng / μl for a total of 50 ng per well in the reaction. Store on ice.
[442] A 4x ATP solution is made to be 20 μM from 100 mM stock in water. Store on ice.
[443] 50 μl of the enzyme solution per well (typically 5 to 50 ng enzyme / well depending on the specific activity of the kinase) is added.
[444] Add 25 μl of 4x inhibitor.
[445] - 25 μl 4x ATP is added for inhibitor assay.
[446] - Incubate at room temperature for 10 min.
[447] The reaction is stopped by adding 50 [mu] l 0.05N HCl per well.
[448] - Wash the plate.
[449] ** Final concentration for reaction: 5 [mu] M ATP, 5% DMSO
[450] 3. Antibody binding
[451] A 1 mg / ml aliquot of PY20-HRP (Pierce) antibody (phosphotyrosine antibody) is diluted to a concentration of 50 ng / ml in 0.1% BSA in PBS with two-step dilution (100x followed by 200x).
[452] Add 100 μl Ab per well. Incubate at room temperature for 1 hour. Incubate at 4 ° C for 1 hour.
[453] - Wash the 4x plate.
[454] 4. Color reaction
[455] - Prepare TMB substrate and add 100 μl per well.
[456] - The OD is monitored at 650 nm until 0.6 is reached.
[457] - Stop using 1M phosphoric acid. Shake on plate reader.
[458] Read the OD immediately at 450 nm.
[459] Optimal incubation times and enzyme reaction conditions vary slightly depending on the enzyme preparation and are determined experimentally for each lot.
[460] For Lck, the Reaction Buffer for use is a black under similar conditions 100mM MOPSO, pH 6.5, 4mM MnCl 2, 20mM MgCl 2, 5mM DTT, 0.2% BSA, 20mM NaVO4.
[461] The compounds of formula (I) have therapeutic utility in the treatment of diseases which have been identified, including those not mentioned herein, and diseases associated with both protein tyrosine kinases which have not yet been identified which are inhibited by the compounds of formula (I) You can have it. All compounds exemplified herein significantly inhibit FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, Blk, Lyn or Src at concentrations below 50 micromolar. Some compounds of the invention also significantly inhibit other tyrosine or serine / threonine kinases such as cdc2 (cdk1) at a concentration of 50 micromolar or less.
[462] Cdc2 source
[463] Human recombinase and assay buffers are either commercially available or can be purified from known natural or recombinant sources using conventional methods [New England Biolabs, Beverly, Mass., USA].
[464] Cdc2 black
[465] The protocol used is a slight modification to the purchased reagent. Briefly, 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM NaCl supplemented with fresh 300 μM ATP (31 μCi / The reaction is carried out in a buffer (commercial buffer) consisting of MgCl ₂ . A reaction volume of 80 [mu] l containing the enzyme units is run at 25 [deg.] C for 20 minutes in the presence or absence of inhibitor. The reaction is terminated by adding 120 쨉 l of 10% acetic acid. The substrate is separated from the unincorporated label by spotting the mixture onto the phosphocellulose paper and then washed three times for 5 minutes each with 75 mM phosphoric acid. Lt; / RTI > in the presence of a liquid scintillator.
[466] Certain compounds of the invention significantly inhibit cdc2 at concentrations of 50 μM or less.
[467] PKC kinase source
[468] Catalytic subunit PKC is commercially available (Calbiochem).
[469] PKC kinase assay
[470] Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3: 166, 1220-1227 (1990) ] Using radioactive kinase assays. Briefly, all reactions are performed in kinase buffer consisting of 50 mM Tris-HCl pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³ P ATP (8 Ci / mM) . The compound and the enzyme are mixed in a reaction vessel, and the reaction is started by adding the substrate mixture with ATP. After the reaction is terminated by adding 10 μl stop buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture is spotted onto a phosphocellulose filter. The thus spotted sample is washed 3 times in 75 mM phosphoric acid for 5 to 15 minutes at room temperature. Liquid scintillation counting to quantify incorporation of radiolabel.
[471] Erk2 enzyme source
[472] Recombinant murine enzymes and assay buffers are commercially available or can be purified from known natural or recombinant sources using conventional methods [New England Biolabs, Beverly, Mass., USA].
[473] Erk2 enzyme assay
[474] Briefly, under conditions recommended by the manufacturer, 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM NaCl supplemented with fresh 100 μM ATP (31 μCi / ml) and 30 μM myelin basic protein The reaction is carried out in a buffer (commercial buffer) consisting of MgCl ₂ . The reaction volume and incorporated radioactivity assays are as described for PKC assays (see above).
[475] In vitro model for T-cell activation
[476] Upon activation by cleavage promoting factors and antigens, T-cells are induced and IL-2, a growth factor that supports their subsequent proliferation phase, is secreted. Thus, IL-2 production from these T-cell lines as well as proliferation of these cells as a surrogate for primary T-cell or T-cell activation can be measured. All of these assays are well described in the literature and their parameters are well known (Current Protocol, Immunology, Vol 2, 7.10.1-7.11.2).
[477] Briefly, T-cells can be activated by incubation with allogeneic stimulator cells, a process termed a one-way mixed lymphocyte reaction. Reaction factors and stimulants. Peripheral blood mononuclear cells are purified by Ficoll-HiPark gradient (Pharmacia) according to the manufacturer's instructions. By mitomycin C (Sigma) or irradiating with gamma radiation, the stimulator cell is mitotically inactivated. Reaction factors and stimulator cells are co-cultured in a 2: 1 ratio in the presence or absence of test compounds. Typically, 10 ⁵ response factors are mixed with 5 x 10 ⁴ stimulants and plated onto U-shaped bottom microtiter plates (Costar Scientific) (200 μl volume). The cells are cultured in RPMI 1640 supplemented with heat-inactivated fetal calf serum (Hyclone Laboratories) or human AB serum collected from a male donor, 5 x 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO. One day prior to collection (typically 3 days), the cultures are pulsed with 0.5 μCi of ³ H thymidine (Amersham). Cultures are collected (Betaplate collector, Wallac) and isotope uptake is assessed by liquid scintillation (Betaplate, Wallac).
[478] The same culture system can be used to assess T-cell activation by measuring IL-2 production. After 18-24 hours of incubation, the supernatant is removed and the IL-2 concentration is measured by ELISA (R and D system) according to the manufacturer's instructions.
[479] In vivo model of T-cell activation
[480] The in vivo efficacy of the compounds can be tested in animal models that are known to directly measure T-cell activation or have been proven to be T-cells as effectors. T-cells can be activated in vivo by linking the constant portion of the T-cell receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB / c mice are intraperitoneally administered 10 [micro] g of anti-CD3 Ab 2 hours prior to salvage. The animals to which the test drug is administered are pretreated with a single dose of the compound 1 hour prior to administration of the anti-CD3 Ab. Serum levels of pro-inflammatory cytokine interferon-gamma (IFN-y) and tumor necrosis factor-alpha (TNF-a), indicators of T-cell activation, are measured by ELISA. A similar model uses a second in vitro challenge to in-vivo T-cell priming with a specific antigen such as keyhole limpet hemocyanin (KLH) and then draining the lymph node cells to the same antigen. As before, cytokine production measurements are used to assess the activated state of the cultured cells. Briefly, C57BL / 6 mice were immunized subcutaneously with 100 μg KLH emulsified in complete Freund's adjuvant (CFA) at day 0. The animals are pre-treated with the compound one day prior to immunization and then again pre-treated one day, two days and three days after immunization. The drained lymph nodes were collected on day 4 and their cells were cultured in tissue culture medium (RPMI 1640 supplemented with heat-inactivated fetal calf serum (Hyclone Laboratories), 5 x 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO) Lt; ⁶ > / ml for 24 hours and 48 hours. Subsequently, the level of autocrine T-cell growth factor interleukin-2 (IL-2) and / or IFN-y is assessed by ELISA in culture supernatants.
[481] Lead compounds may also be tested in animal models of human disease. These are exemplified by experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). An EAE model that mimics the human multiple sclerosis pattern has been described in both rats and mice (FASEB J. 5: 2560-2566, 1991; Rat Model: Lab. Invest. 4 (3): 278,1981; Rodent models: J. Immunol 146 (4): 1163-8, 1991). Briefly, mice or rats are immunized with myelin basic protein (MBP) or its neuropeptide derivative and an emulsion of CFA. Bacterial toxins such as bordetella pertussis may be added to induce acute disease. Diseases with recurrent / progressive pathways are induced by proton-mediated transfer of T-cells from MBP / peptide-immunized animals.
[482] CIA can be induced in DBA / 1 mice by immunizing with type II collagen (J. Immunol: 142 (7): 2237-2243]. Mice will initially exhibit arthritic symptoms as early as 10 days after antigen challenge, and may be recorded for as long as 90 days after immunization. In both EAE and CIA models, compounds may be administered prophylactically or at the time of onset. Effective drugs should decrease the severity and / or incidence.
[483] Certain compounds of the invention that inhibit protein kinases such as one or more angiogenic receptor PTKs and / or lck associated with mediating inflammatory responses may reduce the severity and incidence of arthritis in these models.
[484] The compounds were also tested in a mouse allogeneic transplantation model, skin (see Ann. Rev. Immunol., 10: 333-58, 1992; Transplantation: 57 (12): 1701-17D6, 1994] or heart (see Am. J. Anat: 113: 273, 1963). Briefly, thick skin implants are transplanted from C57BL / 6 mice to BALB / c mice. To check for rejection, the implants are examined daily starting on day 6. In a mouse neonatal heart transplant model, neonatal heart is transplanted externally to C57BL / 6 mouse ear-buds of CBA / J mice grown up. From 4 to 7 days after transplantation, the heart begins to beat, and the rejection can be assessed visually using a dissecting microscope to detect beating.
[485] Cellular receptor PTK assay
[486] The following cellular assays are used to determine the level of activity and effectiveness of the different compounds of the invention for KDR / VEGFR2. A similar receptor PTK assay using specific ligand stimulation can be designed along the same note for other tyrosine kinases using techniques well known in the art.
[487] VEGF-induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC), as measured by Western blot:
[488] 1. HUVEC cells (from the donor collected) are purchased from Clonetics (San Diego, Calif.) And cultured according to the manufacturer's instructions. For this test, only the initial vaccination (3-8) is used. Cells are cultured in 100 mm dishes (Falcon for Tissue Culture; Becton Dickinson; Plymouth, England) using complete EBM medium (Clonetics).
[489] 2. In order to evaluate the inhibitory activity of the compounds, the cells were trypsinized, 6-well cluster plates; and seeding of 0.5 to 1.0 x 10 ⁵ cells / well in each well of (Costar Cambridge, MA).
[490] 3. After 3 to 4 days of seeding, the plates are 90 to 100% densely packed. The medium is removed from all the wells, the cells are washed with 5 to 10 ml of PBS and incubated for 18 to 24 hours with 5 ml of EBM-based medium (i.e., serum deficiency) supplemented with no supplementation.
[491] 4. Add a series of dilutions of the inhibitor to 1 ml of EMB medium (final concentration 25 μM, 5 μM or 1 μM for cells) and incubate at 37 ° C for 1 hour. Human recombinant VEGF ₁₆₅ (R & D system) is then added to all of the wells in 2 ml of EBM medium at a final concentration of 50 ng / ml and incubated at 37 [deg.] C for 10 minutes. Control cells that are not treated or treated with VEGF alone are used to assess background phosphorylation and induction of phosphorylation by VEGF.
[492] All wells were then washed with 5 to 10 ml of cold PBS containing 1 mM sodium orthovanadate (Sigma), and the cells were lysed and incubated with protease inhibitor (PMSF 1 mM, aprotinin 1 ug / ml, pepstatin 1 ug / mL of RIPA buffer [50 mM (1 mM) containing 1 mu g / ml of Dnase (all chemicals from Sigma Chemical Company, St Louis, MO), 1 mu g / ml of leupeptin, 1 mM Na vanadate, 1 mM Na fluoride) Tris-HCl, pH 7, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA]. The lysate is spun at 14,000 rpm for 30 minutes to remove nuclei.
[493] Equal amounts of protein are precipitated by adding cold (-20 < 0 > C) ethanol (2 volumes) for at least 1 hour or up to overnight. Reconstitute the pellet in a Laemli sample buffer (BioRad; Hercules, Calif.) Containing 5% mercaptoethanol and boil for 5 minutes. The protein is digested by polyacrylamide electrophoresis (6%, 1.5 min. Novex, San Diego, Calif.) And transferred onto a nitrocellulose membrane using the Novex system. KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, Calif.) Or anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) overnight. Washed and then incubated for 1 hour with HRP-conjugated F (ab) ₂ of goat anti-rabbit or gut-anti-mouse IgG and then incubated in a radiochemiluminescent (ECL) system (Amersham Life Sciences, Arlington Height, IL) to visualize the band. Certain compounds of the invention significantly inhibit cellular VEGF-induced KDR tyrosine kinase phosphorylation at a concentration of less than 50 μM.
[494] In vivo model of uterine edema
[495] This assay measures the ability of a compound to inhibit the rapid increase in uterine weight in mice that occurs within the first few hours after estrogen stimulation. This initial increase in uterine weight is known to be due to edema induced by increased permeability of the uterine vasculature. It has been suggested that there is a temporal close correlation between estrogen-stimulated uterine edema and increased expression of VEGF mRNA in the uterus in Cullinan-Bove and Koss, Endocrinology (1993), 133: 829-837. These results have been confirmed by using neutralizing monoclonal antibodies against VEGF, which significantly reduce the rapid uterine weight gain associated with estrogen stimulation (WO 97/42187). Thus, the system may serve as a model for in vivo suppression of VEGF signaling and its associated hyperpermeability and edema.
[496] material:
[497] All hormones are purchased as lyophilized powders from Sigma (St. Louis, Mo.) or Cal Biochem (La Jolla, Calif.) And are prepared according to the manufacturer's instructions.
[498] The vehicle component (DMSO, Cremaphor EL) is purchased from Sigma (St. Louis, Mo.).
[499] Mice (Balb / c, 8-12 weeks old) are purchased from Taconic (Germantown, NY) and raised in an animal-free animal facility with no pathogen in accordance with the guidelines of the Public Animal Care and Use Association.
[500] Way:
[501] Day 1: Balb / c mice are intraperitoneally injected with 12.5 units of serum or gonadotropin (PMSG) of pregnant mare.
[502] 3 days: 15 units of human chorionic gonadotropin (hCG) are intraperitoneally administered to mice.
[503] Day 4: The mice are randomly divided into 5 to 10 groups. Depending on solubility and vehicle, the test compound is administered intraperitoneally, intravenously or orally in a dose ranging from 1 to 100 mg / kg. The vehicle control group is administered vehicle only and both groups are left untreated.
[504] After 30 minutes, intraperitoneal injection of 17-estradiol (500 [mu] g / kg) is given to one of the experimental vehicle and the untreated group. After 2 to 3 hours, the animals are sacrificed by inhalation of CO ₂ . After midline incision, each uterus is separated by removing it at the junction of the uterus and the fallopian tubes just below the cervix. Carefully remove fats and connective tissue to prevent destruction of the uterine protoplasm prior to weighing (wet weight). The uterus is blotted to remove fluid by pressurizing between two sheets of filter paper with a 1 liter glass bottle filled with water. After blotting, the uterus is weighed (blotted weight). The difference between the wet weight and the blotted weight is taken as the uterine fluid content. The average fluid content of the treated group is compared to the untreated or vehicle treated group. The significance is determined by the Student's t test. The estradiol reaction is recorded using a non-stimulated control group.
[505] The results showed that certain compounds of the invention inhibit edema formation when administered systemically by various routes.
[506] Certain compounds of the invention that are inhibitors of angiogenic receptor tyrosine kinases may also exhibit activity in a Matrigel transplant model of renal vascularization. This matrigel neovascularization model involves forming new blood vessels in a clean " marble " of subcutaneously implanted extracellular matrix, induced by the presence of pro-angiogenic factors that produce tumor cells For example, Passaniti, A., et al, Lab. Investig. (1992), 67 (4), 519-528; Anat. Rec. (1997), 249 (1), 63-73; Int. J. Cancer (1995), 63 (5), 694-701; Vasc. Biol. (1995), 15 (11), 1857-6]. This model is preferably performed over 3 to 4 days and the end point is used to visualize / record the neovascularization, to crystallize microvessel density using a microscope, And quantifying hemoglobin after the control is removed (the Drakin's method). This model is another alternative, and can use bFGF or HGF as a stimulus.
[507] Certain compounds of the invention that inhibit one or more of the oncogenic, protooncogenic, or proliferative protein kinases, or angiogenic receptor PTKs, also inhibit the growth of primary mouse, rat or human xenograft tumor in a mouse, or It inhibits metastasis in mouse models.
[508] A method for preparing the compound of formula (I) will be described next. These methods form a further aspect of the present invention. The method is preferably carried out under atmospheric pressure.
[509] Compounds of formula (I) may be prepared by condensing a compound of formula (II) optionally in the presence of a catalyst, such as 4-dimethylaminopyridine, in a temperature range of 50-250 ° C with formamide:
[510]
[511] In this formula,
[512] R ₁ , R ₂ , R ₃ , L and ring A are as defined above.
[513] The compounds of formula (I) catalyst, for example palladium (O) compound with a compound of the formula (III) (for _{example: Pd (PPh 3) 4)} R 3 B (OH) in the presence the compound of _2, R ₃ Sn (CH _{3) 3,} or by reacting with one of the compounds of formula (IV) can be prepared:
[514]
[515]
[516] In this formula,
[517] R _x is bromo or iodo bromo or iodo,
[518] R ₃ is as defined above.
[519] R ₁ is an alkyl group or an aralkyl compound of the formula (I) represents alkilgieul is then "represents compound (wherein, R ₁ is an alkyl group or an aralkyl alkilgieul of, X 'of the compound of formula (V) formula R ₁ X is a leaving group, e. For example, halo, mesyloxy or tosyloxy.
[520]
[521] In this formula,
[522] R ₂ and R ₃ are as defined above.
[523] Compounds of formula (I) in which R ₁ represents an optionally substituted cyclic ether such as tetrahydrofuryl or tetrahydropyranyl may be prepared by reacting a compound of formula (VI) with a compound of formula R ₁ X ' X ' is as defined above, and R < ₁ > is an optionally substituted cyclic ether.
[524]
[525] In this formula,
[526] R ₂ and R ₃ are as defined above.
[527] Between the R ₁ a by a formyl, optionally substituted cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl the carbonyl compounds of formula (I) is a compound of Formula (VI) compound R ₁ X [wherein, R ₁ Is a cyclic ether which is protected by a method known to the person skilled in the art, for example via acetal (see Tet. Letts. 30 (46): 6259-6262 (1989)) followed by deprotected formyl groups Alkylation. ≪ / RTI > R ₁ is (optionally substituted amino), for between which is substituted by a methyl group cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl, a compound of formula (I) are cyclic with R ₁ is substituted by a formyl ether Can be prepared by reductive amination of a phosphorus compound.
[528] Compounds of formula (I) wherein R ₁ is an optionally substituted furyl, thienyl or pyrrolyl can be obtained by reacting 4-chloro-5-iodo-7H-pyrrolo [ In the presence of a copper salt catalyst, for example copper (II) acetate, in the presence of a solvent for the reaction, for example a halogenated solvent (e.g. dichloromethane) Can be prepared, for example, by reacting with a suitable heteroarylboric acid in the presence of an organic base, such as triethylamine or pyridine, in the presence of a 4A molecular sieve (Tet. Letts. (1998), 39: 2942-2944 and references therein; All of which are incorporated herein by reference). These compounds can be formulated by methods known to those skilled in the art to give compounds wherein R < ₁ > is a furyl, thienyl or pyrrolyl substituted formyl. The formyl group in these compounds can be productively aminated in a manner known to those skilled in the art to give compounds wherein R < ₁ > is a furyl, thienyl or pyrrolyl substituted by an aminomethyl group. Alternatively, the intermediate wherein R < _{1 >} is a furyl, thienyl or pyrrolyl can be Mannich reaction to give a furyl, thienyl or pyrrolyl intermediate wherein R < ₁ > is substituted by an aminomethyl group.
[529] The compounds of formula (I) can be prepared by reacting a compound of formula (VII) with ammonia or an ammonium salt, for example ammonium acetate, in a temperature range from 15 to 250 ° C, preferably in a pressure vessel:
[530]
[531] In this formula,
[532] R ₁ , R ₂ , R ₃ , L and ring A are as defined above,
[533] R _y is a leaving group, such as halo or phenoxy.
[534] Compounds of formula (I) wherein R ₂ is chloro, bromo or iodo can be prepared by reacting a compound of formula (VIII) with a halogenating agent such as an iodinating agent such as N-iodosuccinimide, For example, N-bromosuccinimide) or a chlorinating agent (e.g. N-chlorosuccinimide):
[535]
[536] In this formula,
[537] R ₁ , R ₃ , L and ring A are as defined above.
[538] Compounds of formula (I) wherein LR ₃ is -NHC (O) R _{3 can be prepared} by reacting a compound of formula (IX) with a compound of formula R ₃ COR _x wherein R _x is a leaving group, : ≪ RTI ID = 0.0 >
[539]
[540] In this formula,
[541] R ₁ , R ₂ and ring A are as defined above,
[542] Y is a protected amine.
[543] Alternatively, a compound of formula (IX) wherein Y is halo, for example chloro, is reacted with a compound of formula R ₃ COR _x and the product is reacted with ammonia to give a compound of formula (I) . Using a similar method, compounds of formula (I) wherein -LR ₃ is NRSO ₂ R ₃ can be prepared. Using a similar method, compounds of formula (I) wherein -LR ₃ is NRCO ₂ -R ₃ or -NRCONR ', wherein R and R' are as defined above, may be prepared.
[544] Compounds of formula (I) wherein LR ₃ is -OSO ₂ - can be prepared by reacting a compound of formula (X) with a compound of formula R ₄ SO ₂ R _x :
[545]
[546] In this formula,
[547] R ₁ , R ₂ and ring A are as defined above.
[548] The compound of formula (I) can then be prepared from the intermediate by performing an alternative to Scheme 2 or Scheme 2 described below.
[549] Compounds of formula (II) may be prepared as shown in Scheme 1, wherein IPA is propan-2-ol:
[550] Scheme 1
[551]
[552] Those skilled in the art will recognize that compounds of formula (I) may be converted to other compounds of formula (I) by known chemical reactions. For example, the alkoxy group can be cleaved to give hydroxy, the nitro group can be reduced to the amine, the amine can be acylated or sulfonylated, and the N-acyl compound can be hydrolyzed to give the amine. By the technique known in the art, may be by oxidizing the compound of formula (I), wherein -L- is S -L- to the give a compound of formula (I) wherein each of SO and SO _2.
[553] The compounds of formula (III) are commercially available or can be prepared by methods known to those skilled in the art.
[554] Compounds of formula (V) wherein R < ₂ > is hydrogen may be prepared as shown in scheme 2. [ The amino group can be protected by methods known to those skilled in the art before the final step of Scheme 2 and then deprotected after the final step. Compounds of formula (V) wherein R < ₂ > is other than hydrogen can be prepared in a similar manner (see J. Med. Chem. (1990), 33, 1984].
[555] Scheme 2
[556]
[557] On the other hand, in Scheme 2, (Ring A) -LR ₃ may be coupled prior to amination. Alternatively, substituent R < ₁ >, as defined above, may be presented prior to performing any one of the processes.
[558] Compounds of formula (VII) wherein R _y is -Cl can be prepared as shown in scheme 3:
[559] Scheme 3
[560]
[561] (Ring A) -LR < ₃ > is prepared according to Scheme 4 and in J. Med. Chem., (1988), 31: 390 and references cited therein). (Ring A) -LR ₃ is other than hydrogen can be prepared in a similar manner:
[562] Scheme 4
[563]
[564] Compounds of formula (VII) may be prepared by coupling 5-iodo compounds in a similar manner as described for the preparation of compounds of formula (V).
[565] R < ₁ > can be modified by the methods shown in Schemes 5 and 6. In schemes 5 and 6, P represents a protecting group:
[566] Scheme 5
[567]
[568] Scheme 6
[569]
[570] One of ordinary skill in the art will recognize that if a particular substituent is the same or similar to the functional group modified in one of the methods, then these substituents must be protected prior to the process and then deprotected after the process. If not, a competitive side reaction will occur. On the other hand, another method of the above-mentioned method, in which the substituent does not interfere, may be used. Examples of suitable protecting groups and methods for their addition and removal are set forth in " Protective Groups in Organic Synthesis " by T. W. Green, John Wiley and Sons, 1981. For example, a suitable protecting group for an amine is formyl or acetyl.
[571] The following synthetic examples are prepared using the abovementioned general preparation process:
[572] Example 1:
[573] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbazole Mate
[574] a) Tetrahydro-2H-4-pyranyltrifluoromethanesulfonate. Pyridine (1.7 ml, 20.97 mmol) is added to a solution of tetrahydro-2H-4-pyranol (2 ml, 20.97 mmol) in dichloromethane (16 ml). The flask was impregnated with 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 is filtered and the solid is washed with a minimum amount of dichloromethane. The combined filtrate is washed with water, 1.0 N HCl, water and brine. The organic layer is dried (MgSO ₄ ) and filtered. The solvent was evaporated to give tetrahydro-2H-4-pyranyltrifluoromethanesulfonate. _{^{1 H NMR (CDCl 3) δ1.99}} (m, 2H), 2.11 (m, 2H), 3.58 (m, 2H), 3.96 (m, 2H), 5.17 (m, 1H).
[575] b) 4-Chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidine. Pyrido [2,3-d] pyrimidine (3.0 g, 10.73 mmol) was added dropwise to a solution of sodium hydride (0.891 g, 1.46 mmol) in N, N-dimethylformamide 22.2 mmol) in tetrahydrofuran. After the addition is complete, the ice bath is removed and the resulting mixture is stirred for 30 minutes. Tetrahydro-2H-4-pyranyltrifluoromethanesulfonate is added dropwise, and the reaction mixture is stirred at room temperature for 24 hours. The mixture was poured into ice water (100 ml) and the solid was collected by filtration and then purified by recrystallization to give 4-chloro-5-iodo-7-tetrahydro-2H-4-pyranyl-7H- 3-d] pyrimidine. ≪ / RTI > _{^{1 H NMR (CDCl 3) δ2.06}} (m, 2H), 3.63 (m, 2H), 4.16 (m, 2H), 5.00 (m, 1H), 7.45 (s, 1H), 8.61 (s, 1H) . LC / MS (MH ^< ⁺ & gt ^; = 364).
[576] pyrrolo [2,3-d] pyrimidin-5-yl) -2-methyl-isobutyramide Methoxyphenyl) carbamate. Phenyl) carbamate (1, < RTI ID = 0.0 > 2-methoxy- 66 g, 4.75 mmol) is degassed by sonication under vacuum for 1 minute. Pyrrolo [2,3-d] pyrimidine (1.1 g, 3.17 mmol), tetrakis (triphenylphosphine) palladium Palladium (O) (0.22 g, 0.19 mmol), sodium carbonate (0.8 g, 7.60 mmol) and 1,2-dimethoxyethane (30 ml) are added to the aqueous mixture. The resulting suspension is degassed for 2 minutes and then heated to 85 [deg.] C for 24 hours. The reaction mixture is cooled to ambient temperature and the solvent is evaporated. The residue is dissolved in ethyl acetate. Then wash the organic layer dried (MgSO _4). The solid was purified by a flash column chromatography on silica using heptane / ethyl acetate (7: 3) as mobile phase to give tert-butyl N- (4- (4-chloro-7-tetrahydro- Pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. _{^{1 H NMR (CDCl 3) δ1.55}} (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, IH), 7.32 (s, IH), 8.13 (br.d, J = 8 Hz, IH), 8.64 (s, IH). LC / MS (MH ^< ⁺ & gt ^; = 459).
[577] d) 4- (4-Chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin- 5-yl) -2-methoxyaniline. A solution of 10% trifluoroacetic acid in dichloromethane (50 ml) was added to a solution of tert-butyl N- (4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H- 3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. After 20 minutes, the ice bath is removed and the resulting solution is stirred at ambient temperature for 4 hours. The solvent is removed and the residue is taken up in dichloromethane. Saturated sodium bicarbonate is added and the layers are separated. The aqueous layer is extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO _4), filtered then concentrated. The solid was purified by passing it through a silica gel pad using heptane / ethyl acetate (3: 2) as mobile phase to give 4- (4-chloro-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [ 2,3-d] pyrimidin-5-yl) -2-methoxyaniline. _{^{1 H NMR (CDCl 3) δ2.09}} (m, 4H), 2.51 (br.s, NH 2), 3.66 (m, 2H), 3.91 (s, 3H), 4.16 (m, 2H), 5.05 (m 2H), 6.93 (d, J = 8 Hz, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 8.63 (s, 1H). LC / MS (MH ^< ⁺ & gt ^; = 359).
[578] e) 5- (4-Amino-3-methoxyphenyl) -7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3-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- Yl) -2-methoxyaniline (0.73 g, 2.03 mmol) in DMF (5 mL). The pressure tube is sealed and heated to 122 占 폚 for 2 days. The tube is cooled to ambient temperature and the solvent is evaporated. Ethyl acetate, and wash the organic layer, dried (MgSO _4), was filtered and concentrated 5- (4-amino-3-methoxyphenyl) -7-tetrahydro-4-pyranyl -2H -7H -Pyrrolo [2,3-d] pyrimidin-4-amine. _{^{1 H NMR (DMSO-d 6}} ) δ1.87 (m, 2H), 2.11 (m, 2H), 3.52 (m, 2H), 3.79 (s, 3H), 3.39 (m, 2H), 4.87 (m, 3H), 6.02 (br.s, NH 2), 6.73 (d, J = 8Hz, 2H), 6.77 (d, J = 8Hz, 1H), 6.88 (s, 1H), 7.33 (s, 1H), 8.10 (s, 1 H). LC / MS (MH ^< ⁺ & gt ^; = 340).
[579] pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) -lH-pyrrolo [2,3- Carbamate. Benzyl chloroformate (16 l, 0.110 mmol) was added to a solution of 5- (4-amino-3-methoxyphenyl) -7-tetrahydro-benzoic acid in pyridine (0.7 ml) and dichloromethane (0.7 ml) 2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol). After 10 minutes, the ice bath is removed and the resulting mixture is 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 benzyl N- (4- (4-amino-7-tetrahydro-2H- Yl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. _{^{1 H NMR (CDCl 3) δ2.07}} (m, 4H), 3.65 (m, 2H), 3.9 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H), 5.23 (s, 2H) (S, 1H), 7.08 (d, J = 8 Hz, 1H), 7.42 1H). LC / MS (MH ^< ⁺ & gt ^; = 474).
[580] Example 2: Synthesis of neopentyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl) carbamate
[581] Neopentyl chloroformate (13 l, 0.110 mmol) was added to a solution of 5- (4-amino-3-methoxyphenyl) -7-tetrahydrobenzo [ -2H-4-pyranyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol). After 10 minutes, the ice bath is removed and the resulting mixture is 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- Pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) carbamate. _{^{1 H NMR (CDCl 3) δ1.00}} (s, 3H), 2.07 (m, 4H), 3.65 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.13 (m, 2H) , 7.07 (d, J = 8 Hz, 1H), 7.25 (s, 1H), 8.19 (br, J = 8 Hz, 1H), 8.33 (s, 1H). LC / MS (MH ^< ⁺ & gt ^; = 454).
[582] Example 3: Phenyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] carbamate
[583] Pyridin-7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.294 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve in dichloromethane (2 ml). Pyridine (2 ml) was added followed by phenyl chloroformate (44 [mu] l, 0.353 mmol). After stirring for 3 hours, 44 μl of phenylmethanesulfonyl chloride is further added, and the reaction mixture is 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 [ 5-yl) -2-methoxyphenyl] carbamate (52 mg, 0.113 mmol). _{1H NMR (CDCl 3 -d) δ2.09} (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 (m, 1H), 5.24 (s, 2H ), 7.09 (m, 3H), 7.23 (m, 4H), 7.41 (m, 2H), 7.62 (s, 1H), 8.20 (bd, J = 7.80Hz, 1H), 8.33 LC / MS (MH ^< ⁺ & gt ^; = 460).
[584] Example 4: Synthesis of tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro- -Yl) -2-methoxyphenyl] carbamate 4-Nitrophenyl tetrahydro-2H-4-pyranylcarnate
[585] Tetrahydro-2H-4-pyriol (1.0 ml, 10.5 mmol) is mixed with 4-methylmorpholine (2.0 ml) in dichloromethane (20 ml). 4-Nitrochloroformate (1.98 g, 9.82 mmol) is slowly added to the reaction mixture. After stirring for 5 hours, the reaction mixture is diluted with dichloromethane. The organic layer was washed with water, 1.0N HCl, saturated sodium bicarbonate, brine, dried over MgSO _4, then filtered and evaporated. The crude product was purified by flash column chromatography using ethyl acetate / heptane (4: 1) as mobile phase to give 4-nitrophenyl tetrahydro-2H-4-pyranylcarnate (1.5 g, 5.62 mmol) do. _{1H NMR (CDCl 3 -d) δ1.87} (m, 2H), 2.06 (m, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m, 1H), 7.40 (bd, J = 9.0 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H).
[586] a) Preparation of tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ) -2-methoxyphenyl] carbamate. Pyridin-7H-pyrrolo [2,3-d] pyrimidin-4-amine (57 mg, 0.168 mmol) and 5- 4-Nitrophenyl tetrahydro-2H-4-pyranylcarnate (90 mg, 0.336 mmol) was mixed in pyridine (1 ml). After stirring for 5 hours, further 90 mg of 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate is added and the reaction mixture is stirred for 2 days. The reaction mixture is heated at 70 < 0 > C for 2 hours. The solvent was removed and the residue was purified by thin layer chromatography to give tetrahydro-2H-4-pyranyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [ , 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.064 mmol). _{1H NMR (CDCl 3 -d) δ1.78} (m, 4H), 2.08 (m, 4H), 3.60 (m, 4H), 3.94 (s, 3H), 3,97 (m, 2H), 4.15 (m J = 8.3 Hz, 1H), 8.16 (bd, J = 8.3 Hz, 2H), 4.98 (s, 7.90 Hz, 1 H), 8.33 (s, 1 H). LC / MS (MH ^< ⁺ & gt ^; = 468).
[587] Example 5: 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 2-methoxyphenyl] carbamate hydrochloride
[588] a) 4-Nitrophenyl (3-pyridylmethyl) carbonate. 4-Nitrochloroformate (2.49 g, 12.3 mmol) in dichloromethane (20 ml) is cooled on an ice-water bath. 3-pyridylmethanol (1.0 ml, 10.3 mmol) and 4-methylmorpholine (2.0 ml, 18.5 mmol) were slowly added. After 20 minutes, the ice bath is removed and the reaction mixture is allowed to warm to room temperature. After 30 minutes, ethyl acetate is added and the reaction mixture is filtered. Sikimyeo the filtrate washed with water, saturated sodium bicarbonate, brine, dried over MgSO _4, filtered and evaporated to give a dark brown solid, which by this screen was recrystallized from ethyl acetate / heptane 4-nitrophenyl (3-pyridylmethyl) (1.52 g, 5.54 mmol). (M, 3H), 7.79 (m, 1H), 8.28 (d, J = 9.09 Hz, 2H), 8.65 (m, 1H), 8.72 (s, 1H).
[589] b) 3-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] carbamate. Pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 <0> 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- 7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol). _{1H NMR (CDCl 3 -d) δ2.08} (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H J = 8.2 Hz, 1H), 7.35 (m, 2H), 7.79 (d, J = 1H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (s, 1H), 8.71 (s, 1H). LC / MS (MH ^&lt; ⁺ & gt ^; = 475).
[590] pyrrolo [2,3-d] pyrimidin-5-yl) -2- (4-fluorophenyl) Methoxyphenyl] carbamate hydrochloride. Pyrrod [2,3-d] pyrimidin-5-yl) -2-methoxypyridin-7-ylmethyl] Phenyl] carbamate (12 mg, 0.025 mmol) is dissolved in ethyl acetate (2.0 ml). 1.0 N HCl in ether (1 ml) is slowly added. The precipitate was collected by filtration under nitrogen to give 3-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (13 mg, 0.25 mmol). _{1H NMR (CDCl 3 -d) δ1.91} (m, 2H), 2.17 (m, 2H), 3.54 (m, 2H), 3.87 (s, 3H), 4.03 (m, 2H), 4.97 (m, 1H ), 5.23 (s, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.51 , 7.95 (m, 1H), 8.42 (s, 1H), 8.60 (s, 1H), 8.71 (s, 1H), 8.82 (s, 1H). LC / MS (MH ^&lt; ⁺ & gt ^; = 475).
[591] Example 6: 2-Morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] carbamate hydrochloride &lt; RTI ID = 0.0 &gt;
[592] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (25 mg, 0.054 mmol) is mixed with 2-morpholino-1-ethanol (0.1 ml) in pyridine (0.7 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reversed phase HPLC to give 2-morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (24 mg, 0.048 mmol). The solid is dissolved in ethyl acetate (2 ml) and 1.0N HCl in ether (0.2 ml) is slowly added. The precipitate was collected by filtration under nitrogen to give 2- morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- Yl) -2-methoxyphenyl] carbamate hydrochloride (24 mg, 0.045 mmol). _{1H NMR (DMSO-d 6)} δ1.88 (m, 2H), 2.16 (m, 2H), 3.55 (m, 8H), 3.90 (s, 3H), 4.03 (m, 4H), 4.49 (m, 2H 1H), 7.75 (s, 1H), 7.75 (s, 1H), 7.92 (s, , 10.95 (bs, 1 H). LC / MS (MH ^&lt; ⁺ & gt ^; = 497).
[593] Example 7: (4-Bromo-1, 3-thiazol-5-yl) methyl N- [4- (4-amino- , 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate
[594] a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde. (3.52 g, 30 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed with dimethylformamide (2.56 ml, 34 mmol). The mixture is then heated at 75 DEG C for 1 hour and then at 100 DEG C for 5 hours. After cooling to room temperature, the mixture is added to ice water (500 ml) and the aqueous layer is extracted with dichloromethane. Sikimyeo combined organic layers were washed with a saturated aqueous sodium bicarbonate, dried over MgSO _4, was filtered and evaporated to give a brown solid, which is washed with petroleum ether. Evaporated to give 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). _{1H NMR (CDCl 3 -d) δ9.90} (S, 1H),
[595] b) (2,4-dibromo-1, 3-thiazol-5-yl) methanol. 2,4-Dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol) is dissolved in methanol (70 ml) at 0 ° C. Sodium borohydride (0.244 g, 6.42 mmol) is added portionwise. After 10 minutes, the ice bath is removed and the reaction mixture is stirred overnight at room temperature. The solvent is removed and saturated ammonium chloride is added. Adjust the pH to 10 by adding 1.0 N NaOH. The aqueous layer is extracted with ethyl acetate. Sikimyeo combined organic layers were washed with brine, dried over MgSO _4, then filtered and evaporated. The residue was purified by flash column chromatography to give (2,4-dibromo-1,3-thiazol-5-yl) methanol (0.946 g, 3.47 mmol). 1 H NMR (CDCl ₃ -d) 2.22 (bs, 1 H), 4.79 (S, 2H).
[596] c) (4-Bromo-1, 3-thiazol-5-yl) methanol. (0.946 g, 3.47 mmol), sodium carbonate trihydrate (1.34 g) and palladium on carbon (10%, 0.07 g) were dissolved in methanol (1, 33 ml). The resulting mixture is hydrogenated at 60 psi for 2 days. The solid is filtered off through a Celite pad. The solvent was evaporated and the residue was purified by flash column chromatography to give (4-bromo-1, 3-thiazol-5-yl) methanol (0.32 g, 2.78 mmol). _{1H NMR (CDCl 3 -d) δ2.29} (bs, 1H), δ4.86 (s, 2H), 8.72 (s, 1H).
[597] methyl-N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3 d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate. Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (28 mg, 0.061 mmol) is mixed with (4-bromo-1, 3-thiazol-5-yl) methanol (50 mg, 0.434 mmol) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; 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- Pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate. 1H NMR (CDCl3): 2.07 (m, 4H), 3.65 (m, 2H), 3.92 1H), 7.31 (s, 1H), 7.40 (s, 1H), 7.40 (s, 8.78 (s, 1 H). LC / MS MH ^&lt; ^{+ &} gt ^; = 481.
[598] Example 8: Synthesis of tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ) -2-methoxyphenyl] carbamate
[599] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with tetrahydro-3-furanol (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase HPLC to give tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [ 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (14 mg, 0.031 mmol). 2H), 4.96 (m, IH), 5.26 (s, 2H), 3.96 (m, 2H) 1H), 5.40 (s, IH), 7.04 (s, IH), 7.08 (d, J = 8.2 Hz, s, 1H). LC / MS MH ^&lt; ^{+ &} gt ^; = 455.
[600] Examples 9 and 10: Synthesis of 1,3-dioxin-5-yl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- 5-yl) -2-methoxyphenyl] carbamate
[601] 7H-pyrrolo [2,3-d] pyrimidin-5-yl) - lH-pyrrolo [2,3- ) -2-methoxyphenyl] carbamate
[602] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with glycerol formal (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase HPLC to give tetrahydro-3-furanyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [ (M, 4H), 3.66 (m, 2H), 3.70 (m, 2H) J = 6.3 Hz, 1H), 3.92 (m, 3H), 4.07 (m, 6H), 4.79 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 6.15 (s, 1H), 7.05 (m, 2H). LC / MS MH ^&lt; ^{+ &} gt ^; = 471] and 1,3-dioxan-4-ylmethyl N- [4- (4-amino-7-tetrahydro- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (6.0 mg, 0.013 mmol). 1H NMR (CDCl3) d 2.06 (m, 4H), 3.66 (m, 2H), 3.75 (m, 2H), 4.34 (s, IH), 4.97 (s, IH), 4.97 (m, IH), 5.10 (s, 7.06 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 471.
[603] Example 11: 2-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 2-methoxyphenyl] carbamate hydrochloride
[604] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with 2-pyridyl methanol (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3 d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid is dissolved in ethyl acetate (2 ml) and 1.0N HCl in ether (0.1 ml) is slowly added. The precipitate was collected by filtration under nitrogen to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol). _{1H NMR (DMSO-d 6)} δ1.92 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.89 (s, 3H), 4.02 (m, 2H), 4.91 (m, 1H 1H), 7.23 (s, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.14 , 3H), 8.42 (s, 1H), 8.57 (d, J = 4.2 Hz, 1H), 8.85 (s, 1H). LC / MS MH ^&lt; ^{+ &} gt ^; = 475.
[605] Example 12: 4-Pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 2-methoxyphenyl] carbamate hydrochloride
[606] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with 4-pyridyl methanol (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3 d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid is dissolved in ethyl acetate (2 ml) and 1.0N HCl in ether (0.1 ml) is slowly added. The precipitate was collected by filtration under nitrogen to give 4-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol). _{1H NMR (DMSO-d 6)} δ1.91 (m, 2H), 2.16 (m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (m, 1H ), 7.34 (s, 2H), 7.06 (d, J = 8.2 Hz, 1H), 7.16 (s, (s, 1 H), 8.76 (d, J = 5.6 Hz, 1 H), 9.05 (s, 1 H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 475.
[607] Example 13: Preparation of (5-methyl-3-isoxazolyl) methyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- 5-yl) -2-methoxyphenyl] carbamate
[608] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with (5-methyl-3-isoxazolyl) methanol (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; 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- Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (18 mg, 0.038 mmol). 2H), 4.96 (m, 2H), 3.91 (s, 3H), 3.91 (s, 3H) , 5.26 (s, 2H), 6.12 (s, IH), 6.95 (s, IH), 7.06 (m, 2H), 7.39 (s, IH), 8.17 (bs, LC / MS: MH ^&lt; ^{+ &} gt ^; = 479.
[609] Example 14: Preparation of [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl N- [4- 2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate
[610] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (30 mg, 0.065 mmol) is mixed with (5S) -5- (hydroxymethyl) tetrahydro-1H-2-pyrrolone (0.05 ml) in pyridine (0.5 ml). The reaction mixture is heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl N- [4- (4-amino-7-tetrahydro- Pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (10 mg, 0.021 mmol). 2H), 3.64 (m, 2H), 3.94 (s, 3H), 2.45 (m, , 4.04 (m, 2H), 4.14 (m, 2H), 4.98 (m, IH), 5.33 (m, 3H) 7.09 (m, IH), 7.31 (s, IH), 8.11 (bs, IH), 8.32 (s, IH). LC / MS: MH ^&lt; ^{+ &} gt ^; = 481.
[611] Example 15: 4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- - methoxyphenyl) carbamate
[612] a) tert-Butyl N- (4- (hydroxymethyl) phenyl) carbamate. (1.23 g, 10 mmol) and diisopropylethylamine (2.6 ml, 15 mmol) were mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 ml) . The mixture is stirred at room temperature overnight. Washed the organic layer was added to ethyl acetate with water, 1.0N HCl, saturated sodium carbonate, water, brine, dried with MgSO ₄ and, 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 (2.16 g, 9.67 mmol). (D, 8.5 Hz, 2H), 7.36 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5 Hz, 2H).
[613] b) 4-Aminobenzyl N- (4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl) carbamate. Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5- Mate (51 mg, 0.111 mmol) is mixed with tert-butyl N- (4- (hydroxymethyl) phenyl) carbamate (119 mg, 0.533 mmol) in pyridine (0.8 ml). The reaction mixture is heated at 100 &lt; 0 &gt; 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- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (9 mg, 0.015 mmol). 1H NMR (CDCl3) d 1.52 (s, 1H), 2.08 (m, 4H), 3.65 (m, 2H), 3.90 (S, 2H), 5.17 (s, 2H), 5.37 (s, 1H), 6.55 7.38 (m, 3H), 8.16 (bs, IH), 8.30 (s, IH). LC / MS: MH ^&lt; ^{+ &} gt ^; = 589.
[614] Example 16: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] Benzamide
[615] Pyrrolo [2,3-d] pyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve in dichloromethane (2.0 ml). Pyridine (2.0 ml) was added, followed by benzyl chloride (41 [mu] l, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] benzamide (64 mg, 0.144 mmol). _{1H NMR (CDCl 3 -d) δ2.12} (m, 4H), 3.67 (m, 2H), 3.99 (s, 3H), 4.17 (m, 2H), 4.99 (m, 1H), 7.03 (s, 1H ), 7.04 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.53 (m, 1H), 7.94 (d, J = 7.8 Hz, 1H), 8.33 , &Lt; / RTI &gt; 1H), 8.63 (d, J = 8.2 Hz, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 444.
[616] Example 17: N2- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] -2-pyridinecarboxamide
[617] Pyrrolo [2,3-d] pyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] benzamide (84 mg, 0.189 mmol). _{1H NMR (CDCl 3 -d) δ2.12} (m, 4H), 3.67 (m, 2H), 4.03 (s, 3H), 4.14 (m, 2H), 5.00 (m, 1H), 5.37 (s, 1H 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 10.62 (s, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 445.
[618] Example 18: N5- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] -1,3-dimethyl-1H-5-pyrazolycarboxide
[619] Pyrrolo [2,3-d] pyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N5- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] -1,3-dimethyl-1H-5-pyrazol c aridade (30 mg, 0.065 mmol). _{1H NMR (CDCl 3 -d) δ2.11} (m, 4H), 2.32 (s, 3H), 3.66 (m, 2H), 3.99 (s, 3H), 4.13 (m, 2H), 4.17 (s, 3H 1H), 7.09 (s, 1H), 7.09 (s, 1H), 7.99 (m, 1H), 5.22 (bs, 2H) (s, 2H), 8.49 (d, J = 8.2 Hz, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 462.
[620] Example 19: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] -2,2-dimethylpropanamide
[621] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] -2,2-dimethylpropanamide (27 mg, 0.064 mmol). _{1H NMR (CDCl 3 -d) δ1.35} (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H), 3.96 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49 (s, (d, J = 8.2 Hz, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 424.
[622] Example 20: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] -1-cyclopentanecarbide
[623] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] -2,2-dimethylpropanamide (33 mg, 0.076 mmol). _{1H NMR (CDCl 3 -d) δ1.66} (m, 2H), 1.81 (m, 2H), 1.95 (m, 4H), 2.06 (m, 4H), 2.77 (m, 1H), 3.65 (m, 2H 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.94 (s, 3H) 8.2 Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H). LC / MS: MH ⁺ = 437.
[624] Example 21: N1- [4- (4-Amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- ] -3-phenylpropanamide
[625] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Dissolve 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 is removed and the residue is dissolved in 1 ml DMSO and methanol (1 ml) is added to form a precipitate. The solid was collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Phenyl] -2,2-dimethylpropanamide (7 mg, 0.015 mmol). _{1H NMR (CDCl 3 -d) δ2.07} (m, 4H), 2.75 (m, 2H), 3.09 (m, 2H), 3.65 (m, 2H), 3.88 (s, 3H), 4.13 (m, 2H 1H), 8.24 (s, IH), 7.26 (m, IH), 7.96 (s, , 8.46 (d, J = 8.2 Hz, 1H). LC / MS: MH ^&lt; ^{+ &} gt ^; = 472.
[626] Example 22: 5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin-
[627] a) Tosyl chloride (12.0 g) was added to a mixture of 3-hydroxytetrahydrofuran (5.0 g) in pyridine (100 ml) under nitrogen at 0 &lt; 0 &gt; C with stirring while dividing into several fractions. The mixture is stirred at 0 &lt; 0 &gt; C for 2 hours and then allowed to warm to ambient temperature. The mixture is stirred at ambient temperature for 72 hours. The mixture is cooled to 0 &lt; 0 &gt; C and 5M hydrochloric acid (200 ml) is added. The mixture is extracted with ethyl acetate and the combined ethyl acetate extracts are washed with 2M hydrochloric acid and then brine, dried, filtered and evaporated to give 3-tosyloxytetrahydrofuran as an oil.
[628] b) A mixture of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (906 mg) and dimethyl Formamide &lt; / RTI &gt; (30 ml). The mixture is stirred for 30 minutes and then a solution of 3- (tosyloxy) tetrahydrofuran (750 mg) in dimethylformamide (10 ml) is added with stirring. The mixture is stirred and heated at 95 &lt; 0 &gt; C for 18 h, then evaporated in vacuo. The residue is partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried and then evaporated to give a residual rubbery solid which was triturated with ether and filtered to give 5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H- Lt; / RTI &gt; [2,3-d] pyrimidin-4-ylamine. Melting point 196-196.5 [deg.] C.
[629] Example 23: 5- (4-phenoxyphenyl) -7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3- d] pyrimidin-
[630] Pyrrolo [2,3-d] pyrimidine was reacted with 4-tosyloxytetrahydropyran in a similar manner to Example 1 to give 1,4-amino-5- (4-phenoxyphenyl) After column chromatography, 5- (4-phenoxyphenyl) -7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained. Melting point 193-193.5 [deg.] C.
[631] Example 24: 4-Amino-5- (4-phenoxyphenyl) -7- [4- (N-tert-butoxycarbonyl) tetrahydroisoxazolyl] -7H-pyrrolo [2,3- d ] Pyrimidin-4-ylamine
[632] a) A solution of 4-hydroxytetrahydroisoxazole (2.4 g) and triethylamine (4.2 g) in tetrahydrofuran (100 ml) with stirring at 0 占 폚 under di-tert-butyl dicarbonate (4.56 g) Lt; / RTI &gt; The mixture is stirred at ambient temperature for 72 hours and then filtered. The filtrate is evaporated under reduced pressure to give N- (tert-butoxycarbonyl) -4-hydroxytetrahydroisoxazole as an oil, which is used directly in the next step of this example.
[633] b) The product from a) (3.6 g) was stirred in pyridine (50 ml) at 0 ° C. under nitrogen and then divided into several fractions at 0 ° C. with stirring tosyl chloride (3.62 g). The mixture is stirred at 0 &lt; 0 &gt; C for 1 hour and then warmed to ambient temperature over 18 hours. The pyridine is removed under reduced pressure and ethyl acetate (50 ml) and citric acid (50 ml of a 1M solution in water) are added. The organic layer was separated and washed with 1 M citric acid solution, then with brine, dried, filtered and evaporated to give an oil which was purified by column chromatography on a petroleum ether containing 20-30% ethyl acetate as the mobile phase (boiling point 40-60 Gt; C) &lt; / RTI &gt; for purification by flash column chromatography. The appropriate fractions are collected and combined to give N- (tert-butoxycarbonyl) -4-tosyloxytetrahydroisoxazole. Melting point 63-65 캜.
[634] c) A solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (1.0 g) in dimethylformamide (40 ml) , Dropwise to a suspension of sodium hydride (0.145 g of a 60% suspension in mineral oil) in dimethylformamide (60 ml). The mixture is stirred at 0 &lt; 0 &gt; C for 1 hour and then the product from b) (1.25 g) is added. The mixture is heated at 100 &lt; 0 &gt; C for 3 hours, then cooled to room temperature, quenched with water and extracted with ethyl acetate to give an oil. The oil was polished with ethyl acetate and the resulting solid was collected by filtration to give 4-amino-5- (4-phenoxyphenyl) -7- [4- (N-tert-butoxycarbonyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine. Melting point 162-163 占 폚.
[635] Example 25:
[636] 7- (4-phenoxyphenyl) -7- (4-tetrahydroisoxazolyl) -7H-pyrrolo [2,3-d] pyrimidin- 4- ylamine dihydrochloride
[637] The product from Example 3 (0.29 g) was dissolved in dichloromethane (8 ml) and then stirred at 0 째 C while adding trifluoroacetic acid (2.0 ml). The mixture is allowed to warm to ambient temperature and stirred at ambient temperature for 2 hours. The mixture is made basic with sodium bicarbonate solution and extracted with dichloromethane to give an oil which is purified by flash column chromatography using ethyl acetate followed by ethyl acetate / methanol (9: 1) as the mobile phase . The appropriate fractions are collected and combined and evaporated to give a solid which is dissolved in ethyl acetate and then treated with etheric hydrogen chloride (3.0 ml of a 1M solution). The resulting solid was collected by filtration, washed with ether and dried under vacuum at 45 캜 for 2 hours to give 5- (4-phenoxyphenyl) -7- (4-tetrahydroisoxazolyl) -7H-pyrrolo [ , 3-d] pyrimidin-4-ylamine dihydrochloride. Melting point: 208 캜 (decomposition).
[638] Example 26: 4-Chloro-5-iodo-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidine
[639] (60% in mineral oil) in dimethylformamide (100 ml) with stirring under nitrogen at 0 &lt; 0 &gt; C was added dropwise to a solution of 4-chloro-5-iodo-7H-pyrrolo [2,3- 0.79 g of the dispersion). The mixture is stirred until hydrogen evolution ceases. 3-tosyloxytetrahydrofuran (4.65 g) was added and the mixture was warmed to 90 &lt; 0 &gt; C. The mixture is stirred at this temperature for 2 hours and then at ambient temperature overnight. Water (100 ml) was carefully added and the mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidine do. Melting point 184-186 [deg.] C.
[640] 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 ° C under nitrogen with stirring for 15 hours . The mixture is cooled to ambient temperature and filtered. Water (500 ml) is added to the filtrate and the mixture is extracted with ethyl acetate to give a solid which is triturated with hot hexane (500 ml). The supernatant is decanted from the residual sword and then cooled. The precipitated solid is collected by filtration to give 2- (4-iodophenoxy) benzaldehyde. Melting point 84.5-86 캜.
[641] c) Toluene (250 ml) is deoxygenated and then nitrated for 30 minutes. To the toluene is added 2- (4-iodophenoxy) benzaldehyde (6.46 g), hexamethyldithine (10.0 g) and tetrakis (triphenylphosphine) palladium (O) (1.4 g). The mixture is refluxed under nitrogen while stirring for 7 hours. The mixture is cooled to ambient temperature and then filtered. The filtrate was evaporated and the residue was purified by flash column chromatography on silica using 3% ethyl acetate in petroleum ether (boiling point 40-60 C) as mobile phase to give 2- (4-trimethylstannylphenoxy) benzaldehyde Oil.
[642] d) A solution of the product from c) (1.80 g), product from b) (1.76 g), tris (dibenzylideneacetone) dipalladium (228 mg), triphenylarsine (383 mg) and dimethylformamide The mixture is heated at 65 [deg.] C under nitrogen with stirring for 70 hours. The mixture is 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, increasing the amount of ethyl acetate from 30-50% in petroleum ether (boiling point 40-60 C) as mobile phase to give a solid Pyrrole [2,3-d] pyrimidin-5-yl) -pyrrolidine The title compound was obtained as a white amorphous solid from 2- [4- (4-chloro-7- (3-tetrahydrofuryl) Phenoxy] benzaldehyde as an oil.
[643] e) The product from d) (360 mg) is dissolved in methanol (5 ml) and sodium borohydride (65 mg) is added at 0 <0> C with stirring. The mixture was allowed to warm to ambient temperature and stirred at this temperature for 1 hour. The mixture was quenched with dilute sodium hydroxide solution and evaporated under reduced pressure to give a residue which was extracted with ethyl acetate to give 2 - [(4- (4-chloro-7- (3-tetrahydrofuryl) Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy] benzyl alcohol.
[644] f) A mixture of the product from (280 mg), 1,4-dioxane (15 ml) and a concentrated aqueous ammonium solution (15 ml, SG 0.88) is heated in a pressure vessel at 120 ° C for 20 hours. The mixture is cooled to ambient temperature and the solvent is 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 mobile phase to give Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzyl alcohol as a glassy solid Melting point 92-96 [deg.] C.
[645] Example 27: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin- Diethylbenzylamine
[646] a) sodium triacetoxyborohydride (264 mg) was added to a solution of 2 - [(4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo Phenoxy] benzaldehyde (330 mg) and diethylamine (121 mg), and the vial bulkhead was sealed. The mixture was stirred at ambient temperature for 20 hours And then quenched with saturated aqueous sodium bicarbonate solution (5 ml). The mixture was extracted with ethyl acetate to give 2- [4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [ ] Pyrimidin-5-yl) phenoxy] -N, N-diethylbenzylamine.
[647] b) A mixture of the product from a) (280 mg), concentrated aqueous ammonia solution (10 ml, SG 0.88) and 1,4-dioxane (10 ml) is heated in a pressure vessel at 120 ° C for 16 hours. The mixture is cooled and the solvent is 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 mobile phase to give 2- [4- (4 -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -N, N-diethylbenzylamine. Melting point 107-110 [deg.] C.
[648] Example 28: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] -benzonitrile
[649] a) A mixture of 2-fluorobenzonitrile (28.8g), 4-bromophenol (36.9g), potassium carbonate (58.9g) and dimethylformamide (30ml) was heated for 5 hours at 120 & do. The mixture is allowed to stand at ambient temperature overnight and is then partitioned between ethyl acetate and water. The organic layer is separated, washed, dried and then evaporated to an oil, which solidifies upon standing. The solid is polished with petroleum ether (boiling point 40-60 DEG C) and filtered to give 2- (4-bromophenoxy) benzonitrile.
[650] b) A mixture of the product from 5.57 g of a), hexamethyldithine (10.0 g), tetrakis (triphenylphosphine) palladium (O) (1.4 g) and degassed toluene (250 ml) Lt; RTI ID = 0.0 &gt; 110 C. &lt; / RTI &gt; The mixture is allowed to stand at ambient temperature for 18 hours and then filtered through a pad of silica. The pad is washed with ethyl acetate and the combined filtrate and washings are evaporated to dryness. The residue is purified by flash column chromatography on silica using petroleum ether (boiling point 40-60 C) and diethyl ether (increasing from 2% to 5%) as the mobile phase. Appropriate fractions are collected, combined and evaporated to give 2- (4-trimethylstannylphenoxy) benzonitrile.
[651] c) A mixture of 4-chloro-5-iodo-7- (3-tetrahydrofuryl) pyrrolo [2,3-d] pyrimidine (1.8 g, prepared as described in example 5) (1.23 g) was reacted and worked up in a similar manner to Example 5d) to give 2- [4- (4-chloro-7- (3-tetrahydrofuryl) -7H-pyrrolo [ , 3-d] pyrimidin-5-yl) phenoxy] -benzonitrile.
[652] d) A mixture of the product from c) (470 mg), concentrated aqueous ammonia (33 ml, SG 0.880) and 1,4-dioxane (33 ml) was heated together in a pressure vessel at 120 ° C for 18 hours, Pyrrole [2,3-d] pyrimidin-5-yl) phenoxy] - (4-methyl- Benzonitrile. Melting point: 201-203 ° C.
[653] Example 29: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5-yl) phenoxy] benzaldehyde
[654] a) 3-tosyloxytetrahydrofuran (1.84 g) was added to a suspension of sodium hydride (0.30 g of a 60% dispersion in mineral oil) and Pyrrolo [2,3-d] pyrimidin-4-ylamine (2.9 g) using 5- (4-benzyloxyphenyl) -7H- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as a solid.
[655] b) A mixture of the product from a) (6.0 g), 10% palladium on charcoal (3.0 g), ammonium formate (4.9 g) and ethanol (500 ml) is heated on a steam bath with stirring under nitrogen for 2 hours . The mixture is cooled and filtered, and the solvent is evaporated. The filtrate was concentrated in half volume and filtered to give a solid which was purified by column chromatography to give 4- [4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- Phenol (melting point: 257-259 DEG C).
[656] c) A mixture of 4- [4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5-yl] phenol (2.55 g), 2-fluorobenzaldehyde g), potassium carbonate (2.13 g) and dimethylformamide (80 ml) was heated at 120 [deg.] C with stirring under nitrogen for 5 hours. The mixture was cooled to ambient temperature and quenched with water and extracted with ethyl acetate to give 2- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- 5-yl) phenoxy] benzaldehyde. &Lt; / RTI &gt; Melting point 185-187 [deg.] C.
[657] Example 30: 4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] tetrahydrofuran-
[658] Pyrrolidine [2,3-d] pyrimidine (902 mg) and sodium hydride (120 mg of a 60% dispersion in mineral oil) with stirring under nitrogen and dimethylformamide (30 ml). The mixture is stirred for 30 minutes, then 3,6-dioxabicyclo [3.1.0] hexane (300 mg) is added and the mixture is warmed to 80 &lt; 0 &gt; C. The mixture is allowed to stand for 64 hours and then evaporated under reduced pressure. When the residue is polished with water, it becomes an oil sword. Ether is added and the mixture is stirred rapidly for 30 minutes to give a solid which is collected by filtration and washed with methanol. Remove the solid. The second solid was collected from the filtrate and recrystallized from ethanol to give 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Tetrahydrofuran-3-ol is obtained. Melting point 234-235.
[659] Example 31: Synthesis of 5- [4- (2-morpholinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin-
[660] 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. A saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with EMPORE Filter into the cartridge. The filtrate is evaporated and the residue is dissolved in dichloromethane (5 ml) and then tris (2-aminoethyl) amine-polymer conjugate (0.3 g) and 2 drops of glacial acetic acid are added and the mixture is stirred overnight at ambient temperature. The polymer is removed by filtration, washed with dichloromethane and then with methanol. The combined organic filtrate and washings were evaporated under reduced pressure to give an oil which was triturated with diethyl ether / ethyl acetate to dissolve the solids and the solution was cooled on ice and filtered to give 5- [4- (2 -Morpholinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine. Melting point 169-171 DEG C.
[661] Example 32: 5- [4- (2-Piperidinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin-
[662] Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde (prepared as described in Example 10) (0.15 g) was reacted with piperidine (63 mg) to give 5- [4- (2-piperidinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3 lt; / RTI &gt; d] pyrimidin-4-ylamine. Melting point 76-78 占 (glassy foam).
[663] Example 33: Preparation of 5- {4- [2- (2-methoxyethyl) aminomethylphenoxy] phenyl} -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidine 4-ylamine
[664] Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde (prepared as described in Example 10) (0.15 g) was reacted with 2-methoxyethylamine (56 mg) to give 5- {4- [2- (2-methoxyethyl) aminomethylphenoxy] phenyl} -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine. Melting point 66-68 캜 (glassy foam).
[665] Example 34: 4- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] benzyl alcohol
[666] a) In a similar manner to Example 9, the title compound was obtained from 4- [4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde was obtained by reacting 4-amino-7- (3-tetrahydrofuryl) .
[667] b) The product from a) (0.35 g) is dissolved in methanol (10 ml) and to this solution is added sodium borohydride (32 mg) at 0 &lt; 0 &gt; C. The mixture was allowed to warm to ambient temperature and stirred at this temperature for 10 minutes. Dissolve 1,2-dichloroethane (4 ml) to aid solubility. The mixture is stirred at ambient temperature for 18 hours, then glacial acetic acid (1 ml) is added and the mixture is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The ethyl acetate was isolated, dried, filtered and evaporated to give 4- [4- (4-amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- Yl) phenoxy] benzyl alcohol. Melting point 92-95 캜.
[668] Example 35:
[669] Pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained in the same manner as in [5- (4-fluorophenoxy)
[670] Pyrrole [2,3-d] pyrimidin-5-yl] phenol (0.59 g), 4-fluorophenylboric acid (0.56 g) , Copper (II) acetate (0.36 g), triethylamine (1.01 g), dichloromethane (20 ml) and activated milled quatemaine (0.5 g) was stirred under nitrogen in anhydrous atmosphere for 64 hours. The reaction mixture was filtered through a small preflushed silica pad, diluted with dichloromethane (200 ml), diluted with ethyl acetate (250 ml) and finally diluted with ethyl acetate / methanol 9: 1 (250 ml) The methane and ethylacetate fractions were combined and purified by flash column chromatography on silica using ethyl acetate / methanol as mobile phase to give 5- [4- (4-fluorophenoxy) phenyl] -7- (3-tetrahydro Furyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, melting point 198-199 DEG C
[671] Example 36: Synthesis of 5- [4- (4-morpholinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin-
[672] Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] benzaldehyde (prepared as described in Example 10) (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine (336 mg) and morpholine (146 mg) ] &Lt; / RTI &gt; pyrimidin-4-ylamine. Melting point 142-144 占 폚.
[673] Example 37: Synthesis of 5- [4- (3-morpholinomethylphenoxy) phenyl] -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin-
[674] a) A mixture of 4- [4-amino-7- (3-tetrahydrofuryl-7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol (0.297 g) Pyrrole [2,3-d] pyrimidin-5-yl) phenoxy) -pyrrolidine The title compound was prepared by reacting 3- [4- (4-amino- ] Benzaldehyde. &Lt; / RTI &gt;
[675] b) The product from part a) (100 mg) and morpholine (44 mg) were reacted together using conditions analogous to those described in Example 10 to give 5- [4- (3-morpholinomethylphenoxy) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained. Melting point 83-85 캜.
[676] Example 38: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] - (4-pyridyl) ethylamino) -benzonitrile
[677] (0.517 g), 2-fluoro-6- (2-fluoro-phenyl) -2,3-dimethyl-7- (0.42 g), potassium carbonate (0.48 g) and dimethylformamide (20 ml) were heated for 8 hours at 120 DEG C. The mixture was cooled, diluted with water and then dissolved in ethyl Acetate was extracted to give a solid which was recrystallized from ethyl acetate to give a solid which was purified by flash column chromatography on silica using ethyl acetate and ethyl acetate / methanol (9: 1, 8: 1, 4: 1) Pyrrolor2.3-dlpyrimidin-5-yl) phenoxy] -6- (2-fluorophenyl) (4-pyridyl) ethylamino) -benzonitrile, melting point 212-213 [deg.] C.
[678] Example 39: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] -Imidazol-1-yl) propylaminobenzonitrile
[679] Pyrrolo [2,3-d] pyrimidin-5-yl] phenol (0.49 g), 2-fluoro-6- (3- (0.45 g) and dimethylformamide were reacted in the similar manner as in Example 17 to give 2- [4- (4-amino-7- (3-tetrahydrofuryl) ) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- ).
[680] Example 40: 4-Amino-6-bromo-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidine
[681] a) A solution of 302 mg of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine in 10 ml of dimethylacetamide and 50 ml of dichloromethane, Was treated with N-bromosuccinimide (178 mg) in methane (10 ml). The mixture was left stirring for 16 hours at ambient temperature. The mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid that was collected by filtration and dried to give 4-amino-6-bromo-5- (4-phenoxyphenyl) -7H-pyrrolo [ , 3-d] pyrimidine. Melting point 282-283 DEG C
[682] b) A solution of the product from a) (1.14 g) in anhydrous dimethylformamide (30 ml) was added with sodium hydride (120 mg of a 60% dispersion in mineral oil) with stirring under nitrogen. Then, 3-tosyloxytetrahydrofuran (0.8 g) in dimethylformamide (10 ml) was added. The mixture was heated at 90 &lt; 0 &gt; C overnight. The 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. This was purified by dissolving it in ethanol, adding water to the supernatant, 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-amino-6-bromo-5- (4- phenoxyphenyl) -7- (3- tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine. Melting point 205-206 [deg.] C.
[683] Example 41: 2- [4- (4-Amino-7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] -Methoxypropylamino) benzonitrile &lt; / RTI &gt;
[684] Pyrrolo [2,3-d] pyrimidine (0.65 g), 2-fluoro-6- (3-fluorophenyl) (0.46 g), potassium carbonate (0.61 g) and dimethylformamide (40 ml) were heated at 120 占 폚 under nitrogen for 2 hours to give 2- [4- (4-amino- 7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-methoxypropylamino) benzonitrile. Melting point 183-184 占 폚.
[685] Example 42: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3- d] pyrimidin- 5- yl) phenoxy] benzonitrile
[686] pyrrolo [2,3-d] pyrimidin-4-ylamine (2.83 g), 10% carbon &lt; RTI ID = 0.0 & (1.41 g), ammonium formate (2.31 g) and ethanol (250 ml) were boiled under reflux under nitrogen with stirring for 1.5 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was cooled and filtered. The filtrate was evaporated to give 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] phenol as a solid.
[687] b) A solution of 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3- d] pyrimidin- 5-yl] phenol (0.082 g, ) Was added to a mixture of 2-fluorobenzonitrile (80 mg) and potassium carbonate (76 mg) in a vial. The vial was flushed with nitrogen and sealed. The mixture was shaken at 120 &lt; 0 &gt; C for 6 hours, then allowed to cool to ambient temperature for 16 hours. The mixture was diluted with water (11 ml) and extracted with ethyl acetate to give 2- [4- (4-amino-7- (4- tetrahydropyranyl) -7H-pyrrolo [2,3- d] pyrimidine -5-yl) phenoxy] benzonitrile. Melting point 125 캜 (softening)
[688] Examples 43-48 were prepared from 4- [4-amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin- Phenol with the appropriate nitrile, except that the mixture was shaken together for 48 hours or less. The reaction was monitored for disappearance of the starting material and heated for the appropriate time.
[689] Example 49: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) - (4-fluorophenyl) Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-imidazol- 1-yl) propylaminobenzonitrile
[690] Example 50: 2- (4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3-d] pyrimidin- ) Phenoxy] -6- (2-morpholinoethoxy) benzonitrile, melting point 110 캜 (free).
[691] Example 51: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-1, 2-benzodiazepin- Pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -6- (2- (4-pyridyl) ethylamino) benzonitrile, melting point 120-123 ° C (free).
[692] Example 52: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [ 2,3-d] pyrimidin-5-yl) phenoxy] -6- (3-methoxypropylamino) benzonitrile, mp 205-207 [deg.] C.
[693] Example 53: 2- [4- (4-Amino-7- (4-tetrahydropyranyl) -7H-pyrrolo [2,3- d] pyrimidin- 5-yl) phenoxy] -5-fluorobenzonitrile, melting point 216-217 [deg.] C.
[694] Examples 54-101
[695] Overall method
[696] A portion of the amines listed in Table 1 (9 molar equivalents to the esters used, weights ranging from 47.5 mg to 184.5 mg) were weighed into individual vials and methanol (1 mL) was added to each vial. A mixture of ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 2,3-d] pyrimidin-7-yl acetate (1 molar equivalent) in tetrahydrofuran was added. The reaction mixture was shaken at 60-65 [deg.] C for 36 hours. Methanol and triethylamine were removed under reduced pressure at 50 &lt; 0 &gt; C for 3 h, and water (3 ml) was added to each vial followed by dichloromethane (3 ml). The vial was stirred for 15 seconds and then left for 18 hours. The mixture was poured into an EMPORE 占 10 mm / 6 ml extraction disc cartridge, the dichloromethane phase was collected and evaporated at 50 占 폚 for 3 hours. It was observed whether the solids were removed in the vials left for 18 hours during the post-treatment. Thereby, the aqueous layer in each cartridge was allowed to pass through the compressed air. Dichloromethane (4 ml) was added to each extraction cartridge. Each filtrate was evaporated under reduced pressure at 50 &lt; 0 &gt; C for 3 hours. The desired product was found in the original dichloromethane extract and appeared to be present in the liquid, or was found in reworking insoluble solids, which is referred to as being present in the solids. Specific products were found in both phases. These images are shown in Table 1.
[697] Each sample was analyzed by LCMS and the target ion was found in each case. Retention times for each product are listed in Table 1. The conditions used are given below.
[698] Column: 5 占 퐉 hypersil BDS c18 (100x2.1 mm)
[699] Mobile phase: 0.1 M NH ₄ OAc [H 4.55]: MeCN (gradient - see below)
[700] Conditions: After 8 minutes 10-100% MeCN
[701] (Gradient) 100% MeCN
[702] After 2 minutes 100-10% MeCN
[703] (Total analysis execution time: 11 minutes)
[704] Flow rate: 1 ml / min (without splitting in MS)
[705] Wavelength range: 250-320nm
[706] Injection volume: 20 μl
[707] MS
[708] Method: APCI11H
[709] Ionization: APcI + ve / -ve
[710] Mass range: 100-700m / z
[711] Cone voltage: 20
[712] In an analogous manner to Examples 54-101, the amines listed in Table 2 were reacted with ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- 7-yl] propionate to give the products described in Examples 102-146, respectively. The post-treatment and analysis conditions were the same as those used for Examples 54-101. In each case, the target ion was revealed by LCMS.
[713] AmineCompound namePrizeRT / min product 54Ethanolaminesolid3.44 55d1-2-amino-1-propanolsolid3.58 561-amino-2-propanolsolid3.56 572-methoxyethylamineLiquid3.78 583-amino-1-propanolBoth3.50 59(S) - (+) - 2-amino-1-propanolBoth3.58 60(R) - (-) - 1-amino-2-propanolBoth3.56 61N, N-dimethylethylenediamineBoth3.31 62(+/-) - 2-amino-1-butanolsolid3.77 631-amino-2-butanolBoth3.77 643-amino-1,2-propanediolsolid3.32 65(S) -3-amino-1,2-propanediolsolid3.32 66(R) -3-amino-1,2-propanediolsolid3.32 671-methylpiperazineBoth3.28 68N, N-dimethyl-1,3-propanediamineLiquid3.29 69N2, N2-dimethyl-1,2-propanediamineBoth3.37 701-dimethylamino-2-propylamineLiquid3.44 71d1-2-amino-3-methyl-1-butanolsolid3.98 72N- {2- (1- (N-morpholine) -1-oxo] ethyl} piperazineLiquid3.56 732-Amino-2-methyl-1-propanolBoth3.86 742-amino-2-methyl-1,3-propanediolBoth3.49 752- (2-aminoethoxy) ethanolBoth3.47 761- (2-aminoethyl) pyrrolidineLiquid3.40 77N-methyl homopiperazineLiquid3.32 781-Amino-1-cyclopentanemethanolBoth4.16 792-aminocyclohexanolsolid3.98 80N, N-diethylethylenediamineLiquid3.44 81N- (3-hydroxypropyl) ethylenediamineBoth3.24 822 - ((2-aminoethyl) thio) ethanolBoth3.69 832- (2-aminoethyl) pyridineLiquid3.89 843 (2-aminoethyl) pyridineLiquid3.79 85N- (3-aminopropyl) amidazoleLiquid3.37 861- [2- (N-morpholine) ethyl] piperazineLiquid3.39 872- (Aminomethyl) -1-ethylpyrrolidineBoth3.48 881- (2-aminoethyl) piperidineBoth3.49 891-pyrrolidine &lt; / RTI &gt;Liquid3.37 90(R) - (+) - 2-Aminomethyl-1-ethylpyrrolidineBoth3.48 914- (2-aminoethyl) morpholineBoth3.39 923-diethylaminopropylamineBoth3.43 93N, N-Dimethylen neopentanediamineBoth3.47 94Ethyl 1-piperazinecarboxylateLiquid4.34 952- (Aminomethyl) -2-ethyl-1,3-propanediolBoth3.69 961- (3-Aminopropyl) -2-pyrrolidinoneBoth3.68 971-PiperidinepropylamineLiquid3.46 984- (3-aminopropyl) morpholineLiquid3.33 99N, N-diisopropylethylenediamineLiquid3.59 100N, N-bis (3-aminopropyl) methylamineLiquid3.03 101Tris (2-aminoethyl) amineLiquid3.01`
[714] The prepared compounds are described below.
[715] Example 54:
[716] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2- hydroxyethyl) acetamide
[717] Example 55:
[718] Pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxyprop-2-yl) acetamide
[719] Example 56:
[720] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2- hydroxypropyl) acetamide
[721] Example 57:
[722] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2- methoxyethyl) acetamide
[723] Example 58:
[724] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (3-hydroxypropyl) acetamide
[725] Example 59:
[726] (S) -4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- Acetamide
[727] Example 60:
[728] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2- hydroxypropyl) acetamide
[729] Example 61:
[730] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [2- (N, N-dimethylamino) ethyl] acetamide
[731] Example 62:
[732] Pyrrolo [2,3-d] pyrimidin-7-yl-N- (1-hydroxybut-2-yl) acetamide
[733] Example 63:
[734] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2- hydroxybutyl) acetamide
[735] Example 64:
[736] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2,3- dihydroxypropyl) acetamide
[737] Example 65:
[738] Pyrrolo [2,3-d] pyrimidin-7-yl-N- (2,3-dihydroxypropyl) acetamide
[739] Example 66:
[740] Pyrrolo [2,3-d] pyrimidin-7-yl-N- (2,3-dihydroxypropyl) acetamide
[741] Example 67:
[742] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N, N- (3-azapentamethylene) acetamide
[743] Example 68:
[744] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (N, N-dimethylamino) propyl] acetamide
[745] Example 69:
[746] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [1- (N, N- dimethylamino) Yl] acetamide
[747] Example 70:
[748] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [2- (N, N-dimethylamino) propyl] acetamide
[749] Example 71:
[750] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- (1 -hydroxy-3-methylbut- amides
[751] Example 72:
[752] 2-oxoethyl) piperazin-1-yl] -2-oxo-ethyl} -5- (4- phenoxyphenyl) -7H-pyrrolo [ 2,3-d] pyrimidin-4-ylamine
[753] Example 73:
[754] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1 -hydroxy- Acetamide
[755] Example 74:
[756] Pyrrolo [2,3-d] pyrimidin-7-yl-N- (1,3-dihydroxy-2-methylprop- Yl) acetamide
[757] Example 75:
[758] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxyethoxy) ethyl] acetamide
[759] Example 76:
[760] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (pyrrolidin- 1-yl) ethyl] acetamide
[761] Example 77:
[762] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N, N- (3-azahexamethylene) acetamide
[763] Example 78:
[764] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [1- (hydroxymethyl) cyclopentyl] acetamide
[765] Example 79:
[766] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-hydroxycyclohexyl) acetamide
[767] Example 80:
[768] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [2- (N, N-diethylamino) ethyl] acetamide
[769] Example 81:
[770] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (3-hydroxypropylamino) ethyl] acetamide
[771] Example 82:
[772] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxyethylthio) ethyl] acetamide
[773] Example 83:
[774] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (pyrid-2- yl) ethyl] acetamide
[775] Example 84:
[776] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [2- (pyrid-3- yl) ethyl] acetamide
[777] Example 85:
[778] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (imidazol- 1-yl) propyl] acetamide
[779] Example 86:
[780] 7- {2- [4- (2-morpholinoethyl) piperazin-1-yl] -2-oxo- ethyl} d] pyrimidin-4-ylamine
[781] Example 87:
[782] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- (N-ethylpyrrolidin-2-yl) methylacetamide
[783] Example 88:
[784] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-piperidinoethyl) acetamide
[785] Example 89:
[786] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [3- (pyrrolidin- 1-yl) propyl] acetamide
[787] Example 90:
[788] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -N- (N-ethylpyrrolidin- Methyl acetamide
[789] Example 91:
[790] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (2-morpholinoethyl) acetamide
[791] Example 92:
[792] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [3- (N, N-diethylamino) propyl] acetamide
[793] Example 93:
[794] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [3- (N, N- dimethylamino) -2,2- Dimethylpropyl] acetamide
[795] Example 94:
[796] Pyrrolo [2,3-d] pyrimidin-4-ylmethyl) -piperidine-l-carboxylic acid tert- 4-ylamine
[797] Example 95:
[798] Pyrrolo [2,3-d] pyrimidin-7-yl-N- [2,2-bis (hydroxymethyl) butyl] acetamide
[799] Example 96:
[800] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (2- pyrrolidon- 1- yl) propyl] Acetamide
[801] Example 97:
[802] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (3-piperidinopropyl) acetamide
[803] Example 98:
[804] 7H-pyrrolo [2,3-d] pyrimidin-7-yl-N- (3-morpholinopropyl) acetamide
[805] Example 99:
[806] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- (3-hydroxy-1-methylprop- Acetamide
[807] Example 100:
[808] Pyrrolo [2,3-d] pyrimidin-7-yl) -N- [3- (N-3-aminopropyl, N-methyl) amino Propyl] acetamide
[809] Example 101:
[810] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -N- [N- bis (2- aminoethyl) aminoethyl] acetamide
[811] AmineCompound namePrizeRT / min product 102EthanolamineBoth3.68 103d1-2-amino-1-propanolBoth3.78 1041-amino-2-propanolBoth3.81 1052-methoxyethylamineBoth4.08 1063-amino-1-propanolBoth3.73 107(S) - (+) - 2-amino-1-propanolBoth3.78 108(R) - (-) - 1-amino-2-propanolLiquid3.81 109N, N-dimethylethylenediamineLiquid3.50 110(+/-) - 2-amino-1-butanolBoth3.96 1111-amino-2-butanolBoth4.06 1123-amino-1,2-propanediolBoth3.52 113(S) -3-amino-1,2-propanediolBoth3.53 114(R) -3-amino-1,2-propanediolBoth3.53 115N, N-dimethyl-1,3-propanediamineLiquid3.47 116N2, N2-dimethyl-1,2-propanediamineLiquid3.57 1171-dimethylamino-2-propylamineLiquid3.67 118Amino-3-methyl-1-butanolBoth4.15 1192- (2-aminoethylamino) ethanolLiquid3.40 1202-Amino-2-methyl-1-propanolBoth4.17 1212-amino-2-methyl-1,3-propanediolBoth3.76 1222- (2-aminoethoxy) ethanolLiquid3.71 1231- (2-aminoethyl) pyrrolidineBoth3.61 1241-Amino-1-cyclopentanemethanolBoth4.48 1252-aminocyclohexanolBoth4.19 126N, N-diethylethylenediamineBoth3.68 127N- (3-hydroxypropyl) ethylenediamineBoth3.42 1282 - ((2-aminoethyl) thio) ethanolLiquid3.94 1292- (2-aminoethyl) pyridineLiquid4.13 1303- (2-aminoethyl) pyridineBoth4.05 131N- (3-aminopropyl) amidazoleLiquid3.58 1322- (2-aminoethylamino) -1-methylpyrrolidineBoth3.56 1332- (Aminomethyl) -1-ethylpyrrolidineBoth3.70 1341- (2-aminoethyl) piperidineBoth3.70 1351-pyrrolidine &lt; / RTI &gt;Both3.60 136(R) - (+) - 2-Aminomethyl-1-ethylpyrrolidineBoth3.70 1374- (2-aminoethyl) morpholineBoth3.63 1383-diethylaminopropylamineBoth3.64 139N, N-Dimethylen neopentanediamineBoth3.68 1402- (Aminomethyl) -2-ethyl-1,3-propanediolBoth3.94 1411- (3-Aminopropyl) -2-pyrrolidinoneLiquid3.91 1421-PiperidinepropylamineBoth3.70 1434- (3-aminopropyl) morpholineLiquid3.53 144N, N-diisopropylethylenediamineLiquid3.86 145N, N-bis (3-aminopropyl) methylaminesolid3.21 146Tris (2-aminoethyl) amineBoth3.17
[812] Example 102:
[813] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxyethyl) propanamide
[814] Example 103:
[815] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxyprop-2-yl) Propanamide
[816] Example 104:
[817] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxypropyl) propanamide
[818] Example 105:
[819] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-methoxyethyl) propanamide
[820] Example 106:
[821] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-hydroxypropyl) propanamide
[822] Example 107:
[823] (S) -1- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 2-yl) propanamide
[824] Example 108:
[825] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxypropyl) propane amides
[826] Example 109:
[827] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N, N-dimethylamino) ethyl ] Propanamide
[828] Example 110:
[829] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxybut-2-yl) propane amides
[830] Example 111:
[831] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxybutyl) propanamide
[832] Example 112:
[833] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2,3-dihydroxypropyl) propanamide
[834] Example 113:
[835] (S) -1- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Propyl) propanamide
[836] Example 114:
[837] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2,3-dihydroxyphenyl) Propyl) propanamide
[838] Example 115:
[839] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (N, N-dimethylamino) propyl] ] Propanamide
[840] Example 116:
[841] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N, N-dimethylamino) propyl] ] Propanamide
[842] Example 117:
[843] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [1- (N, N-dimethylamino) propyl] 2-yl] propanamide
[844] Example 118:
[845] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-3-methylbut- Yl) propanamide
[846] Example 119:
[847] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxyethylamino) ethyl ] Propanamide
[848] Example 120:
[849] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1-hydroxy-2-methylprop- 2-yl) propanamide
[850] Example 121:
[851] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (1, 3-dihydroxy-2- methyl Prop-2-yl) propanamide
[852] Example 122:
[853] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxyethoxy) ethyl ] Propanamide
[854] Example 123:
[855] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (pyrrolidin- 1 -yl) Ethyl] propanamide
[856] Example 124:
[857] Pyrrolor2,3-dlpyrimidin-7-yl] -N- [1- (hydroxymethyl) cyclopentyl] propane amides
[858] Example 125:
[859] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-hydroxycyclohexyl) propanamide
[860] Example 126:
[861] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N, N-diethylamino) Ethyl] propanamide
[862] Example 127:
[863] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (3-hydroxypropylamino) ethyl ] Propanamide
[864] Example 128:
[865] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (2-hydroxyethylthio) ethyl ] Propanamide
[866] Example 129:
[867] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (pyrid- ] Propanamide
[868] Example 130:
[869] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (pyrid-3-yl) ethyl] ] Propanamide
[870] Example 131:
[871] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (imidazol-1-yl) propyl] ] Propanamide
[872] Example 132:
[873] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N-methylpyrrolidin- Yl) ethyl] propanamide
[874] Example 133:
[875] Pyrrolo [2,3-d] pyrimidin-7-yl] -N - [(N-ethylpyrrolidin-2-ylmethoxy) ) Methyl] propanamide
[876] Example 134:
[877] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-piperidinoethyl) propanamide
[878] Example 135:
[879] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (pyrrolidin- 1 -yl) Propyl] propanamide
[880] Example 136:
[881] Pyrrolo [2,3-d] pyrimidin-7-yl] -N - [(N-ethylpyrrolidine Yl) methyl] propanamide
[882] Example 137:
[883] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-morpholinoethyl) propanamide
[884] Example 138:
[885] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (N, N-diethylamino) Propyl] propanamide
[886] Example 139:
[887] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (N, N-diethylamino) -2,2-dimethylpropyl] propanamide
[888] Example 140:
[889] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2,2-bis (hydroxymethyl) butyl ] Propanamide
[890] Example 141:
[891] Pyrrolo [2,3-d] pyrimidin- 7-yl] -N- [3- (2-pyrrolidinone-l- Yl) propyl] propanamide
[892] Example 142:
[893] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-piperidinopropyl) propanamide
[894] Example 143:
[895] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (3-morpholinopropyl) propanamide
[896] Example 144:
[897] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [2- (N, N-di-isopropyl Amino) ethyl] propanamide
[898] Example 145:
[899] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3- (N-aminopropyl, N-methyl ) Aminopropyl] propanamide
[900] Example 146:
[901] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [N-bis (2-aminoethyl) aminoethyl ] Propanamide
[902] Example 147:
[903] Pyrrolo [2,3-d] pyrimidin-7-yl] - butyrolactone
[904] a) A mixture of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (1.0 g) in tetrahydrofuran (0.158 g of a 60% dispersion in mineral oil). The mixture was stirred for 1 hour at 0 ° C, then α-bromo-γ-butyrolactone (0.60 g) in dimethylformamide (6 ml) was added dropwise with stirring at 0 ° C. The mixture was stirred at room temperature for 18 hours, then quenched with water (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- , Which was used directly in b).
[905] 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 at 100 &lt; 0 &gt; C for 2 hours and then evaporated to dryness under reduced pressure. The residue was suspended in ethyl acetate and washed with water. Then, the organic extract was extracted with 5M hydrochloric acid (3x50ml), and the acidic extract was washed with ethyl acetate, then basified with 6M sodium hydroxide solution at 0 ° C, extracted again with ethyl acetate, and extracted with dichloromethane. The combined organic extracts were dried, filtered and evaporated to give an oil which was crystallized from ethyl acetate / ether to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3 -d] pyrimidin-7-yl] -4-hydroxy-N- [2- dimethylamino) ethyl] butyramide. Melting point. 178-179 占 폚.
[906] Example 148: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] propionate
[907] Sodium hydride (120 mg, 60% dispersion in mineral oil) was added to a solution of 4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidine (906 mg) in anhydrous dimethylformamide And the mixture was stirred at ambient temperature for 30 minutes under nitrogen. A solution of ethyl 2-bromopropionate (543 mg) in anhydrous DMF (10 ml) was added dropwise via syringe for 10 minutes. The mixture was stirred for 2 hours at ambient temperature and then left for 18 hours. The mixture was evaporated in vacuo 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 [ 3-d] pyrimidin-7-yl] propionate. Melting point 139-140 占 폚.
[908] Example 149: N- (2-Dimethylaminoethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- amides
[909] 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, filtered and the filtrate was diluted with water (50 ml) and stirred with ether. The mixture was allowed to stand for 18 hours and the precipitated solids were collected by filtration, washed with water, then washed with ether and dried to give N- (2-dimethylaminoethyl) -2- [4-amino- 4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) propionamide. Melting point 163-164 占 폚.
[910] Example 150: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[911] (90 mg), sodium hydride (120 mg, 60% dispersion in mineral oil) and anhydrous dimethylformamide (30 ml) were added to a solution of 4-amino- 5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- Was stirred under nitrogen at ambient temperature for 30 min. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added at 0-5 [deg.] C over 5 minutes with stirring. The mixture was stirred at ambient temperature for 30 minutes and then allowed to stand for 18 hours. The mixture was left under vacuum and the residue was triturated with water and ether. The resulting solid was collected by filtration, washed with water and then washed with ether to give ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidine Yl] acetate. &Lt; / RTI &gt; Melting point 161-161.
[912] Examples 151-156
[913] Overall method
[914] Yl) acetate (194 mg) was heated at 62 占 폚, and methanol (12 ml) was added dropwise to a solution of 2- (4-amino-5-methoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- ) &Lt; / RTI &gt; for 18 hours to give the following compounds after work-up.
[915] Example 151
[916] (Hydroxymethyl)] - 2- [4-amino-5- ((2-hydroxyethyl) 4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide. Melting point 222-223 占 폚 (decomposition)
[917] Example 152
[918] 2- [4-amino-5 - [(4-phenoxyphenyl) -7H-pyrrolo [ 2,3-d] pyrimidin-7-yl] acetamide. Melting point 138-140 DEG C
[919] Example 153
[920] (2-morpholinoethyl) -2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] acetamide. Melting point 164-165 占 폚.
[921] Example 154
[922] (1-imidazolyl) propyl] -2- [4-amino-5- (4-phenoxyphenyl) 3-d] pyrimidin-7-yl] acetamide. Melting point 170-171 占 폚.
[923] Example 155
[924] 2- [4-Amino-5- (4-phenoxyphenyl) - [Lambda] / - 7H-pyrrolo [2,3-d] pyrimidin-7-yl] acetamide. Melting point 122-122.5 占 폚.
[925] Example 156
[926] (2-hydroxyethyl) ethyl] -2- [4-amino-5- (4-phenoxyphenyl) 2,3-d] pyrimidin-7-yl] acetamide. Melting point 145-147 [deg.] C.
[927] Example 157: 2- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[928] (201 mg) and potassium hydroxide aqueous solution (4 ml of a 2M solution) were added to a solution of ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- ) And methanol (20 ml) was boiled under reflux for 1 hour. The mixture was concentrated under reduced pressure to about 5 ml and then diluted with water (30 ml). The mixture was hot filtered and the filtrate was allowed to cool and then acidified with dilute acetic acid until no further precipitation occurred. The mixture was heated on a hot plate until the resulting gel became a finely divided solid. The solid was collected by filtration to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] propionic acid. Melting point 239.5-241 [deg.] C.
[929] Example 158: Ethyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[930] A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (1.5 g) was dissolved in DMF (30 ml) and sodium hydride And treated with ethyl 4-bromobutyrate (1.08 g) in DMF (15 ml) in a similar manner to Example 95 to give ethyl 4- [4-amino-5- (4- Phenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] butyrate. Melting point 104-104.
[931] Example 159: Ethyl 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[932] Pyrrole [2,3-d] pyrimidin-4-ylamine (1.0 g), sodium hydride (1.032 g, 60 in mineral oil) in a similar manner to Example 97. [ (0.55 g) and dimethylformamide (50 ml) were reacted together to obtain a solid after work-up, which was recrystallized from isopropanol to give ethyl 2- [4-amino-5- -Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] carboxamide. Melting point 232-233 [deg.] C.
[933] Example 160: 2- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] -2-methylpropionamide
[934] Pyrrolo [2,3-d] pyrimidine (200 mg) was stirred to obtain 1,3-dimethyl-3,4,5,6-tetrahydro- 2 (1H) -pyrimidinone (1.5 ml), sodium hydride (0.158 g) was added at ambient temperature, and the mixture was stirred for 15 minutes. 2-Bromo-2-methylpropanamide (0.5 g) was added and the mixture was vigorously stirred at ambient temperature for 18 hours under anhydrous atmosphere, then an additional amount of 2-bromo-2-methylpropanamide g) was added and stirred for an additional 24 hours. The pH of the reaction mixture was adjusted to 0 by the addition of diluted hydrochloric acid (5M) with water (3 ml). The suspension was added to water (60 ml) and the mixture was allowed to stand at ambient temperature for 18 hours. The solids were collected by filtration, washed well with water and dried under high vacuum at 50 &lt; 0 &gt; C. The solids were purified by preparative HPLC (reverse phase). The appropriate fractions were collected and combined and extracted with dichloromethane. The dichloromethane was evaporated to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -2-methylpropionamide. Melting point 227-228 [deg.] C.
[935] Example 161: 4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- amides
[936] A mixture of ethyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] butyrate (100 mg) in 30 ml of methanol was stirred for 18 hours Was heated under reflux with 0.6 ml of 2-dimethylaminoethylamine. The mixture was evaporated under reduced pressure and the residue was heated with 2-dimethylaminoethylamine (10 ml) in a steam bath for 18 hours. Excess amine was removed under reduced pressure. To the residue was added water and the mixture was filtered to give 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 2-dimethylaminoethyl) butyramide was obtained.
[937] Examples 162, 163 and 164 were prepared by reacting the same esters with the appropriate amines described in the same manner as in Example 108.
[938] Example 165
[939] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (4-methoxyphenyl) [3- (1-Imidazolyl) propyl] butyramide.
[940] Example 166
[941] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- (2-morpholinophenyl) Polynoethyl) butyramide.
[942] Example 167
[943] Pyrrolo [2,3-d] pyrimidin-7-yl] -N- [3-morpholinopropylamine Polynopropyl) butyramide.
[944] Preparation of starting material
[945] a) tert-Butylamine (15 ml) was added dropwise to a stirred solution of 2-bromo-4'-phenoxyacetophenone (12.7 g, 4 ', according to Tetrahedron Letters, 1993, 34 , 3177) -Phenoxyacetophenone) in DMF (2 mL) and the mixture was heated at 80 &lt; 0 &gt; C for 3 h. The mixture was cooled to 0 &lt; 0 &gt; C and concentrated hydrochloric acid (10 ml) was added. The suspension was stirred at ambient temperature for 18 hours and the solids were collected by filtration to give 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g). Melting point 210-212 [deg.] C.
[946] 1) 4'-Phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g) was added in one go to sodium ethoxide (prepared by dissolving sodium (93 mg) in ethanol (50 ml) The mixture was stirred under nitrogen at 40 &lt; 0 &gt; C for 30 min.
[947] 2) In a separate flask, sodium (331 mg) was dissolved in ethanol (50 ml) and malononitrile (858 mg) was added. This solution was stirred for 5 minutes at ambient temperature, and 4'-phenoxy-2- (tert-butylamino) acetophenone solution obtained in 1) above was added in one go, while sodium chloride precipitated in this solution was eliminated . The resulting mixture was heated at 50 &lt; 0 &gt; C for 3 hours and then at 80 &lt; 0 &gt; C for 2 hours. The solvent was removed under reduced pressure and the oil formed 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, ground with water, filtered and dried to give 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert- butyl) .
[948] b) A mixture of 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert- butyl) pyrrole (1.9 g), formamide (30 ml) and 4- dimethylaminopyridine The mixture was heated at 180 &lt; 0 &gt; C for 6 hours. The mixture was cooled to ambient temperature and black solids precipitated upon addition of water. The solid was collected by filtration, washed with water and then boiled with ethanol, and the insoluble material was 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 7-3 tert-butyl 5- (4- phenoxyphenyl) - Pyrrolo [2,3-d] pyrimidin-4-ylamino) -7- Pyrimidine). Melting point 157-158 [deg.] C. _{^{1 HN, R (d 6 DMSO}} ) δ8.15 (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).
[949] c) A mixture of 4-amino-5- (4-phenoxyphenyl) -7- (tert -butyl) pyrrolo [2,3-d] pyrimidine (5.8 g), glacial acetic acid (55 ml) 55 ml) was boiled under reflux under nitrogen for 18 h. The mixture was allowed to cool and the solids were collected by filtration. This solid was washed with methanol and then washed with ether to give 4-amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3- d] pyrimidine hydrobromide Respectively. Melting point. 288-292 占 폚. The diluted sodium hydroxide solution (100 ml of 5% w / v solution) and ethanol (60 ml) were warmed while stirring the hydrobromide salt and the ethanol was removed by distillation to convert to the free base. The mixture was cooled and the solid was removed by filtration and washed with water to give 5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3- d] pyrimidin- . Melting point: 272 캜.
[950] Example 168: 7-cyclopentanesulfonyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[951] Sodium hydride (0.132 g of a 60% dispersion in mineral oil) was added dropwise to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- -Ylamine &lt; / RTI &gt; (1.0 g). The mixture was stirred for 30 minutes and cyclopentanesulfonyl chloride (0.558 g, prepared as described in JOC 1952, 17 , 1529-1533) in anhydrous dimethylformamide (5 ml) was added dropwise. The mixture was left for 72 h and evaporated in vacuo. The residue was triturated with water and filtered to give a solid which was washed well with water, stirred with ethyl acetate and then filtered. The filtrate was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. The appropriate fractions were collected and evaporated to give 7-cyclopentanesulfonyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine. Melting point 188-188.5 占 폚.
[952] Example 169: 5- (4-phenoxyphenyl) -7- (8-phthalimidoctyl) -7H-pyrrolo [2,3- d] pyrimidin-
[953] Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added dropwise to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Yl amine (906 mg). The mixture was stirred under nitrogen for 30 min before N- (8-bromooctyl) phthalimide (1.4 g) in dimethyl-formamide (5 ml) was added. The mixture was stirred under nitrogen at ambient temperature for 18 hours and then partitioned between water and ethyl acetate. The ethyl acetate layer was separated and purified by flash column chromatography using ethyl acetate as mobile phase to give 5- (4-phenoxyphenyl) -7- (8-phthalimidoctyl) -7H-pyrrolo [ 3-d] pyrimidin-4-ylamine. Melting point 85-86 ° C.
[954] Example 170: 7- (8-Aminooctyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamine dihydrochloride dihydrate
[955] Pyrrolo [2,3-d] pyrimidin-4-ylamine (1.0 g) and hydrazine hydrate (1.0 ml) were added to a solution of 5- (4- phenoxyphenyl) -7- 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 the precipitated solids were collected by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, dried and treated with a concentrated solution of hydrochloric acid in isopropanol drop until no further precipitation occurred. The mixture was left to stand overnight, the supernatant was discarded 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 dihydrate. Melting point 120 캜.
[956] Example 171: N- {2- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] ethyl} phthalimide
[957] Pyrrolo [2,3-d] pyrimidin-4-ylamine was reacted with 2-bromoethyl (2-bromoethyl) Pyrido [2,3-d] pyrimidin-7-yl] ethyl} phthalimide was reacted with phthalimide to give N- {2- [ . Melting point 111-112 [deg.] C.
[958] Example 172: 7- (2-aminoethyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamine hydrochloride
[959] In a similar manner to Example 469, the product from the above example was treated with hydrazine hydrate to give 7- (2-aminoethyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] Pyrimidin-4-ylamine hydrochloride. Melting point 284-285 [deg.] C.
[960] Example 173: 7-Isobutyryl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[961] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (4.32 g) in anhydrous Was added dropwise to a mixture of dimethylformamide (200 ml) and anhydrous pyridine (2 ml). The mixture was stirred at ambient temperature for 1 hour and evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The ethyl acetate was isolated, dried, evaporated and the obtained residue was recrystallized from toluene to give 7-isobutyryl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- Lt; / RTI &gt; amine was obtained. Melting point 160.5-161 ° C.
[962] Example 174: 5- (4-phenoxyphenyl) -7- (1,4-dioxaspiro [4,5] decan-8-yl) -7H-pyrrolo [2,3- d] pyrimidine- 4-ylamine
[963] Sodium hydride (0.26 g of a 60% dispersion in mineral oil) was added to a solution of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- -Ylamine &lt; / RTI &gt; (1.94 g). The mixture was stirred until the evolution of hydrogen ceased and then 8-tosyloxy-1,4-dioxaspiro [4,5] decane (2.0 g, 1,4-dioxaspiro [4, 5] decan-8-one (prepared according to the literature (J. Med. Chem. 1992, 2246)). The mixture was heated at 120 &lt; 0 &gt; C under nitrogen for 5 h, cooled to ambient temperature, quenched with water and extracted with ethyl acetate to give a residue which was purified by column chromatography using ethyl acetate Ethyl acetate in hexanes to give 5- (4-phenoxyphenyl) -7- (1,4-dioxaspiro [4,5] decan-8-yl) -7H- Lt; / RTI &gt; [2,3-d] pyrimidin-4-ylamine. Melting point 193-194 占 폚.
[964] Example 175: 4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexanone
[965] The product from the above example (500 mg), acetone (20 ml) and 3M hydrochloric acid (10 ml) was stirred under nitrogen at ambient temperature for 20 minutes. The mixture was heated at 60 &lt; 0 &gt; C for 1 hour and then the acetone was removed under reduced pressure. The residue was basified with aqueous 5M sodium hydroxide solution and 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. Melting point 252-254 [deg.] C.
[966] Example 176 and Example 177: cis-5- (4-phenoxyphenyl) -7- (4-morpholinocyclohex-1-yl) -7H- pyrrolo [2,3- d] pyrimidin- 4-ylamine and trans-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[967] Sodium triacetoxyborohydride (42 mg) and glacial acetic acid (18 mg) were added to the product from Example 175 (120 mg) and morpholine (31 mg) in 1,2-dichloroethane. The mixture was stirred at 40 &lt; 0 &gt; C for 2 h, then an additional portion of morpholine (0.15 g) and sodium triacetoxyborohydride (0.21 g) was added. The mixture was stirred at ambient temperature for 20 hours and quenched with saturated aqueous bicarbonate solution. The mixture was filtered through an EMPORE (TM) cartridge and the filtrate was extracted with 3M hydrochloric acid. The acidic extract was basified with 5M sodium hydroxide solution and extracted with dichloromethane to give a residue which was purified by chromatography on silica to give cis-5- (4-phenoxyphenyl) -7- Yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-5- (4- phenoxyphenyl) -7- (4-morpholinocyclo Hex-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine.
[968] Example 178 and Example 179: cis-7- (4-N-ethoxycarbonyl) piperazin-1-ylcyclohexyl) -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3 (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-7- (4- 2,3-d] pyrimidin-4-ylamine
[969] In a manner similar to the previous example, the title compound was obtained from 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- (158 mg) in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 ml) containing glacial acetic acid (60 mg) and 1-ethoxycarbonyl-piperidine (4-phenoxycarbonyl) piperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [ 3-d] pyrimidin-4-ylamine and trans-7- (4-N-ethoxycarbonyl) piperazin-1 -ylcyclohexyl) [2,3-d] pyrimidin-4-ylamine.
[970] Example 180: 2- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] pyridine-
[971] Pyrrolo [2,3-d] pyrimidin-4-ylamine (906 mg) was treated with sodium hydride (150 mg) in dimethylformamide (30 ml) (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] pyridine-3-carbonitrile. Melting point 242-242.5 占 폚.
[972] Example 181: 7- [3- (aminomethyl) pyrid-2-yl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Maleate
[973] The product from the previous example (468 mg), ethanol saturated with ammonia (200 ml) and Raney (registered trademark) nickel (2 ml) were shaken under hydrogen at 80 ° C and 26 bar pressure for 6 hours, then 68 hours Allowed to stand at ambient temperature. The mixture was filtered, and the residue was washed well with ethanol. The filtrate was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and filtered. Maleic acid (135 mg) dissolved in ethyl acetate (20 ml) was added to the filtrate until the precipitation no longer occurred. The mixture was warmed and taken up from the remaining small amount of sword. The gum was further heated with ethyl acetate and decanted. The combined ethyl acetate extracts were cooled and the precipitated solids were collected by filtration to give 7- [3- (aminomethyl) pyrid-2-yl] -5- (4- phenoxyphenyl) -7H- pyrrolo [ lt; / RTI &gt; d] pyrimidin-4-ylamine dimaleate. Melting point 131-134 [deg.] C.
[974] Example 182:
[975] Pyrrolo [2,3-d] pyrimidin-7-yl] -8-methyl-8-azabicyclo [3.2.1] octane
[976] Pyrrolo [2,3-d] pyrimidin-4-ylamine (770 mg, dimethylformamide (30 ml), sodium hydride (168 mg, 60% dispersion in mineral oil) &Lt; / RTI &gt; in water). To a stirred solution of 3-mesyloxy-8-methyl-8-azabicyclo [3.2.1] octane (900 mg, prepared as described in JACS 1958, 80 , 4679) in dimethylformamide (10 ml) / RTI &gt; The mixture was allowed to warm (and left at ambient temperature for 7 days) at 75 ° C for 5 hours. The solvent was removed under reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate to give a residue, ethyl acetate / methanol (50:50) was used as mobile phase to remove the starting material, ethyl acetate Purification by flash column chromatography on silica using acetate / methanol / triethylamine (5: 5: 1). The appropriate fractions 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- -Yl] -8-methyl-8-azabicyclo [3.2.1] octane. Melting point 238-250 占 폚.
[977] Example 183 and Example 184: Synthesis of cis-7- (N-methyl homopiperazin-1-ylcyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Pyrrolor2,3-d] pyrimidin-4-yl (4-fluoropyridin-2-yl) Amine
[978] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexanone (40 mg, N-methyl homopiperazine (114 mg), sodium 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-methyl homopiperazin-1-ylcyclohexyl) -5- (4- phenoxyphenyl) Pyrrolo [2,3-d] pyrimidin-4-ylamine and trans-7- (N-methyl homopiperazin-1-ylcyclohexyl) [2,3-d] pyrimidin-4-ylamine.
[979] Pyrrolo [2,3-d] pyrimidin-4-ylmethyl) -4- (4-fluorobenzyloxy) Pyran [2,3-d] pyrimidin-4-ylamine &lt; / RTI &gt;
[980] In a similar manner to the previous example, N-methylpiperazine (100 mg) was reacted with the same amount of cyclohexanone derivative and other reagents to give cis-7- (N-methylpiperazin-1-ylcyclohexyl) -5 Pyrimidin-4-ylamine and trans-7- (N-methylpiperazin-1 -ylcyclohexyl) -5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- -Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine.
[981] Example 187: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] -cyclopentan-
[982] (100 mg), activated manganese dioxide (100 mg), &lt; RTI ID = 0.0 &gt; (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-one hydrochloride, which is used in the next example, -LH-pyrrolo [2,3-d] pyrimidin-7-yl] -cyclopentan-l-one.
[983] Example 188: cis-7- (3-morpholinocyclopent-1-yl) -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- And trans-7- (3-morpholinocyclopent-1-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[984] Morpholine (45 mg) was added to the solution obtained in the previous example, followed by the addition of sodium triacetoxyborohydride (151 mg) and glacial acetic acid (47 mg). The mixture was stirred at ambient temperature under nitrogen for 18 hours, during which the dichloromethane was evaporated. Tetrahydrofuran (100 ml) was added and the mixture was stirred for an additional 8 hours. The mixture was worked up to give cis-7- (3-morpholinocyclopent-1-yl) -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Amine and trans-7- (3-morpholinocyclopent-1-yl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Respectively.
[985] Example 189: 3- (4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- ) -Carbamate &lt; / RTI &gt; hydrochloride
[986] a) To a solution of 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl) cyclopentanol (20 mg) in dichloromethane To the solution was added N-methylmorpholine (7 ml) at 0 C and the mixture was stirred for 20 minutes. The cooling bath was removed, 4-nitrophenyl chloroformate (12.5 mg) was added and the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate and evaporated to give the crude product.
[987] b) The crude product from a) in dichloromethane (2 ml) was added to 2-morpholinoethylamine (0.2 ml) and the mixture was stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic material was dried, filtered and evaporated to give the 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-morpholinoethyl) -carbamate.
[988] c) The product from b) was dissolved in ethyl acetate (2 ml) and hydrogen chloride gas was bubbled through the solution for 2 min. A precipitate formed and was stirred continuously for an additional 10 minutes. The solvent was evaporated and water was added to dissolve the solids. Lyophilized to give 3- (4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-7-yl) cyclopentyl N- Naphthyl) -carbamate hydrochloride. &Lt; / RTI &gt;
[989] Example 190: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl 2-aminoacetate hydrochloride
[990] a) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7- yl] cyclopentanol (50 mg, 0.129 mmol) Tert-Butoxycarbonylglycine (34 mg, 0.194 mmol) was mixed in N, N-dimethylformamide (1 ml). Was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) and 4-dimethylaminopyridine (16 mg, 0.129 mmol). 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 chlorine, dried (MgSO _4), filtered and evaporated. The solids were 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 2 - [(tert-butoxycarbonyl) amino] acetate. This structure was confirmed by ¹ H NMR.
[991] b) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] cyclopentyl 2 - [(tert-butoxycarbonyl ) Amino] acetate (39 mg, 0.072 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen gas was passed for 1 minute. The flask was capped and the solution was stirred for an additional 30 minutes. Upon addition of diethyl ether, a 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 2-aminoacetate hydroo Chloride. This structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 444).
[992] Example 191: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] cyclopentyl (2S) -Methyl butanoate hydrochloride
[993] a) Preparation of 2S-1 - [(tert-butoxycarbonyl) amino] -2-methylbutano 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 , 0.171 mmol). The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed, dried (MgSO _4), filtered and evaporated. The solids were 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-butoxycarbonyl) amino] -3-methyl butanoate. This structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 586).
[994] b) 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl (2S) Butoxycarbonyl) amino] -3-methyl butanoate (35 mg, 0.060 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed for 5 minutes. The flask was capped and the solution was stirred for an additional 30 minutes. Upon addition of diethyl ether, a precipitate formed. The solid was collected and filtered to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl (2S) -3-methylbutanoate &lt; / RTI &gt; hydrochloride. This structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 486).
[995] Example 192: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] cyclopentyl N- ) Carbamate hydrochloride
[996] a) N-Methylmorpholine (0.007 ml, 0.062 mmol) was added dropwise to a solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) with stirring at 0 ° C under nitrogen. After 20 minutes, the ice bath was removed and the mixture was allowed to warm to ambient temperature. Pyrrolor2.3-d] pyrimidin-7-yl] cyclopentanol (20 mg, 0.052 mmol) was added to the mixture, The formed solution was stirred for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried (MgSO _4), filtered and evaporated 3- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl (4-nitrophenyl) carbonate. This structure was confirmed by ¹ H NMR.
[997] b) To a solution of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl (4-nitrophenyl) ) Carbonate (0.052 mmol) were 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 with ethyl acetate, 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- Morpholinoethyl) carbamate. &Lt; / RTI &gt; This structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 543).
[998] c) Preparation of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl N- (2-morpholinoethyl) (10 mg, 0.018 mmol) was dissolved in ethyl acetate (2.5 ml). Upon passage of the hydrogen chloride gas for 2 minutes, a precipitate formed. The flask was capped and the solution was stirred for an additional 10 minutes. The solids were collected by filtration to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl N- Polynoethyl) carbamate hydrochloride. &Lt; / RTI &gt; This structure was confirmed by ¹ H NMR and LC / MS (MH ⁺ = 543).
[999] Preparation of starting material
[1000] a) tert-Butylamine (15 ml) was added with stirring to a solution of 2-bromo-4'-phenoxyacetophenol (12.7 g, 4 ', according to Tetrahedron Letters, 1993, 34 , 3177) -Phenoxyacetophenone) in DMF (2 mL) and the mixture was heated at 80 &lt; 0 &gt; C for 3 h. The mixture was cooled to 0 &lt; 0 &gt; C and concentrated hydrochloric acid (10 ml) was added. The suspension was stirred at ambient temperature for 18 h and the collected solid was filtered to give 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g). Melting point 210-212 [deg.] C.
[1001] b) (1) 4'-Phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g) was dissolved in sodium ethoxide (prepared by dissolving 93 mg of sodium in ethanol (50 ml) Was added in one portion, and the mixture was stirred at 40 &lt; 0 &gt; C under nitrogen for 30 min.
[1002] (2) In a separate flask, sodium (331 mg) was dissolved in ethanol (50 ml) and malononitrile (858 mg) was added. The solution was stirred for 5 minutes at ambient temperature and the 4'-phenoxy-2- (tert-butylamino) acetophenone solution obtained in (1) above was added in one go, with the sodium chloride precipitated in this solution being eliminated . The resulting mixture was heated at 50 &lt; 0 &gt; C for 3 hours and then at 80 &lt; 0 &gt; C for 2 hours. The solvent was removed under reduced pressure and the oil formed 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, triturated with water, filtered and dried to give 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert- butyl) .
[1003] c) A mixture of 1.9 g of 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert- butyl) pyrrole, 30 ml of formamide and 10 mg of 4-dimethylaminopyridine RTI ID = 0.0 &gt; 180 C &lt; / RTI &gt; The mixture was cooled to ambient temperature and a black solid precipitated upon addition of water. The solids were collected by filtration, washed with water and then boiled in ethanol, and the insoluble material was 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 7-3 tert-butyl 5- (4-phenoxyphenyl) -7H Pyrrolo [2,3-d] pyrrolo [2,3-d] pyrimidin-4-ylamine (prepared by reacting 4-amino- Lt; / RTI &gt; Melting point 157-158 [deg.] C. _{^{1 H NMR (d 6 DMSO)}} δ8.15 (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).
[1004] d) Pyrrolo [2,3-d] pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (48% 55 ml of the solution) was boiled under reflux for 18 hours under nitrogen. The mixture was allowed to cool and the solids were collected by filtration. This solid was washed with methanol and then washed with ether to give 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] -pyrimidine hydrobromide. Melting point 288-292 占 폚. The hydrobromide salt was converted to the free base by stirring with distillation and heating with dilute sodium hydroxide solution (100 ml of 5% w / v solution) and ethanol (60 ml) while 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.
[1005] e) A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (600 mg) and tetrakis (triphenylphosphine) palladium (40 ml) The mixture of the side (30 ml) was stirred under nitrogen in ice / water, 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 temperature (under light exclusion) for 66 h, then the tetrahydrofuran was removed under reduced pressure and water was added to the residue. The 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 / heptane methyl acetate (9: 1) as mobile phase to give 4- [4 -Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] -cyclopent-2-enol as an oil. This structure was confirmed by ¹ H NMR and mass spectrum.
[1006] f) A mixture of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- Hydrogenation was carried out with gaseous hydrogen at atmospheric pressure in ethanol (20 ml) using 10% palladium on carbon (50 mg). 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 Lt; / RTI &gt; as an oil. This structure was confirmed by ¹ H NMR and mass spectrum.
[1007] Example 193: cis-5- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3- d] pyrimidin-
[1008] Pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained in the same manner as in the step for the preparation of trans-5- (4-phenoxyphenyl)
[1009] Pyrrolo [2,3- d] pyrimidin-7-yl] cyclohexanone (2.34 g, 0.36 mmol) in 1,2- (1.25 g, 17.6 mmol) and glacial acetic acid (1.00 ml, 17.6 mmol) were added under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion and the resulting mixture was stirred for 70 hours. The mixture was extracted with a 2M aqueous hydrochloric acid solution (2 x 200 ml). The combined extracts were washed with dichloromethane (300 ml), made basic with 12.5 M aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 200 ml). The combined extracts were dried over sodium sulfate and chromatographed on a Biotage 40S column using ethyl acetate / triethylamine (95: 5) and ethyl acetate / triethylamine / methanol (85: 10: To give 7- (4-phenoxyphenyl) -7- (4-pyrrolidinocyclohex-1-yl) -7H-pyrrolo [2,3- d] pyrimidin-4-ylamine (melting point 101-104 ° C. LC / MS (Hypersil BDS c18 (100 × 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile within 8 min): MH ⁺ 454 t _r = 3.56 minutes) and a white solid (0.93g, 2.1mmol) of trans-5- (4-phenoxyphenyl) -7- (4-pyrrolidino cyclo hex-1-yl) -7H- as pyrrolo [ 2,3-d] pyrimidin-4-ylamine (melting point 183-185 ° C. LC / MS (Hypersil BDS c18 (100 × 2.1 mm) 0.1M ammonium acetate / acetonitrile, 10-100% acetonitrile within 8 min) : MH ^& lt ^{; + &} gt ^; 454 t _r = 3.68 min).
[1010] Example 194:
[1011] Pyrrolo [2,3-d] pyrimidin-4-ylamine hydrochloride (prepared according to the method described in Example 1)
[1012] Pyrrolo [2,3-d] pyrimidin-4-ylamine (prepared as described in Example 1)
[1013] Pyrrolo [2,3- d] pyrimidin-7-yl] cyclohexanone (2.34 g, 0.36 mmol) in 1,2- (1.50 g, 17.6 mmol) and glacial acetic acid (1.00 ml, 17.6 mmol) were added under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added in one portion and the resulting mixture was stirred for 70 hours. The mixture was extracted with a 2M aqueous hydrochloric acid solution (2 x 200 ml). The combined extracts were washed with dichloromethane (300 ml), made basic with 12.5 M aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 200 ml). The combined extracts were dried over sodium sulfate and purified by chromatography on a Biotage 40S column using ethyl acetate / triethylamine (95: 5) as the mobile phase to give cis-5- (4-phenoxyphenyl) -7 (LCMS) (Hypersil BDS c18 (100x2.1 mm)) was added to a solution of 2- (4-piperidinocyclohex- 1-yl) -7H-pyrrolo [2,3- d] pyrimidin- (4-phenoxyphenyl) -methanesulfonamide as a gray solid (193 mg, 0.4 mmol), and 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile in 8 min): MH ⁺ 486 t _r = 3.67 min) Pyrrolo [2,3-d] pyrimidin-4-ylamine (melting point 192-195 ° C. LC / MS (Hypersil BDS c18 100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile (within 8 min)): MH ⁺ 468 t _r = 3.71 min).
[1014] Example 195:
[1015] Pyrrolo [2,3-d] pyrimidin-4-ylamine was dissolved in ethyl acetate (1: 1, 50 ml), diluted with diethyl ether (50 ml) and treated with a 1 M solution of hydrogen chloride in diethyl ether until no further precipitation occurred. The resulting solid was collected and recrystallized from pure ethanol to give cis-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohex-1-yl) -7H -Pyrrolo [2,3-d] pyrimidin-4-ylamine hydrochloride. Melting point 185-189 [deg.] C.
[1016] Example 196: Synthesis of trans-7- (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1017] (4-dimethylaminocyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
[1018] To a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexanone (3.24g, 8.1mmol) in dichloromethane Was added N-methylpiperidine (1.20 g, 12.0 mmol) and glacial acetic acid (0.69 ml, 12.0 mmol) under nitrogen atmosphere and the resulting mixture was stirred for 10 minutes at room temperature. Sodium triacetoxyborohydride (1.70 g, 8.0 mmol) was added in one portion and the resulting mixture was stirred for 6 h. The additions were repeated on the same scale and the formed solution was stirred for 70 hours. The solution was extracted with a 2 M aqueous hydrochloric acid solution (2 x 300 ml). The combined extracts were washed with dichloromethane (300ml), made basic with 0.880M aqueous ammonia solution and extracted with ethyl acetate (3x250ml). The combined extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and purified by chromatography on a Biotage 40M column using ethyl acetate / methanol / triethylamine (8: 1: 1) as mobile phase to give a gray solid Pyrrolo [2,3-d] pyrimidin-4-ylamine (melting point: 180 - 182 nm) as cis-7- (4-dimethylaminocyclohexyl) Deg.] C, LC / MS (Hypersil BDS c18 (100 x 2.1 mm) 0.1M ammonium acetate / acetonitrile, 10-100% acetonitrile (within 8 min)): MH ⁺ 428 t _r = 3.43 min.
[1019] The column was washed with ethyl acetate / methanol / triethylamine (4: 1: 1, 500 ml) and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (200 ml) and purified by chromatography on a Biotage 40M column using dichloromethane / methanol (9: 1 to 7: 3) to give trans- Pyrrolo [2,3-d] pyrimidin-4-ylamine (melting point: 207.5-210 [deg.] C, LC / MS Hypersil BDS c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10-100% acetonitrile (within 8 min)): MH ⁺ 428 t _r = 3.48 min.
[1020] R - (+) - 4- [4-amino-5- (4-phenoxyphenyl) -7- (3-tetrahydrofuryl) -7H-pyrrolo [2,3-d] pyrimidine.
[1021] Example 197: 4 - {(S) -tetrahydrofuran-3-yl} toluenesulfonate
[1022] To a solution of (S) -3-hydroxytetrahydrofuran (2.0 g, 23 mmol) in pyridine (40 ml) was added tosyl chloride (4.8 g, 25 mmol) in portions at 0 ° C. The solution was stirred at 0 &lt; 0 &gt; C for 1 h and then overnight at room temperature. The pyridine was evaporated in vacuo and the residue was partitioned between EtOAc and a saturated aqueous citric acid solution (200 ml each). The aqueous layer was extracted with EtOAc (2x200ml) and the combined organics were dried (sodium sulfate), filtered and evaporated to give an oil (4.5g, 85%). _{^{1 H NMR (CDCl 3, 250MHz}} ): 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).
[1023] 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) 60% Sodium hydride in mineral oil (0.75 g, 19 mmol) was added and the mixture was stirred at room temperature for 30 min. The resulting darkish solution was treated with 2 ml aliquots in a solution of 4 - {(S) -tetrahydrofuran-3-yl} toluenesulfonate (4.20 g, 18 mmol) in N, N-dimethylformamide (20 ml). The formed solution was stirred at room temperature for 30 minutes and then at 95 &lt; 0 &gt; C for 18 hours. The solution was cooled to ambient temperature and then poured into ice / water (200ml). The aqueous solution was extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with water (4x150ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was warmed to dichloromethane (1000 ml) until a solution was obtained, cooled to ambient temperature and ethyl acetate / triethylamine (95: 5) was used as the mobile phase and then diluted with ethyl acetate / triethylamine / methanol (4-amino-5- (4-phenoxyphenyl) -7- (tert-butyldimethylsilyloxy) phenyl) -methanone as a gray solid (4.35 g, 12 mmol) (Hypersil BDS c18 (100 x 2.1 mm), 0.1 M ammonium acetate / acetonitrile, 10- 100% acetonitrile (within 8 min)): MH ⁺ 373 t _r = 4.44 min, [] _D +20.5 0.6 (dichloromethane, 22.6 캜).
[1024] Example 198: 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1025] N-tert-Butoxycarbonylpiperidinol
[1026] Sodium borohydride (1.9 g, 50 mmol) was added portionwise to a solution of N-tert-butoxycarbonylpiperidone (10.0 g, 50 mmol) in MeOH (100 ml) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 20 hours. Quenched with 2N NaOH (20ml), the solvent was evaporated and the residue was partitioned between ethyl acetate and water (100m each). The aqueous layer was extracted with ethyl acetate (3x100ml) and the combined organic layers were washed with brine and water (1x100ml each). Dried (Na ₂ SO _4), filtered and concentrated to give N-3 difference as a colorless oil (10.5g, 100%) - to give the sub-ethoxycarbonyl-piperidinol. R _f = 0.05 (KMnO ₄ dip) in 20% EtOAc / hexane. IR (thin film): 3428, 2939, 1693 cm ^-1 .
[1027] Example 199: tert-Butyl 4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate
[1028] Tosyl chloride (9.94 g, 0.052 mol) was added portionwise to a solution of N-tert-butoxycarbonylpiperidinol (10.5 g, 0.052 mol) in pyridine (150 ml) at 0 ° C under nitrogen. Warmed to room temperature, and stirred overnight at room temperature. The solvent was evaporated and partitioned between citric acid solution (1M, 100ml) and ethyl acetate (200ml). The acidic layer was extracted with ethyl acetate (1x100ml) and the combined organic phases were washed with citric acid solution (1M, 2x100ml), brine (100ml) and water (100ml). Dried and purified by (Na ₂ SO _4), filtered, Evaporation of remaining oil, and this, using 10% EtOAc / cyclohexane, the following 15% EtOAc / cyclohexane flash column chromatography, as a white solid ( 11.0 g, 60%) F 30-68 tert-Butyl 4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate was obtained. 20% EtOAc / Rf = 0.17 in cyclohexane. _{^{1 H NMR (CDCl 3, 250MHz}} ): δ7.79 (2H, d), 7.34 (2H, d), 4.67 (1H, m), 3.58 (2H, m), 3.27 (2H, m), 2.45 (3H , s), 1.59-1.83 (4H, m), 1.43 (9H, s).
[1029] Example 200: tert-Butyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Decylate
[1030] To a solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (2.0 g, 6.6 mmol) in anhydrous DMF (100 ml) g, 60% dispersion, 6.6 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Tert-Butyl 4 - [(4-methylphenyl) sulfonyl] oxy-1-piperidinecarboxylate (2.34 g, 6.6 mmol) was added and the resulting solution was heated at 95 ° C for 72 h. The reaction was quenched by the careful addition of water (150 ml). Extract with EtOAc (3x100ml), wash with water (4x100ml) and brine (2x100ml). Dry the organic solution and (Na ₂ SO _4), filtered, Evaporation of solids remaining, and absorb it on the silica, by flash silica gel column chromatography using EtOAc as the eluant with the following 5% MeOH / EtOAc To give F13-22 tert-butyl 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- -Piperidine carboxylate (1.0 g, 31%). Melting point 168.5-169.5 占 폚. Rf = 0.4 in 10% EtOAc / cyclohexane. _{^{1 H NMR (d 6 DMSO,}} 250MHz): δ8.14 (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 spectrum. _{C 28 H 31 O 3 N 5} (485.2430). IR (KBr disc): 3059, 1695, 1588, 1235 cm ^-1 .
[1031] Example 201: 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1032] The third of the at 0 ℃ anhydrous CH ₂ Cl ₂ (25ml) - butyl-4- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3-d] pyrimidin-7 -1-piperidinecarboxylate (0.69 g, 1.4 mmol) in THF (5 ml) was added TFA (5 ml). The solution was stirred at room temperature for 20 hours and the solvent was evaporated. NaOH solution (5N, 10ml) was added and the resulting slurry was extracted with EtOAc (3x50ml). Washed with brine (1 x 50 ml). Dried, filtered and concentrated to leave a solid which was triturated with diethyl ether and filtered to give 5- (4-phenoxyphenyl) -7- (4-piperidyl) as a white solid (500 mg, 91% ) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (433258). Melting point 209-211 [deg.] C. R _f = 0.1 in 1: 1 EtOAc: MeOH. _{^{1 H NMR (d 6 DMSO,}} 250MHz): δ8.13 (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 spectrum. C ₂₃ H ₂₃ ON ₅ (385.1902). IR (KBr disc): 3278, 1620, 1585, 1490, 1245 cm ^-1 .
[1033] Example 202: 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamine dihydrochloride
[1034] To a solution of 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine ( 433258) (200 mg) was added ether-HCl solution (1.0 M, 3 ml). The resulting white precipitate was filtered under a stream of nitrogen and dried under vacuum for 6 hours to give 5- (4-phenoxyphenyl) -7- (4-piperidyl) -7H-pyrrolo [ 3-d] pyrimidin-4-ylamine dihydrochloride. Melting point. 304 ° C (decomposition). ¹ H NMR (D ₂ O, 250 MHz): 8.48 (1H, s), 7.69 (1H, s), 7.50-7.58 (4H, m), 7.18-7.34 ), 3.81 (2H, d), 3.46 (2H, m), 2.49 (4H, m). IR (KBr disc): 3937, 1657, 1231 cm ^-1 .
[1035] Example 203: tert-Butyl 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- Decylate
[1036] N-tert-Butoxycarbonylpyrrolidin-3-ol
[1037] Triethylamine (22.2 g, 30.5 ml, 0.22 mol) was added to a solution of pyrrolidin-3-ol (10.0 g, 0.11 mol) in dichloromethane (200 ml) at 0 ° C, Rebonate (28.8 g, 0.13 mol) was added. Warmed to room temperature, and stirred overnight at room temperature. Quenched with saturated aqueous citric acid solution (150 ml) and the organic layer washed with water, brine and back water (1 x 100 ml each). The organic layer was dried (sodium sulfate), filtered and evaporated to give N-tert-butoxycarbonylpyrrolidin-3-ol (20.0 g, 93% crude) as a golden oil.
[1038] Example 204: tert-Butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate
[1039] Tosyl chloride (22.3 g, 0.117 mol) was added portionwise to a solution of N-tert-butoxycarbonylpyrrolidin-3-ol (19.8 g, 0.106 ml) in pyridine (200 ml) at 0 ° C under nitrogen. Stir at 0 &lt; 0 &gt; C for 2 hours, warm to room temperature and stir overnight at room temperature. The pyridine was evaporated in vacuo and the residue was partitioned between EtOAc and a saturated aqueous citric acid solution (200 ml each). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organics were dried (sodium sulfate), filtered and evaporated to leave an oil which was purified by flash silica gel column chromatography using 10% EtOAc / cyclohexane as eluent To give an F40-85 oil. The oil was dissolved in a small amount of cyclohexane / diethyl ether (5: 1, 50 ml), cooled and scratched with a spatula to induce crystallization. The solid formed was filtered to give tert-butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate (10.5 g, 29%) as a white solid. R _f = 0.13 in EtOAc / cyclohexane. _{^{1 H NMR (CDCl 3, 250MHz}} ): δ7.79 (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).
[1040] To a solution of 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine (2.0 g, 6.6 mmol) in anhydrous DMF (120 ml) g, 60% dispersion, 6.6 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. Tert-Butyl 3 - [(4-methylphenyl) sulfonyl] oxy-1-pyrrolidinecarboxylate (2.25 g, 6.6 mmol) was added in portions and the mixture was heated at 95 <0> C for 72 h. Quenched with water and extracted with EtOAc (4 x 100 mL). The combined organic solution was washed with water (4x100ml) and brine (2x100m). The organics were dried (sodium sulfate), filtered and evaporated to leave a solid which was dissolved in EtOAc / MeOH and adsorbed onto silica. Purification by flash silica gel column chromatography using 5% MeOH / EtOAc as eluent gave F 17-25 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. Melting point 168-170 占 폚. R _f = 0.46 in 9: 1 EtOAc: MeOH. _{^{1 H NMR (d 6 DMSO,}} 250MHz): δ8.17 (1H, s), 7.38-7.50 (5H, m), 6.19 (2H, bs), 5.31 (1H, m), 3.77 (1H, m), 3.42-3.60 (3H, m), 2.38 (2H, m), 1.40 (9H, s). Mass spectrum. 471.2250 (C ₂₇ H ₂₉ O ₃ N ₅ ). IR (KBr disc): 3130, 1683, 1585, 1404, 1245 cm ^-1 .
[1041] Example 205: 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1042] To a solution of tert-butyl 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- -Pyrrolidinecarboxylate (0.8 g, 1.7 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 20 hours. The solvent was evaporated and diluted NaOH (5N, 10 ml) was added. The resulting residual solution was extracted with EtOAc (3x50ml) and the combined organic phases washed with brine (1x75ml). The organic solution was dried (sodium sulfate), filtered and evaporated in vacuo to give 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H- pyrrolo [ Pyrimidin-4-ylamine (0.5 g, 79%). Melting point 182-184 占 폚. R _f = 0.15 in 1: 1 EtOAc: MeOH. _{^{1 H NMR (d 6 DMSO,}} 250MHz): δ8.14 (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 spectrum. _{371.1758 (C 22 H 21 ON 5} ). IR (KBr disc): 3106, 1585, 1489, 1232 cm ^-1 .
[1043] Example 206: 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamine dihydrochloride
[1044] To a solution of 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine ( Was added ether-HCl (1.0 M, 3 ml) and the resulting precipitate was filtered under nitrogen to give 5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H- (2, 3-d] pyrimidin-4-ylamine dihydrochloride (0.4 hydrate) (190 mg). Melting point 298 캜 (decomposition). IR (KBr disc): 2909, 1658, 1249 cm ^-1 .
[1045] Example 207: 7-Perhydro-1-pyrrolizinyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 4-amine dihydrochloride salt.
[1046] a) Preparation of perhydro-1-pyrrolidinol
[1047] Prepared as described in Schnekenburger J, Briet E, Arch. Pharm. (Wienheim) 310, 152-160 (1977).
[1048] b) Perhydro-1-pyrrolidinyl methanesulfonate
[1049] A mixture of perhydro-1-pyrrolidinol (0.5 g, 3.94 mmol) and triethylamine (0.60 g, 5.91 mmol) in dichloromethane (10 ml) was stirred at 0 ° C under a nitrogen atmosphere. Methanesulfonyl chloride (0.68 g, 5.91 mmol) was added and 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 sodium bicarbonate (10 ml) were added. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure to give a residue. The material was purified by flash chromatography on silica gel using heptane / ethyl acetate (1: 3) as the eluent to give perhydro-1-pyrrolidinyl methanesulfonate (0.54 g). ¹ H NMR (DMSO-d ₆ , 400 MHz) 4.96 (m, 1H), 3.61 (m, 1H), 2.9-3.3 (m, 6H), 2.35 ),
[1050] c) Preparation of 7-perhydro-1-pyrrolizinyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 4-amine dihydrochloride salt
[1051] A mixture of 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-4-amine (0.49 g, 1.62 mmol) and 60% sodium hydride in oil (100 mg, 2.43 mmol) Was stirred at ambient temperature under a nitrogen atmosphere for 15 minutes. The mixture was heated at 100 &lt; 0 &gt; C for 18 hours and then cooled to ambient temperature. Additional 60% sodium hydride in oil (100 mg, 2.43 mmol) was added and heating continued for a further 2 h. The mixture was cooled to ambient temperature and the solvent was 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 reduced pressure. The resulting residue was purified by preparative C-18 RP HPLC to give 150 ml of a white solid which was dissolved in ethyl acetate (10 ml) and treated with 1N hydrogen chloride in ethyl ether to give 7-perhydro-1-pyrrolizinyl- Pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride salt as a white solid. _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ8.52 (s, 1H), 7.95 (s, 1H), 7.02-7.58 (m, 1H), 5.38 (m, 1H), 4.40 (m, 1H), 1.9-3.9 (m, 10H); (Hypersil HS C18 5 [mu] m, 100 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.62 min; MS: MH ^&lt; ^{+ &} gt ^;
[1052] Example 208: 7- (2-Methylperhydrocyclopenta [c] pyrrol-5-yl) -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- Amine dihydrochloride salt
[1053] a) 2-Methylperhydrocyclopenta [c] pyrrol-5-ol
[1054] As described in literature (Bohme H, Setiz G, Arch. Pharm. Wienheim 301, 341, (1968)),
[1055] b) 4-Chloro-5-iodo-7- (2-methylpyrrolocyclopenta [c] pyrrol- 5- yl) -7H-pyrrolo [2,3- d] pyrimidine
[1056] To a solution of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (0.38 g, 1.36 mmol), 2-methylferrocyclopenta [ (0.23 g, 1.63 mmol) and triphenylphosphine (0.71 g, 2.72 mmol) was treated with diethyl azodicarboxylate (0.474 g, 2.72 mmol) and stirred at ambient temperature for 2 hours . The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (10 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride (10 ml), dried over magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified by flash chromatography using dichloromethane / methanol (8: 2) as the mobile phase to give 4-chloro-5-iodo-7- (2-methylperhydrocyclopenta [ Yl) -7H-pyrrolo [2,3-d] pyrimidine (0.25 g) was obtained. _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 5.36 (m, 1H), 2.88 (m, 2H), 2.68 ( m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2.06-2.02 (m, 4H); TLC (dichloromethane / methanol 8: 1) _Rf = 0.29; RP-HPLC (Hypersil HS C18 5 m, 100 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 6.50 min; MS: MH ^{&lt; + &} gt ^;
[1057] c) 7- (2-Methylperhydrocyclopenta [c] pyrrol-5-yl) -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Hydrochloride salt
[1058] Pyrrolo [2,3-d] pyrimidine (0.25 g, 0.622 mmol), 4-chloro-5-iodo-7- (2-methylferrocyclopenta [ A mixture of 4-phenoxyphenylboronic 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 dimethyl ether (8 ml) and water (4 ml). The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (30 ml). The layers were separated, the organic solvent was dried over magnesium sulfate, filtered and the filtrate was concentrated 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 &lt; 0 &gt; C for 20 hours and then cooled to ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica using dichloromethane / methanol 7: 3 as eluent to give 7- (2-methylpyrrolocyclopenta [c] pyrrol-5-yl) Pyrrolo [2,3-d] pyrimidin-4-amine (0.05 g) was obtained. ¹ H NMR (DMSO-d ₆ , 400 MHz) shows two sets of peaks due to the cis and trans isomers of the desired compound: δ 10.6-10.8 (bs, 1H), 8.49 (s, 1H), 6.99-7.98 (m, 1H), 5.39 and 5.48 (m, 1H0, 2-3.8 (m, 10H); PH 454098: RP- HPLC (Hypersil HS c18, 5 탆, 100 A, 250 x 4.6 mm; 25-100% acetonitrile -0.1M ammonium acetate, 1ml / min) t _r = 7.53 ^{minutes, MS: MH + 426. 7- (} 2- methyl-flops tetrahydro-cyclopenta [c] pyrrol-5-yl) -5- (4-phenoxy Phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was prepared by dissolving the free base in 10 ml of 1N hydrochloric acid and freeze-drying.
[1059] Example 209: Synthesis of cis and trans 7- [4- (N-tert-butoxycarbonyl-S, 4S-2,5-diaza [2.2.1] heptanyl) cyclohexyl] Phenoxy) -7H-pyrrolo [2,3-d] pyrimidin-4-amine
[1060] To a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] -1-cyclohexanone , 1.68 mmol) was treated with tert-butyl (1S, 4S) - (-) 2,5-diazabicyclo [2.2.1] heptane- 2-carboxylate (1.0 g, 5.04 mmol) and glacial acetic acid (0.30, 5.04 mmol). Na (OAc) ₃ BH (0.46 g, 2.17 mmol) was then added and stirred at 80 &lt; 0 &gt; C for 8 days. To the cooled reaction mixture was added to NaHCO in water _{(15ml) 3 (0.377g, 10.08mmol} ) and stirred for 15 minutes. The layers were separated and the organic layer was washed with water and brine (3x100ml each). The aqueous layer was extracted with CH ₂ Cl ₂ and the organic layers were combined, dried (MgSO ₄ ), filtered and concentrated. The solids were purified by flash silica gel column chromatography (2 L, 6% MeOH in CH ₂ Cl ₂ , then ₂ L in CH ₂ Cl ₂ , 10% MeOH / 5% NH ₄ OH) to give the following compounds:
[1061] Example 210: Preparation of cis-7- [4- (N-tert-butoxycarbonyl-S, 4S-2,5-diaza [2.2.1] heptanyl) cyclohexyl] -5- Phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (605 mg, 64%).
[1062] _{^{1 H NMR (d 6 DMSO,}} 400MHz): δ8.13 (1H, s), 7.39-7.49 (4H, m), 7.32 (1H, m), 7.07-7.17 (5H, m), 6.09 (2H, bs ), 4.63 (1H, m), 4.15 (1H, m), 3.30-3.70 (2H, m), 3.03-3.08 (2H, m), 2.80-2.90 ), 2.29-2.35 (1H, m), 2.09-2.21 (1H, m), 1.81-1.92 (4H, m), 1.60-1.80 (4H, m), 1.39 (9H, m). HPLC / MS: Perkin Elmer Pecosphere C18, 3 μM, 33 x 4.6, 3.5 ml / min 100-100% 50 mM ammonium acetate to acetonitrile (within 4.5 min), C ₃₆ H ₄ N ₆ O ₃ 581.2), 95%.
[1063] Example 211: Synthesis of trans-7- [4- (N-tert-butoxycarbonyl-S, 4S-2,5-diaza [2.2.1] heptanyl) cyclohexyl] -5- Phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (183 mg, 20%).
[1064] ¹ H NMR (d ₆ DMSO, 400 MHz): 8.13 (1H, s), 7.39-7.49 (4H, m), 7.15-7.17 (1H, m), 7.07-7.17 (2H, m), 2.32 (2H, m), 1.93-2.01 (6H, m) 1.60-1.68 (2H, m), 1.40 (9H, m). HPLC / MS: Perkin Elmer Pecosphere C18, 3 μM, 33 x 4.6, 3.5 ml / min 100-100% 50 mM ammonium acetate to acetonitrile (within 4.5 min), C ₃₀ H ₃₆ N ₆ O (581.2 ), 99%.
[1065] Example 212: Synthesis of cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- N2, N2-trimethyl-1,2-ethanediamine trimaleate salt
[1066] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2- Trimethyl-1,2-ethanediamine trimaleate salt
[1067] To a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] -1-cyclohexane The mixture of rice paddy (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) was stirred for 30 minutes at room temperature under a nitrogen atmosphere. Sodium triacetoxyborohydride (0.69 g, 3.26 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. Water (20 ml) and sodium bicarbonate (1.26 g, 15.1 mmol) were added and the mixture was stirred for 1 h, filtered through a celite pad and the pad washed with dichloromethane (75 ml). The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using dichloromethane / methanol (7: 3) as the eluent to give cis-N1- {4- [4-amino-5- (4- phenoxyphenyl) Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2-trimethyl- Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2-trimethyl-1,2-ethanediamine (0.336 g). 7-yl] cyclohexyl} -N1, N2, N2-N, N-diisopropylcarbodiimide, Trimethyl-1,2-ethanediamine (0.44 g, 0.909 mmol) was dissolved in warmed ethyl acetate (100 ml) and maleic acid (0.32 g, 2.73 mmol) in ethyl acetate (30 ml) was added. The salt formed formed an oily residue on the bottom and sides of the flask. The supernatant was poured out and the residue was dissolved in water and lyophilized to give cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] -7-yl] cyclohexyl} -N1, N2, N2-trimethyl-1,2-ethanediamine trimaleate salt (0.55 g). _{^{1 H NMR (DMSO-d 6}} , 400MHz): δ8.22 (s, 1H), 7.41-7.50 (m, 5H), 7.08-7.19 (m, 5H), 6.5 (bs, 2H), 6.15 (s, 2H), 2.80 (m, 2H), 2.80 (m, 2H), 2.79 (s, ), 1.99 (m, 2H), 1.78 (m, 4H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 × 4.6, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 9.27; MS: MH ^{&lt; + &} gt ^; 485.
[1068] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N1, N2, N2- Trimethyl-1,2-ethanediamine trimaleate salt was prepared from the free base in the same manner: ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.20 (s, 1H), 7.41-7.48 ), 7.08-7.19 (m, 5H), 6.45 (bs, 2H), 6.15 (s, 6H), 4.62 (m, s, 3H), 1.9-2.2 (m, 6H), 1.73 (m, 2H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 × 4.6, 25-100% acetonitrile-0.1 M ammonium acetate for 10 minutes, 1 ml / min) t _r = 8.17 min; MS: MH ^{&lt; + &} gt ^; 485.
[1069] The following compounds were synthesized from cis-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} , &Lt; / RTI &gt; N2-trimethyl-l, 2-ethanediamine.
[1070] Example 214: cis-7- [4- (4-Isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- _{^{amine: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.13 (1H, s), 7.39-7.50 (4H, m), 7.28 (1H, s), 7.07-7.16 (5H, m), 6.08 (2H m), 1.70-1.72 (2H, m), 1.53-1.59 (2H, m), 0.97 (d, , J = 6.5 Hz, 6H), mass spectrum, C ₃₁ H ₃₈ N ₆ O (511.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml / min) t _r = 7.817 min, 99% TLC: 90% CH ₂ Cl ₂ / R _f = 0.30 (UV visible) in MeOH.
[1071] Example 215: Synthesis of trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- _{^{amine: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.13 (1H, s), 7.40-7.47 (5H, m), 7.08-7.18 (5H, m), 6.08 (2H, bs), 4.53 (1H (2H, m), 0.97 (d, J = 5.5 Hz, 6H, m), 2.45-2.55 (9H, m), 2.17-2.20 (1H, m), 1.86-1.96 ), Mass spectrum, C ₃₁ H ₃₈ N ₆ O (511.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.367 min, 91% TLC: 90% CH ₂ Cl ₂ / R _f = 0.21 (UV visible) in MeOH.
[1072] Example 216: Preparation of cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- d] _{^{pyrimidin-4-amine: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.13 (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 = 5.9Hz), 3.22 (3H, s), 2.43-2.55 m), 1.60-1.71 (2H, m), 1.52-1.59 (2H, m). Mass spectrum, C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.317 min, 95% TLC: R _f = 0.22 (UV visible) in 90% CH ₂ Cl ₂ / MeOH.
[1073] Example 217: Synthesis of trans-7- {4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- _{^{4-amine: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.13 (1H, s), 7.39-7.47 (5H, m), 7.07-7.16 (5H, m), 6.09 (2H, bs), 4.55 (1H, m), 3.36-3.42 (2H, m), 3.23 (3H, s), 2.33-2.55 (11H, m), 1.90-1.96 (6H, m), 1.44-1.47 (2H, m). Mass spectrum, C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.200 min, 99% TLC: 90% CH ₂ Cl ₂ / R _f = 0.31 (UV visible) in MeOH.
[1074] Example 218: cis-7- [4- (4-Ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1075] _{^{1 H NMR (d 6 DMSO,}} 400MHz): δ8.23 (1H, s), 7.41-7.49 (4H, m), 7.07-7.17 (6H, m), 6.57 (2H, bs), 6.20 (5H, s ), 4.77 (1H, m), 2.04-2.13 (8H, m), 1.62-1.77 (5H, m), 1.21 (3H, t). HPLC (Waters delta pack C18, 150 x 3.9 mm; 5-95% acetonitrile-0.1 M ammonium acetate for 30 minutes, 1 ml / min) t _r = 13.851, 100%.
[1076] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine
[1077] _{^{1 H NMR (d 6 DMSO,}} 400MHz): δ8.19 (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, 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 ammonium acetate for 30 minutes, 1 ml / min) t _r = 13.701, 96%.
[1078] The following compounds were synthesized from trans-N1- {4- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} , N2-trimethyl-1,2-ethanediamine trimaleate salt.
[1079] Example 219: cis-7- [4- (4-Isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- amine tris _{^{maleate: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.23 (1H, s), 7.40-7.49 (5H, m), 7.07-7.19 (5H, m), 6.55 (2H, bs), (6H, s), 4.74 (1H, m), 3.26 . Mass spectrum, C ₃₁ H ₃₈ N ₆ O (511.1). HPLC (Hypersil HS C18, 5 uM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 N ammonium acetate for 10 min, 1 ml / min) t _r = 7.967 min, 99%.
[1080] Example 220: Synthesis of trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- amine tris _{^{maleate: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.20 (1H, s), 7.40-7.65 (5H, m), 7.08-7.19 (5H, m), 6.46 (2H, bs), M), 1.50-1.59 (2H, m), 1.20 (d, J = 6.5 Hz, 1H), 6.14 (6H, s), 4.60 (1H, m), 2.50-3.45 6H). Mass spectrum, C ₃₁ H ₃₈ N ₆ O (511.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 N ammonium acetate for 10 min, 1 ml / min) t _r = 7.733 min, 90%.
[1081] Example 221: Synthesis of cis-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin-4-amine tris _{^{maleate: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.23 (1H, s), 7.41-7.49 (5H, m), 7.07-7.19 (5H, m), 6.55 ( (2H, s), 3.17 (6H, bs), 2.50 (9H, m), 2.02-2.16 (5 H, m), 1.74 (5 H, m). Mass spectrum, C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 N ammonium acetate for 10 min, 1 ml / min) t _r = 7.750 min, 99%.
[1082] Example 222: Synthesis of trans-7- {4- [4- (2-methoxyethyl) piperazino] cyclohexyl} -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin-4-amine tris _{^{maleate: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.21 (1H, s), 7.41-7.48 (5H, m), 7.08-7.19 (5H, m), 6.53 ( M), 1.64 (2H, m), 1.64 (3H, s), 2.50-3.56 . Mass spectrum, C ₃₁ H ₃₈ N ₆ O ₂ (527.2). HPLC (Hypersil HS C18, 5 μM, 254 nm, 250 x 4.6, 25-100% acetonitrile-0.1 N ammonium acetate for 10 min, 1 ml / min) t _r = 7.383 min, 99%.
[1083] Example 223: cis-N1- {4- [4-Amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} N2-dimethyl-1,2-ethanediamine trimaleate salt
[1084] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N2, N2-dimethyl- 1,2-ethanediamine monomaleate salt
[1085] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -N2, N2-dimethyl- 1,2-ethane diamine tree maleate _{^{salt: 1 H NMR (d 6 DMSO}} , 400MHz): δ8.19 (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 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 8.90 min; MS: MH ^{&lt; + &} gt ^; 471.
[1086] Example 224: Trans-N1- {4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} N2- dimethyl-1,2-ethane diamine mono maleate ^{salt: 1 H NMR (DMSO-d} 6, 400MHz): δ9.5 (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, m, 2H), 1.99-2.05 (m, 4H), 1.67-1.75 (m, 2H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 8.6 min; MS: MH ^{&lt; + &} gt ^; 471.
[1087] Example 225: Synthesis of cis-7- (4 - {[3- (lH-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3 -d] pyrimidin-4-amine trimaleate salt
[1088] Example 226: Synthesis of trans-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3 -d] pyrimidin-4-amine dimaleate salt
[1089] Example 227: Synthesis of cis-7- (4- {3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4- phenoxyphenyl) d] pyrimidin-4-amine trimaleate salt: ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.78 (bs, 1H), 8.48 (bs, 2H), 8.18 (s, 1H), 7.55 (s, 1H), 7.41-7.49 (m, 5H), 7.08-7.19 (m, 5H), 6.33 (bs, 2H) , 4.27 (t, 2H), 2.99 (m, 3H), 1.8-2.25 (m, 10H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 9.07 min; MS: MH ^{&lt; + &} gt ^;
[1090] Example 228: Synthesis of trans-7- (4 - {[3- (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3 -d] pyrimidin-4-amine dimaleate ^{salt: 1 H NMR (DMSO-d} 6, 400MHz): δ8.76 (bs, 1H), 8.51 (bs, 1H), 8.18 (s, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.40-7.47 (m, 5H), 7.08-7.21 (m, 5H) ), 4.26 (t, 2H), 3.14 (m, 1H), 2.97 (m, 2H), 1.9-2.25 (m, 8H), 1.53-1.61 (m, 2H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 8.72 min; MS: MH ^{&lt; + &} gt ^;
[1091] Example 229: Synthesis of cis-7- [4- (dimethylamino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-4-amine dimaleate salt :
[1092] _{^{1 H NMR (DMSO-d 6}} , 400MHz): δ9.06 (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 CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.38 min; MS: MH ^{&lt; + &} gt ^; 428.
[1093] Example 230: Preparation of trans-5- (4-phenoxyphenyl) -7- (4-piperidinocyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-
[1094] _{^{1 H NMR (DMSO-d 6}} , 400MHz): δ8.92 (bs, 1H), 8.18 (s, 1H), 7.4-7.5 (m, 5H), 7.08-7.19 (m, 5H), 6.3 (bs, 2H), 6.13 (s, 4H), 4.63 (m, 1H), 3.15-3.5 (m, 3H), 2.9-3.1 (m, 2H), 1.16-2.18 (m, 14H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml / min) t _r = 7.98 min; MS: MH ⁺ 468.
[1095] Pyrrolo [2,3-d] pyrimidin-4-amine dimaleate (2-pyrrolidinyl) salt
[1096] _{^{1 H NMR (DMSO-d 6}} , 400MHz): δ9.54 (bs, 1H), 8.18 (s, 1H), 7.40-7.47 (m, 5H), 7.08-7.18 (m, 5H), 6.3 (bs, (M, 2H), 1.86 (m, 2H), 1.67 (m, 2H), 2.63 , 2H); RP-HPLC (Hypersil CPS, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.82 min; MS: MH ^{&lt; + &} gt ^; 454.
[1097] Example 231: Synthesis of cis-7- [4- (4-methyl-1,4-diazepan-1-yl) cyclohexyl] d] pyrimidin-4-amine dihydrochloride salt
[1098] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine &lt; / RTI &gt; -4-amine dihydrochloride salt
[1099] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine &lt; / RTI &gt; 4-amine dihydrochloride ^{salt: 1 H NMR (DMSO-d} 6, 400MHz): δ11.7 (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) -2.57 (10H); RP-HPLC (Hypersil HS C-18, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.67 min; MS: MH ^{&lt; + &} gt ^;
[1100] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine &lt; / RTI &gt; 4-amine dihydrochloride ^{salt: 1 H NMR (DMSO-d} 6, 400MHz): δ11.94 (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), 1.78-2.4 (m, 10H); RP-HPLC (Hypersil HS C-18, 5 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 7.42 min; MS: MH ^{&lt; + &} gt ^;
[1101] Example 232:
[1102] Pyrrolo [2,3-d] pyrimidin-4-amine tincaleate salt (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl)
[1103] Pyrrolo [2,3-d] pyrimidin-4-amine trimaleate salt (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl)
[1104] a) cis and trans-tert-butyl 4- {4- [4- amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl -1-piperazinecarboxylate
[1105] Example 233
[1106] Pyrido [2,3-d] pyrimidin-7-yl] cyclohexyl-1-piperazin-1- ^{l-carboxylate: 1 H NMR (DMSO-d} 6, 400MHz): δ8.14 (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 μM, 100 A, 250 x 4.6 mm, 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 13.60 min.
[1107] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -1- (4-methylpiperidin- ^{piperazinecarboxylate: 1 H NMR (DMSO-d} 6, 400MHz), δ8.13 (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 RP-HPLC (HyperSyl HS C-18, 5 탆, 100 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 10.40 min.
[1108] b) Preparation of cis-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1109] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} -1- (4-methylpiperidin- (1.85 g, 3.27 mmol) was treated with 20% trifluoroacetic acid / dichloromethane solution (60 ml) and stirred at ambient temperature for 30 minutes. After removal of the solvent under reduced pressure, the residue was partitioned between dichloromethane (200 ml) and aqueous sodium bicarbonate solution (30 ml). The organic solution was dried over magnesium sulfate, filtered and the filtrate was evaporated to a residue (1.55 g). A portion of this material (1.0 g, 2.15 mmol) was dissolved in warmed ethyl acetate (220 ml) and then treated with maleic acid (0.75 g, 0.44 mmol) in warmed ethyl acetate (75 ml). The mixture was cooled at ambient temperature and the solid was collected by filtration and dried to give cis-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H- pyrrolo [ 3-d] pyrimidin-4-amine trimaleate salt (1.15 g) as a white solid. _{^{1 H NMR (DMSO-d 6}} , 400MHz), δ8.5 (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 (HyperSilver HS C-18, 5 탆, 100 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 8.63 min; MS: MH ^{&lt; + &} gt ^; 469.
[1110] c) Preparation of trans-5- (4-phenoxyphenyl) -7- (4-piperazinocyclohexyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1111] _{^{1 H NMR (DMSO-d 6}} , 400MHz), δ8.22 (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, 17H); RP-HPLC (HyperSilver HS C-18, 5 탆, 100 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate for 10 min, 1 ml / min) t _r = 8.08 min; MS: MH ^{&lt; + &} gt ^; 469.
[1112] Example 234
[1113] Pyrrolo [2,3-d] pyrimidin-4-amine tri-maleate (Compound No. 7)
[1114] To a solution of 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] cyclopentan- mol) was stirred with 12 g of active manganese dioxide for 5 hours, filtered and a new manganese dioxide (8 g) was added to the filtrate. After stirring for an additional 17 h, the mixture was filtered and used directly. HPLC / MS was carried out using 62.7% of the starting material and 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- t _r 4.38 minutes. The dichloromethane solution was stirred with 1.0 g of N-methylpiperazine (0.01 mol) and acetic acid (0.6 g, 0.01 mol) for 15 minutes and then sodium triacetoxyborohydride (0.89 g, 0.0042 mol) Respectively. After 2 hours, 1.0 g of N-methylpiperazine, 0.6 g of acetic acid and 0.89 g of sodium triacetoxyborohydride were added and the mixture was stirred for 17 hours. In addition, 2.0 g of N-methylpiperazine, 1.2 g of acetic acid and 1.2 g of sodium triacetoxyborohydride were added and stirred for 3 days to give a mixture which was evaporated under reduced pressure. The residue was treated with water (200 ml) and 6M-hydrochloric acid (50 ml), then washed with ethyl acetate (discarded) and basified with excess aqueous ammonia solution. The mixture was extracted with ethyl acetate and the extract was dried (sodium sulfate) and then purified by flash chromatography in 9: 1 ethyl acetate: ethanol to remove impurities and eluted with 8: 1: 1 ethyl acetate: ethanol: triethylamine &Lt; / RTI &gt; to elute the product. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, treated with a solution of maleic acid in ethyl acetate and dried at 80 &lt; 0 &gt; C under reduced pressure, then treated with 7- [3- Pyrrolino [2,3-d] pyrimidin-4-amine tri-maleate (444395) (0.95 g, 0.001 mol) was added to a solution of . Melting point. 168-170 DEG C (decomposition).
[1115] Example 235
[1116] Phenyl] - (phenyl) -methanol &lt; / RTI &gt; &lt; RTI ID = 0.0 &
[1117] 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- Phenyl] (phenyl) methanone (0.1 g, 0.00026 mol) in dichloromethane, followed by Amberlyst-15H ⁺ . The mixture was stirred for 15 minutes at ambient temperature in a nitrogen atmosphere, filtered through a celite pad, and the solvent was removed under reduced pressure. The residue was purified by preparative RP-HPLC (Rainin, Hypersil C18, 8 [mu] m, 100 A, 250 cm; 5-85% acetonitrile-0.1% ammonium acetate over 20 min, 21 ml / min) Yl) phenyl] (phenyl) -methanol (0.005 g, 0.000013 mol) was obtained as a white amorphous solid.
[1118] _{^{1 H NMR (DMSO-d 6}} , 400MHz), δ8.12 (s, 1H), 7.31 (m, 10H), 6.01 (br, 2H), 5.91 (d, 1H), 5.75 (d, 1H), 5.06 (br, 2H), 1.88 (br, 4H), 1.67 (br, 2H0, RP-HPLC (Delta Pak C-18, 5 m, 300 A, 15 cm; 5-85% Acetonitrile-0.1 M ammonium acetate, 1 ml / min) Rt = 16.74 min MH ^& _lt ; ^{+ &} gt ^;
[1119] Example 236
[1120] Pyrrolo [2,3-d] pyrimidin-4-amine tri-maleate (prepared as in Example 1)
[1121] To a solution of trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4- phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 4-amine (1.30 g, 0.0027 mol) was treated with a solution of maleic acid (0.94 g, 0.0081 mol) in 100 ml of ethyl acetate and cooled. The colorless solid was collected, washed with ethyl acetate and dried to constant weight at 90 [deg.] C / 3 mbar to give 1.85 g (0.0022 mol) of trans-7- [3- (4- methylpiperazino ) Cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-maleate. Melting point 189 캜 (decomposition).
[1122] Example 237
[1123] Pyrrolo [2,3-d] pyrimidin-4-amine tri-hydrochloride (prepared according to the method described for the synthesis of trans-7- [3- (4-methylpiperazino) cyclohexyl]
[1124] To a solution of trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- -Amine (0.36 g, 0.00075 mol) was treated with a solution of 0.225 ml of 12 M hydrochloric acid (0.0027 mol) in 2 ml of isopropanol, the suspension was briefly heated and boiled, and the volatiles were removed under reduced pressure. The resulting colorless solid was dried to constant weight at 84 [deg.] C / 5 mbar to give trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4- Phenoxy) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri- hydrochloride (444626) (0.25 g, 0.0004 ml). Melting point 304-306 占 폚 (decomposition).
[1125] Example 238
[1126] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-maleate salt
[1127] 7- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (prepared as described for the synthesis of cis-7- [3- (4-methylpiperazino) cyclohexyl] (0.0091 mol) of maleic acid to give a colorless solid which was dried to constant weight at 90 &lt; 0 &gt; C / 3 mbar to yield 2.15 g of the title compound which was solubilized in 0.14 mol of ethyl acetate and 0.5 mol of water (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri- Maleate salt (0.0025 mol) was obtained. Melting point 186 캜 (decomposition).
[1128] Example 239
[1129] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-hydrochloride
[1130] (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (0.80 mmol) in isopropanol g, 0.0017 mmol) was treated with 0.5 ml of 12 M hydrochloric acid (0.006 mol). The formed solids were filtered and dried at 80 ° C / 3 mbar until they reached a constant weight to give cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4- phenoxyphenyl) 7H-pyrrolo [2,3-d] pyrimidin-4-amine tri-hydrochloride (0.75 g, 0.0011 mol). Melting point 224.5-226.5 (decomposition).
[1131] Example 240: trans-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4- methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidine -4-amine trimaleate
[1132] A mixture of 3-phenoxy toluene (2.5 g, 0.0136 mol) and N-bromosuccinimide (2.54 g, 0.0142 mol) was stirred in acetonitrile (20 ml) under a nitrogen atmosphere for 2.5 hours. The solvent was removed under reduced pressure. Carbon tetrachloride was added to the residue and the formed solids were removed by filtration. The filtrate was concentrated to give 4-bromo-3-methylphenyl phenyl ether (3.5 g, 0.0133 mol) as a yellow oil.
[1133] ¹ H NMR (chloroform -d, 400MHz), δ7.45 (d , 1H), 7.33 (m, 2H), 7.12 (t, 1H), 7.00 (d, 2H), 6.89 (s, 1H), 6.71 ( d, 1 H), 2.34 (s, 3 H). RP-HPLC (Hypersil C18, 5㎛ , 250x4.6mm; 1ml / min 25% - 100% over 23 minutes of acetonitrile -0.1M ammonium acetate,) R _t = 14.72 min.
[1134] (1.7 g, 0.00646 mol), diboronpinacole ester (2.0 g, 0.00775 mol), [1, 1 ' -bis A mixture of dichloromethane (1: 1) (0.16 g, 0.00019 mol) and potassium acetate (1.9 g, 0.01938 mol) was stirred at 80 ° C Lt; / RTI &gt; The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. Dichloromethane was added to the residue, and the formed solids were removed by filtration through Celite pad. The filtrate was concentrated to a black mixture which was purified by flash chromatography on silica using ethyl acetate / n-heptane (3:97) as mobile phase to give 3-methyl-4- (4,4,5,5-tetra Yl) phenyl phenyl ether (1.05 g, 0.00338 mol).
[1135] ¹ H NMR (chloroform -d, 400MHz), δ7.73 (d , 1H), 7.33 (m, 2H), 7.08 (t, 1H), 7.01 (d, 2H), 6.79 (d, 2H), 2.51 ( s, 3H), 1.34 (s, 12H). TLC (ethyl acetate / n-heptane = 3: 97) _Rf 0.28.
[1136] To a solution 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 6N HCl (aq) (60 ml, 360 mmol) was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and 6 N HCl (aq) (20 ml), tetrahydrofuran (60 ml), and acetone (300 ml) were added to the mixture. The mixture was stirred at ambient temperature under a nitrogen atmosphere for 4.5 hours. The solvent was removed under reduced pressure and the yellow residue was washed with water to give 4- (4-chloro-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- (12.3 g, 32.7 mmol). RP-HPLC (Hypersil C18, 5㎛ , 250x4.6mm; -100% 25% acetonitrile for 15 minutes -0.05M ammonium acetate, 1ml / min) R _t = 10.20 min.
[1137] Pyrrolo [2,3-d] pyrimidin-7-yl) -1-cyclohexanone (5.6 g, 14.9 mmol) in dichloroethane (100 ml) A mixture of N-methylpiperazine (3.3 ml, 29.8 mmol), acetic acid (2.6 ml, 44.7 mmol) and trimethylorthoformate (9.9 ml, 89.4 mmol) was stirred for 1 hour at ambient temperature under a nitrogen atmosphere. Sodium triacetoxyborohydride (14.2 g, 67.05 mmol) was added to the mixture and stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine / dichloromethane (2:98) as mobile phase followed by methanol / triethylamine / dichloromethane (2: 3: To give trans-4-chloro-5-iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidine mmol). _{^{1 H NMR (DMSO-d 6}} , 400MHz), 8.63 (s, 1H), 8.12 (s, 1H), 4.63 (br, 1H), 2.15 (s, 3H), 1.94 (br, 6H), 1.45 (br , 2H). RP-HPLC (Hypersil C18, 5㎛ , 250x4.6mm; 1ml / min 15 minutes 25% -100% acetonitrile in ammonium acetate over -0.05M,) R _t = 6.17 min.
[1138] To a solution of trans-4-chloro-5-iodo-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3 d] pyrimidine (0.89 g, 1.9 mmol) was heated at 120 <0> C in a pressure vessel for 18 h. The mixture was cooled 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 aqueous phase was further extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give trans-4-chloro-5-iodo-7- [4- (4- methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidine , 0.8 mmol). HPLC (Hypersil C18, 5㎛, 250x4.6mm ; 1ml / min 15 minutes 25% -100% acetonitrile in ammonium acetate over -0.05M,) R _t = 4.01 min. MS: MH ^{&lt; + &} gt ^;
[1139] 7-r4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-2-one in 15 ml of N, N-dimethylformamide ] Pyrimidin-4-amine (0.347 g, 0.000788 mol), 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- A mixture of ether (0.27 g, 0.000867 mol), tetrakis (triphenylphosphine) palladium (0) (0.054 g, 0.000047 mmol) and sodium carbonate (0.209 g, 0.00197 mol) And heated. The mixture was cooled 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 aqueous phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine / dichloromethane (5:95) as mobile phase and then methanol / triethylamine / dichloromethane (3: 5: To give trans-5- (2-methyl-4-phenoxyphenyl) -7- [4- (4- methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidine -4-amine (0.376 g, 0.000757 mol). Pyrrolo [2,3-d] pyrimidin-4-amine (4-methylpiperazino) cyclohexyl] (0.376 g, 0.000757 mol) was dissolved in refluxing ethanol (10 ml) and a warmed solution of maleic acid (0.264 g, 0.00227 mol) in ethanol (5 ml) was added. The mixture was refluxed for 15 minutes, cooled to ambient temperature and the precipitate was collected by filtration, washed with cold ethanol and dried to give trans-5- (2-methyl-4-phenoxyphenyl) Cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine tinctureate (0.153 g, 0.000181 mol). _{^{1 H NMR (DMSO-d 6}} , 400MHz), 8.22 (s, 1H), 7.42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s 3H), 2.22 (s, 3H), 2.01 (br, 1H), 6.89 (d, 6H), 1.57 (br, 2H). RP-HPLC (Hypersil C18, 5㎛ , 250x4.6mm; -100% 25% for 23 minutes, acetonitrile -0.1M ammonium acetate, 1ml / min) R _t = 7.30 min. MS: MH ^{&lt; + &} gt ^;
[1140] Example 241: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentyl 2-aminoacetate hydrochloride
[1141] Pyrrolor2.3-dlpyrimidin-7-yl] cyclopentanol (50 mg, 0.129 mmol) in DMF (1 ml) Ethyl carbodiimide hydrochloride (31 mg, 0.155 mmol) and 4 - [(tert-butoxycarbonyl) amino] acetic acid (34 mg, 0.194 mmol) - (dimethylamino) pyridine (16 mg, 0.129 mmol) was stirred under nitrogen for 24 hours. The mixture was poured into ice water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were 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- -Yl] cyclopentyl 2 - [(tert-butoxycarbonyl) amino] acetate (39 mg, 0.072 mmol). HPLC: _Γ t = 19.22 min. (Delta Pak C-18, 5 [mu] m, 300 A, 15 cm; 5-85% acetonitrile-0.1 M ammonium acetate for 20 minutes, 1 ml / min).
[1142] Cyclopentyl 2 - [(tert-butoxycarbonyl) amino] -1H-pyrrolo [2,3-d] pyrimidin- ] Acetate (39 mg, 0.072 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was bubbled through the solution for 3 hours. The reaction mixture was stirred for an additional 30 minutes. Ether was added and the precipitate was collected by filtration under nitrogen to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Pentyl 2-aminoacetate hydrochloride (39 mg) as a white solid. _{^{1 H NMR (DMSO-d 6}} , 400MHz), 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, IH), 7.50 (m, IH), 7.68 (m, IH), 8.26 (bs, 2H), 8.40 (s, IH). ^{LS / MS: MH + 444,} t Γ = 2.25 minutes (Pecospher, 3C-18, 3㎛ , 4.6x33mm; 5 min for 0% -100% acetonitrile -0.1M ammonium acetate, 3.5ml / min).
[1143] Example 242: 3- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl] cyclopentyl N- ) Carbamate hydrochloride
[1144] 4-Nitrochloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) was cooled in an ice bath. 4-Methylmorpholine (7 [mu] L, 0.062 mmol) was slowly added. After 20 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. Cyclopentanol (20 mg, 0.052 mmol) was added and the reaction mixture was poured into ice-water Stir for 4 days. The reaction mixture was diluted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate, washed with brine, dried over MgSO ₄ and, 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 organic layer was washed with water (3 times), washed with brine, dried over MgSO ₄ 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- Morpholinoethyl) carbamate (17 mg, 0.031 mmol). _{^{1 H NMR (CDCl 3 -d)}} , 2.08 (m, 4H), 2.43 (m, 7H), 2.73 (m, 1H), 3.29 (m, 2H), 3.67 (m, 4H), 5.28 (m, 5H ), 7.09 (m, 6H), 7.40 (m, 4H), 8.30 (s, 1H). ^{LS / MS: MH + 543,} t Γ = 2.13 minutes (Pecospher, 3C-18, 3㎛ , 4.6x33mm; 5 min for 0% -100% acetonitrile -0.1M ammonium acetate, 3.5ml / min).
[1145] Pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentyl N- (2-morpholinoethyl) carbamate (10 mg, 0.0184 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred for an additional 10 min. The precipitate was collected by filtration under nitrogen to give 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclopentylN - (2-morpholinoethyl) carbamate hydrochloride. _{^{1 H NMR (CDCl 3 -d)}} , δ1.99 (m, 4H), 2.55 (m, 2H), 3.32 (m, 12H), 5.08 (m, 1 / 2H), 5.19 (m, 1 / 2H) , 7.16 (m, 5 H), 7.45 (m, 5 H), 8.26 (s, 1 H). ^{LS / MS: MH + 543,} t Γ = 2.16 minutes (Pecospher, 3C-18, 3㎛ , 4.6x33mm; 5 min for 0% -100% acetonitrile -0.1M ammonium acetate, 3.5ml / min).
[1146] Example 243: 4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexanol
[1147] (500 mg, 13 mmol) was added to a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Cyclohexan-1-one (780 mg, 2.0 mmol), and the mixture was stirred for 1 hour under a nitrogen atmosphere and then left overnight. The solvent was removed under reduced pressure and the residue was partitioned between 1 M aqueous sodium hydroxide (100 ml) and dichloromethane (100 ml). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2 x 100 ml). The combined organic extracts were washed with water (150 ml), dried over potassium carbonate and concentrated in vacuo using ethyl acetate / triethylamine (98: 2 to 95: 5) and ethyl acetate / ethanol (95: 5) 7H-pyrrolo [2,3-d] pyrimidin-7-yl] -pyridine as a white solid. Cyclohexanol (750 mg, 1.9 mmol) was obtained. Melting point: 199-200 占 폚. C. LC / MS: (Hypersil BDS, c18 (100 x 2.1 mm) 0.1 M ammonium acetate / acetonitrile, 10% -100% acetonitrile (in 8 min)). MH ⁺ 401, t _Γ = 4.12 min.
[1148] Example 244
[1149] Phenyl N -4- [4- (amino-7-tetrahydro -2 H -4- pyranyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] Carbamate
[1150] (4-amino-3-methoxyphenyl) -7-tetrahydro -2 H 4-pyranyl -7 H - pyrrolo [2,3-d] pyrimidin-4-amine (100mg, 0.294mmol) of And dissolved in dichloromethane (2 m). Pyridine (2 ml) was added followed by phenyl chloroformate (44 [mu] L, 0.353 mmol). After stirring for 3 hours, an additional 44 [mu] l of phenyl methanesulfonyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and purified by preparative LC / MS of the residue by phenyl N -4- [4- (amino-7-tetrahydro -2 H -4- pyranyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (52 mg, 0.113 mmol). _{^{1 H NMR (CDCl 3 -d)}} , 2.09 (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 (m, 1H), 5.24 (s, 2H 2H), 7.62 (s, 1H), 8.20 (bd, J = 7.80 Hz, 1H), 8.33 (s, 1H), 7.09 (m, 3H) / MS: MH ^{&lt; + &} gt ^;
[1151] Example 245
[1152] Pyrrolo [2,3-d] pyrimidin-5-yl) -pyrrolidin-1- -2-methoxyphenyl] carbamate A mixture of 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate
[1153] 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 slowly added to the reaction mixture. After stirring for 5 hours, the reaction mixture was diluted with dichloromethane. Water, 1.0N HCl, saturated sodium bicarbonate, the organic layer was washed with brine, dried over MgSO _4, filtered and evaporated. The crude product was purified by flash column chromatography using mobile phase ethyl acetate / heptane (4: 1) to give 4-nitrophenyl tetrahydro-2H-4-pyranyl carbonate (1.5 g, 5.62 mmol) &Lt; / RTI &gt;
[1154]
[1155] pyrrolo [2,3-d] pyrimidin-5-ylamino) -thiophene-2- Yl) -2-methoxyphenyl] carbamate
[1156] Pyrrolo [2,3-d] pyrimidin-4-amine (57 mg, 0.168 mmol) and 5- (4-aminomethylphenyl) -7-tetrahydro- 4-Nitrophenyl tetrahydro-2H-4-pyranyl carbonate (90 mg, 0.336 mmol) was mixed in pyridine (1 mL). After stirring for 5 hours, further 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 &lt; 0 &gt; 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- 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (30 mg, 0.064 mmol).
[1157]
[1158] Example 246
[1159] Pyrrod [2,3-d] pyrimidin-5-yl) -2-methoxy-pyridin-2- Phenyl] carbamate hydrochloride
[1160] a) 4-Nitrophenyl (3-pyridylmethyl) carbonate
[1161] 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) were slowly added. After 20 minutes, the ice-water bath was removed and the reaction mixture was allowed to warm to room temperature. After 30 minutes, ethyl acetate was added and the reaction mixture was filtered. The filtrate was washed with water, saturated sodium bicarbonate, brine, dried over MgSO _4, filtered, and evaporated to give a dark brown solid was to recrystallized from ethyl acetate / heptane 4-nitrophenyl (3-pyridylmethyl) carbonate ( 1.52 g, 5.54 mmol).
[1162]
[1163] pyrrolo [2,3-d] pyrimidin-5-yl) -2- (4-fluorophenyl) Methoxyphenyl] carbamate
[1164] Pyrrolo [2,3-d] pyrimidin-4-amine (25 mg, 0.074 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Was dissolved in dichloromethane (0.7 mL). After pyridine (0.7 mL) was added, 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol) was added. After heating at 100 &lt; 0 &gt; 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- 7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (12 mg, 0.025 mmol).
[1165]
[1166] pyrrolo [2,3-d] pyrimidin-5-yl) -2- (4-fluorophenyl) Methoxyphenyl] carbamate hydrochloride
[1167] Pyrrod [2,3-d] pyrimidin-5-yl) -2-methoxy-pyridin-2- Phenyl] carbamate (12 mg, 0.025 mmol) was dissolved in ethyl acetate (2.0 mL). 1.0 N HCl in ether (1 mL) was slowly added. The precipitate was collected by filtration under nitrogen to give 3-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (13 mg, 0.25 mmol).
[1168]
[1169] Example 247
[1170] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methyl-pyridin- Lt; / RTI &gt; phenyl] carbamate hydrochloride
[1171] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (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 &lt; 0 &gt; C 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, 0.048 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.2 mL) was slowly added. The precipitate was collected by filtration under nitrogen to give 2- morpholinoethyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl-7H- pyrrolo [2,3- d] Yl) -2-methoxyphenyl] carbamate hydrochloride (24 mg, 0.045 mmol).
[1172]
[1173] Example 248
[1174] (4-bromo-1, 3-thiazol-5-yl) methyl N- [4- ] Pyrimidin-5-yl) -2-methoxyphenyl] carbamate
[1175] a) 2,4-Dibromo-l, 3-thiazole-5-carbaldehyde
[1176] 1,3-thiazolane-2,4-dione (3.52 g, 30 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed with dimethylformamide (2.56 g, 34 mmol). The mixture was then heated at 75 캜 for 1 hour and at 100 캜 for 5 hours. After cooling to room temperature, the mixture was added to ice water (500 ml) and the aqueous layer was extracted with dichloromethane. Wash the collected organic layer was washed with a saturated aqueous sodium bicarbonate and dried over MgSO _4, filtered and evaporated to give a brown solid was washed with petroleum ether. The solvent was evaporated to give 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol).
[1177]
[1178] b) (2,4-dibromo-1,3-thiazol-5-yl) methanol
[1179] 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 to the bovine portion. After 10 minutes the ice-water bath was removed and the reaction mixture was stirred overnight at room temperature. The solvent was removed and saturated ammonium chloride was added. The pH was adjusted to 10 by the addition of 1.0 N NaOH. The aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine, dried over MgSO _4, filtered and evaporated. The residue was purified by flash column chromatography to give (2,4-dibromo-1,3-thiazol-5-yl) methanol (0.946 g, 3.47 mmol).
[1180]
[1181] c) (4-Bromo-1, 3-thiazol-5-yl) methanol
[1182] (0.94 g, 3.44 mmol), sodium carbonate trihydrate (1.34 g) and palladium on carbon (10%, 0.07 g) were dissolved in methanol (33 mL). The resulting mixture was hydrogenated at 60 psi for 2 days. The solids were removed by filtration through a pad of celite. The solvent was evaporated and the residue was purified by flash column chromatography to give (4-bromo-1, 3-thiazol-5-yl) methanol (0.32 g, 2.78 mmol).
[1183]
[1184] yl) methyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl-7H-pyrrolo [2,3 d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate
[1185] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (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 &lt; 0 &gt; 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- Pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate.
[1186]
[1187] Example 249
[1188] Pyrrolo [2,3-d] pyrimidin-5-yl) -2- (4-fluoropyridin-2-yl) Methoxyphenyl] carbamate
[1189] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (30 mg, 0.065 mmol) was mixed with tetrahydrofuran (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 &lt; 0 &gt; 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- 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (14 mg, 0.031 mmol).
[1190]
[1191] Example 250
[1192] Pyrrolo [2,3-d] pyrimidin-5-yl) -N- [4- (4-amino-7-tetrahydro- -2-methoxyphenyl] carbamate
[1193] 7H-pyrrolo [2,3-d] pyrimidin-5-yl) -lH-pyrrolo [2,3- ) -2-methoxyphenyl] carbamate
[1194] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (30 mg, 0.065 mmol) was mixed with glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 &lt; 0 &gt; 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- 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (2 mg, 0.004 mmol)
[1195]
[1196] Pyrrolo [2,3-d] pyrimidin-5-ylmethyl) -1H-pyrrolo [2,3-d] pyrimidin- Yl) -2-methoxyphenyl] carbamate
[1197]
[1198] (6.0 mg, 0.013 mmol).
[1199] Example 251
[1200] Pyrrod [2,3-d] pyrimidin-5-yl) -2-methoxy-2-pyridylmethyl N- [4- Phenyl] carbamate hydrochloride
[1201] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (30 mg, 0.065 mmol) was mixed with 2-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated overnight at 100 DEG C. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro- Pyran-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 1.0N HCl in ether (0.1 mL) was slowly added. The precipitate was collected by filtration under nitrogen to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol).
[1202]
[1203] Example 252
[1204] Pyrrod [2,3-d] pyrimidin-5-yl) -2-methoxy- Phenyl] carbamate hydrochloride
[1205] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (30 mg, 0.065 mmol) was mixed with 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give 2-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl- 3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was slowly added. The precipitate was collected by filtration under nitrogen to give 4-pyridylmethyl N- [4- (4-amino-7-tetrahydro-2H-4- pyranyl-7H-pyrrolo [2,3- d] pyrimidin- 5-yl) -2-methoxyphenyl] carbamate hydrochloride (12 mg, 0.023 mmol).
[1206]
[1207] Example 253
[1208] (5-methyl-3-isoxazolyl) methyl N- [4- (4-amino-7-tetrahydro- Yl) -2-methoxyphenyl] carbamate
[1209] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (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 &lt; 0 &gt; 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- 7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (18 mg, 0.038 mmol).
[1210]
[1211] Example 254
[1212] [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl N- [4- (4-amino- d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate
[1213] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- (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 &lt; 0 &gt; C overnight. The solvent was removed and the residue was purified by preparative reverse phase LC / MS to give [(2S) -5-oxotetrahydro-1H-2-pyrrolyl] methyl N- [4- (4-amino- 2H-pyran-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbamate (10 mg, 0.021 mmol).
[1214]
[1215] Example 255
[1216] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) -2,3-dimethyl-lH-pyrrolo [2,3- ] Carbamate
[1217] a) tert-Butyl N- (4- (hydroxymethyl) phenyl) carbamate
[1218] (1.23 g, 10 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) were mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL) . The mixture was stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with water, 1.0N HCl, saturated sodium carbonate, water, brine, dried over MgSO _4, filtered and evaporated. The crude product was purified by flash column chromatography using ethyl acetate / heptane (2: 3) to give tert-butyl N- (4- (hydroxymethyl) phenyl) carbamate (2.16 g, 9.67 mmol) .
[1219]
[1220] b) 4-Aminobenzyl N- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] carbamate
[1221] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] carbazo [4,5-c] pyridin- Mate (51 mg, 0.111 mmol) was mixed with tert-butyl N- (4-hydroxymethyl) phenyl) carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 100 &lt; 0 &gt; 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, 0.015 mmol).
[1222]
[1223] Example 256
[1224] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide
[1225] Pyrrolor2.3-dlpyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] benzamide (64 mg, 0.144 mmol).
[1226]
[1227] Example 257
[1228] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2-methoxyphenyl) -2 - [(4- Pyridinecarboxamide
[1229] Pyrrolor2.3-dlpyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] -2-benzamide (84 mg, 0.189 mmol).
[1230]
[1231] Example 258
[1232] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1,2,3,4-tetrahydro- 3-dimethyl-1H-5-pyrazolecarboxamide
[1233] Pyrrolor2.3-dlpyrimidin-4-amine (80 mg, 0.236 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N5- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] -1,3-dimethyl-1H-5-pyrazolecarboxamide (30 mg, 0.065 mmol).
[1234]
[1235] Example 259
[1236] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -2,2-dimethyl-lH-pyrrolo [2,3- 2-dimethylpropanamide
[1237] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Was dissolved in dichloromethane (1.5 ml). Pyridine (1.5 ml) was added followed by 2,2-dimethylpropanol 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] -2,2-dimethylpropanamide (27 mg, 0.064 mmol).
[1238]
[1239] Example 260
[1240] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -1- (2-methylpiperidin- Cyclopentanecarboxamide
[1241] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] -2,2-dimethylpropanamide (33 mg, 0.076 mmol).
[1242]
[1243] Example 261
[1244] Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -3- Phenylpropanamide
[1245] Pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.147 mmol) was reacted with 5- (4-amino-3-methoxyphenyl) -7-tetrahydro- Was dissolved in dichloromethane (1.5 ml). Pyridine (1.5 ml) was added followed by 3-phenylpropanyl 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 and methanol (1 mL) was added to form a precipitate. The solids were collected by filtration to give N1- [4- (4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo [2,3- d] pyrimidin- Methoxyphenyl] -2,2-dimethylpropanamide (7 mg, 0.015 mmol).
[1246]
[1247] Examples 262 to 267 were synthesized using the following method.
[1248] (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- (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 stirred at ambient temperature for 1 hour under a nitrogen atmosphere. The solvent was removed under 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) and then treated with maleic acid (160 mg, 1.38 mmol) dissolved in ethyl acetate (10 ml) and the mixture was cooled to ambient temperature and stirred for 1 hour . The solids were collected by filtration and dried to give the compound as trimaleate (370 mg).
[1249] Analytical RP-HPLC RT shown in the table was carried out on a Hypersil HS C18 column ((5 um, 100 A) 250 x 4) using a linear gradient of 25-100% acetonitrile / 0.1 M ammonium acetate over 1 minute / .6 mm). The retention time is indicated by "RT" and the mass spectral molecular weight is indicated by "MH +".
[1250]
[1251]
[1252]
[1253]
[1254]
[1255] Typical salt formation methods:
[1256] Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-methoxyphenyl) carbamate was dissolved in ethyl acetate and treated with maleic acid in ethyl acetate (280 mg). The resulting solid was filtered under a nitrogen stream and dried under vacuum for 4 hours to give cis-benzyl-N- (4- {4-amino-7- [4- (4- methylpiperazino) cyclohexyl] -7H- [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) trimaleate salt (580 mg) as a cream solid.
[1257]
[1258] The following salt was prepared in a similar manner. LCMS conditions are described below.
[1259] LSMS data: Perkin Elmer
[1260] Pecosphere C18, 3mM, 33X4.6, 3.5ml / min 100-
[1261] In 4.5 min, 100% 50 mM ammonium acetate to acetonitrile
[1262]
[1263] Example 268: Synthesis of cis and trans-N1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- Yl-2-methoxyphenyl) -3-phenylpropanamide
[1264] Pyridine To a solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) ] -1-cyclohexanone (0.8 g, 2.3 mmol) was added hydrocinnamyl chloride (0.57 g, 3.4 mmol) in dichloromethane (2 ml) at 0 ° C under a stream of nitrogen. The solution was stirred at 0 &lt; 0 &gt; C for 2 hours. The solution was quenched with saturated aqueous citric acid solution (50ml) and the organic layer was washed with saturated aqueous citric acid solution (2x50ml). Dried, filtered and concentrated to leave 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 mmol) were added. Sodium triacetoxyborohydride (0.67 g, 3.15 mmol) was added portionwise under nitrogen and the mixture was stirred overnight at room temperature. It was quenched with saturated aqueous NaHCO ₃ solution (50 ml) and extracted with dichloromethane (3 x 100 ml). The collected organics were dried (sodium sulfate), filtered and evaporated to leave the sludge and purified by flash silica gel column chromatography using dichloromethane / methanol (100/0 to 50/50 in 5% increments). The fraction corresponding to the faster flowing material was collected to give cis-N1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [ Pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide (0.26 g) as a glassy material. This was dissolved in ethyl acetate (5 ml) and maleic acid (160 mg) in ethyl acetate (2 ml) was added. The resulting solid was filtered to give cis-N1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- Yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate salt (260 mg) as a white solid. Analytical LC / MS conditions: Column: Pecosphere, C18, 3 um, 33 x 4.6 mm. Eluent: from 0% B / A in 4.5 min to 100% B / A (B: acetonitrile, A: 50mM ammonium acetate buffer, pH4.5), 3.5mL / min ( r t = 2.86 min, 568.4).
[1265] The fractions corresponding to the slower flowing material were collected to give trans-N1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [ Pyrimidin-5-yl-2-methoxyphenyl) -3-phenylpropanamide (0.11 g) as a glassy material. This was dissolved in ethyl acetate (5 ml) and treated with a solution of maleic acid (160 mg) in ethyl acetate (2 ml). The resulting solid was filtered to obtain trans-N1- (4-4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- Yl-2-methoxyphenyl) -3-phenylpropanamide trimaleate salt (94 mg) as a white solid. Analytical LC / MS conditions: Column: Pecosphere, C18, 3 um, 33 x 4.6 mm. Eluent: from 0% B / A in 4.5 min to 100% B / A (B: acetonitrile, A: 50mM ammonium acetate buffer, pH4.5), 3.5mL / min ( r t = 2.86 min, 568.2).
[1266]
[1267] 7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclohexanone (2.25 g, 6.5 mmol), acetic acid (1.17 g, 19.5 mmol) and N-methylpiperazine (1.95 g, 19.5 mmol) were dissolved in dichloroethane (200 ml). Sodium triacetoxyborohydride (2.07 g, 9.75 mmol) was added in portions and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution (150 ml) was added and the aqueous layer was extracted with dichloromethane (3 x 100 ml). The collected organics were washed with water, dried (sodium sulfate), filtered and evaporated to leave a semi-solid which was purified by flash silica gel column chromatography using CH ₂ Cl ₂ / methanol (0% MeOH to 5% Lt; / RTI &gt; The fraction corresponding to the faster flowing material was collected and evaporated to give cis-5- (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H- [2,3-d] pyrimidin-4-amine (1.2 g, 43%) as a cream solid.
[1268]
[1269] The fractions corresponding to the slower flowing material were collected and evaporated to give trans-5- (4-amino-3-methoxyphenyl) -7- [4- (4- methylpiperazino) cyclohexyl] -7H- [2,3-d] pyrimidin-4-amine (0.4 g, 14%) as a white solid.
[1270]
[1271] (4-amino-3-methoxyphenyl) -7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- Pyrimidin-4-amine (30 mg, 0.069 mmol) in dichloromethane (5 mL) was added the appropriate acid chloride (2 eq, 0.138 mmol). The vial lid was closed and shaken overnight on an orbital shaker. Two equivalents of the acid chloride (0.138 mmol) were added in two portions (one equivalent each) and the resulting mixture was again shaken overnight. (B: acetonitrile, A: acetonitrile) in 4.5 minutes with LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33 x 4.6 mm) 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL / min) indicated that the product was present in all cases. The solution was evaporated to dryness and the resulting residue was redissolved in a small volume of DMF and purified by reverse phase preparative HPLC. The structures are listed below in accordance with the appropriate LCMS data.
[1272] Examples 269 to 293 were prepared in a similar manner to Example 268. [
[1273]
[1274]
[1275]
[1276]
[1277]
[1278]
[1279]
[1280]
[1281]
[1282]
[1283] General synthesis methods for Examples 294 to 301:
[1284] Method A
[1285] (7.60 mmol) of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Cyclohexanone (2.53 mmol), and glacial acetic acid (7.60 mmol) 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 h. The organic portion was separated, dried over magnesium sulfate, filtered and the filtrate was concentrated to give a brown oil. The residue was purified by flash chromatography on silica gel to give cis- and trans-7 - [(4-piperazino) cyclohexyl] -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- Amine &lt; / RTI &gt;
[1286] Method B
[1287] (7.53 mmol) of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- -Cyclohexanone (2.51 mmol), and glacial acetic acid (7.35 mmol) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.26 mmol) was added and the mixture was stirred at room temperature for 22 hours. A solution of 1.35 g of sodium bicarbonate in 50 ml of water was added and the reaction mixture was stirred for 1 h. The organic portion was separated, dried over magnesium sulfate, filtered and the filtrate was concentrated to give a brown oil. The residue was purified by flash chromatography on silica gel to give cis- and trans-7 - [(4-pyrrolidino) cyclohexyl] -5- (4- phenoxyphenyl) -7H- pyrrolo [2,3- Amine &lt; / RTI &gt;
[1288] Salt formation
[1289] To a warm solution of pyrrolopyrimidine (2.48 mmol; from Method A or B) in ethanol was added a solution of maleic acid (7.28 mmol) in ethanol. A white precipitate formed when the solution was cooled to ambient temperature. The resulting solid was isolated by filtration and dried under vacuum to give the desired trimaleate salt. The analytical RP-HPLC RT shown in the table was run on a Hypersonic High Purity Elite C18 column ((5 uM, 200 A) 250 x 4.6 mm) over 10 min (gradient a) or 25 min (gradient b) 25-100% acetonitrile / A linear gradient of 0.1 M ammonium acetate was used at 1 ml / min.
[1290]
[1291]
[1292]
[1293] ]
[1294] Example 302: Synthesis of cis and trans 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] -l-hydroxycyclohexylmethyl Cyanide
[1295] A solution of diisopropylamine (0.649 g, 0.0050 mol) in tetrahydrofuran (10 mL) was cooled to 0 &lt; 0 &gt; C. A solution of 1.6 M n-butyllithium in hexane (3.14 mL, 0.0050 mol) was added in portions and the temperature was kept below 5 &lt; 0 &gt; C. After the addition was complete, the mixture was stirred at 0 &lt; 0 &gt; C for 20 min. The mixture was cooled to -78 [deg.] C and dry acetonitrile (0.175 g, 0.0043 mol) was added and the temperature was kept below -70 [deg.] C. After the addition was complete, the mixture was stirred at -78 [deg.] C for 20 min and a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] 7-yl] -1-cyclohexanone (1.000 g, 0.0025 mmol) and hexamethylphosphoramide (10 mL) was added and the temperature was kept below -70 &lt; 0 &gt; C. After the addition was complete, the mixture was stirred at -78 &lt; 0 &gt; C for 30 minutes and then 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 sulphate. The solvent was removed in vacuo and the cis and trans isomers were separated by flash column chromatography on silica using dichloromethane / methanol (95: 5) as eluent to give 4- [4-amino-5- (4 -7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-hydroxycyclohexylmethyl cyanide (0.120 g, 0.00027 mol) Pyrido [2,3-d] pyrimidin-7-yl] -1-hydroxycyclohexylmethyl cyanide (0.170 g, 0.00038 mol) Respectively.
[1296] Less polarity:
[1297]
[1298] C18, 5 m, 300 A, 15 cm; 5% to 85% acetonitrile-0.1 M ammonium acetate over 20 minutes, 1 mL / min) R _t 15.90. MH ⁺ 440.
[1299] Larger polarity: assumed to be trans, aryl-axis, OH-axis)
[1300]
[1301] 5 m, 300 A, 15 cm; 5% to 85% acetonitrile-0.1 M ammonium acetate over 20 minutes, 1 mL / min) R _t 15.88. MH ⁺ 440.
[1302] Example 303: Synthesis of cis- and trans-5- (4-amino-3-fluorophenyl) -7- [4- (4- methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d ] Pyrimidin-4-amine
[1303] a) tert-Butyl N- (4-bromo-2-fluorophenyl) carbamate
[1304] A solution of sodium bis (trimethylsilyl) amide (1.0 M solution in THF, 2.05 eq., 270 mL, 270 mmol) was added to a solution of 4-bromo-2-fluoroaniline (24.78 g, 130.4 mmol) in THF Lt; / RTI &gt; After an additional 15 minutes di-tert-butyl dicarbonate (1.2 eq, 34.12 g, 156.3 mmol) was added in portions (note: slight exotherm was observed). The reaction became very viscous and was complete after 4 h (tlc analysis using 1: 9 EtOAc: heptane as eluent). The reaction is concentrated in vacuo and partitioned the residue between EtOAc (300mL) and saturated aqueous NaHCO ₃ (150mL). The aqueous layer was further extracted with EtOAc (2 x ₂₀₀ mL) and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification by column chromatography using 10% to 15% ETOAc: heptane gradient gave tert-butyl N- (4-bromo-2-fluorophenyl) carbamate as a light brown waxy solid , 79%).
[1305]
[1306] b) Preparation of tert-butyl N- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate
[1307] Tert-butyl N- (4-bromo-2-fluorophenyl) carbamate (54.0 g, 0.186 mmol), bis-pinacolatodiborane (1.2 eq., 56.8 g, 223.3 mmol) in degassed DMF mmol), potassium acetate (3.0 eq, 54.7 g, 558 mmol) and PdCl ₂ (dppf) (0.03 eq, 4.65 g, 5.58 mmol) in DMF (10 mL) was heated at 80 <0> C for 16 h. The DMF was removed under reduced pressure and the resulting dark solid residue was dissolved in CH ₂ Cl ₂ (500 mL). The inorganic residue was removed by filtration through a pad of silica gel and the filtrate was purified by column chromatography using 10% to 15% EtOAc: heptane gradient 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%).
[1308]
[1309] RP-HPLC (Hyper chamber high purity C18, 5m, 200Å, CH ₃ CN from 5 to 100% of the 250x4.6mm column, using 0.1N aqueous ammonium acetate with 1mL / min over 15 min) t _r = 10.16 min, 90%.
[1310] c) Preparation of tert-butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -7H- pyrrolo [2,3- d] -5-yl] -2-fluorophenylcarbamate
[1311] To a solution of 4-chloro-7- (1,4-dioxaspiro [4,5] dec-8-yl) -5-iodo-7H- pyrrolo [2, , 3-d] pyrimidine (31.18 g, 74.41 mmol), tert-butyl N- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) phenyl] carbamate (1.5 eq, 37.6g, 111.6mmol), sodium carbonate (2.5 eq, 19.72g, 186mmol) and Pd (PPh _{3) 4 (4} mol%, 3.44g, 2.98mmol) Was heated at 80 &lt; 0 &gt; C under nitrogen for 17 h. The reaction was completed by addition of Pd catalyst (1 mol%, 86 g, 0.74 mmol) and reaction was continued at 80 ° C for a further 24 hours (tlc analysis with 3: 7 EtOAc: heptane as eluent, Rf = 0.7 ). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (500 ml) and the inorganic material was removed by filtration through a pad of celite. The filtrate was washed with 10% aqueous Na ₂ CO ₃ (200mL) and brine (200mL), dried (MgSO _4), and concentrated in vacuo. Column chromatography on silica gel using 1: 2 EtOAc: heptane gave tert-butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4,5] ) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenylcarbamate as a semi white solid (21.0 g, 56%).
[1312]
[1313] RP-HPLC (Hyper chamber high purity C18, 5m, 200Å, CH ₃ CN from 5 to 100% of the 250x4.6mm column, using 0.1N aqueous ammonium acetate with 1mL / min over 15 min) t _r = 10.48 min, 100%.
[1314] d) Pyrrolo [2,3-d] pyrimidin-5-yl) -7H-pyrrolo [2,3- Amin-4-amine
[1315] Pyrrolo [2,3-d] pyrimidin-5-one [0156] To a solution of tert- butyl N-4- [4-chloro-7- (1,4- dioxaspiro [ (10.5 g, 20.92 mmol), aqueous ammonium hydroxide (28-30%, 100 mL) and dioxane (100 mL) was placed in a sealed vessel at ambient temperature, Heated to 120 &lt; 0 &gt; C with stirring for 24 h (tlc analysis using 9: 1 EtOAc: heptane as eluent). The reaction was concentrated in vacuo, diluted with EtOAc (300 mL), washed with brine (2 x 150 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure and carefully dried to give 5- (4-amino- Pyrrolo [2,3-d] pyrimidin-4-amine as a yellow solid (7.93 g, 99%). .
[1316]
[1317] e) 4- [4-Amino-5- (4-amino-3-fluorophenyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1318] 5M HCl (300 mL) was added to a solution of 5- (4-amino-3-fluorophenyl) -7- (1,4-dioxaspiro [4,5] 7H- pyrrolo [2,3-d] was slowly added to a solution of pyrimidin-4-amine (18.49g, 48.28mmol), such as a dark brown solution was heated at 60 ℃ for 4 h (CH ₂ Cl Tlc analysis using ₂ % 10% MeOH). To remove the acetone under reduced pressure and the acidic layer using saturated aqueous Na ₂ CO ₃ was alkalized to about pH 8. The resulting precipitate was collected by filtration and carefully dried to give 4- [4-amino-5- (4-amino-3-fluorophenyl) -7H-pyrrolo [2,3- d] pyrimidin- Yl] -cyclohexanone as a light brown solid (12.67 g, 77%). A second collection was also obtained from the uncollected mother liquor.
[1319]
[1320] (4-amino-3-fluorophenyl) -7- (4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidine- 4-
[1321] Example 304: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide Trimaleate
[1322] Pyrrolo [2,3-d] pyrimidin-7-yl] -1- (4-fluorophenyl) To a solution of cyclohexanone (1.0 g, 2.95 mmol), N-methylpiperazine (3 eq., 0.885 g, 8.85 mmol, 0.98 mL) and glacial acetic acid (3 eq, 0.51 mL, 8.85 mmol) was added sodium triacetoxyborohydra (1.3 eq, 0.81 g, 3.84 mmol) were added. After the solution was stirred for 18 hours, additional sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added and the reaction was continued for a further 48 hours. The reaction was concentrated in vacuo and partitioned between dichloromethane (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The aqueous layer was further extracted with dichloromethane (4x100ml) and the collected organic layer was dried over magnesium sulfate and evaporated to dryness to give a yellow foam (0.95g). Purification by column chromatography on silica gel using a gradient of dichloromethane: methanol (9: 1 to 5: 1) gave the more highly flowing component cis-5- (4-amino-3-fluorophenyl) Cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine as a cream solid (400 mg, 32%).
[1323]
[1324] RP-HPLC (Waters Symmetry (Waters Symmetry) C18, of 10 to 90% of 0.1N aqueous ammonium acetate in 2mL / min over 12 minutes by using the 250x4.6mm column, CH ₃ CN) t _r = 8.619 min, 96% .
[1325] (4-amino-3-fluorophenyl) -7- [4- (4-methylpiperidin-4-yl) Piperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine as a yellow solid (110 mg, 9%).
[1326]
[1327] RP-HPLC (Waters Symmetry (Waters Symmetry) C18, 250x4.6mm column of using the 10 to 40% of 0.1N aqueous ammonium acetate in 2mL / min over 12 minutes CH ₃ CN) t _r = 7.595 min, 97% .
[1328] Example 305: trans-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide Trimaleate
[1329] 4-Fluorobenzenesulfonyl chloride (45.9 mg, 0.236 mmol) was added to a solution of trans-5- (4-amino-3-fluorophenyl) -7- [4- Pyrrolino] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.236 mmol) in dichloromethane . Purification by column chromatography on silica gel using 10% to 50% MeOH in dichloromethane as a gradient afforded a colorless oil (0.78 mmol). The product was dissolved in ethanol and maleic acid (3 eq, 27 mg, 0.233 mmol) was added. The mixture was heated to homogeneity and cooled to give trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] Pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate crystallized as a light tan solid (37 mg, 17%).
[1330] RP-HPLC (Waters Symmetry (Waters Symmetry) C18, 250x4.6mm column of using the 10 to 40% of 0.1N aqueous ammonium acetate in 2mL / min over 12 minutes CH ₃ CN) t _r = 14.528 min, 96% And m / z 582.0 ( MH ^& lt; ⁺ & gt ^; ).
[1331] Example 306: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide
[1332] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] Fluoro-phenyl) -4-fluoro-1-benzenesulfonamide was used in place of 0.036 mmol of trans-N1- (4- {4-Amino-7- [4- Pyrrolo [2,3-d] pyrimidin-5-yl} -2-fluorophenyl) -4-fluoro-1-benzenesulfonamide as described for the free base of &Lt; / RTI &gt; method.
[1333] (400mg, 32%), RP -HPLC ( Waters Symmetry _{(Waters Symmetry) C18, CH 3} CN in 250x4.6mm column, using a 10 to 40% of 0.1N aqueous ammonium acetate in 2mL / min over 12 minutes) t _r = 15.232 min, 94% and m / z 582.1 ( MH ^&lt ; ⁺ & gt ^; ).
[1334] Example 307 : 5- (4-Amino-3-fluorophenyl) -7- (l-benzyl-4-piperazinyl) -7H-pyrrolo [2,3- d] pyrimidin-
[1335] a) 7- (l-Benzyl-4-piperidyl) -4-chloro-5-iodo-7H- pyrrolo [2,3- d] pyrimidine
[1336] Diethyldiazodicarboxylate (2.0 eq, 18.19 g, 41.2 mL, 104.8 mmol) was added to a solution of 4-chloro-3-iodopyrrole [2,3- d] pyrimidine (14.55 g, 52.4 mmol ), 1-benzyl-4-hydroxypiperidine (3.0 eq., 30.06 g, 157.16 mmol) and triphenylphosphine (2.0 eq., 27.51 g, 104.8 mmol) . After 72 hours, the reaction was complete (tlc analysis using 1: 1 EtOAc: heptane as eluent, Rf = 0.2). The reaction was concentrated in vacuo and 1: 4 ethyl acetate: heptane was added until a precipitate was observed in the clear solution. The precipitate was collected by filtration (Ph3PO) and the filtrate was concentrated, dissolved in ethyl acetate (500 mL) and extracted with aqueous HCl (IM, 3 x 200 mL). The collected acidic layers were alkalized with aqueous NaOH to pH 12 then extracted with ethyl acetate (3 x 300 mL), dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography on silica gel using 5: 4 light oil (30-60 DEG C): ethyl acetate gave two main fractions, the first fraction containing the product as a light yellow crystalline solid and containing ethyl Acetate to give 7- (l-benzyl-4-piperidyl) -4-chloro-5-iodo-7H-pyrrolo [2,3- d] pyrimidine as a cream- .
[1337]
[1338] pyrrolo [2,3-d] pyrimidin-5-yl] -pyridin-2-yl] -2-fluorophenylcarbamate
[1339] To a solution of 7- (l-benzyl-4-piperidyl) -4-chloro-5-iodo-7H-pyrrolo [2,3- d] pyrimidine (5.7 g, g, 12.6 mmol), tert-butyl N- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 17 hours a suspension of carbamate (1.5 eq, 18.9g, 6.38mmol), sodium carbonate (2.5 equivalent, 3.34g, 31.5mmol) and Pd (PPh _{3) 4 (4} mol%, 0.58g, 0.5mmol) under a nitrogen (Tlc analysis using 1: 1 EtOAc: heptane as eluent). The reaction mixture was concentrated in vacuo was dissolved in ethyl acetate (400ml) and washed with 10% aqueous Na ₂ CO ₃ (3x200mL). The organic layer was dried (MgSO ₄ ), concentrated and purified by column chromatography using 1: 1 ethyl acetate: heptane as eluent to give tert-butyl N-4- [7- (1-benzyl- Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenylcarbamate as a white crystalline solid (5.2 g, 9.7 mmol, 77%).
[1340]
[1341] pyrrolo [2,3-d] pyrimidin-4-amine (2-fluoro-phenyl)
[1342] Pyrrole [2,3-d] pyrimidin-5-yl] -2-fluoro-5,7-dihydro- A mixture of phenylcarbamate (5.2 g, 9.7 mmol), aqueous ammonium hydroxide (28-30%, 100 mL) and 1,4-dioxane (100 mL) was placed in a sealed vessel at ambient temperature and stirred for 16 h (Tlc analysis using EtOAc as the eluent). The reaction was concentrated in vacuo and diluted with EtOAc (300 mL), washed with brine (2 x ₂₀₀ mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give a brown solid which was triturated with ether 3-fluorophenyl) -7- (l-benzyl-4-piperidyl) -7H-pyrrolo [2,3- d] pyrimidin- As a creamy solid (3.0 g, 74%).
[1343]
[1344] Example 308:
[1345] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4- Fluoro-1-benzenesulfonamide
[1346] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4- Fluoro-1-benzenesulfonamide (470981) was reacted with 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. Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro -1-benzenesulfonamide was converted to m / z 575 (MH +) and mp (3.2g, 80%) as a creamy solid, &lt; RTI ID = 0.0 &gt; 256-6 C. &lt; / RTI &gt;
[1347] Example 309:
[1348] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-2,2- 3-Dichloro-1-benzenesulfonamide
[1349] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-2,2- 3-Dichloro-1-benzenesulfonamide was prepared in the same manner as described above with 5.04 mmol. The resulting N1-4- [4-amino-7- (1-benzyl-4-piperidyl) -7H-pyrrolo [2,3- d] pyrimidin- 4-fluoro-1-benzenesulfonamide a m / z 625 (MH +) and RP-HPLC (water Delta pack _{5m C18, 300Å, CH 3 CN} 5 in using 150x3.9mm column, 0.1N ammonium acetate for 20 min To 85%, 1 mL / min) t _r = 14.963 min., 95% brown solid (1.0 g, 32%).
[1350] Example 310:
[1351] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-l- - benzenesulfonamide
[1352] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4- A mixture containing fluoro-1-benzenesulfonamide (2.40 g, 4.18 mmol), ammonium formate (10 equiv., 41.8 mmol, 2.62 g), palladium on carbon (10%, 1.2 g) and ethanol Heated at reflux for 6 hours with vigorous stirring, filtered and concentrated in vacuo. The solids were partitioned between dichloromethane (50 mL) and water (50 mL). Brown solids were collected and analyzed at the upper boundary to give N1-4- [4-amino-7- (4-piperidyl) -7H-pyrrolo [2,3- 2-fluoro-1-benzenesulfonamide (0.33 g) was obtained.
[1353] Example 311:
[1354] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl) -4H-pyrrolo [ -Fluoro-1-benzenesulfonamide
[1355] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-l- -Benzenesulfonamide was prepared by separating the combined organic layers after drying, drying (Na ₂ SO ₄ ), removing the solvent under reduced pressure, performing on a smaller scale (0.35 mmol) and performing preparative HPLC (Hypersil 5m BDS C18, 100x, using a 21.2mm column 1.5 minutes while maintaining 100% pH 4.5 50mM ammonium acetate to 100% for 8.5 minutes, 25mL / min CH ₃ CN) to give the m / z = 512.9 (MH + ) and RP-HPLC (CH ₅ CN 5 to 85% in 0.1 N ammonium acetate over 20 min at 1 mL / min using a water Delta pack 5 m C18, 300 Å, 150 x 3.9 mm column) t _r = 13.091 min., 95% white solids Pyrido [2,3-d] pyrimidin-5-yl] -2- (pyridin- Fluorophenyl-4-fluoro-1-benzenesulfonamide was obtained.
[1356] Example 312:
[1357] 7H-pyrrolo [2,3-d] pyrimidine &lt; / RTI &gt; -5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate
[1358] 1-Methylimidazol-4-ylsulfonyl chloride (1.1 equiv., 0.068 mmol, 12.3 mg) was added to a solution of 5- (4-amino-3-fluorophenyl) To a suspension of triethylamine (3 equiv., 0.186 mmol, 26 l) in tetrahydrofuran (1 ml) was added a suspension of 3-amino-benzyl-4-piperidyl) And stirred at ambient temperature for 24 h. The reaction was concentrated in vacuo and partitioned between dichloromethane (100 mL) and water (50 mL), then the aqueous layer was further extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel using 10% methanol in dichloromethane gave a waxy white solid (10 mg). Maleic acid (2equiv., 4mg) was added to the product in hot methanol and RP-HPLC (Water Delta pack 5m C18, 300Å, using 150x3.9mm column, 1mL / min to 20 minutes 0.1N ammonium acetate in CH ₃ CN for 5 to 85%) t _r = 14.186, 100% min. And m / z = 629 (MH &lt; + &gt;), N1-4- [4-amino- (2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate salt was crystallized on cooling (10 mg).
[1359] Example 313:
[1360] Pyrrolo [2,3-d] pyrimidin-7-ylmethyl) -1H-pyrrolo [2,3-d] ] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide
[1361] 7H-pyrrolo [2,3-d] pyrimidin-4-yl] -N- [4- (4-amino- Yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate, N1- [4- (4- Pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1 H-pyrrolo [ -Benzenesulfonamide &lt; / RTI &gt; was used to synthesize the free base of mp (9 mg) which was obtained as a creamy solid, 217-8 [deg.] C and m / z = 643.2 (MH +).
[1362] Example 314:
[1363] Pyrrolo [2,3-d] pyrimidin-7-one [0194] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide
[1364] (1.5 equiv., 14.8 mg, 0.093 mmol) was added to a solution of 5- (4-amino-3-fluorophenyl) -7 (30 mg, 0.062 mmol) and potassium carbonate (2 equiv., 17.1 mg, 0.124 mmol) in anhydrous THF Was added to the stirred suspension and the resulting mixture was stirred under nitrogen for 16 h at ambient temperature. The solvent was removed in vacuo and the mixture was purified by column chromatography on silica gel using 5% methanol in dichloromethane as eluent to give N1- [4- (4-amino-7-1- [(1,3-dimethyl- Pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzene a sulfonamide RP-HPLC (Perkin Elmer Pecosphere 3m C18 (33x4.6mm) with a column for 0.5 minutes while maintaining 100% pH 4.5 50mM ammonium acetate to 100% for 4.5 minutes _{CH 3 CN, 3.5mL / min)} t r = 2.98 min, 96% min. And m / z = 629 (MH &lt; + &gt;).
[1365] Example 315:
[1366] Pyrrolo [2,3-d] pyrimidin-5-yl} - (2-pyridin- 2-fluorophenyl) -4-fluoro-1-benzenesulfonamide
[1367] Pyrrolo [2,3-d] pyrimidin-5-yl} - (2-pyridin- Fluoro-phenyl) -4-fluoro-1-benzenesulfonamide was reacted with N1- [4- (4-amino- Pyrrolido [2,3-d] pyrimidyl-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide using RP-HPLC HPLC (Perkin Elmer Pecosphere 3m C18 (33x4.6mm) with a column for 0.5 minutes while maintaining 100% pH 4.5 50mM ammonium acetate to 100% for 4.5 minutes _{CH 3 CN, 3.5mL / min)} t r = 2.73 min, 98%. And m / z = 590.2 (MH +) (12 mg).
[1368] Example 316:
[1369] Pyrrolo [2,3-d] pyrimidin-5-yl) - lH-pyrrolo [2,3-d] pyrimidin- }) - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide Trimaleate
[1370] Sodium triacetoxyborohydride (28.1 mg, 0.134 mmol) was added to a solution of N1-4- [4-amino-7- (4-piperidyl) -7H-pyrrolo [ 2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-1- 0.0 &gt; mmol) &lt; / RTI &gt; The reaction was stirred at room temperature for 20 h and then additional sodium triacetoxyborohydride (1.3 equiv.) Was added. After an additional 24 h the reaction was allowed to proceed fully and concentrated in vacuo and partitioned between dichloromethane (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The aqueous layer was further extracted with dichloromethane (4 x 100 mL) and the combined organic layers were dried over magnesium sulfate and then evaporated to dryness. Purification by column chromatography on silica gel using dichloromethane: methanol: ammonium hydroxide as eluant afforded a brown solid. The trimaleate salt was then formed by standard methods and purified by RP-HPLC (5 to 85% CH ₃ CN in 0.1 N ammonium acetate aqueous solution for 20 min using a Water Delta pack 5 m C18, 300 Å, 150 x 3.9 mm column, _{/ min) t r = 10.658min.} , 95% and m / z 582 (MH +) of a brown solid (45mg, as 75%) N1-4- (4-amino-7-f 4- [1- (1 Methylpiperid-4-yl) piperidyl] -7H-pyrrolo [2,3-d] pyrimidin- 5-yl}) - 2- fluorophenyl-4-fluoro- Maleate.
[1371] Example 317:
[1372] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylbenzenamide
[1373] a) A mixture of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (25.0 g, 0.09 mol), 1,4- dioxaspiro [4.5] decane- Diethyl azodicarboxylate (30.9 g, 0.178 mol) was added to a solution of 8-ol (35.8 g, 0.0267 mol) and triphenylphosphine (46.7 g, 0.178 mol) under nitrogen. The solution was stirred for 20 hours and most of the solvent was evaporated (250 mL remained). EtOAc (450 mL) was then added and the resulting solid was filtered and 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 (22.5 g, 60%). _{^{1 H NMR (d 6 DMSO,}} 400MHz) 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). R _f = 0.12 in EtOAc: heptane 1: 4.
[1374] b) To a solution of tert-butyl N- [2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane Yl) phenyl] carbamate (8.2 g, 23.5 mmol), 4-chloro-7- (1,4-dioxaspiro [4.5] dec- A solution of tetraquistriphenylphosphine palladium (1.1 g, 0.93 mmol), sodium carbonate (4.16 g, 39.2 mmol) in toluene (10 ml) And heated for 20 hours. The resulting solution was cooled to room temperature and partitioned between EtOAc (300 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organics were washed with water (1 x 150 mL). The organics were dried (sodium sulfate), filtered and then evaporated to give a solid. Upon dissolving in EtOAc / heptane (1: 4), it was decomposed into a creamy solid (2.5 g). The filtrate was taken up on silica and purified by flash silica gel column chromatography using heptane: EtOAc 10: 1, heptane: EtAOc 4: 1, heptane: EtOAc 1: 1 and EtOAc: heptane 4: 1. A white solid which was triturated with heptane / EtOAc (5: 1) in the appropriate ratio to give tert-butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4.5] dec- Yl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbomate (3.2 g) was obtained and the combined yield was 71%.
[1375] _{^{1 H NMR (d 6 DMSO,}} 400MHz): 8.66 (1H, s), 7.93 (2H, m), 7.74 (1H, m), 7.19 (1H, s), 7.07 (1H, d), 4.81 (1H, m), 3.93 (4H, m), 3.91 (3H, s), 2.18 (2H, m), 1.99 (2H, m), 1.79 (4H, m), 1.48 (9H, s). HPLC (conditions: CH ₃ CN 5 to 95% in 0.1 N ammonium acetate aqueous solution for 20 minutes) t _r = 21.24 min, 100%.
[1376] c) Preparation of tert-butyl N-4- [4-chloro-7- (1,4-dioxaspiro [4.5] dec-8-yl) -7H-pyrrolo [2,3- d] pyrimidin- (5.7 g, 0.011 mol), concentrated ammonia solution (100 mL) and dioxane (100 mL) were heated in a pressure vessel at 120 &lt; 0 &gt; C for 20 hours. The solvent was evaporated and the residue was reconstituted in EtOAc / water (250 mL / 100 mL). The organic layer was separated, dried (sodium sulfate), and was filtered and evaporated HPLC: by (Condition CH ₃ CN 5% to 95% of 0.1N ammonium acetate aqueous solution for 20 min), tert-butyl N-4- [4- Pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate and (4-amino-7- Pyrrolo [2,3-d] pyrimidin-4-ylmethyl) -1H-pyrrolo [2,3-d] pyrimidin- A 2: 1 mixture of amines gave the observed solid. The mixture was dissolved in acetone (200 mL) and HCl (5 N, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred overnight at room temperature and then the solvent was evaporated. The acidic solution was basified with 2N NaOH (ice-cold) and extracted with EtOAc (3 x 150 mL). The combined organics were washed with water (2 x 100 mL). The solids precipitated during the extraction process. This solid was filtered and triturated in hot EtOAc / MeOH. The insoluble material was filtered off and the filtrate was evaporated, and the resulting solid was decomposed with diethyl ether / ethyl acetate to give a yellow solid. The organic layer from the first extraction was dried (sodium sulfate), 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- 7H-pyrrolo [2,3-d] pyrimidin-7-yl] -1-cyclohexanone. _{^{1 H-NMR (d 6 DMSO}} , 400MHz): 8.17 (1H, s), 7.32 (1H, s), 6.88 (1H, s), 6.77 (1H, m), 6.73 (1H, m), 6.71 (1H m), 6.07 (2H, bs), 5.14 (1H, m), 3.81 (3H, s), 2.72 (2H, m), 2.35 (4H, m), 2.18 (2H, m). HPLC: (5 to 95% of the 0.1N aqueous solution of ammonium acetate over 20 min _{CH 3 CN) tr = 11.24,} 95%
[1377] d) pyridine (2 mL) and a solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Benzoyl chloride (63 mg, 0.45 mmol) in dichloromethane (1 mL) was added at 0 <0> C under nitrogen to a solution of 1-cyclohexanone (0.105 g, 0.3 mmol). The solution was stirred at 0 &lt; 0 &gt; C for 2 h and then quenched with water (5 mL). HCl (IN, 40 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with water (1 x 30 mL). The organic layer was dried (sodium sulfate), filtered, evaporated and purified by flash silica gel column chromatography using 2% -10% MeOH / EtOAc as eluent to give N1-4- [4-amino- Oxo-cyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylbenzamide as a white solid (0.130 g, 96%). M.pt 234-237 [deg.] C. Rf = 0.30 in EtOAc: MeOH = 9: 1. HPLC: (CH in 0.1N ammonium acetate aqueous solution over 20min ₃ CN 5 to _{95%) t r = 14.82,} 96%. _{^{1 H NMR (d 6 DMSO,}} 400MHz): 9.43 (1H, s), 8.19 (1H, 2), 7.94 (3H, m), 7.59 (4H, m), 7.18 (1H, s), 7.06 (1H, d, J = 8 Hz), 6.18 (2H, bs), 5.20 (1H, m), 3.92 (3H, s), 2.76 (2H, m), 2.35 (4H, m), 2.22
[1378] Example 318:
[1379] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate &lt; EMI ID =
[1380] To a solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- ] -1-cyclohexanone (0.40 g, 1.15 mmol) in dichloromethane (5 mL) was added benzyl chloroformate (0.29 g, 1.73 mmol) at -5 ° C under nitrogen. The solution was warmed to 0 &lt; 0 &gt; C and stirred for 1 hour. The reaction was quenched with water (5 mL) and the solvent was evaporated. The residue was partitioned between EtOAc and water (100 mL each) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (sodium sulfate), filtered and evaporated to leave a solid which was triturated with EtOAc / Et ₂ O to give benzyl N-4- [4-amino-7- (oxocyclohexyl) -7H- 2,3-d] pyrimidin-5-yl] -2-methoxyphenylcarbamate (0.28 g). Mp 175-176 [deg.] C. Rf = 0.24 in EtOAc: MeOH = 9: 1. HPLC: (CH in 0.1N ammonium acetate aqueous solution over 20min ₃ CN 5 to _{95%) t r = 16.69min,} 98%. _{^{1 H NMR (d 6 DMSO,}} 400MHz): 8.64 (1H, s), 8.17 (1H, s), 7.75 (1H, d, J = 8.4Hz), 7.50 (1H, s), 7.36 (5H, m) , 7.10 (1H, s), 7.02 (1H, d, J = 8 Hz), 6.15 (2H, bs), 5.19 (3H, m), 3.81 , &lt; / RTI &gt; m), 2.22 (2H, m).
[1381] Example 319:
[1382] Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (1 H) -quinolin- (4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ 3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate tri-maleate
[1383] To a solution of benzyl N-4- [4-amino-7- (4-oxocyclohexyl) -7H-pyrrolo [2,3- d] pyrimidin- (0.55 g, 2.61 mmol) was added to a solution of 2-amino-4-methoxyphenylcarbamate (0.83 g, 1.74 mmol), N-methylpiperazine (0.52 g, 5.22 mmol) and glacial acetic acid (0.31 g, 5.22 mmol) ). The solution was stirred for 6 hours then quenched by the addition of sodium hydroxide (2N, 20 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organics were washed with brine (1 x 50 mL), dried (sodium sulfate), filtered and evaporated to give flash silica gel with EtOAc, EtOAc: MeOH 9: 1, CH ₂ Cl ₂ and CH ₂ Cl ₂ : MeOH 9: The oil purified by column chromatography was left to give an oil (480 mg) at F20-25. This day was dissolved in ethyl acetate and treated with maleic acid in ethyl acetate (280 mg). The resulting solid was filtered under a stream of nitrogen and dried under vacuum for 4 hours to give cis-benzyl N- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- [2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate tri-maleate salt (580 mg) as a cream solid. M.pt. ^{158 ℃ (dec) 1 H NMR} (d 6 DMSO, 400MHz): 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 ), 2.51 (3H, m) , 2.41 (1H, s), 2.09 (4H, 1.70 (4H, m) HPLC:. ( of 0.1N ammonium acetate aqueous solution for 20 minutes, CH ₃ CN 5 to 95%) t _r = 13.30 min, 94%.
[1384] F28-45 was dissolved in ethyl acetate (10 mL) and was treated with maleic acid (114 mg) in ethyl acetate (3 mL) to provide the glassy foam. The resulting solid was filtered under nitrogen and dried in vacuo for 4 hours to give trans-benzyl N- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [ 2,3-d] pyrimidin-5-yl} -2-methoxyphenyl) carbamate trimaleate salt (250 mg) as a cream solid. M.pt 146-148 [deg.] C. HPLC (of 0.1N ammonium acetate aqueous solution for 20 minutes, CH ₃ CN 5 to _{95%) t r = 13.54min,} 94.6%. _{^{1 H NMR (d 6 DMSO,}} 400MHz): 8.72 (1H, s), 8.25 (1H, s), 7.77 (1H, d), 7.51 (1H, s), 7.35 (5H, m), 7.10 (1H, s), 7.04 (1H, d), 6.16 (6H, s), 5.17 (2H, s), 4.59 (1H, m), 3.86 (3H, s), 2.70-3.10 , &lt; / RTI &gt; s), 1.97 (6H, m), 1.56 (2H, m).
[1385] Example 320:
[1386] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) benzamide
[1387] Pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxyphenylbenzamide (prepared from N1-4- [4-amino-7- (4-oxycyclohexyl) Sodium triacetoxyborohydride (0.85 g, 3.99 mmol) was added portionwise under nitrogen to a solution of N-methylpiperazine (0.80 g, 7.98 mmol) and glacial acetic acid (0.48 g, 7.98 mmol) . The solution was stirred overnight at room temperature and then quenched by the addition of sodium hydroxide (2N, 20 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL) and the combined organics were dried (sodium sulfate), filtered and then evaporated to give 5% MeOH / dichloromethane to 20% MeOH / dichloromethane To give a purified solid by flash silica gel column chromatography. F23-36 were combined and evaporated to give a creamy 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 solids were filtered under a stream of nitrogen to give trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [ Pyrimidin-5-yl} -2-methoxy
[1388] Phenyl) benzamide (0.108 g) as a cream solid. _{^{1 H NMR (d 6 DMSO,}} 400MHz): 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 (2H, m). HPLC / MS (column = picosphere 3 C ₁₈ 3 microns, condition = 100% 100 mM ammonium acetate over 100% acetonitrile over 5 minutes), t _r = 1.83 min, MH + = 540.8.
[1389] Example 321:
[1390] Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] (4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d ] Pyrimidin-5-yl} -2-methoxyphenyl) -3-phenylpropanamide
[1391] a) A solution of 4- [4-amino-5- (4-amino-3-methoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- To a solution of 1-cyclohexanone (0.8 mg, 2.3 mmol) and dichloromethane (32 mL) was added hydrocinnamoyl chloride (0.57 g, 3.4 mmol) in dichloromethane (35 mL) under nitrogen. The solution was stirred at 0 &lt; 0 &gt; C for 2 hours, warmed to room temperature and quenched by the addition of saturated citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2 x 50 mL), dried (sodium sulfate), filtered and evaporated to give N1- (4- [4-amino- 7- (4- oxocyclohexyl) -7H- pyrrolo [ , 3-d] pyrimidin-5-yl] -2-methoxyphenyl} -3-phenyl-propanamide a (1.0g, 92% crude) of the title compound as a brown _{^{foam. 1 H NMR (d 6 DMSO}} , 400MHz (1H, m), 7.09 (1H, m), 6.99 (1H, s) d), 6.21 (2H, bs ), 5.18 (1H, m), 3.88 (3H, s), 1.99-2.93 (12H, m). CH 3 CN in 0.1N ammonium acetate aqueous solution over a HPLC (20 min, 5 to 95%), t _r = 14.48 min, 92.2.
[1392] c) A solution of 92% purity N1- {4- [4-amino-7- (4-oxocyclohexyl) -7H-pyrrolo [2,3- d] pyrimidin- To a solution of 2-methoxyphenyl} -3-phenylpropanamide (1.0 g, 2.1 mmol), N-methylpiperazine (0.63 g, 6.3 mmol), acetic acid, sodium triacetoxyborohydride (0.67 g, 3.15 mmol ) Were added and added under nitrogen. The solution was stirred for 20 hours and then quenched by the addition of a saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and evaporated to give purified sludge by flash silica gel chromatography using 50% MeOH / dichloromethane with dichloromethane increasing by 10%. F84-96 was mixed and evaporated to give cis-N1- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidine -5-yl} -2-methoxyphenyl) -3-phenylpropanamide (0.26 g) as a creamy foamy glass. _{, T r = 12.61min, 96.2%} (CH 3 CN 5 % to 95% of 0.1N aqueous solution of ammonium acetate over 20 min) HPLC. _{^{1 H NMR (d 6 DMSO,}} 400MHz): 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 ), 2.50 (4H, m), 2.30 (5H, m), 2.14 (3H, s), 1.89 (6H, m), 1.46 (2H, m).
[1393] A general method for preparing substituted pyrrolopyrimidine arylsulfonamides is as follows:
[1394] LH-pyrrolo [2,3-d] pyrimidin-4-amine &lt; / RTI &gt;Lt; / RTI &gt; was added 1 eq. Of arylsulfonyl chloride substituted in 0.19M solution of &lt; RTI ID = 0.0 &gt; The mixture was vibrated in an incubator shaker for 24 h while being heated to 450 &lt; 0 &gt; C. The reaction mixture was subjected to preparative RP-HPLC (Micromass / Gilson, Hypersil BDS C18, 5u, 100x21.2mm; 100-100% ammonium acetate (0.05M, pH 4.5) - acetonitrile, 25mL / min over 12.5min) .
[1395] Compounds synthesized by the methods described above include:
[1396] nameHPLC rt minm / z Example 322: Trans-N-l- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- - yl} 2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide Trimaleate3.18648.39 Example 323: Preparation of trans-N1- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -5-chloro-2-thiophenesulfonamide benzenesulfonamide Trimaleate3.14604.3 Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide Benzenesulfonamide Trimaleate3.07616.1 Example 325: trans-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) 2,3-dichloro-1-benzenesulfonamide Trimaleate3.39632.12 Example 326: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide Trimaleate2.82616.2 Pyrrolo [2,3-d] pyrimidin-5-yl- [l, 7] naphthyridin- 2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide Trimaleate2.66600.3 Example 328: Preparation of trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide Trimaleate2.53600.3 Example 329: Synthesis of trans-N4- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate2.63622.1 Example 330: Synthesis of trans-N1- (4- {4-amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide Trimaleate2.87618.1 Example 331: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate3.13609.1 Example 332: Synthesis of cis-N1- (4- {4- amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-1-benzenesulfonamide Trimaleate2.89528.1 Example 333: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide Trimaleate3.4668 Example 334: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide Trimaleate3.04632.1 Example 335: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-chloro-1-benzenesulfonamide Trimaleate2.94598.1 Example 336: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate2.76582.1 Example 337: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -5-chloro-2-thiophenesulfonamide dimaleate3.01604.3
[1397] Example 338: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide Trimaleate3.38718.3 Example 339: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -3-chloro2.98616.3 Example 340: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-iodo-1-benzenesulfonamide trimaleate3.02690.3 Example 341: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide Trimaleate3.22648.3 Example 342: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide Trimaleate2.97600.3 Example 343: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide Trimaleate3.12612.3 Example 344: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide Trimaleate3.02623.2 Example 345: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide Trimaleate3.08618.3 Example 346: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -3,4-dichloro-1-benzenesulfonamide Trimaleate2.98600.3 Example 347: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide Trimaleate3.13660.2 Example 348: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-thiophenesulfonamide Trimaleate3.16648.1 Example 349: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,4-dichloro-1-benzenesulfonamide Trimaleate3.09632.1 Example 350: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide Trimaleate3.41668.1 Example 351: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide trimaleate3.29683.9 Example 352: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate2.73622.1 Example 353: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate2.8606.1
[1398] Example 354: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,5-dichloro-1-thiophenesulfonamide tramylate3.18638 Example 355: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H- pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate2.84640.2 Example 356: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate2.89636.2 Example 357: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate2.82656.2 Example 358: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate2.82656.2 Example 359: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -3chloro-2-methyl-1-benzenesulfonamide Trimaleate3.01612 Example 360: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2-bromo-1-benzenesulfonamide Trimaleate2.81644.2 Example 361: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide Trimaleate3.29758.1 Example 362: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide Trimaleate2.77632 Example 363: cis-N1- (4- {4-Amino-7- [4- (4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3- d] pyrimidin- } -2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate2.73623.2
[1399] Typical synthesis methods
[1400] Pyrrolo [2,3-d] pyrimidin-7-yl] - (4-fluorophenyl) A mixture of 1-cyclohexanone (1.0 g, 2.51 mmol), the appropriate amine (7.54 mmol), and acetic acid (0.45 g, 7.54 mmol) was stirred at ambient temperature for 30 minutes under a nitrogen atmosphere. Sodium triacetoxyborohydride (0.69 g, 3.26 mmol) was added and 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 a period of time. The mixture was then filtered through a pad of celite and the pad was washed with dichloromethane (75 mL). The organic layer was extracted from the filtrate, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The cis and trans isomers were purified by flash chromatography on silica gel using a methanol: dichloromethane component.
[1401] Method (b)
[1402] Suitable salts are prepared as follows:
[1403] The amine (0.090 mmol) was dissolved in warm ethyl acetate (100 mL) and 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 a salt.
[1404] Method (c)
[1405] Guanidine was prepared as follows. Amine (0.536 mmol) was dissolved in DMF (5 mL) and cooled to -5 [deg.] C followed by the addition of 1-H pyrazole-1-carbonamide (95 mg, 0.644 mmol) followed by diisopropylethylamine mmol). The reaction mixture was allowed to warm to room temperature over 16 h and then concentrated in vacuo. The reaction was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was freeze-dried and purified by RP-HPLC. HPLC Protocol:
[1406] 1. RP-HPLC-Hypersil HyPurity Elite C18, 5 mm, 200 A, 250 x 4.6 mm; 25-100% acetonitrile-0.1M ammonium acetate over 25 min, 1 ml / min.
[1407] 2. RP-HPLC-HyperSilf Hyperi Elite C18, 5 mm, 200 A, 250 x 4.6 mm; 5-100% acetonitrile-0.1M ammonium acetate over 25 min, 1 ml / min.
[1408] Consideration should be given to the use of protecting groups where appropriate.
[1409] The following examples were prepared using the methods described above.
[1410] nameSynthesis methodHPLC-RT (min) (protocol)m / z (MH &lt; + &gt;).Additional chemical properties Pyrrole [2,3-d] pyrimidin-7-yl] cyclohexyl} -1-piperazin-1- Razine carboxyimidamidec14.56 (2)511.7Example 365 trans-4- {4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} Razine carboxyimidamidec14.25 (2)511.72,3-d] pyrimidin-2-one hydrochloride The title compound was obtained as a white amorphous solid from the title compound. Pyrimidin-4-amine trimaleatea, b8.55 (2)519.6Example 367 cis-3 - ({4- [4-Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} mountaina10.21 (2)472.6Prepared by hydrolysis of esters Example 368 cis-3 - ({4- [4-Amino-5- (4-phenoxyphenyl) -7H- pyrrolo [2,3- d] pyrimidin- 7-yl] cyclohexyl} mountaina6.33 (1)472.6Prepared by hydrolysis of esters Example 369 Ethylcis-3 - ({4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin- Propanedione dimaleatea, b10.42 (1)500.6
[1411] General method
[1412] Method (d)
[1413] To the solution of sodium hydride (22 mg, 0.553 mmol) in THF (2 mL) was added the appropriate phosphate (0.553 mmol) at 0 ° C and the resulting mixture was stirred at this temperature for 20 minutes and at ambient temperature for 10 minutes . The reaction mixture was cooled to 0 C and a solution of 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3d] pyrimin-7-yl] cyclohexanone (200 mg, 0.503 mol) Was added to TFH (10 mL) and the resulting mixture was allowed to warm to ambient temperature and stirred for 16 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was further extracted with ethyl acetate (3 x 5 mL) and the combined organic phases were washed with water (3 x 5 mL), dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash column chromatography on silica gel (for intermediate) or RP-HPLC (for final compound) gave the desired compound.
[1414] Method (e)
[1415] The hydrogenation reaction was carried out as follows. A mixture of alkene (0.068 mmol) and 10% Pd / C (12 mg) in ethanol (18 nmL) was stirred under hydrogen (4 atm) for 14 h. Filtration removed the solids and the filtrate was concentrated in vacuo. Purification by RP-HPLC gave the final compound.
[1416] Method (f)
[1417] Lithium aluminum hydride reduction was performed as follows. A mixture of the substrate (0.19 mmol), lithium aluminum hydride (40 mg, 1.07 mmol) in THF (5 mL) was stirred at room temperature for 16 h. After completion of the Fieser, RP-HPLC purification was performed to obtain the desired compound. HPLC conditions: RP-HPOC Pico Spear 3 3 C ₁₈ 3 microns, condition = over 5 min
[1418] 0-100% acetonitrile to 0.1M ammonium acetate, flow 4 ml / min. Consideration should be given to the use of protecting groups where appropriate.
[1419] nameSynthesis methodHPLC-RTRT (Min)m / z (MH &lt; + &gt;).Additional chemical properties Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexylidene} methyl cyanided3.1422.5Pyrrole [2,3-d] pyrimidin-7-yl] cyclohexylidene) acetate (100 mg,d3.97497.1Example 372 Ethyl 2- [4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine- 7-yl] cyclohexylidene} acetated3.56469.0Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexylidene} acetate &lt; EMI ID =d2.69441.5Prepared by hydrolysis of ethyl ester Pyrrolo [2,3-d] pyrimidin-4-amine (compound 1) was prepared in accordance with the general method of Example 1 from 4- (4-phenoxyphenyl)f2.11428.5Prepared by reducing unsaturated cyanide with lithium aluminum hydride Pyrrolo [2,3-d] pyrimidin-7-yl] cyclohexyl} acetic acid &lt; EMI ID =e2.64443.5Prepared by hydrogenation of unsaturated acids

权利要求:
Claims (72)
[1" claim-type="Currently amended] Compounds of the formula: &lt; EMI ID =

In this formula,
Ring A is a 6-membered aromatic ring; Or a 5 or 6 membered heteroaromatic ring selected from the group consisting of a substituted or unsubstituted aliphatic group, a halogen, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted Substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR ₄ R ₅ , -C (O) ₂ H, -OH, substituted or unsubstituted alkoxycar carbonyl, -C (O) ₂ - haloalkyl, optionally substituted alkylthio ether, are optionally substituted alkyl sulfoxide, a substituted or unsubstituted alkyl sulfonamide, unsubstituted or substituted unsubstituted arylthio ether, a substituted or unsubstituted Unsubstituted aryl sulfoxide, substituted or unsubstituted arylsulfone, substituted or unsubstituted alkylcarbonyl, -C (O) -haloalkyl, substituted Substituted or unsubstituted aliphatic ethers, substituted or unsubstituted aromatic ethers, carboxamido, tetrazolyl, trifluoromethylsulfonamido, trifluoromethylcarbonylamino, substituted or unsubstituted alkynyl, substituted or substituted Unsubstituted alkylamido, substituted or unsubstituted arylamido, -NR ₉₅ C (O) R ₉₅ (R ₉₅ is an aliphatic or aromatic group), substituted or unsubstituted styryl or substituted or unsubstituted ar Alkylamino, &lt; / RTI &gt;
L is -O-; -S-; -S (O) -; -S (O ₂₎ -; -N (R) -; -N (C (O) OR) -; -N (C (O) R) -; -N (SO ₂ R) -; -CH ₂ O-; CH ₂ S-; -CH ₂ N (R) -; -CH (NR) -; _{-CH 2 N (C (O)} R)) -; _{-CH 2 N (C (O)} OR) -; _{-CH 2 N (SO 2 R)} -; -CH (NHR) -; -CH (NHC (O) R) -; -CH (NHSO ₂ R) -; -CH (NHC (O) OR) -; -CH (OC (O) R) -; -CH (OC (O) NHR) -; -CH = CH-; -C (= NOR) -; -C (O) -; -CH (OR) -; -C (O) N (R); -N (R) C (O) -; -N (R) S (O) -; -N (R) S (O) _2- ; -OC (O) N (R) -; -N (R) C (O) N (R) -; -NRC (O) O-; -S (O) N (R) -; _{-S (O) 2 N (R} ) -; N (C (O) R) S (O) -; N (C (O) R) S (O) ₂ -; -N (R) S (O) N (R) -; -N (R) S (O) 2 N (R) -; -C (O) N (R) C (O) -; -S (O) N (R) C (O) -; _{-S (O) 2 N (R} ) C (O) -; -OS (O) N (R) -; -OS (O) ₂ N (R) -; -N (R) S (O) O-; -N (R) S (O) ₂ O-; -N (R) S (O) C (O) -; -N (R) S (O) ₂ C (O) -; -SON (C (O) R) -; _{-SO 2 N (C (O)} R) -; -N (R) SON (R) -; _{-N (R) SO 2 N (} R) -; -C (O) O-; -N (R) P (OR &apos;)O-; -N (R) P (OR &apos;)-; -N (R) P (O) (OR &apos;)O-; -N (R) P (O) (OR &apos;)-; -N (C (O) R) P (OR &apos;)O-; -N (C (O) R) P (OR &apos;)-; Wherein R and R 'are each independently selected from the group consisting of -H, acyl (O) R (O) , A substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted cycloalkyl group);
L is _{-R b N (R) S (} O) 2 -, -R b N (R) P (O) -, or _{-R b N (R) P (} O) O- ( wherein, R _b is that this Or an alkylene group which when fused together with a sulfonamide, phosphinamide, or phosphonamide group forms a 5 or 6 membered ring fused to ring A;
L is represented by one of the following formulas:

In this formula,
R ₈₅ , when combined with a phosphinamide or phosphonamide, forms a 5, 6 or 7 membered aromatic, heteroaromatic or heterocycloalkyl system;
R ₁ is a substituted aliphatic group; Substituted cycloalkyl; Substituted bicycloalkyl; Substituted cycloalkenyl; An optionally substituted aromatic group, an optionally substituted heteroaromatic group; Optionally substituted heteroaralkyl; Optionally substituted heterocycloalkyl; Optionally substituted heterocycycloalkyl; An optionally substituted alkylamine; Optionally substituted arylamido; Optionally substituted -S (O) ₂ -alkyl or optionally substituted -S (O) ₂ -cycloalkyl; -C (O) -alkyl or optionally substituted -C (O) -alkyl; Provided that when R &lt; _{1 &gt;} is an aliphatic group or a cycloalkyl group, R &lt; ₁ &gt; is not substituted by one or more substituents selected from the group consisting of hydroxyl and lower alkyl ethers; Heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl; The aliphatic group is not substituted by one or more aliphatic groups wherein one or more substituents are substituted or unsubstituted aliphatic groups, substituted or unsubstituted aromatic groups, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aralkyl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ether, substituted or unsubstituted aliphatic ether, substituted or unsubstituted alkoxycarbonyl , Substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aryloxycarbonyl, -OH, substituted or unsubstituted aminocarbonyl , Oxime, substituted Substituted or unsubstituted heterocycloalkyl, heterocycloalkyl, oxo, aldehyde, substituted or unsubstituted alkylsulfonamido groups, substituted or unsubstituted arylsulfonamido groups, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted hetero is selected from aza-bicyclo-alkyl, cyano, -NH _2, alkylamino, ureido, thioureido group consisting -BE);
B is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, alkylene, aminoalkyl, alkylenecarbonyl or aminoalkylcarbonyl ;
E is selected from substituted or unsubstituted azacycloalkyl, substituted or unsubstituted azacycloalkylcarbonyl, substituted or unsubstituted azacycloalkylsulfonyl, substituted or unsubstituted azacycloalkylalkyl, substituted or unsubstituted heteroaryl , Substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, Substituted or unsubstituted bicycloalkyl, substituted or unsubstituted ureido, substituted or unsubstituted thioureido or substituted or unsubstituted aryl;
R ₂ is selected from the group consisting of -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl, a halogen, -OH, a cyano, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, Unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, -NR ₄ R ₅ or -C (O) NR ₄ R ₅ ;
R ₃ is a substituted or unsubstituted aliphatic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted hetero Cycloalkyl;
R ₃ when seen alkenyl group which is unsubstituted or substituted aliphatic group or substituted or non-substituted, L is -SN (R) -, -S ( O) N (R) -, -S (O) 2 N (R ) -, -N (R) S- , -N (R) S (O) -, -N (R) S (O) 2 -, -N (R) SN (R ') -, -N (R ) S (O) N (R ') - or -N (R) S (O) ₂ N (R') -;
L is _{-O-, -CH 2 NR-, -C (} O) NR- or -NRC (O) - and; When R &lt; ₃ &gt; is an azacycloalkyl or an azaheteroaryl, j is 0;
When L is -O- and R &lt; ₃ &gt; is phenyl, j is 0;
R ₄ , R ₅ and the nitrogen atom are taken together to form a substituted or unsubstituted 3, 4, 5, 6 or 7 membered heterocycloalkyl, a substituted or unsubstituted heterocycloalkyl or an optionally substituted heteroaromatic ;
R ₄ and R ₅ are each independently -H, azabicycloalkyl, heterocycloalkyl, substituted or unsubstituted alkyl group or YZ;
Y is -C (O) -, - ( CH 2) p -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) p O- , - (CH ₂ ) _p NH-, - (CH ₂ ) _p S-, - (CH ₂ ) _p S (O) - and - (CH ₂ ) _p S (O) ₂ -;
p is an integer from 0 to about 6;
Z is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
j is an integer of 0 to 6;
[2" claim-type="Currently amended] The compound according to claim 1, wherein R ₃ is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazole, substituted Substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxane, substituted or unsubstituted dioxolane, substituted or unsubstituted quinoline, substituted or unsubstituted thiazole, Substituted or unsubstituted isoxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanyl, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzisoxazole, substituted or unsubstituted benzisothiazole Sol, substituted or unsubstituted benzothiazole, substituted or unsubstituted Is selected from the group consisting of benzooxazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline , Substituted or unsubstituted quinoxaline, substituted or unsubstituted indole, or substituted or unsubstituted pyrazole.
[3" claim-type="Currently amended] A compound according to claim 2, wherein R ₃ is 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 , Substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted (Substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -NR &lt; _f R _g , alkynyl, -C (O) NR _f R _g , R _c and CH ₂ OR _c ,
R _f , R _g and the nitrogen atom are taken together to form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycycloalkyl or a substituted or unsubstituted Or &lt; / RTI &gt;
R _f and R _g are each independently -H, a substituted or unsubstituted aliphatic group or an unsubstituted or substituted aromatic group;
R _c is hydrogen; Substituted or unsubstituted alkyl; Substituted or unsubstituted aryl; -W- (CH ₂ ) _t -NR _d R _e ; -W- (CH ₂ ) _t -O-alkyl; -W- (CH ₂ ) _t -S-alkyl; -W- (CH _{2) t} -OH; Or -W- (CH ₂ ) _t -OR _f ;
Wherein t is an integer from 0 to about 6;
W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR _k -;
R _k is -H or alkyl;
R _d and R _e together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicyclic group;
R _d and R _e are each independently -H, alkyl, alkanoyl, or -KD;
K is -S (O) ₂ -, -C (O) -, -C (O) NH-, -C (O) _2- or a direct bond;
D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aminocycloalkyl, COOR _i, or substituted or unsubstituted alkyl;
Wherein R &_lt; 1 &gt; is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
[4" claim-type="Currently amended] 4. A compound according to claim 3, wherein R &lt; ₃ &gt; is optionally substituted phenyl.
[5" claim-type="Currently amended] The compound according to claim 1, wherein ring A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted indole.
[6" claim-type="Currently amended] The method of claim 5, wherein the ring A is 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 Substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted (Substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -NR &lt; _f R _g , alkynyl, -C (O) NR _f R _g , R _c and CH ₂ OR _c ,
R _f , R _g and the nitrogen atom are taken together to form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycycloalkyl or a substituted or unsubstituted Or &lt; / RTI &gt;
R _f and R _g are each independently -H, a substituted or unsubstituted aliphatic group or an unsubstituted or substituted aromatic group;
R _c is hydrogen; Substituted or unsubstituted alkyl; Substituted or unsubstituted aryl; -W- (CH ₂ ) _t -NR _d R _e ; -W- (CH ₂ ) _t -O-alkyl; -W- (CH ₂ ) _t -S-alkyl; -W- (CH _{2) t} -OH; Or -W- (CH ₂ ) _t -OR _f ;
t is an integer from 0 to about 6;
W is a bond or -O-, -S-, -S (O) -, -S (O) ₂ - or -NR _k -;
R _k is -H or alkyl;
R _d and R _e together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicyclic group;
R _d and R _e are each independently -H, alkyl, alkanoyl, or -KD;
K is -S (O) ₂ -, -C (O) -, -C (O) NH-, -C (O) _2- or a direct bond;
D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aminocycloalkyl, COOR _i, or substituted or unsubstituted alkyl;
Wherein R &_lt; 1 &gt; is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
[7" claim-type="Currently amended] The compound according to claim 6, wherein Ring A is a substituted or unsubstituted phenyl group.
[8" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

Wherein m is an integer from 0 to about 3;
[9" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
m is an integer of 0 to 3
t is an integer from 1 to 6;
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 a substituted or unsubstituted hetero Form a bicycloalkyl group;
R ₈ and R ₉ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[10" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
m is an integer from 0 to 3;
s and t are each independently an integer of 1 to 6;
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 a substituted or unsubstituted hetero Form a bicycloalkyl group;
R ₈ and R ₉ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
R ₇₇ is -OR ₇₈ or -NR ₇₉ R ₈₀ ;
R ₇₈ is -H or a substituted or unsubstituted aliphatic group;
R ₇₉ , R ₈₀ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted Form a heterocyclyl alkyl group;
R ₇₉ and R ₈₀ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[11" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
v is an integer from 1 to 3;
R ₁₀ is -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[12" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
m is an integer from 0 to 3;
R ₁₀ is -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
R ₁₁ is 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 unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxy Alkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl, and substituted or substituted , And the carbon atom adjacent to the nitrogen atom is not substituted by a hydroxy group.
[13" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
R ₁₀ is -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[14" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
r is an integer from 1 to about 6;
R ₈ and R ₉ , together with the nitrogen atom, form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaromatic or a substituted or unsubstituted hetero Form a bicycloalkyl group;
R ₈ and R ₉ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[15" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
w is an integer from 0 to 4;
t is an integer from 0 to 6;
u is 0 or 1;
R ₁₂ is hydrogen or an optionally substituted alkyl group;
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 a substituted or unsubstituted hetero Form a bicycloalkyl group;
R ₈ and R ₉ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[16" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
w is an integer from 0 to 4;
t is an integer from 0 to 6;
R ₁₀ is hydrogen or an optionally substituted alkyl group;
R ₁₂ is -H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - or _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[17" claim-type="Currently amended] _15. A compound according to claim 14 wherein R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl group of the formula:

In this formula,
R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently lower alkyl or hydrogen;
Substituents R ₁₃ and R ₁₄ ; R ₁₅ and R ₁₆ ; R ₁₇ and R ₁₈ ; Or at least one pair of R &lt; ₁₉ &gt; and R &lt; ₂₀ &gt; together are an oxygen atom;
At least one of R ₁₃ and R ₁₅ is cyano, CONHR ₂₁ , COOR ₂₁ , CH ₂ OR ₂₁ or CH ₂ NR ₂₁ (R ₂₂ );
R ₂₁ , R ₂₂ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted Form a heterocyclyl alkyl group;
R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
X is _{-O-, -S-, -SO-, -SO 2} -, -CH 2 -, -CH (OR 23) - or NR _23, and;
R ₂₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R ₂₄ or -C ₂₄ ;
R ₂₄ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
u is 0 or 1;
[18" claim-type="Currently amended] _15. A compound according to claim 14 wherein R &lt; ₈ &gt;, R &lt; ₉ &gt;, and the nitrogen atom together form a heterocycloalkyl of the formula:

In this formula,
R ₂₅ and R ₂₆ are each independently hydrogen or lower alkyl;
R ₂₅ and R ₂₆ together are an oxygen atom;
R ₂₁ , R ₂₂ and the nitrogen atom together form a 3,4,5 or 6-membered substituted or unsubstituted heterocycloalkyl group;
R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) s -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) s O _{-, - (CH 2) s} NH-, - (CH 2) s S-, - (CH 2) s S (O) - and _{- (CH 2) s S (} O) 2 - (s is 0 to 6 Lt; / RTI &gt;;
Z ₃ is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
i is an integer from 1 to 6;
t is an integer of 0 to 6;
[19" claim-type="Currently amended] _15. A compound according to claim 14 wherein R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl group of the formula:

In this formula,
i is an integer from 1 to 6;
R ₂₇ is CH ₂ OH, C (O) NR ₂₄ R _28, or COOR ₂₄ ;
R ₂₄ and R ₂₈ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl group.
[20" claim-type="Currently amended] _15. A compound according to claim 14 wherein R ₈ , R ₉ and the nitrogen atom together form a heteroaromatic group of the formula:

In this formula,
R ₂₉ is -Cl, substituted or non-unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl group, carboxylic acid, _{cyano, C (O) OR 30,} CH 2 OR 30, CH 2 NR ₂₁ R ₂₂ , or C (O) NR ₂₁ R ₂₂ ;
R ₃₀ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl or heterocycloaryl group;
R ₂₁ , R ₂₂ and the nitrogen atom together are a 3,4,5 or 6-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or an optionally substituted heterocycycloalkyl;
R ₂₁ and R ₂₂ are each independently H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) t -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) t O _{-, - (CH 2) t} NH-, - (CH 2) t S-, - (CH 2) t S (O) - and _{- (CH 2) t S (} O) 2 - (t is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[21" claim-type="Currently amended] 15. The method according to claim 14, wherein at least one of R ₈ and R ₉ is the formula Y ₃ -D, Y ₃ is -C (O) -, - ( CH 2) t -, -S (O) 2 -, -C _{(O) O-, -SO 2 NH-} , -CONH-, (CH 2) t O-, - (CH 2) t NH-, - (CH 2) t S-, - (CH 2) t S ( O) - and - (CH ₂ ) _t S (O) ₂ - (q is an integer from 0 to 6), and D is of the formula:

In this formula,
T is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -CH 2 -, -CH (OR 24) - or -N (R ₂₄₎ - and, R ₂₄ Is hydrogen or an optionally substituted alkyl, aryl or aralkyl group;
x is 0, 1 or 2;
[22" claim-type="Currently amended] 15. The method according to claim 14 wherein, R ₈ and R ₉ is one or more of a general formula _{Y 3 -N (R 31) R} 32, Y 3 is -C (O) -, - ( CH 2) t -, -S (O _{) 2 -, -C (O)} O-, -SO 2 NH-, -CONH-, (CH 2) t O-, - (CH 2) t NH-, - (CH 2) t S-, - ( CH ₂ ) _t S (O) - and - (CH ₂ ) _t S (O) ₂ - wherein t is an integer from 0 to 6;
t is an integer from 0 to 6;
R ₃₁ and R ₃₂ are each independently selected from the group consisting of substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, Unsubstituted alkylcarbonyl or substituted or unsubstituted cyanoalkyl;
R ₃₁ and R ₃₂ together with the nitrogen atom form a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or an optionally substituted heterocycloalkyl.
[23" claim-type="Currently amended] 16. A compound according to claim 15 wherein R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl of the formula:

In this formula,
R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently lower alkyl or hydrogen;
Substituents R ₁₃ and R ₁₄ ; R ₁₅ and R ₁₆ ; R ₁₇ and R ₁₈ ; Or at least one pair of R &lt; ₁₉ &gt; and R &lt; ₂₀ &gt; together are an oxygen atom;
At least one of R ₁₃ and R ₁₅ is cyano, CONHR ₂₁ , COOR ₂₁ , CH ₂ OR ₂₁ or CH ₂ NR ₂₁ (R ₂₂ );
R ₂₁ , R ₂₂ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted Form a heterocyclyl alkyl group;
R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) s -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) s O _{-, - (CH 2) s} NH-, - (CH 2) s S-, - (CH 2) s S (O) - and _{- (CH 2) s S (} O) 2 - (s is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
X is _{-O-, -S-, -SO-, -SO 2} -, -CH 2 -, -CH (OR 23) - or NR _23, and;
R ₂₃ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -C (NH) NH ₂ , -C (O) R _24, or -C (O) OR ₂₄ ;
R ₂₄ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
y is 0 or 1;
[24" claim-type="Currently amended] 16. A compound according to claim 15 wherein R ₈ , R ₉ and the nitrogen atom together form a heterocycloalkyl of the formula:

In this formula,
R ₂₅ and R ₂₆ are each independently hydrogen or lower alkyl;
R ₂₅ and R ₂₆ together are an oxygen atom;
R ₂₁ , R ₂₂ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted Form a heterocycycloalkyl group;
R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) s -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) s O _{-, - (CH 2) s} NH-, - (CH 2) s S-, - (CH 2) s S (O) - and _{- (CH 2) s S (} O) 2 - (s is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group;
r is an integer from 1 to 6;
and z is an integer of 0 to 6.
[25" claim-type="Currently amended] 16. A compound according to claim 15 wherein R &lt; ₈ &gt;, R &lt; ₉ &gt; and the nitrogen atom together form a heterocycloalkyl group of the formula:

In this formula,
i is an integer from 1 to 6;
R ₂₇ is CH ₂ OH, C (O) NR ₂₄ R _28, or COOR ₂₄ ;
R ₂₄ and R ₂₈ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl group.
[26" claim-type="Currently amended] 16. A compound according to claim 15 wherein R ₈ , R ₉ and the nitrogen atom together form a heteroaromatic group of the formula:

In this formula,
R ₂₉ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, carboxyl, cyano, C (O) OR ₃₀ , CH ₂ OR ₃₀ , CH ₂ NR ₂₁ R ₂₂ , Or C (O) NR &lt; ₂₁ &gt; R &lt; _{22 &} gt ;;
R ₃₀ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloaryl group;
R ₂₁ , R ₂₂ and the nitrogen atom together are a 3,4,5 or 6-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or an optionally substituted heterocycycloalkyl;
R ₂₁ and R ₂₂ are each independently -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) s -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) s O _{-, - (CH 2) s} NH-, - (CH 2) s S-, - (CH 2) s S (O) - and _{- (CH 2) s S (} O) 2 - (s is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[27" claim-type="Currently amended] The method of claim 15 wherein at least one of R ₈ and R ₉ is the formula Y ₃ -D, Y ₃ is -C (O) -, - ( CH 2) s -, -S (O) 2 -, -C _{(O) O-, -SO 2 NH-} , -CONH-, (CH 2) s O-, - (CH 2) s NH-, - (CH 2) s S-, - (CH 2) s S ( O) - and - (CH ₂ ) _s S (O) ₂ - (s is an integer from 0 to 6), and D is of the formula:

In this formula,
T is -O-, -C (O) -, -S-, -SO-, -SO ₂ -, -CH ₂ -, -CH (OR ₃₃ ) - or -N (R ₃₃ ) -;
R ₃₃ is hydrogen, non-substituted alkyl, or unsubstituted optionally substituted aryl, optionally substituted aralkyl, -C (NH) NH ₂ -, -C (O) R _34, or -C (O) OR ₃₄ ;
R ₃₄ is hydrogen, substituted or unsubstituted alkyl, aryl or aralkyl;
x is 0, 1 or 2;
[28" claim-type="Currently amended] The method of claim 15 wherein at least one of R ₈ and R ₉ is the formula _{Y 3 -N (R 31) R} 32,
Y ₃ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;
R ₃₁ and R ₃₂ are each independently selected from the group consisting of substituted or unsubstituted carboxyalkyl, substituted or unsubstituted alkoxycarbonylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, Unsubstituted alkylcarbonyl or substituted or unsubstituted cyanoalkyl;
R ₃₁ and R ₃₂ together with the nitrogen atom form a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or substituted or unsubstituted heterobicycloalkyl.
[29" claim-type="Currently amended] 13. Compounds of formula I according to claim 12, wherein Z ₂ is of the formula N (R ₃₅ ) R ₃₆ and R ₃₅ and R ₃₆ are each independently hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, &Lt; / RTI &gt; alkylcarbonyl or aralkyl.
[30" claim-type="Currently amended] 13. A compound according to claim 12, wherein Z &lt; ₂ &gt;

In this formula,
X ₁ is each independently CH or N;
R ₃₇ is hydrogen, cyano or substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, Substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl group.
[31" claim-type="Currently amended] 13. A compound according to claim 12, wherein Z &lt; ₂ &gt;

In this formula,
g is an integer from 0 to 3;
T is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -CH 2 -, -CH (OR 34) - or -N (R ₃₄₎ - is;
R ₃₄ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R ₃₇ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, A substituted or unsubstituted alkylcarbonyl, or a substituted or unsubstituted aralkyl group.
[32" claim-type="Currently amended] 13. A compound according to claim 12, wherein Z &lt; ₂ &gt;

In this formula,
g is an integer from 0 to 3;
R ₃₇ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, A substituted or unsubstituted alkylcarbonyl, or a substituted or unsubstituted aralkyl group.
[33" claim-type="Currently amended] 13. A compound according to claim 12, wherein Z &lt; ₂ &gt;

In this formula,
T is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -CH 2 -, -CH (OR 34) - or -N (R ₃₄₎ - and;
R ₃₄ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
g is an integer from 0 to 3;
R ₃₇ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, A substituted or unsubstituted alkylcarbonyl, or a substituted or unsubstituted aralkyl group.
[34" claim-type="Currently amended] 13. A compound according to claim 12, wherein Z &lt; ₂ &gt;

In this formula,
R ₃₇ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, A substituted or unsubstituted alkylcarbonyl, or a substituted or unsubstituted aralkyl group;
R ₃₈ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, perhaloalkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl.
[35" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
u is 0 or 1;
R ₃₉ , R ₄₀ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ and R ₄₆ are each independently methyl or hydrogen;
Substituents R ₃₉ and R ₄₀ ; R ₄₁ and R ₄₂ ; R ₄₃ and R ₄₄ ; Or at least one of R ₄₅ and R ₄₆ is an oxygen atom;
R ₄₇ is H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) t -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) t O _{-, - (CH 2) q} NH-, - (CH 2) t S-, - (CH 2) t S (O) - or _{- (CH 2) t S (} O) 2 - (t is 0 to 6 Lt; / RTI &gt;
Z ₂ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group; or
R ₄₇ is of the formula:

In this formula,
y is 0 or 1;
R ₄₈ , R ₄₉ , R ₅₀ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently methyl or hydrogen;
Substituents R ₄₈ and R ₄₉ ; R ₅₀ and R ₅₁ ; R ₅₂ and R ₅₃ ; Or at least a pair of R ₅₄ and R ₅₅ together are an oxygen atom;
R ₅₆ is -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[36" claim-type="Currently amended] 2. A compound according to claim 1, wherein R &lt; ₁ &gt; is of the formula:

In this formula,
e, f, h, u and y are independently 0 or 1;
R ₅₇ , R ₅₈ , R ₅₉ , R ₆₀ , R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ , R ₆₅ and R ₆₆ are each independently methyl or hydrogen;
Substituents R ₅₇ and R ₅₈ ; R ₅₉ and R ₆₀ ; R ₆₁ and R ₆₂ ; Or at least one of R ₆₃ and R ₆₄ together are an oxygen atom;
R ₆₇ is H, azabicycloalkyl, heterocycloalkyl or Y ₂ -Z ₂ ;
Y ₂ is -C (O) -, - ( CH 2) q -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) q O _{-, - (CH 2) q} NH-, - (CH 2) q S-, - (CH 2) q S (O) - and _{- (CH 2) q S (} O) 2 - (q is 0 to 6 Lt; / RTI &gt;;
Z ₂ is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group; or
R ₆₇ is of the formula:

In this formula,
d is 0 or 1;
R ₆₈ , R ₆₉ , R ₇₀ , R ₇₁ , R ₇₂ , R ₇₃ , R ₇₄ and R ₇₅ are each independently lower alkyl or hydrogen;
Substituents R ₆₈ and R ₆₉ ; R ₇₀ and R ₇₁ ; R ₇₂ and R ₇₃ ; Or at least one of R ₇₄ and R ₇₅ together are an oxygen atom;
R ₇₆ is -H, azabicycloalkyl, heterocycloalkyl or Y ₃ -Z ₃ ;
Y ₃ is -C (O) -, - ( CH 2) t -, -S (O) 2 -, -C (O) O-, -SO 2 NH-, -CONH-, (CH 2) t O _{-, - (CH 2) t} NH-, - (CH 2) t S-, - (CH 2) t S (O) - and _{- (CH 2) t S (} O) 2 - (t is 0 to 6 Lt; / RTI &gt;;
Z ₃ is -H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl group.
[37" claim-type="Currently amended] _2. A compound according to claim 1, wherein R &lt; _{2 &gt;} is -H.
[38" claim-type="Currently amended] According to claim 1, L is _{-O-, -NHSO 2 R-, -NC (} O) O- , or NHC (O) - compound, characterized in that.
[39" claim-type="Currently amended] A compound of claim 1; Or a physiologically acceptable salt, prodrug or biologically active metabolite thereof, for the manufacture of a medicament for inhibiting protein kinase activity.
[40" claim-type="Currently amended] 40. The method of claim 39, wherein the protein kinase is selected from the group consisting of KDR, FGFR-1, PDGFR , PDGFR , IGF-1R, c-Met, Flt-1, TIE-2, Lck, Src, fyn, &Lt; / RTI &gt;
[41" claim-type="Currently amended] 40. The method of claim 39, wherein the activity of the protein kinase affects the hyperproliferative disorder.
[42" claim-type="Currently amended] 41. The method of claim 39, wherein the activity of the protein kinase affects angiogenesis, vascular permeability, immune response or inflammation.
[43" claim-type="Currently amended] A method of treating a patient having an interventional disorder due to protein kinase activity comprising administering to a patient a compound of formula (I) according to claim 1; Or a physiologically acceptable salt, prodrug or biologically active metabolite thereof, in a therapeutically effective amount.
[44" claim-type="Currently amended] 43. The method of claim 43, wherein the protein kinase is selected from the group consisting of KDR, Flt-1, PDGFR , PDGFR , IGF-1R, c-Met, TIE-2, Lck, Src, fyn, How to.
[45" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is hyperproliferative disorder.
[46" claim-type="Currently amended] 44. The method of claim 43, wherein the activity of the protein kinase affects angiogenesis, vascular permeability, immune response or inflammatory response.
[47" claim-type="Currently amended] 44. The method of claim 43, wherein the protein kinase is a protein serine / threonine kinase or a protein tyrosine kinase.
[48" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by the protein kinase is at least one ulcer.
[49" claim-type="Currently amended] 49. The method of claim 48, wherein the ulcers or ulcers are caused by bacterial or fungal infections; Ulcers or ulcers are Mooren ulcers; Wherein the ulcer or ulcers are ulcerative colitis.
[50" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is selected from the group consisting of Lyme disease, sepsis, or infection with herpes simplex, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasma disease . &Lt; / RTI &gt;
[51" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is Von Hippel Linda disease, pemphigoid, psoriasis, Paget's disease or polycystic kidney disease.
[52" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is selected from the group consisting of fibrosis, sarcoidosis, cirrhosis, thyroiditis, systemic hyperintense syndrome, Osler-Weber-Rendu disease, , Edema due to asthma, exudates, ascites, pleural effusion, pulmonary edema, cerebral edema, or burn, injury, radiation, stroke, hypoxia or ischemia.
[53" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is ovarian hyperstimulation syndrome, endometriosis, preeclampsia, or functional uterine bleeding.
[54" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis or transplant rejection .
[55" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is sickle cell anemia.
[56" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is a visual disorder.
[57" claim-type="Currently amended] 57. The method of claim 56, wherein the visual disorder is eye or spot swelling; Neovascular disease of the eye; Scleritis; Radiation keratotomy; Uveitis; Vitreous salt; nearsighted; City; Chronic retinal detachment; Complications after laser treatment; conjunctivitis; Stargardt's disease; Eales disease; Retinopathy or degenerative spots.
[58" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is cardiovascular disease.
[59" claim-type="Currently amended] 59. The method of claim 58, wherein the disease mediated by protein kinase activity is atherosclerosis, restenosis, ischemia / reperfusion injury, vascular occlusion, venous malformation, or carotid occlusive disease.
[60" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is cancer.
[61" claim-type="Currently amended] 60. The method of claim 60, wherein the cancer is a solid tumor, sarcoma, fibrosarcoma, osteoma, black tumor, retinoblastoma, transverse myosoma, syngeneic, neuroblastoma, teratoma, hematopoietic malignancy and malignant ascites.
[62" claim-type="Currently amended] 62. The method of claim 61, wherein the cancer is Kaposi's sarcoma, Hodgson's disease, lymphoma, myeloma or leukemia.
[63" claim-type="Currently amended] 44. The method of claim 43, wherein the disease mediated by protein kinase activity is Crow-Fukase (POEMS) syndrome or a diabetic disease.
[64" claim-type="Currently amended] 63. The method of claim 63, wherein the diabetes disease is insulin dependent diabetes mellitus glaucoma, diabetic retinopathy or microvascular disease.
[65" claim-type="Currently amended] CLAIMS What is claimed is: 1. A method of reducing the fertility of a patient comprising administering to a patient a compound of formula (I) Or a physiologically acceptable salt, prodrug or biologically active metabolite thereof.
[66" claim-type="Currently amended] 44. The compound of claim 43, which is a compound of formula (I); Or a physiologically acceptable salt, prodrug or biologically active metabolite thereof is administered in an effective amount to promote angiogenesis or angiogenesis.
[67" claim-type="Currently amended] 67. The method of claim 66, wherein the protein kinase is Tie-2.
[68" claim-type="Currently amended] 67. The compound of claim 66, wherein the compound of formula (I) Or a physiologically acceptable salt, prodrug or biologically active metabolite thereof is administered in combination with a pro-angiogenic growth factor.
[69" claim-type="Currently amended] 69. The method of claim 68, wherein the pro-angiogenic growth factor is selected from the group consisting of VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF- &Lt; / RTI &gt;
[70" claim-type="Currently amended] 67. The method of claim 66, wherein the protein kinase mediated disease is anemia, ischemia, infarction, graft rejection, wound, necrosis or necrosis.
[71" claim-type="Currently amended] 44. The method of claim 43, wherein the protein kinase activity is associated with T cell activity, B cell activity, mast cell granulation, monocytic activity, uptake of an inflammatory response, or a combination thereof.
[72" claim-type="Currently amended] 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;
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-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 [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 dihydrochloride;
5- (4-phenoxyphenyl) -7- (3-pyrrolidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine dihydrochloride;
Cis-7- [4- (4-isopropylpiperazine) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
Trans-7- [4- (4-isopropylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine;
Cis-7- [4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
Trans-7- [4- (4-ethylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tris maleate ;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tris maleate ;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine tris maleate;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4 - amine tris maleate;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylmethyl) &Lt; / RTI &gt; 4-amine trimaleate salt;
(4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin- 4-amine dimaleate salt;
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;
Pyrrolo [2,3-d] pyrimidin-4-amine dimaleate (2-pyrrolidinyl) 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;
7- [3- (4-methylpiperazino) cyclopentyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine tinctureate;
Trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;
Trans-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trimaleate;
7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trihydrochloride;
Pyrrolo [2,3-d] pyrimidin-4-amine tincaleate salt (4-methylpiperazino) cyclohexyl] -5- ;
Cis-7- [3- (4-methylpiperazino) cyclohexyl] -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine trihydrochloride;
Pyrrolo [2,3-d] pyrimidin-4-amine (4-methylpiperazino) cyclohexyl] Trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (1 H) -quinolin- -Methoxyphenyl) carbamate &lt; / RTI &gt;trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (1 H-pyrrolo [2,3- d] pyrimidin- -Methoxyphenyl) carbamate &lt; / RTI &gt;trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) benzamide;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) benzamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] Methoxyphenyl) -3-phenylpropanamide;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Methoxyphenyl) -3-phenylpropanamide;
Pyrrolo [2,3-d] pyrimidin-5-yl-2-methoxyphenyl) -7- Phenyl) -3-phenylpropanamide trimaleate salt;
Pyrrolo [2,3-d] pyrimidin-5-yl-2-methoxyphenyl) -7- Phenyl) -3-phenylpropanamide &lt; / RTI &gt;trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - [(3-methoxypropyl) amino] benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - [(3-methoxypropyl) amino] benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -7H-pyrrolo [2,3- Yl) benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -7H-pyrrolo [2,3- Yl) benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - [(4-methylphenyl) sulfanyl] benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6 (4-methylpiperazino) cyclohexyl] - (2-pyridylsulfanyl) benzonitrile trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-ylphenoxy) -6- (4-methylpiperazino) cyclohexyl] - (2-pyridylsulfanyl) benzonitrile trimaleate;
(4-methylpiperazino) cyclohexyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine Trimaleate;
Pyrrolo [2,3-d] pyrimidin-4-amine (4-methylpiperazino) cyclohexyl] Trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazino) cyclohexyl] Fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2- (4-methylpiperazin-1- Fluorophenyl) -4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4- Fluoro-1-benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl) -2,2-dimethyl- , 3-dichloro-1-benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl-4-fluoro-l- - benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-5-yl] -2-fluorophenyl) - 4-fluoro-1-benzenesulfonamide;
7H-pyrrolo [2,3-d] pyrimidin-4-yl] -N- [4- (4-amino- 5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide dimaleate;
Pyrrolo [2,3-d] pyrimidin-7-ylmethyl) -1H-pyrrolo [2,3-d] ] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-7-one [0194] Pyrimidin-5-yl) -2-fluorophenyl] -4-fluoro-1-benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-5-yl} -2 (2-pyridyl) -Fluorophenyl) -4-fluoro-1-benzenesulfonamide;
Pyrrolo [2,3-d] pyrimidin-5-yl) - lH-pyrrolo [2,3-d] pyrimidin- }) - 2-fluorophenyl-4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-chloro-2-thiophenesulfonamide benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl-2- (4-methoxyphenyl) cyclohexyl] Fluorophenyl) -2,5-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-chloro-2-thiophenesulfonamide dimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2,6-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-iodo-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-bromo-2-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2, 4-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-bromo-5-chloro-2-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dichloro-1-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylsulfanyl) 2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-nitro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-fluoro-1-benzenesulfonamide dimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-4-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-iodo-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -5-bromo-2-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2, 4-dichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,3,4-trichloro-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-bromo-5-chloro-2-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dichloro-1-thiopensulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (7-chloro-2,1,3-benzoxadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (7-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (5-methyl-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (5-chloro-2,1,3-benzothiadiazole) -4-sulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2-bromo-1-benzenesulfonamide trimaleate;
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1-benzenesulfonamide trimaleate; or
Pyrrolo [2,3-d] pyrimidin-5-yl} - (4-methylpiperazino) cyclohexyl] 2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide trimaleate.

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同族专利:

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公开号 | 公开日

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IL141866D0|2002-03-10|

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HU0200403A2|2002-06-29|

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AU753555B2|2002-10-24|

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AU6048499A|2000-04-10|

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AU753555C|2003-07-03|

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TR200101186T2|2001-10-22|

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CA2344249A1|2000-03-30|

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NZ510588A|2003-08-29|

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EP1114053A1|2001-07-11|

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PL346700A1|2002-02-25|

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BG105346A|2001-12-31|

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CN1335849A|2002-02-13|

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NO20011356D0|2001-03-16|

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HU0200403A3|2004-07-28|

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JP2002526500A|2002-08-20|

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BR9913887A|2001-10-23|

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NO20011356L|2001-05-16|

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WO2000017203A1|2000-03-30|

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ID29028A|2001-07-26|

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CZ2001960A3|2001-10-17|

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SK3842001A3|2002-04-04|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-09-18|Priority to US60/100,833

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1998-09-18|Priority to US10083498P

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1998-09-18|Priority to US10083398P

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1998-09-18|Priority to US10083298P

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1998-09-18|Priority to US10094698P

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1998-09-18|Priority to US60/100,832

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1998-09-18|Priority to US60/100,946

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1998-12-03|Priority to US60/100,834

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1999-09-17|Application filed by 스타르크, 카르크, 바스프 악티엔게젤샤프트

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1999-09-17|Priority to PCT/US1999/021560

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2001-09-07|Publication of KR20010085824A

优先权:

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申请号 | 申请日 | 专利标题

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US10083498P| true| 1998-09-18|1998-09-18|

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US10083398P| true| 1998-09-18|1998-09-18|

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US10083298P| true| 1998-09-18|1998-09-18|

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US10094698P| true| 1998-09-18|1998-09-18|

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US60/100,832|1998-09-18|

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US60/100,833|1998-09-18|

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US60/100,946|1998-09-18|

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US60/100,834|1998-12-03|

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PCT/US1999/021560|WO2000017203A1|1998-09-18|1999-09-17|Pyrrolopyrimidines as protein kinase inhibitors|